STATIC 2024 Review

STATIC

ST ANDREWS STUDENT-RUN SCIENTIFIC JOURNAL

ISSUE 2 | AUG 24

Committee Co-Founders Thomas Burton Ideja Bajra​

Innovative Writers Lydia Mao Nimue Lilith Romeikat Shiksha Guru Hannah Betts Rishi Ravishankar Leo Elliott Violet Melcher Teddy Henderson

Head of Editing

CoFounders Address What began 2 years ago as an ambitious dream to enhance scientific communication and foster innovation across the University of St Andrews has blossomed into the creation of STATIC and the production of our second Scientific Innovation Review.

This Review showcases the recent and significant advancements made in the fields of Natural Science and Medicine. Our team of dedicated and passionate writers have meticulously researched their report topics, drawing upon a wide range of scientific journals, databases, and other reputable sources.

Laila Deen

Deputy Head of Editing Sushmhitah Sandanatavan

STATIC is a rapidly growing initiative, and we are committed to hosting inspiring and influential collaborations with powerhouses within the fields of STEM. Our aspiration is to continue establishing a robust networking system that connects like-minded, accomplished, and motivated individuals.

This Review is a testament to the synergy and collaboration within the STATIC amongst the committee members, innovative writers and editors.

Together, we have worked to outline the groundbreaking innovations that have contributed to the betterment of our society.

We are immensely proud of the work presented in this year's Review and are grateful for the support and contributions of the University of St Andrews community. We look forward to the continued growth and impact of STATIC in the years to come.

Sincerely,

Thomas. B

Ideja. B

Head Editors Address

Editors

We are so thrilled to have had the opportunity to be part of this year's editorial process, working alongside the innovative writers who contributed to this journal. It has been a rewarding experience to help refine articles, focusing on sentence structure, content flow, and meticulous referencing. The dedication and creativity we've witnessed have truly inspired us, and we are grateful to have played a role in bringing these ideas to life.

Our journey with STATIC has been nothing short of extraordinary.

We have thoroughly enjoyed attending the various events throughout the year, which have not only enriched our understanding but also strengthened our sense of community within the university. Being part of this team has been a highlight of our university experience, and we look forward to continuing this journey alongside such a talented and passionate group of individuals.

Thank you for allowing us to contribute to this journal, and we hope that the efforts of both the writers and the editorial team resonate with you as much as they have with us.

Warm Regards,

Sushmhitah . S Laila. D

Laila Deen Sushmhitah Sandanatavan Thomas Burton

00 CONTENTS 01 Review of Current Surgical Management of Diabetic Foot Burns Using SplitThickness Skin Grafts

02 A new hope for Alzheimer's – is Deep Brain Stimulation advancing beyond Parkinson's?

03 Brief Exploration of the Molecular Basis of the Different Types of Multiple Sclerosis (specifically Relapsing Remitting and Primary Progressive) 04 Earning Their Stripes: The Zebrafish (Danio rerio)’s Promising Future as a Developmental Alternative In Vivo Model of Neurodegenerative Diseases

05 Neuroplasticity-Based Interventions in Stroke Rehabilitation 06 Bioengineering Breakthroughs: Transforming Clinical Psychology for the Future 07 Exploring the Complexities and Innovations within Electric Vehicle Battery Technology

08 Improving Crop Resilience to Climate Change

Innovative Writers​ Lydia Mao Nimue Lilith Romeikat Shiksha Guru Hannah Betts Rishi Ravishankar Leo Elliott Violet Melcher Teddy Henderson

Review of Current Surgical Management Of Diabetic Foot Burns Using Split Thickness Skin Grafts Lydia Mao Bsc (Hons) Medicine

Sushmhitah Sandanatavan Bsc (Hons) Medicine

Abstract—This review aims to evaluate the quality of current surgical management of lower extremity burns using split-thickness skin grafts amongst diabetic patients. The escalating figures of diabetics and the associated comorbidities that act as risk factors for diabetic burns are not adequately addressed in the current literature and in published clinical guidelines. This work provides an extensive overview of the factors affecting both the clinical, and cosmetic outcomes of the relevant grafting procedure in the short and long term. The review concludes that specialised units and patient education are recommended to prevent recurrence in high-risk demographics for diabetic burns.

D IABETES IS ONE OF THE MOST PREVALENT conditions globally, affecting 1 in 10 people (Saeedi, 2019). It is a complex disease, often accompanied by a range of serious complications. Among the most significant of these are peripheral neuropathy and vascular compromise, particularly chronic endothelial injury (Galliero, 2023). This neurovascular compromise slows the rate of wound healing and furthers complications such as infections and cosmetic scarring.

One of the prevalent manifestations of these issues is diabetic foot burns, which are often prolonged due to neuropathy and absent reflexes resulting from autonomic dysfunction (Barsun, Palmieri, and Greenhalgh, 2013).

When burns are too large and are unable to be managed through primary wound closure by stitching it together, skin grafts are used instead. Approximately 60% of diabetic patients with a foot burn injury undergo wound excision such as debridement, and skin graft (Momeni et al, 2018). Amongst the various forms of tissue reconstruction (Figure 1, Reavey and

Gottlieb, 2019), this review will primarily focus on skin grafting using either autografts, which are skin grafts taken from the patient themselves, or allografts, which are sourced from a human cadaver. These grafts are then meshed, stretched, and applied to the site of the burn injury. Specifically, the studies referenced in this review analyse a type of human skin graft called the split-thickness skin grafts (STSG), which contains the epidermis and part of the dermis is used commonly for large wounds for extremity burns. Wound healing in skin graft poses significant challenges in diabetic patients due to damaged blood vessels in lower extremities. Since the graft does not contain its own blood supply, a well-vascularised wound bed on the recipient is essential for graft uptake and optimal wound closure. However, this is often compromised in diabetic feet because of avascular, necrotic tissue commonly associated with foot ulcers (Galliero, 2023).

Long-term complications such as immobility and scar contractures can occur in the foot, leading to prolonged recovery impacting both gait and cosmetic outcomes (Yammine et al, 2019). Additionally, the demographic factors of diabetic patients suffering from foot burns

Published by STATIC Student Journal

LAILA DEEN, 2024

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of the selected articles to provide broader context and understanding.

Inclusion criteria and study selection Studies were independently identified and manually compared by the author against specific inclusion criteria. Literature that examined the challenges and complications of general burn management amongst diabetic patients, and specifically, operative management were selected. The selected literature included both patients with Type I and Type II diabetes, irrespective of age and gender.

Figure 1. Reconstructive Ladder (Rievey and Gottlieb, 2019)

also influence the healing process.

This review aims to disseminate the factors above to evaluate the quality of current surgical management of diabetic foot burns with skin grafts and propose relevant clinical recommendations. Additionally, it aims to highlight current limitations in diabetic wound management and the relevant gaps in treatment protocols.

The review hypothesises that poor graft uptake, along with insufficient monitoring and specialised care for long-term wound management, are the primary challenges associated with STSG in diabetic foot burns.

METHODS Information sources, Selection strategy Studies were manually identified by the author through searches in PubMed, Google Scholar, Science Direct, JSTOR and Europe PMC. Clinical guidelines and recommendations were sourced from Cochrane Library, Wiley Online Library, NICE and the NHS public database. Most of the studies selected are systematic reviews, followed by meta-analyses, cohort studies and cross-sectional studies. The following search terms were used : “diabetes melllitus”, “diabetic burns”, “peripheral burns”, “peripheral neuropathy”.

Further studies were identified through the references

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Exclusion criteria and quality assessment Case studies were excluded to ensure a representative scope of patients. Only papers published in peerreviewed journals, in English, and in between 20022023 were included.

The author identified individual studies denoting the challenges and complications of burn management amongst diabetic patients, as well as retrospective cohort studies on the clinical outcomes of surgical management of diabetic burns. For context and relevant discussion, epidemiological analyses of diabetic burns were also identified and referenced.

RESULTS The effectiveness of skin grafts largely depends on the specific condition of the patient and the quality of post-graft care. This review will explore the main aspects of wound healing associated with skin grafts (amongst other less commonly performed surgical procedures for third degree burns), as well as flap reconstruction, although it is not the primary focus of this review.

Wound healing time The underlying biochemical and cellular processes of wound healing is vital to understanding the prolonged and often, less optimal graft outcomes for burns amongst diabetic patients. Several publications have confirmed that skin grafts used with standard care increase the healing rate of foot ulcers and wounds (Santema et al, 2016). The healing rate is typically assessed based on the reduction in wound area. However, the inability to precisely measure wound size, along with the exclusion of wound depth - a critical factor in evaluating the severity of the burn site - makes it difficult to accurately compare healing rates with and without a skin graft. The long-term outcome of skin

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graft on the wound would need to be further investigated considering that most of the relevant studies being retrospective cohort studies with uncontrolled patient variables, making it challenging to establish a clear association between skin grafts and improved outcomes (Landsman, 2015).

Eligibility for Skin Graft and long-term clinical outcomes Complete wound closure is not always achieved in diabetic patients due to preexisting diabetic ulcers (e.g. pressure wounds on sole) as well as comorbidities such as chronic hyperglycaemia and peripheral arterial disease (Ramanujam et al, 2013). The varied definitions of “complete wound closure” limits rigorous analysis of its frequency in diabetic wounds. Some definitions describe it as “full epithelialisation with absence of drainage” while others include “...absence of dressing” or the presence of smooth scars (Santema et al, 2016). There are more novel forms of tissue replacements such as bioengineered or artificial skin that contain growth factors and cultures of fibroblasts which can promote complete closure, though the limited research done on these techniques excludes them for the purpose of this review. In standard care of burn wounds where saline-soaked dressings are applied, only 65% of diabetic patients with foot wounds healed after a year, with 15% requiring amputations (Oyibo et al, 2001). Amongst diabetic patients admitted with foot burns, 75% required grafting, and 20% of those required re-grafting (Momeni et al, 2018).

This prolongs hospitalisation, often exposing them to increased risk of nosocomial HAIs. Re-operation was necessary in 33% of cases due to graft rejection, poor wound adherence, or even amputation (Momeni et al, 2018). At first glance, the higher rates of amputation with skin grafts compared to standard care appear contradictory to the very purpose of the intervention.

However, skin graft requires specific conditions for successful uptake which diabetic patients often do not fulfil. Neuropathy, which affects an estimated 30% of diabetic patients (Barsun et al., 2013), can result in hypoesthesia, leading to burns. Additionally, the loss of neurological transmission can cause flattened foot arches and unequal weight distribution on the sole, resulting in pressure wounds where the skin graft is unable to adhere to the burn site, leading to failed graft uptake and an increased need for regrafting.

According to Duke et al, 2016, unstable clinical outcomes for diabetic burns are denoted by an increase

in post burn admissions. Diabetic, pre-diabetic and non-diabetic patients utilised more long-term hospital service for diabetes after their discharge for their burn injury within the past 5 years, than those who did not experience a burn in that period. Sustained disruption to glucose metabolism was reported within 5 years post-injury, associated with insulin resistance and endoplasmic reticulum stress response (Jeschke et al, 2012), all contributing to a hypermetabolic and hyperinflammatory state in the patient. The study, however, did not account for each participant’s individual medical history in its study model, making it unclear whether the burn caused diabetes mellitus or exacerbated pre-existing metabolic conditions, causing diabetic-related hospital admissions. In this context, skin grafts should be viewed as a temporary, shortterm solution that can biologically cover the burn site for healing. However, their long-term outcomes are not guaranteed, as the patient’s ability to heal wounds and fight infections remains compromised.

Functional outcomes of skin grafting Burn wounds result in wound contracture, a normal physiological response of fibroblasts in wound healing.

However, scar contractures can also occur due to excess fibrotic tissue made by myofibroblasts, presenting as hypertrophic scars. This causes a reduced area of the skin or skin graft, in addition to increased tension in that area. Contractures around a joint can result in long-term limited mobility of the joint and even deformity. Several studies have attempted to assess the prevalence of skin graft scarring and resulting deformities. Contractures were found to form in the early stages of burn rehabilitation (within 2 weeks post-graft), with their aetiology more closely linked to “therapeutic positioning” and “intensive care therapy” rather than the skin graft procedure itself (Goverman et al, 2017). This suggests that post-operative care, rather than the grafting process, plays a significant role in the development of contractures. Different studies have devised various methods to assess the severity of contractures (Oosterwijk et al, 2016). Some rely on visual, subjective determination of the amount of scarring; while others measure objectively the degree of movement of an isolated joint, which can often be underestimated due to surrounding soft tissue padding and patient’s pain. Clinically, there is no standardised method of assessing the severity of burn contractures through an accurate measurement of their functional outcomes. In cases involving deeper joints with ex-

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tensive grafting, it may be necessary to renew the skin graft cover to relieve superficial skin tension and restore a functional range of movement of tendon, ligaments and joints. Initially, it was thought that the existing superficial skin graft can be removed and replaced in a single operation. However, repeated operations are needed as deeper structures such as bones and joints had to be manipulated and repositioned from the contracture (Shakirov, 2006). Hence, this reflects the inadequate pre-operative planning in management of post-burn contractures and the longterm rehabilitation of patients, as this area remains ambiguous and under-researched. Preventive strategies, such as active and passive joint movements can help manage less severe contractures (Goverman, 2017).

These strategies are applicable to all patients who have undergone a recent skin graft procedure. However, their effectiveness depends on factors such as the patient’s natural mobility. Older age, diabetes mellitus, pain or weakness from age-related neuromotor deficits can all impact the range of movement available in the joint. Therefore, the effectiveness of these preventative strategies is hugely dependent on the patient’s compliance and physical condition. Diabetic patients with severe and/or chronic diabetic ulcers often require more extensive wound debridement. Ulcerated skin may warrant removing healthy tissue in excess of the avascularised necrotic tissue to expose a sufficiently vascularised wound bed for skin grafting. This results in a larger area of skin graft and consequently, greater surface area where wound and scar contractures would take place. Plantar foot burns, the most common site of foot burn in diabetes, and diabetic foot ulcers can lead to hyperflexion of toes, a decreased longitudinal arch of the foot and increased flattening (pes planus), all of which can exacerbate the gait disturbances and delay the wound closure process (Yammine et al, 2019).

Burns in the elderly diabetic patients With the mean age of diabetic burn patients being 62.7 years old, managing burn injuries in elderly patients presents unique challenges, especially in addition to diabetes. There is a disproportionately high incidence of diabetic burn patients admitted aged 65 and older, exceeding the proportion seen in the general population (Abu-Sittah et al, 2016). Moreover, there is a higher risk of comorbidities alongside diabetes, such as diabetic retinopathy, amputations, stroke and end-stage renal disease (McCampbell et al, 2002).

Elderly patients have thinner dermal layers which can

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complicate the healing of STSG. In these cases, the patient’s healthy skin may struggle to integrate with the graft, leading to graft failure (graft does not stick to the patient as part of the wound). Additionally, a STSG is strictly contraindicated in wounds that are poorly vascularised, hence, this poses a concern to elderly patients, many of whom have peripheral vascular disease and diabetes. The slower rate of tissue regeneration with age further decreases the likelihood of successful graft uptake (Abu-Sittah et al, 2016).

These factors underscore the necessity for careful and intensive burn management in elderly diabetic patients.

Early excision and grafting have been key milestones in burn care, first introduced in 1970. Excision, the removal of burned, necrotic tissue, has been shown to reduce mortality and shorten hospital stays in selected study participants (Keck et al, 2009). However, this approach is contradicted by studies such as Housinger et al (Housinger et al, 1984), which concluded that patients aged 60 or above experienced less complications and better outcomes in long term rehabilitation compared to patients treated with excision and grafting.

Although the measurement of the quality of long-term rehabilitation of the patients in this study was ambiguously defined as functional outcomes and the study is rather outdated so may not apply to current burn care, it suggests that conservative management may offer better short-term outcomes than skin grafting for elderly patients. This raises further questions about the most effective long-term management of elderly diabetic burn patients. Regardless of the presence of peripheral neuropathy in a patient, elderly individuals are more likely to have slower reaction times, delayed withdrawal reflexes, and potentially deteriorating cognitive capacity (Mandell et al, 2013). These factors could explain Goei et al’s (2020) finding that burn cooling strongly declines with age. Elderly patients in the study cohort did not cool their burns or delayed doing so for more than 10 minutes, which resulted in exacerbated burn severity and more pressingly, led to further appraisal delays when presenting themselves to medical assistance (Wood et al, 2016). This suggests that pre-hospital burn care and preventative fire education may be more effective for managing burn injuries in the elderly than excision and grafting. It was also observed that elderly burn patients had shorter wait times between hospital admission and their first surgical procedure, as well as more primary wound closure (Goei et al, 2020). However, excision and grafting typically occurred a week after admission, possibly

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DISCUSSION This review provides a multi-faceted evaluation of the surgical management of skin burns in diabetic patients, focusing on the use of skin grafting.

Figure 2. Comparison of full-thickness and splitthickness skin grafts (British Society for Dermatological Surgery)

due to delays in admission and a generally conservative approach to elderly burn injuries. Overall, predicting survival rates and the length of hospital stays for elderly burn patients remains under-researched. From the myriad of studies referenced above, it is suggested that burn management of the elderly varies by hospital and countries, potentially due to the conflicting evidence of whether early excision and grafting or conservative wound care is preferred in the elderly.

However, many authors commonly express a need for preventative education, specialised guidelines for elderly burn care and long-term community care for comprehensive rehabilitation.

Current Clinical Guidelines As of now, the National Institute of Clinical Excellence (NICE) has not published any specific guidance on the management of diabetic burns using skin grafts. This complicates clinical decision-making due to a lack of standard protocol. In addition to the choice between a skin graft and conservative dressing, surgeons are required to account for uncontrolled variables in the patient’s long-term outcomes, such as their nutritional status, non-compliance and wound care practices. Additionally, the choice of using a split-thickness skin graft (STSG) or a full-thickness skin graft is not determined by any set criteria and solely relies on the surgeon’s estimation. Full-thickness skin grafts offer greater durability and better cosmetic outcomes due to less shrinkage compared to STSG and are often preferred for grafting the sole of the foot, whilst the latter has a lower risk of failure as seen in Table 1 (British Society for Dermatological Surgery). This requires cosmetic outcomes, functional outcomes and optimal wound healing to be balanced on the individual patient’s site, potentially leading to treatment delay.

Summary of the main findings of this review The skin graft itself provides a rapid and immediate relief for burn injuries in diabetic patients, significantly reducing the rate of primary infections caused by wound exposure.

However, the success of skin graft uptake postprocedure remains the greatest challenge due to predisposing factors such as immunopathy, poor tissue perfusion, and vascularisation issues, as well as the hypermetabolic response to burn injuries characteristic in diabetic patients. All of which prolongs graft uptake and wound closure which exposes patients to a higher risk of contractures, infections and further interventions such as re-grafting and amputation.

The long-term complications of skin grafting in diabetic patients are explored in terms of clinical outcomes, specifically wound healing time; and functional outcomes, such as the severity of contractures. The referenced publications on these areas highlighted poor outcomes for diabetic patients. Additionally, studies measuring functional outcomes of skin grafts applied to diabetic burns lack clarity due to the absence of a standardised measurement. The severity of contractures were mainly evaluated in the form of case studies (excluded from this review’s criteria), varied greatly based on age, pre-existing foot ulcerations and wounds.

Key problem- How can we improve skin graft uptake?

Barriers to skin graft uptake in diabetic patients are difficult to eradicate. Donegan et al’s (Donegan et al, 2014) study provides an overview of factors that can be improved to optimise graft uptake. Wound bed preparation is identified as a critical factor to ensure a well-vascularised wound bed. The study suggests that surgical bypass to arteries in the lower extremities (e.g. posterior tibial artery, dorsalis pedis artery and tarsal arteries) is effective in increasing tissue perfusion in theory, although in practice, many diabetic patients are ineligible for surgical revascularisation due to coronary heart disease and uncontrolled hyperglycaemia for some; in addition, vascular by-pass is performed electively often as it necessitates prior imaging studies and optimal renal function (Siah et al, 2019). Such

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prerequisites exclude its application to acute burn injuries in diabetic patients. Alternatively, percutaneous transluminal angioplasty (PTA) was proposed to reperfuse diabetic patients with peripheral artery disease.

(Siracuse et al, 2014)’s retrospective review concluded PTA together with stenting and atherectomy as the gold-standard treatment for diabetic patients. 65% of patients did not experience re-stenosis in one year, as well as a generally lower short-term restenosis rate in diabetic than in non-diabetic patients. Its extensive application in emergencies deems it suitable for acute burn injuries with the caveat of this procedure being long-term statin use post operatively. Overall, its usage before a skin graft procedure provides a much more promising clinical outlook in future prevention of limb ischaemia.

Context and comparison with previous work The present findings of this review align with those of (Sharma et al, 2023), which observed the relationship between aetiology of burn injuries and the resulting skin graft outcomes in diabetic patients. Both Sharma et al’s publication and this review identified prolonged or failed wound closure as a consequence of co-morbidities, operative complications, and the unique pathology of wound healing such as peripheral neuropathy and vasculopathy, in diabetic patients compared to their non-diabetic counterparts. Although this review did not include case reports and case series, in contrast to Sharma et al’s, conveying the therapeutic complications of skin grafting in deep, aggravated foot burns, the conclusion remains consistent: skin graft outcomes had no significant difference between diabetic and non-diabetic patients in the short term, but the former had exacerbated complications in the long term. The systematic review also addressed the root causes of burns amongst diabetic patients which falls outside the scope of this review, although future studies may evaluate the varying outcomes of skin graft in different mechanisms of burn injuries to better consolidate this research question.

Limitations and Bias The findings of this review must be interpreted in light of some limitations, mainly being the lack of available studies within the outlined inclusion criteria and non-standardised methods of measurement and definitions pertaining to the research question. A major downside identified with the current surgical management is the lack of clear treatment algorithm

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for specific vulnerable populations, including diabetic patients and the elderly, particularly those with diabetes. Although most studies referenced in this review accounted for variables such as co-morbidities, age, and location of burns, it cannot be accurately determined as to whether these interindividual variations affected the efficacy of skin grafts or whether skin graft is itself a flawed surgical technique. This may limit the application of the conclusions of this review to diabetic patients specifically. This review specifically focuses on the application of skin grafts for lower extremity burns in diabetic patients, which, whilst being the most common site of burn injuries in this demographic, is an area with limited targeted and valid studies.

To broaden the scope, the author also considered general studies on burns in diabetic patients and lower extremity burns in patients of any type. The variability in complications of foot burns in diabetic patients are best explored through case studies. However, these fall short in reliability and evidence quality compared to the meta-analyses and systematic reviews referenced in this review. Case studies underscore the need for specialised education in handling diabetic burns with both clinical and cosmetic intentions to optimise longterm wound healing and functional mobility. They also narrow down on wound size, depth and location which provides greater precision as the latter two are often negated in large-scale studies. However, larger cohorts and more rigorous study designs are essential to create a comprehensive understanding of diabetic burns, incorporating factors such as age, weight and vascular health in an epidemiological context.

Future outlook and implications There has been a longstanding debate on the timing of wound excision prior to grafting– whether early or delayed excision is more effective. Early excision is associated with decreased bacterial colonisation and initial infections, although graft uptake rates tend to be similar. Limited studies have been conducted on the outcomes of early and delayed excision in diabetic patients specifically, although double-blind randomised controlled trials have reported a greater restoration of foot function, less joint deformities and contractures (Shakirov, 2011) (Ayaz et al, 2019). Various artificial skin substitutes, such as AlloDerm® and Biobrane®, have been used as temporary dressings to manage wounds before human skin grafts are available. These substitutes can reduce occurrences of pain and wound desiccation (Niţescu et al, 2012). However, they are

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not without limitations; they are more costly than human skin grafts and carry a risk of immunological rejection and infection. Despite their benefits in the short term, these substitutes pale in comparison to human autografts or allografts, which remain the gold standard for permanent wound coverage.

Novel research should equally be considered, such as the role of honey in adhering the graft to the wound bed, which has heavy implications in optimising graft uptake (Maghsoudi and Moradi, 2015). However, the research on this method is limited by small sample sizes and has not been tested on diabetic patients or those with pre-existing skin conditions, making it difficult to generalise the findings. Therefore, while innovative, these alternatives require further investigation before they can be considered viable options for broader clinical use. STSG is a versatile technique which offers a higher chance of graft uptake and complete wound closure, but may not be the most resistant with direct pressure in weight-bearing in foot burns. Hence, this necessitates evaluation of wound location and co-morbidities of the patient in preoperative planning. Tighter glycaemic control is an effective preventative strategy in promoting skin graft uptake and a solution to the root of the problem burns. Moreover, hyperglycaemia remains in the body after a burn injury and acute insulin resistance may develop as a result. In Rael et al, 2019, regular exercise results in prolonged graft survival, although further human studies are needed to establish a clear cellular mechanism for wider clinical application. Nonetheless, the study supports exercise as a clinical recommendation following skin graft procedures.

Future implications For burn patients, with or without diabetes, regular check-ups after discharge can reduce the rates of readmission by monitoring blood glucose levels, which may help prevent progression to a diabetic state.

Specialised cutaneous burn unit and a recovery plan should be devised for high-risk groups such as the elderly and diabetic patients. A standardised protocol should be constructed to include quantitative metrics of wound depth and percentage of tissue oxygenation that can categorise the wound and translate into specific treatment decisions, using functional nearinfrared spectroscopy which is shown to be promising (Kim et al, 2023). This is so the decision of skin graft and dressing is not subjected to gross visual inspection. Fire education and first-aid management of

burns should be promoted among diabetic patients to help prevent burn injuries and ensure prompt cooling and dressing before medical assistance arrives. For elderly diabetic burn patients, social prescriptions may help maintain joint mobility and reduce contractures.

Community care should also be considered for wound dressing changes.

Recommendations Future studies may explore the variability of skin graft outcomes across different skin colours and ethnicities to better understand the range of suitability in diverse demographics. The surgeon’s expertise and experience may also have an impact on the quality of specialised burn care for high-risk diabetic patients with uncontrolled hyperglycaemia. There are gaps in the literature regarding standardised preventative and recovery regimens for burn injuries in diabetic patients that must be addressed. More studies are needed to investigate whether early or delayed excision optimises the clinical course of skin grafting, aiming to reach a well balanced conclusion which would come from high levels of evidence.

CONCLUSION As diabetes and its complications remain an increasingly central problem in patient’s lives, burn prevention and management must be addressed. This review established an overview of factors such as rate of wound healing, skin graft criteria, elderly management, and functional and cosmetic outcomes; all of which significantly influence the long-term clinical course of diabetic foot burns. To provide personalised care for diabetic patients and their co-morbidities such as neuropathy and vasculopathy, appropriate pre-operative planning and specialised post-operative management should be implemented in a standardised manner. *Disclaimer: This author declares no conflict of interests and no affiliations or involvement in any organisation with any financial or non-financial interests.

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181–184.

Niţescu, C. et al. (2012) ‘Surgical options in extensive burns management’, Journal of Medicine and Life, 5(Spec Issue), pp. 129–136.

‘Outcomes and complications of diabetic burn injuries: a single center experience’ (no date).

Available at:https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC8310877/.

Oosterwijk, A et al (2016) ‘Prevalence of scar contractures after burn: A systematic review – ScienceDirect”. Available at: https://www.sciencedirect.com /science/article/abs/pii/S0305417916302716bib0155 (Accessed: 21 May 2024).

Rael, V.E. et al. (2019) ‘Exercise Increases Skin Graft Resistance to Rejection’, American journal of transplantation: official journal of the American So-

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ciety of Transplantation and the American Society of image. Available at: https://plasticsurgerykey.com/theTransplant Surgeons, 19(5), pp. 1560–1567. Available pertinence-of-the-reconstructive-ladder-and-theat: https://doi.org/10.1111/ajt.15266. reconstructive elevator/ (Accessed: 3 June 2024).

Ramanujam, C.L. et al. (2013) ‘Impact of diaSkin Grafts — British Society for betes and comorbidities on split-thickness skin grafts Dermatological Surgery (no date). Available at: for foot wounds’, Journal of the American Podiatric https://bsds.org.uk/members/workshop/skin-grafts/ Medical Association, 103(3), pp. 223–232. Available (Accessed: 3 June 2024). at: https://doi.org/10.7547/1030223.

Lydia Mao is a 1st year Medicine Student at the Rh, D. (2023) ‘A Clinicopathological Study on University of St Andrews, Contact at: lem29@stSplit Thickness Skin Graft Uptake in Diabetics and andrews.ac.uk Factors Affecting Graft Uptake’, General Surgery, 6.

Saeedi, P. (2019) ‘Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition’. Available at: https://pubmed.ncbi.nlm.nih.gov/31518657/.

Santema, T.B., Poyck, P.P. and Ubbink, D.T. (2016) ‘Skin grafting and tissue replacement for treating foot ulcers in people with diabetes’, The Cochrane Database of Systematic Reviews, 2016(2), p. CD011255. Available at: https://doi.org/10.1002/14651858.CD011255.pub2.

Shakirov, B.M. (2011) ‘Deep foot burns: effects of early excision and grafting’, Burns: Journal of the International Society for Burn Injuries, 37(8), pp. 1435–1438. Available at: https://doi.org/10.1016/j.burns.2011.07.007.

Siah, M.C. and Abramowitz, S. (2019) ‘Perfusion Assessment and Treatment in the Diabetic Patient’, Clinics in Podiatric Medicine and Surgery, 36(3), pp. 361–370. Available at: https://doi.org/10.1016/j.cpm.2019.03.001.

Siracuse, J.J. et al. (2014) ‘Endovascular treatment of lesions in the below-knee popliteal artery’, Journal of Vascular Surgery, 60(2), pp. 356–361. Available at: https://doi.org/10.1016/j.jvs.2014.02.012.

Wood, F.M. et al (2016) ‘Water First Aid Is Beneficial In Humans Post-Burn: Evidence from a Bi National Cohort Study’ - PMC. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725848/ (Accessed: 21 May 2024).

Yammine, K. and Assi, C. (2019) ‘A MetaAnalysis of the Outcomes of Split-Thickness Skin Graft on Diabetic Leg and Foot Ulcers’, The International Journal of Lower Extremity Wounds, 18(1), pp. 23– 30. Available at: https://doi.org/10.1177/1534734619832123.

Reavey P.L. and Gottlieb L. J. (2019) The Pertinence of the Reconstructive Ladder and the Reconstructive Elevator — Plastic Surgery Key, digital

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A new hope for Alzheimer’s – is Deep Brain Stimulation advancing beyond Parkinson’s?

Nimue Lilith Romeikat Bsc (Hons) Medicine

Sushmhitah Sandanatavan Bsc (Hons) Medicine

Abstract—The significance and rising popularity of Deep Brain Stimulation (DBS) in treating Parkinson’s disease (PD) is unmistakably evident, demonstrated by its’ feature in our previous STATIC edition. An increasing number of researchers engage with its revolutionary benefits. The focus currently lies upon establishing DBS’ possible role in the treatment of non-motor conditions. This review will focus on the published evidence on DBS’ application to Alzheimer’s Disease.

DBS IS A NEUROMODULATION TECHNIQUE that begins with a comprehensive brain mapping. The procedure involves using a stereotactic head frame to guide the placement of a thin wire attached to electrodes into the specific brain region to be stimulated. These electrodes are connected to a pulse generator sitting under the skin close to the collar bone - similar to a conventional pacemaker (Senevirathne et al., 2023). Following surgery, a series of consultations are conducted, in which a variety of parameters will be adjusted. The parameters that can be altered include pulse frequency, voltage, and impulse duration.

This “fine-tuning” process relies on patient feedback, typically focusing on minimising motor symptoms, such as tremors. The effects of the stimulation are said to include synaptic plasticity, neuroprotection, and neurogenesis (Herrington et al., 2016), which are key improvements waiting to be utilised for several more conditions.

Clinical Application Currently, DBS is primarily used to treat latestage PD, focusing on the minimisation of motor deficiencies. The target stimulation areas include the subthalamic nucleus and the globus pallidus internus (Hariz and Blomstedt, 2022). DBS has been routinely

applied to other closely related motor disorders such as dystonia, epilepsy, and essential tremor.

Presently, efforts are underway to replicate this success in treating non-motor conditions, i.e. cognitive and neuropsychiatric disorders such as major depressive disorder (MDD). However, it is essential to note the limitations of DBS application to neuropsychiatric conditions, due to the scarcity of predictive animal models and prominent ethical challenges with conducting clinical trials in psychiatric patient populations when referring back to capacity of consent (Rabins et al., 2009). Another point sparking hesitation in this field would be the potential for sudden relapse if the stimulation is abruptly terminated, such as due to battery failure, which can be detrimental to an individual experiencing psychiatric symptoms.

Parkinson’s Disease & Alzheimer’s Disease Hence, this review is focusing on evidence exploring DBS to mitigate cognitive decline in dementia, specifically Alzheimer’s disease (AD). A reason for this focus is that while PD and AD present very differently clinically, they share significant similarities in their underlying pathogenesis. Both are protein misfolding disorders resulting in aggregation of misfolded amyloid proteins in neurons – in PD this is alphasynuclein protein, in contrast to tau and alpha-beta proteins in AD (Senevirathne et al., 2023).

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An additional reason for exploring AD is the limited efficacy of its current first line treatment.

Pharmacological treatment options are centred around symptom minimisation rather than curative treatment.

Available agents act by increasing cholinergic or antagonising glutaminergic transmission (F. Massoud, 2011) and are only mildly and temporarily beneficial, reflecting a need for more effective therapies. In contrast, DBS offers reversible, adaptable and individualised treatment, in addition to a lower risk of brain-wide or systemic effects which can often limit the effectiveness of conventional drug therapy (Sankar et al., 2014).

Methods The evidence for this review report was collated by inputting the key words “Deep Brain Stimulation”, “DBS”, “Alzheimer’s Disease”, and “AD” into the search engines Cochrane, Embase, Google Scholar, Medline and PubMed. Clinical trials of all stages as well as case-control studies were included. Despite the statistical limitations due to small sample sizes of the case-control studies, they were chosen to be included in this review due to the sparsity of resources available in this new field. The invasive nature of the procedure and following hesitation of patients are big factors contributing to this lack of completed clinical trials (Targum et al., 2021).

DISCUSSION To ensure clarity, the studies which are being investigated have been grouped according to area of stimulation. The areas that were targeted in the studies consist of the fornix, hippocampus, frontal lobe and nucleus basalis of Meynert. Each study has differing grounds for their target and its relation to the pathogenesis of Alzheimer’s Disease.

The study with the most extensive progress is the ADvance trial (Ponce et al., 2016) – a phase II trial (Lozano et al., 2016) that included a follow-up (Leoutsakos et al., 2018) which was multi centred, double-blind and randomised. It concentrated on the stimulation of the bilateral fornix (“DBS-f”) which is a working memory bundle which constitutes a core element of the limbic circuits, as well as one of the most important anatomical structures related to memory (Oishi and Lyketsos, 2014). This area is unequivocally significant to the progression of AD. The initial aim of this study was focused on proving safety of DBS rather than efficacy – an important step to facilitate further studies using this method.

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In phase II, the primary objective still remained to evaluate the safety of DBS-f in patients with mild AD, but with the secondary aim of assessing change in clinical and functional imaging outcomes. The participants were individuals aged 45 to 85 with mild, probable AD, enrolled between 2012-2014. They had the DBSf implanted without receiving any stimulation for 12 months and then progressed into active stimulation that was continuous and delivered at 130 Hz, between 3.0 and 3.5 Volts, and a pulse width of 90 microseconds.

There were no adjustments made to this during the 12 months. Through assessment by cognitive function tests and PET imaging at 6 and 12 months, DBS-f was shown to initially increase glucose metabolism, although this was not sustained at 12 months. The older patient population exhibited clear clinical benefit, but this was offset by the younger patient population, which resulted in DBS-f not showing a significant clinical benefit overall. The follow-up investigated the effect of early-on and delayed treatment – one group received 2 years of active stimulation and the other received one year of active stimulation after one year delay. Although no significant differences were found in this aspect, the results did support the finding of previous trials, that patients over 65 years old experienced greater benefits.

Around the same time, a 2015 study investigated the effects of DBS on the Hippocampus (Sankar et al., 2015), which is a significant area involved with the process of learning, memory processing, and the generation of episodic memory. In the early stages of AD, the hippocampus shows significant atrophy and is being used as a structural marker in magnetic resonance imaging (MRI). The study consisted of 6 patients with early AD who were followed for three years with active DBS. The assessment consisted of MRI scanning to assess structural volume changes of the brain which were associated with levels of glucose metabolism. It was found that the mean rate of hippocampal atrophy was significantly lower in the DBS group when compared to their matched AD group. In 2 out 6 patients a 5-8% increase in hippocampal volume was even found which appears to be of a magnitude sufficient to bring hippocampal volume back to pre-disease state. In addition to the MRI assessment, the ADAS-Cog scale was used to conclude that hippocampal volume may be linked to cognitive function.

An area which was investigated but has not proven to find clinical benefit is the nucleus basalis of Meyn-

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ert (NBM). It is a cholinergic nucleus in the basal forebrain which provides extensive projections to all cortical areas – this cortical cholinergic input from the NBM is important for cognitive processing (Nazmuddin et al., 2021). Thus far, only a few phase I trials have been completed with no significant outcome to be noted (Kuhn et al., 2015, Turnbull, 1985). Although these studies did not demonstrate clinical benefits, they did reaffirm the safety of the procedure.

A more recent study from 2018 was investigating the effect of DBS on the frontal lobe (Scharre, 2018).

The frontal lobe plays a crucial role in cognition and behaviour – including energisation (the process of initiating and sustaining a response), monitoring, task setting, and behavioural and emotional self-regulation.

The adjacent septal nuclear complex is an important source of acetylcholine. This study was the first study not focusing on the dementia element of AD. While the impact of dementia on patients with AD is severe, this study mentioned the hardship that comes with other factors such as apathy, decreased initiative and curiosity, as well as poor decision-making.

This study was a very small, non-randomised phase I trial consisting of 3 subjects with mild AD, who were matched to comparison groups. Continuous stimulation was applied for at least 18 months and the primary outcome measure was CDR-SB which is a widely used global measure summating six domains of cognitive and functional performance. A noteworthy aspect of this study was the adjustment of parameters based on the best-observed neurocognitive task response and feedback from the patient and caregiver – this is similar to the process used in PD where the parameters are adjusted in response to motor control feedback. While the sample size is too small to draw definite conclusions, one needs to highlight the significant improvements that the patients have made within this trial as patients and their caregivers reported feelings of increased energy, focus, alertness, and attention with DBS. One patient highlights this effect very well; prior to DBS she was unable to do any meal preparation but after 2 years of DBS she was able to organise transportation and remember to bring money to independently buy groceries and prepare a simple meal for herself, even regaining independence to select her own attire.

RESULTS AND LIMITATIONS One must note the safety of the procedure being reconfirmed, which is a crucial step for further in-

vestigations to be launched exploring the efficacy of the treatment. Most trials investigated the efficacy as a secondary objective by using cognitive scales such as ADAS-Cog and PET imaging to monitor cognitive improvement and glucose metabolism levels – the study from 2015 also included hippocampal volume as a measurement. While most studies, with the exception of the ADvance trial, were at the early phase I trials, some promising results have been found - especially in elderly patients with mild AD, as noted by the ADvance trial.

The improved response by elderly patients is unexpected and typically contrasts with outcomes seen in other treatments. One explanation for this finding is that the younger patients had more severe brain pathology than older patients despite being symptomatically comparable, such that DBS-f could no longer be of benefit. This aspect highlights the heterogeneity of AD and the need for further understanding of the underlying mechanisms and more concise inclusion criteria which can reflect this heterogeneity within the trials. Further research on new biomarkers could be instrumental in achieving this goal.

Another issue that prevents coherent comparison of these early studies is their varying level of progress as well as the differing methods of assessing DBS’ effect on preventing AD progression. Thus, in order to fully be able to support the use of DBS and determine in which area it is the most effective, we require not only a higher number of participants in later trial stages, but also a better understanding of the molecular background of AD to facilitate more concise inclusion criteria.

A really important factor that has not been explored in all of these studies, except for the most recent one, is the aspect of adjusting parameters postoperation. When treating PD this is one of the most crucial steps that have been seen in aiding in DBS’ success in PD treatment. The adjustment of parameters (e.g., voltage, pulse width and frequency) is done with external devices that can communicate with the neuromodulator of the patient. This adjustment is performed usually in response to motor symptoms which provides instant feedback during the adjustment session (Lozano et al., 2016). However, AD lacks this kind of instant feedback – there is no tremor that can visibly reduce. Thus, there is a need to establish the best cognitive tests to use in this instance. The omission of adjusting parameters in the current studies could account for the lack of statistically significant

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results and cognitive effect, its beneficence is shown by the outcomes of the most recent study which did utilise the parameters.

Adverse Effects While the safety of the procedure has been proven through a number of these studies, it is important to acknowledge the occurrence of some adverse effects.

In the early phase of the ADvance trial, other brain areas that are usually spared in AD progression but were not specifically targeted, were also stimulated and produced results, presumably related to subcorticalcortical or cortical-cortical trans-synaptic effects of stimulation.

Aside from usual surgical complications such as infection, notable side effects in response to the DBS procedure, included falls and headaches to altered mental status and seizures.

A number of emerging papers have discussed DBS’ role in personality change in patients after or during treatment (Pham et al., 2015). Opinions on this topic vary (Gilbert et al., 2018) and most of the research that has been conducted in DBS’ PD treatment continues to lack empirical evidence, while the new areas of stimulation proposed by AD treatment are yet to be investigated. Nonetheless, it opens up critical ethical concerns.

Ethical and Legal Implications More neuroethical research is essential to incorporate findings regarding personality changes into clinical practice, especially when establishing informed consent. A patient’s perception of their identity might play a crucial role in their decision to undergo the procedure.

These new findings will have to be evaluated within a legal context (Klaming and Haselager, 2013).

Take the hypothetical scenario of a person accused of violating the law and that individual has just recently started DBS. Could the individual blame their actions on the newly found impulsiveness and aggression due to the procedure and thus, be regarded as not be liable for their actions? Further work needs to go into assessing the mental competence and responsibility of DBS patients in order to formulate fitting guidelines.

CONCLUSION Overall, current studies provide limited certainty of the efficacy of DBS in AD patients, they do however provide certainty of its safety and promising results

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that need to be investigated further in more extensive trials. Future work needs to target an increased understanding of the underlying mechanism of AD and diagnostic methods which can account for the heterogeneity of the disease for this to be reflected in the trials themselves. Once studies can accustom coherent ways of assessing efficacy and adjusting parameters for each area of stimulation, comparison of the best mechanism and application of DBS will be evident.

The introduction of DBS not only unlocks remarkable treatment breakthroughs surpassing pharmacological alternatives but also introduces a realm of ethical complexity. This rapidly evolving sphere of innovation in technology demands attention and exploration, presenting unparalleled opportunities that should not be missed.

REFERENCES F. MASSOUD, G. C. L. (2011). Pharmacological treatment of Alzheimer disease. Canadian Journal of Psychiatry, 56, 579-588.

GILBERT, F., VIAÑA, J. N. M. & INEICHEN, C. (2018). Deflating the “DBS causes personality changes” bubble. Neuroethics, 14, 1-17.

HARIZ, M. & BLOMSTEDT, P. (2022). Deep brain stimulation for Parkinson’s disease. J Intern Med, 292,764-778.

HERRINGTON, T. M., CHENG, J. J. & ESKANDAR, E. N. (2016). Mechanisms of deep brain stimulation. J Neurophysiol, 115, 19-38.

KLAMING, L. & HASELAGER, P. (2013). Did My Brain Implant Make Me Do It? Questions Raised

by DBS Regarding Psychological Continuity, Responsibility for Action and Mental Competence. Neuroethics, 6, 527-539.

KUHN, J., HARDENACKE, K., LENARTZ, D., GRUENDLER, T., ULLSPERGER, M., BARTSCH, C., MAI, J. K., ZILLES, K., BAUER, A., MATUSCH, A., SCHULZ, R. J., NOREIK, M., BUHRLE, C. P., MAINTZ, D., WOOPEN, C., HAUSSERMANN, P., HELLMICH, M., KLOSTERKOTTER, J., WILTFANG, J., MAAROUF, M., FREUND, H. J. & STURM, V. (2015). Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia.

Mol Psychiatry, 20, 353-60.

LEOUTSAKOS, J. S., YAN, H., ANDERSON, W. S., ASAAD, W. F., BALTUCH, G., BURKE, A., CHAKRAVARTY, M. M., DRAKE, K. E., FOOTE, K. D., FOSDICK, L., GIACOBBE, P., MARI, Z., MCANDREWS, M. P., MUNRO, C. A., OH, E. S.,

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OKUN, M. S., PENDERGRASS, J. C., PONCE, F. A., ROSENBERG, P. B., SABBAGH, M. N., SALLOWAY, S., TANG-WAI, D. F., TARGUM, S. D., WOLK, D., LOZANO, A. M., SMITH, G. S. & LYKETSOS, C. G. (2018). Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. J Alzheimers Dis, 64, 597-606.

LOZANO, A. M., FOSDICK, L., CHAKRAVARTY, M. M., LEOUTSAKOS, J. M., MUNRO, C., OH, E., DRAKE, K. E., LYMAN, C. H., ROSENBERG, P. B., ANDERSON, W. S., TANGWAI, D. F., PENDERGRASS, J. C., SALLOWAY, S., ASAAD, W. F., PONCE, F. A., BURKE, A., SABBAGH, M., WOLK, D. A., BALTUCH, G., OKUN, M. S., FOOTE, K. D., MCANDREWS, M. P., GIACOBBE, P., TARGUM, S. D., LYKETSOS, C. G. & SMITH, G. S. (2016). A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer’s Disease. J Alzheimers Dis, 54, 777-87.

NAZMUDDIN, M., PHILIPPENS, I. & VAN LAAR, T. (2021). Electrical stimulation of the nucleus basalis of meynert: a systematic review of preclinical and clinical data. Sci Rep, 11, 11751.

OISHI, K. & LYKETSOS, C. G. (2014).

Alzheimer’s disease and the fornix. Front Aging Neurosci, 6, 241.

PHAM, U., SOLBAKK, A. K., SKOGSEID, I. M., TOFT, M., PRIPP, A. H., KONGLUND, A. E., ANDERSSON, S., HARALDSEN, I. R., AARSLAND, D., DIETRICHS, E. & MALT, U. F. (2015). Personality changes after deep brain stimulation in Parkinson’s disease. Parkinsons Dis, 2015,490507.

PONCE, F. A., ASAAD, W. F., FOOTE, K. D., ANDERSON, W. S., REES COSGROVE, G., BALTUCH, G. H., BEASLEY, K., REYMERS, D. E., OH, E. S., TARGUM, S. D., SMITH, G. S., LYKETSOS, C. G., LOZANO, A. M. & GROUP, A. D. R. (2016).

Bilateral deep brain stimulation of the fornix for Alzheimer’s disease: surgical safety in the ADvance trial. J Neurosurg, 125, 75-84.

RABINS, P., APPLEBY, B. S., BRANDT, J., DELONG, M. R., DUNN, L. B., GABRIELS, L., GREENBERG, B. D., HABER, S. N., III, P. E. H., MARI, Z., MAYBERG, H. S., MCCANN, E., MINK, S. P., RASMUSSEN, S., SCHLAEPFER, T. E., VAWTER, D. E., VITEK, J. L., WALKUP, J. & MATHEWS, D. J. H. (2009). Scientific and ethical issues related to deep brain stimulation for disorders

of mood, behavior, and thought. Archives of General Psychiatry, 66, 931-937.

SANKAR, T., CHAKRAVARTY, M. M., BESCOS, A., LARA, M., OBUCHI, T., LAXTON, A. W., MCANDREWS, M. P., TANG-WAI, D. F., WORKMAN, C. I., SMITH, G. S. & LOZANO, A. M. (2015). Deep Brain Stimulation Influences Brain Structure in Alzheimer’s Disease. Brain Stimul, 8,645-54.

SANKAR, T., LIPSMAN, N. & LOZANO, A. M. (2014). Deep brain stimulation for disorders of memory and cognition. Neurotherapeutics, 11, 527-34.

SCHARRE, D. W. (2018). Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer’s Disease. Journal of Alzheimer’s Disease, 62, 621-633.

SENEVIRATHNE, D. K. L., MAHBOOB, A., ZHAI, K., PAUL, P., KAMMEN, A., LEE, D. J., YOUSEF, M. S. & CHAARI, A. (2023). Deep Brain Stimulation beyond the Clinic: Navigating the Future of Parkinson’s and Alzheimer’s Disease Therapy.

Cells, 12.

TARGUM, S. D., FOSDICK, L., DRAKE, K. E., ROSENBERG, P. B., BURKE, A. D., WOLK, D. A., FOOTE, K. D., ASAAD, W. F., SABBAGH, M., SMITH, G. S., LOZANO, A. M. & LYKETSOS, C. G. (2021). Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer’s Disease. J Alzheimers Dis, 82, 1243-1257.

TURNBULL, I. M. (1985). Stimulation of the basal nucleus of Meynert in senile dementia of Alzheimer’s type. A preliminary report. Applied Neurophysiology, 48, 216-21.

Nimue Lilith Romeikat is a 2nd year Medicine Student at the University of St Andrews, Contact at: nlr6@st-andrews.ac.uk

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Brief Exploration of the Molecular Basis of the Different Types of Multiple Sclerosis Shiksha Guru Bsc (Hons) Medicine

Sushmhitah Sandanatavan Bsc (Hons) Medicine

Abstract—Multiple sclerosis is a type IV hypersensitivity reaction that results in the formation of fibrous overgrowths which cover the damaged sections of the axons. These overgrowths gradually harden, forming plaques known as scleroses. It is a disabling condition caused by T cells that destroy myelin sheaths around neurons and attack oligodendrocytes (myelin-producing glial cells of the central nervous system (CNS)), therefore slowing conduction, resulting in motor, sensory and cognitive deficits. The reactions manifest in different neurological patterns (types), with the most common being Relapsing-Remitting MS (RRMS), where patients have intermittent bouts of symptoms flaring up with periods of improvement in the middle; and the most severe being Primary Progressive MS (PPMS) where the patient gets one attack that is a constant progression of disabilities (Osmosis).

This paper aims to understand the difference between RRMS and PPMS at a molecular level by discussing the gross differences in MRI findings of the two types, foundational pathophysiology of the disease, and lastly exploring the potential mechanisms that cause the patterns.

O NE OF THE DIAGNOSTIC TOOLS FOR MULTIPLE SCLEROSIS is MRI, which is also used to determine the specific pattern the patient is inflicted with.

Gadolinium, a transparent agent, makes lesions more apparent in MRIs, hence making them representatives of active inflammation within the CNS (Siger, 2022).

As such, gadolinium-enhancing lesions are a characteristic feature of RRMS. Even in later phases of the disease, PPMS patients have fewer lesions than RRMS patients. This is reinforced by information from T2weighted MRI results. The frequency of active lesions (plaques) is found to be far higher in RRMS than in PPMS. Instead, PPMS has been shown to have increased plaques in the spinal cord. On the other hand, atrophy in the cerebral cortex (Ritccitelli, 2010), deep grey matter structures (like thalamus, putamen, hippocampus and cingulate gyrus) (Fisher, 2008), and cerebellum was much further along in PPMS. This cerebral atrophy explains the rapid rate at which PPMS

patients developed disabilities, and cerebellar atrophy corresponded to the physical and cognitive impairment patterns. This was also cited as evidence that RRMS and PPMS have different underlying molecular mechanisms, given that their grey matter lesion patterns were so dissimilar.

Basic pathogenesis The initiation (Loma, 2011) of this reaction is driven by the interaction between antigen presenting cells (APCs like B cells, microglia) and T-cells. This activates the T cells—in this scenario, the CD4+ and CD8+ types—which travel to the blood brain barrier (BBB) from the thymus to infiltrate it. Three types of T cells are involved in the disease progression once the T cells have crossed the BBB: Th1, Th2 and Th17. They produce the multiple types of cytokines responsible for axonal loss and demyelination (as shown in Figure 1).

These series of reactions contribute to the three main components of MS pathology that are: CNS plaques, inflammation and axonal loss. Although T

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Figure 1. Summarising the immune reactions responsible for causing multiple sclerosis in CNS

cells are not alone in this autoimmune reaction, the demyelination can also be associated with the involvement of CNS-specific glial cells like astrocytes that act as though they are responding to an active injury, therefore producing scars in the brain.

Molecular differences in the pathophysiology of RRMS vs. PPMS A paper from CellPress Review (Baecher-Allan, 2018) explains the difference between RRMS and PPMS: RRMS is an immune-dependent reaction (i.e. driven by immune cells migrating to CNS) whereas PPMS is both immune-dependent and immuneindependent. That is, along with cytokine-mediated inflammation and plaque formation, there is also injury as a result of oxidative stress and mitochondrial injury. RRMS is primarily immune-dependent. It progresses because of autoreactive T cells that attack the CNS. Dendritic cells that are antigen-presenting activate naı̈ve T cells, which mature to become either CD4+ T cells or CD8+ T cells, as previously discussed. CD4+ T cells are also classed as T helper cells (Th), while CD8+ T cells are classed as cytotoxic T cells (CT). This is particularly relevant to the progression of RRMS because of its role in the maturation of immune cells and the production of memory B cells. RRMS is, however, known to progress into secondary-progressive MS (SPMS) in later stages because immune-independent reactions often become responsible for inflammatory mediators after CNS has been damaged.

Dysfunction of mitochondria (Correale, 2017) can lead to axonal loss by causing an energy deficiency in the cell, leading to ionic imbalance that eventually results in oxidative distress which in turn causes toxic

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hypoxia in the cell and eventually kills it. Exploring this further in conjunction with data from a review that used PET scans on SPMS (which has the same symptoms as PPMS) (Rissanen, 2014); showed PET scans picked up signs of diffuse microglial inflammation in SPMS patients in contrast to control. Hence, this expands on the proposition that progressive MS is caused by the CNS’s glial cells including astrocytes and microglia. Another paper (Liddelow, 2017) identified a particularly neurotoxic variety of astrocytes called A1 whose primary driver is microglia. From this point, especially post-CNS damage, inflammatory molecules are released in cascade reactions primarily by non-T cells (i.e. B cells). B cells themselves can either activate CD4+ T cells (again) or cross the BBB, become “follicle-like germinal centres” within the CNS, or differentiate and become antigen-secreting plasma cells themselves. They can also simply secrete pro-inflammatory markers as seen in Figure 1 and cause CNS inflammation. This would explain why immunomodulatory therapy works with PPMS only until it does not evolve into SPMS, and does not work at all for PPMS.

CONCLUSION Both RRMS and PPMS are demyelinating autoimmune diseases that cause physical and cognitive disability as they progress. From the collection of reviews above, it can be concluded that RemittingRelapsing MS is driven by T cells from the peripheral adaptive immune system, whereas Primary-Progressive MS is driven by microglia, astrocytes and B cells which are part of the innate immune system of the CNS itself. Understanding this difference in the underlying mechanism between the various types of MS can help make more accurate interventions to combat the afflictions they present.

REFERENCES Osmosis Notes CNS Demyelinating Disorders.

Available at: https://www.osmosis.org/notes/CNS Demyelinating Disorderspage-1 (Accessed: 19th September 2023) Siger, M. (2022) ‘Magnetic Resonance Imaging in Primary Progressive Multiple Sclerosis Patients’, Clinical Neuroradiology, 32(3), 625-641. doi: 10.1007/s00062-022-01144-3 Riticcelli, G., Rocca, M., Pagani, E. Rodegher, M., Rossi, P., Falini, A., Comi, G., Filippi, M., (2010) ‘Cognitive impairment in multiple sclerosis is asso-

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ciated to different patterns of grey matter atrophy according to clinical phenotype’, Human Brain Mapping, 32(10), 1535-1543. doi: 10.1002/hbm.21125 Fisher, E., Lee, J., Nakamura, K., Rudick, R., (2008) ‘Gray matter atrophy in multiple sclerosis: a longitudinal study’, Annals of Neurology, 64(3), 255265. doi: 10.1002/ana.21436 Loma, I., Heyman, R., (2011) ‘Multiple Sclerosis: Pathogenesis and Treatment’, Current Neuropharmacology, 9(3).

409-416. doi: 10.2174/157015911796557911 Baecher-Allan, C., Kaskow, B., Weiner, H., (2018) ‘Multiple Sclerosis: Mechanisms and Immunotherapy’, Neuron, 97(4), 742-768.

Correale, J., Gaitán, I., Ysrraelit, C., Fiol, P., (2017) ‘Progressive multiple sclerosis: from pathogenic mechanisms to treatment’, Brain, 140(3), 527-546. doi: 10.1093/brain/aww258 Rissanen, E., Tuisku, J., Rokka, J., Paavilainen, T., Parkkola, R., Rinne, J., Airas, L., (2014) ‘In Vivo Detection of Diffuse Inflammation in Secondary Progressive Multiple Sclerosis Using PET Imaging and the Radioligand 11C-PK11195’, The Journal of Nuclear Medicine, 55(6), 939-944.

Liddelow, S., Guttenplan, K., Clarke, L., Bennett, F., Bohlen, C., Schirmer, L., Bennett, M., Münch, A., Chung, W., Peterson, T., Wilton, D., Frouin, A., Napier, B., Panicker, N., Kumar, M., Buckwalter, M., Rowitch, D., Dawson, V., Dawson, T., Stevens, B., Barres, B., (2017), ‘Neurotoxic reactive astrocytes are induced by activated microglia’, Nature, 541, 481-487. doi: 10.1038/nature21029 Shiksha Guru is a 3rd Medicine Student at the University of St Andrews, Contact at: sg341@standrews.ac.uk

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Earning Their Stripes: The Zebrafish (Danio rerio)’s Promising Future as a Developmental Alternative In Vivo Model of Neurodegenerative Diseases Hannah Betts Bsc (Hons) Neuroscience

Laila Deen Bsc (Hons) Physics

Thomas Burton Bsc (Hons) Mathematics

Abstract—Neurodegenerative diseases are debilitating with a detrimental effect on the lives of the millions of patients suffering from them. These diseases are notably complex in aetiology and onset.

Consequently, the modern pharmaceutical industry struggles to develop drugs which successfully treat or significantly improve patients’ symptoms. The development of innovative disease models aims to further investigate neurodegenerative diseases to achieve more successful pathogenesis-targeting therapies. The zebrafish (Danio rerio) model of neurodegenerative diseases is providing novel findings regarding neurodegeneration, and promising discoveries in the future of neurodegenerative disease research.

N EURODEGENERATIVE DISEASES ARE A SIG NIFICANT PUBLIC HEALTH CONCERN . In 2019, 57 million people suffered from Alzheimer’s disease (IHME, 2022). By 2050, this number is estimated to rise to 139 million (Alzheimer’s Society, 2024).

Neurodegenerative diseases account for more than 500 billion USD in healthcare costs annually in the United States (US) (Cornblath et al., 2020). Predictions from the World Health Organization (WHO) forecast neurodegenerative diseases as the second leading cause of death by 2040 (Wang et al., 2021). With this significant health crisis looming on the horizon, the development

of novel drugs to treat neurodegeneration is essential.

Developing novel disease models to test these treatments is crucial to the future of drug development.

With aims to facilitate the safest transition from the laboratory to patients. This essay will explore the revolutionary utilisation of zebrafish (Danio rerio) as a developmental alternative to common in vivo models of neurodegenerative diseases and report some of the remarkable findings.

A drug can show enormous promise in preclinical models but still fail in human patients. This gap in research is partially due to the largely distinct physiologies of humans and animals. This barrier is

Published by STATIC Student Journal

LAILA DEEN, 2024

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relevant in neurodegenerative disease (NDD) research and has impeded successful drug development. Thus, there is a constant search for alternative preclinical models which better simulate and predict the results of neurodegeneration combatting drugs and therapeutics (Fontana et al., 2021)

Introduction to Neurodegenerative Diseases Neurodegenerative diseases affect millions of people worldwide and are infamous for their particularly debilitating hallmark symptoms (Lamptey et al., 2022).

The NDDs that I will focus on in this paper are the most common: Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). I will briefly cover Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Disease (HD) (Lamptey et al., 2022). Age is the primary contributor to NDD onset, but genetic and environmental factors have also been attributed to causation (Lamptey et al., 2022). NDD is primarily characterised by neurodegeneration, the progressive loss of neurons, neuronal structure, and functions (Lamptey et al., 2022). Protein aggregation or misfolding is the primary culprit of the disease process (Cornblath et al., 2020). NDDs are challenging to study and treat predominantly due to their diverse and complex aetiology (Wang et al., 2021). Today, there is a severe lack of pathogenesis-targeting therapies to treat NDD (Lamptey et al., 2022).

Aetiology of Alzheimer’s Disease Alzheimer’s Disease is the most common type of dementia (Alzheimer’s Society, 2024). The disease is characterised by the accumulation of amyloid-beta (A) and tau proteins. Accumulation of A leads to the formation of A-containing plaques. These plaques link to neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Plaque formation correlates with disruption of the hippocampal circuitry, interrupting the brain’s ability to consolidate memories from short to long term. This leads to AD’s hallmark characteristics: memory loss and memory impairment (Cornblath et al., 2020).

Aetiology of Parkinson’s Disease Parkinson’s disease is defined by its characteristic symptoms; tremors, muscle stiffness, unsteady walking, and difficulties with balance and coordination.

This disease is characterised by frontal cortex atrophy, ventricular enlargement, the presence of Lewy bodies within neuronal cell bodies, misfolding of tau protein,

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Figure 1. Examples of In Vitro, In Vivo, and In Silico Research Models (Fontana et al., 2021).

NFT formation from hyperphosphorylated tau, and the death of dopaminergic neurons (Cornblath et al., 2020). The onset of PD is usually around age 50, after which life expectancy significantly declines as PD progresses (Chia et al., 2022). PD is incurable and modern treatments are only effective in providing a slightly increased quality of life and life expectancy (Chia et al., 2022).

Introduction to Disease Models Models are essential to ensure the safety, efficacy, and bodily response to new drugs and therapeutics prior to clinical trial testing in human patients. These models can be in vivo, in vitro, or in silico (Fig. 1) (Fontana et al., 2021).

In silico models include bioinformatic tools and computer models. These are beneficial due to their ability to screen compounds cost-efficiently, availability of large datasets, and usefulness when repurposing older drugs for novel applications. The downside of this model is that it is heavily dependent upon highprecision data when building the models and clarity in the algorithms used. The strongest benefits of in silico models are found in their integration with other models (Fontana et al., 2021). In vitro models include cell cultures, tissue cultures, and organ models. These models are fast, simple, and cheap (Fontana et al., 2021). With high reproducibility and output data that is easy to analyse and integrate with other models, in-

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vitro models are common and favoured in research.

Nonetheless, this model has its setbacks: changes in physiology can make this model inapplicable in clinical trial targets. Further it is susceptible to unnatural growth kinetics and data collection may not correlate with results later seen in in vivo models (Fontana et al., 2021). Finally, there are in vivo models. These models can include large vertebrates: mice, rats, rabbits, and non-human primates (primarily macaque). These models have shorter life cycles than humans, allowing researchers to observe drug effects throughout a life span. Many of these models additionally present genetic similarity to humans, lessening the risk of unforeseen complications in clinical trials. Furthermore, animal models can be genetically modified, allowing for the study of specific physiology and pathophysiology of diseases (Fontana et al., 2021). Although highly beneficial in research, the issues surrounding in vivo models are significant. Firstly, ethical issues are raised in animals being purposely bred for experiments. The process of conducting research on live animals fails to account for the emotional and mental impact on researchers and animal caretakers. Additionally, these models are expensive, requiring daily care, licenses to work with them, housing, painkillers, anesthetics, and associated instruments. Alternative living organisms like microorganisms (e.g., Saccharomyces cerevisiae (yeast), lower vertebrates (e.g., fish), and invertebrates (e.g., roundworms, fruit fly) are also used as in-vivo research models. These models are beneficial as they are not recognised to present ethical barriers and are more cost-effective models that can still be widely applied to study mechanisms of drug effects (Fontana et al., 2021). However, it is worth noting that their lack of mammalian physiology reduces translatability to higher organisms and humans (Fontana et al., 2021).

Ethics of Animal Models in Research Animal models remain indispensable in research.

Despite efforts to find alternative models and expand the usage of in vitro or in silico models, they will likely stay this way for the foreseeable future. There is a significant demand for more research to be invested in developing and optimizing alternatives to in vivo models to overcome the established and significant ethical concerns in modern research strategies (Fontana et al., 2021).

The Rise of the Zebrafish Model in Research The zebrafish (Danio rerio) model is an alternative in vivo model utilised in research. It has become increasingly popular as a replacement for larger vertebrate animals (Fontana et al., 2021). Over the past two decades, zebrafish have gained significant traction as a model organism informing our understanding of the pathology of diseases and drug toxicity (Steven et al., 2020). Initially, the zebrafish model was used to monitor water contamination and test for toxic substances (Wang et al., 2021). Its applications in medical research originated from the University of Oregon, where scientists first used the model to explore the genetic basis of vertebrate neural development (Eisen, 2020). The zebrafish is a tropical freshwater fish that is about 5 cm long when mature. It has been used in laboratory settings in experiments on social behaviour, somatic mutations and recombinant tests, developmental biology, and seizure assays (Freires et al., 2017). These fish are used extensively to research the biological and toxicological effects of chemicals, including environmental contaminants and pharmaceutical toxicology (Steven et al., 2020). Further, they are useful in locomotion studies and are used to study convulsant and antiepileptic drugs (Steven et al., 2020).

Genetic manipulation in zebrafish has even allowed for the analysis of neurodevelopmental disorders (autism), neuropsychiatric disorders (anxiety and depression), and neurodegenerative diseases (AD and PD) (Steven et al., 2020).

The zebrafish was established as an excellent research model based on several developmental characteristics. Unlike many fish species and other prospective models, the zebrafish is not a seasonal breeder, meaning embryos can be obtained throughout the year.

Additionally, a single female zebrafish can produce hundreds of eggs in a single spawning, allowing for the potential of high numbers of closely related embryos to be used within a single experiment. Zebrafish embryos develop rapidly, hatching in three days, at which point the development of individual cells/structures can already be observed. Additionally, unlike mice or humans, zebrafish can regenerate their limbs, hearts, retinas, spinal cords, and even brains (Eisen, 2020).

Zebrafish models are easy to handle in the lab, and as a low-cost model, present fewer obstacles than larger vertebrates in their care and study.

Further, their bodies are nearly transparent during early development (Fontana et al., 2021). This

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transparency allows for detailed visualisation of the zebrafish anatomy and non-invasive observation in research (Freires et al., 2017; Steven et al., 2020).

Additionally, the zebrafish’s rapid development cycle means its blood-brain barrier is developed just 72 hours post fertilisation (Wang et al., 2021).

Humans and zebrafish have a high homology of 71%, which is crucial to their translation to treating diseases in humans (Freires et al., 2017). With the zebrafish’s whole genome sequence already available, these models are an understandably appealing alternative for molecular and genetic studies in cancers, heart diseases, and neurodegenerative diseases. It is also emerging as a promising preclinical model for screening nanomedicines (Fontana et al., 2021).

Chemicals and drugs can be efficiently delivered to the zebrafish simply by adding them to their water enclosure (Freires et al., 2017). Additionally, zebrafish are small enough to fit into individual wells on a multiwell plate, allowing for hundreds of whole organisms to be studied all at once within a platform that can fit in a person’s hand. Experiments like this apply test substances necessary for the dosage of only one or two mice to hundreds of zebrafish at once (Steven et al., 2020).

With advances in novel imaging strategies, traceable behavioural tests, and innovative high-throughput drug screening methods, zebrafish are being widely accepted as models for many new drug targets, including a promising future in NDD treatment (Wang et al., 2021).

Zebrafish as Models of NDD Zebrafish are showing great promise in studying the underlying mechanisms and pathology of neurological diseases via neurotoxicity and behavioural analyses (Steven et al., 2020). The zebrafish’s central nervous system (CNS) is comparatively similar to other vertebrates and is well-established in multiple stages of its lifespan. Further, behavioural studies have shown a strong association between zebrafish neural functions and human brain regions (Steven et al., 2020). It presents neurotransmitter systems relevant to neuropharmacology, including dopamine, GABA, glutamate, acetylcholine, and more (Steven et al., 2020).

Zebrafish models additionally have human-resembling neurochemical pathways and display hallmarks of human brain disorder pathology such as protein aggregation, neurodegeneration, and activation of glial cells (Chia et al., 2022).

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Figure 2. The NDD Zebrafish Models and High Throughput Drug Screening Platform (Wang et al., 2021).

Figure 3. Zebrafish Model Compared to Human Disease Condition of AD: Human Left, Zebrafish Right (Chia et al., 2022).

Zebrafish have successfully been applied to model AD, PD, HD, and ALS (Chia et al., 2022). Further, they have been found to share many risk genes with humans that have been identified in various neurodegenerative diseases (Chia et al., 2022). Through imaging, researchers can observe the migration of neuronal precursors, movements of microglia, and even neuronal cell death within the zebrafish model (Fig. 2), (Chia et al., 2022).

Zebrafish as a Model of AD The Zebrafish model of AD is successful in recapitulating A-sheet aggregation, increased neuronal toxicity and neuronal death (Fig. 3)(Chia et al., 2022).

The zebrafish AD model acts as a tau transgenic model, expressing tau hyperphosphorylation, tau accumulation, and neuronal cell death, closely resembling

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the neurofibrillary tangles (NFTs) seen in human AD. In a recent study, a zebrafish line generated expression of a mutant human tau: A152T. This increased cellular apoptosis, neurodegeneration, and impaired locomotor behaviour in response to stimuli. It recapitulated classic hallmarks of AD pathology, including tau hyperphosphorylation and NFT formation. However, the tau zebrafish model has limitations. Tau hyperphosphorylation only accumulated in the spinal cord and not in the brain of the larval zebrafish. Additionally, hyperphosphorylation of another mutant human tau did not result in neurodegeneration or NFTs formation in the zebrafish brain (Chia et al., 2022).

Another zebrafish AD model is the A model. In the zebrafish, A plays a significant role in maintaining healthy cerebrovascular functioning, but increased A can lead to unordinary cerebrovascular branching in the hindbrain. In the zebrafish model of A, the zebrafish receives microinjections of synthetic A peptides; this is the most direct approach to modelling A aggregation, tau protein phosphorylation, and induced toxicity of AD pathology in zebrafish.

Okadaic Acid (OKA), most widely used in pharmacologically inducing AD-like phenotypes, has also been applied to produce zebrafish AD models. OKA successfully induced tau hyperphosphorylation, deposition of A, and formation of senile plaques, mimicking the hallmarks of AD pathology. It also resulted in learning and memory deficits in the zebrafish (Chia et al., 2022).

Zebrafish AD models can also be used to model PSEN genes, which are implicated in the hereditary forms of AD and play a role in plaque-building A peptides. While complete PSEN1 was found to be lethal in mice models, zebrafish were viable as PSEN models (Chia et al., 2022).

Overall, the AD model in zebrafish is limited but has remarkable potential as a developing model for modern research into potential AD treatments.

Potential Treatments for AD in the Zebrafish AD Model The end goal of utilising zebrafish as a model of AD and other neurodegenerative diseases is to develop related drugs that minimise side effects and avoid triggering unwanted pathways, a goal that has yet to be achieved (Wang et al., 2021). Current AD therapies are only temporarily effective in improving learning and memory. These treatments work through the maintenance of ACh levels and cholinergic trans-

Figure 4. Drugs Identified for AD Treatment in Zebrafish Models (Wang et al. 2021)

mission by AChE inhibitors and regulating glutamatergic transmission by blocking NMDA receptors (Wang et al., 2021). Based on findings from research on the zebrafish AD model’s aetiology and behaviour, several hypotheses have been proposed regarding what may induce AD development. These include the amyloid cascade hypothesis, tau hyperphosphorylation, the cholinergic hypothesis, neuroinflammation, and metal ions (Tbl. 1), (Wang et al., 2021).

The protein inhibitor, GSK3, is known to phosphorylate tau at multiple sites. Its isoform, GSK-3, is crucial in the hyperphosphorylation of abnormal tau, an AD pathology similar to that seen in human AD patients and zebrafish models of AD. In embryonic zebrafish AD models, where A42, a common biomarker of AD pathology, was injected into the hindbrain ventricle, Lithium chloride was found to act as an inhibitor of GSK-3, reversing cognitive deficits and tau hyperphosphorylation. This was further established when Lithium chloride was applied in additional zebrafish models, where it was found to control and protect zebrafish locomotor function and dephosphorylate tau. Furthermore, it demonstrated the prevention of memory impairment and regulation of AChE activity in other zebrafish models of AD. The commercially available inhibitor of GSK-3, TDZD-8, effectively reduced the zebrafish mortality rate and improved cognitive impairment induced by okadaic acid. Another GSK-3 inhibitor, AR-534, was found to minimise tau hyperphosphorylation in zebrafish embryos. Overall, GSK-3 inhibitors show promise in

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the development of AD treatment. However, there are still limitations to be overcome in these models, and further research is needed to determine which inhibitor is the most effective and least likely to cause secondary effects (Wang et al., 2021).

Numerous drug targets have also been identified and are actively being researched in the regulation of the cholinergic system, which has guided AD treatment. Additionally, many natural compounds have raised interesting leads for AD drug design. Further, novel anti-tauopathy drugs for AD treatment have been discovered in the prevention of tau hyperphosphorylation. One such example is the cyclin-dependent kinase 5 (CDK5) inhibitors, which have been effective against neurodegeneration, neuroinflammation, and synapse density in zebrafish AD models by modulating the phosphorylation of microtubule-associated proteins. Nanoparticle research has also accelerated AD drug discovery, with studies being conducted to develop nanomedicines against AD or human amyloid diseases using the zebrafish model (Wang et al., 2021).

Nanoparticle treatment research has provided neuroprotection from A-induced toxicity in AD zebrafish models (Chia et al., 2022).

Zebrafish as a Model of PD The PD model is one of the most established in zebrafish research. The zebrafish model presents systems with a high resemblance to those of humans, including the synuclein family. Synucleins are a family of neuron proteins, including -, -, and -synuclein. Zebrafish and human synucleins share high sequence similarity. The most recognisable PD-associated gene in humans, SCNA, which encodes -synuclein, is present in the zebrafish model. Mutations in -synuclein are associated with early-onset familial and sporadic cases of PD. Studies found that the aggregation of human -synuclein protein in zebrafish larvae models led to a reduction in mitochondrial activity and an overall increase in the presence of reactive oxygen species (ROS). This consequently led to neuronal apoptosis and cell death, reflecting PD pathology (Chia et al., 2022). This model also successfully replicates classic PD symptoms, including neuroinflammation, locomotion, and behavioural dysfunction (Fig. 4).

Further, these models allow for behavioural tests, enabling researchers to measure depression, anxiety, social interaction aversion, and aggression. These are all mood changes noted in patients with PD (Chia et al., 2022). This model is also good for investigating

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Figure 5. Zebrafish Model Compared to Human Disease Condition of PD: Human Left, Zebrafish Right (Chia et al., 2022).

the mechanisms of aggregate formation and the consequences of gene mutation or pesticide exposure in the CNS (Chia et al., 2022).

While providing novel insights into PD, this model has its limitations. Firstly, the zebrafish midbrain lacks dopaminergic neurons, and the degeneration of dopaminergic neurons is a hallmark of PD pathology.

Additionally, results from studies using this model have been found to vary, and there is a noted need to enhance behavioural screens for psychiatric symptoms of PD in the zebrafish model (Chia et al., 2022).

Potential Treatments for PD from the Zebrafish PD Model Current PD treatments have shown temporary relief of motor and non-motor PD symptoms and a simultaneous slowing of PD progression. However, there is still no ideal treatment that can effectively delay the progression of this debilitating disease. This is done through L-DOPA dopamine agonists, MAO inhibitors, catechol-O-methyltransferase (COMT) inhibitors, and anticholinergics (Wang et al., 2021).

The replacement of L-DOPA dopamine precursor is the most effective treatment for improving motor function, but in long-term application, this therapy has been found to worsen dyskinesia. Research into drug discovery using the zebrafish PD model has advantageously employed high-throughput screening to evaluate numerous potential drug targets and proposed therapies.

MAO-B inhibitors with high potency have been designed to improve therapeutic benefits and decrease the secondary effects of these therapies. Further, PD therapies targeting the mitochondrial dysfunction implicated in PD pathology have shown promise in research (Wang et al., 2021). One study tested 1600 FDA-approved bioactive drugs in zebrafish models and highlighted novel molecules with antiparkinsonian potential. These discoveries could be transformed into

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drug targets and significantly impact the future of PD treatment (Wang et al., 2021).

The increase in modern nanoparticle research has also reached PD drug discovery, as nanoparticles are being developed for zebrafish PD models to protect DA neurons against cytotoxicity with no specific toxic secondary effects (Wang et al., 2021). Additionally, a growing body of evidence has supported the use of immune-targeted therapies as potential treatments for PD. Epidemiological studies have confirmed that nonsteroidal anti-inflammatory drugs may play a beneficial role in drugs being developed to treat PD. Zebrafish models of PD were used to verify these findings, and anti-inflammatory drugs were also found to be effective in improving PD’s motor symptoms.

Further Neurodegenerative Disease Models Using Zebrafish Other neurodegenerative diseases, such as ALS and HD, have employed the zebrafish as an in-vivo disease model in treatment development and the furthering of knowledge of disease pathology (Wang et al., 2021).

In ALS, genetic zebrafish models have significantly accelerated the development and proposal of new drug candidates for treatment. From studying the pathology and disease onset of ALS in zebrafish, it has been found that calcium channel agonist treatment of zebrafish can restore behavioural and cellular deficiencies consequent to ALS onset (Wang et al., 2021).

However, current ALS therapies that have achieved FDA approval only provide a moderate improvement in survival (Wang et al., 2021).

Further, in HD, genetic zebrafish models are also being used to study disease characteristics to develop future treatments. Researchers have found that amyloid precursor proteins (APP) may control neuronal excitability via their interaction with prion proteins, making them a potential pharmaceutical target for future therapies for prion diseases and associated neurodegenerative disorders (Wang et al., 2021).

Limitations of the Zebrafish Model This model comes with its limitations. For example, zebrafish lack some of the mammalian organs humans have, including lungs, prostate, skin, and mammary glands (Freires et al., 2017). Additionally, they lack a neocortex, meaning this model cannot be used to study cognitive processes that rely on that region (Steven et al., 2020). Although displaying incredible

innovative potential as a model in neurodegenerative diseases, the zebrafish model faces some limitations.

The use of MO knockdowns in zebrafish models has produced discrepancies between morphant phenotypes and mutations, leading to gene deletion, premature stop codons, and off-target effects such as morphological deformities (Chia et al., 2022).

Further, due to the gap between zebrafish and humans in terms of neurodegenerative disorder morbidity and drug treatment, challenges have arisen in translating drugs from model to clinical trial. Many drug screenings performed in zebrafish models have a short therapeutic window, and it is difficult for these drugs to cross the blood-brain barrier before degrading without employing suitable drug delivery approaches.

Additionally, the genetic and environmental factors involved in the pathogenesis of some neurodegenerative disorders, and the general necessity for a deepened understanding of neurodegenerative diseases, present obstacles in attempting to treat uniformly and increase the potential need to personalise treatment approaches (Wang et al., 2021).

There is a necessity for further development of the zebrafish model and the experimental methods associated with it. Better-designed behavioural assays could better mirror the repertoire of progressive motor disorders in neurodegenerative diseases. Additionally, more research needs to be done into how zebrafish metabolise and excrete drugs in their aqueous environments compared to mammalian models (Chia et al., 2022).

Undeniable Innovation and the Future of Zebrafish in Neurodegenerative Disease Research The zebrafish model has numerous advantages, providing essential foundations for NDD pathology, drug discovery, and innovation in the future of treatment for NDD. More research is being performed to understand the mechanisms behind modern drug discoveries in the zebrafish model to further the understanding of secondary effects, predict the viability of drugs in clinical trials, and identify more potential drug targets, further instigating the promise and permanence of this model in NDD research.

The most significant innovation utilised in zebrafish research is the development of rapid, highthroughput readouts on large sample sizes. This is particularly beneficial in clinical drug discovery and is unique to zebrafish, as hundreds of samples can

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CONCLUSION

Figure 6. Vertebrate Automated Screening Technology (VAST) Bioimager for High Throughput Screening of Zebrafish and Drug Candidates (Chia et al., 2022).

be placed into a well plate and simultaneously chemically screened. One example of innovative technology further developing this lab technique for future studies using zebrafish is the vertebrate automated screening technology (VAST) Bioimager (Fig. 5). This technology is showing significant promise in assessing blood-brain barrier permeability, which is essential to developing novel neuro-specific therapies. It is also an excellent technology to test novel nanoparticle research and evaluate biocompatibility and toxicity.

Furthermore, innovative pigmentation mutants are being developed in the hopes they can be applied in the imaging of adult zebrafish (Chia et al., 2022).

Modern innovations in CRISPR/Cas gene editing have shown significant potential in overcoming a limitation of the zebrafish model: MO knockdown discrepancies. MO knockdown discrepancies are responsible for secondary morphological deformities and off-target effects. Gene editing using CRISPR/Cas is being employed to prevent such effects and improve zebrafish models, especially for AD research (Chia et al., 2022).

Finally, arguments have been made that the zebrafish model’s use is limited to its larval stage, where it presents as transparent. However, innovative research is proving that this isn’t entirely true, as the zebrafish proves useful as a model throughout its lifespan. An increasing amount of research is examining zebrafish adulthood and working to define developmental ages and model maturity (Singleman Holtzman, 2014).

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Neurodegenerative diseases are a prevalent and increasing public health issue. These particularly debilitating diseases, characterised by their extremely complex aetiology, affect millions of people worldwide and cost billions in healthcare.

A number of pharmacological drugs have been designed for use in NDD treatment, but over the past several decades, there has been a struggle to translate from model to clinical trial (Wang et al., 2021). The development of innovative disease models that can serve as alternatives to modern in-vivo and in-vitro models is imperative in testing these new treatments and carrying them from the lab to patients.

The zebrafish model is contributing to groundbreaking progress in drug discovery. Diseasemodifying treatments have gained traction due to their effectiveness in altering the early stages of disease onset (Wang et al., 2021). The zebrafish model has proposed numerous breakthroughs in unravelling the mysteries behind NDD aetiology and aiding in drug development and new treatment therapies.

From its beginnings in examining water contaminants and toxicology at a lab in Oregon, this little fish has come a long way, proving itself to be a model with significant benefits in research. Its transparency during developmental stages, cost-effectiveness, and efficiency as a laboratory model are key advantages. Furthermore, the integration of the zebrafish model with new technologies and adaptations of high-throughput drug screening platforms has further established its role in NDD research.

It has led to the identification of the protein inhibitor GSK3 in tau phosphorylation in AD onset and further investigated the applications of lithium chloride, natural component therapies, regulation of the cholinergic system, and nanoparticle treatments in treating AD. Additionally, it has underlined the importance of L-DOPA dopamine agonists and MAO inhibitors in PD pathology and allowed for the testing of over 1600 FDA-approved bioactive drugs, highlighting novel drug targets for protecting DA neurons in PD onset. The zebrafish model has also unveiled novel findings in further NDD research as a model for ALS and HD. Needless to say, this little fish has earned its stripes and has undeniably cemented its place in the future of NDD research and drug development.

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REFERENCES Alzheimer’s Society (2024) Facts for the media about dementia. Available at: https://www.alzheimers.org.uk/about-us/news-andmedia/facts-media: :text=How Cassar, S., Adatto, I., Freeman, J., Gamse, J., Iturria, I., Lawrence, C., Muriana, A., Peterson, R., Cruchten, S., and Zon, L. (2019) ‘Use of Zebrafish in Drug Discovery Toxicology’, Chemical Research in Toxicology, 33(1), pp. 95-118. doi: 10.1021/acs.chemrestox.9b00335.

Chia, K., Klingseisen, A., Sieger, D., and Priller, J. (2022) ‘Zebrafish as a mdoel organism for neurodegenerative disease’, Frontiers in Molecular Neuroscience, 15, pp. 1-27. doi: 10.3389/fnmol.2022.940484.

Cornblath, E., Robinson, J., Irwin, D., Lee, E., Lee, V., Trojanowski, J., and Bassett, D. (2020) ‘Defining and predicting transdiagnostic categories of neurodegenerative disease’, Nature biomedical engineering, 4(8), pp. 787–800. doi: 10.1038/s41551-020-0593-y.

Eisen, J. (2020) ‘History of Zebrafish Research’, AP Academic Press, pp. 3-14. doi: 10.1016/B978-012-812431-4.00001-4.

Fontana, F., Figueiredo, P., Martins, J., Santos, A. (2021) ‘Requirements for Animal Experiments: Problems and Challenges’, Small, 17 (5), pp. 2004182. doi: 10.1002/smll.202004182.

Freires, I., Sardi, J., de Castro, R., Rosalen, P. (2017) ‘Alternative Animal and Non- Animal Models for Drug Discovery and Development: Bonus or Burden?’. SpringerLink, 34, pp. 681–686. doi: 10.1007/s11095-016-2069-z.

Lamptey, R. N. L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., Singh, J. (2022) ‘A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics’, International journal of molecular sciences, 23(3), pp. 1851. doi: 10.3390/ijms23031851.

Singleman, C. and Holtzman, N. (2014) ‘Growth and Maturation in the Zebrafish, Danio Rerio: A Staging Tool for Teaching and Research’, Zebrafish, 11(4), pp. 396-406. doi: 10.1089/zeb.2014.0976.

Wang, X., Zhang, J.B., He, K.J., Wang, F., and Liu, C.F. (2021) ‘Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery’, Frontiers in Pharmacology, 12 (713963), pp. 1-19. doi: 10.3389/fphar.2021.713963.

at the University of St Andrews, Contact at: hkb2@standrews.ac.uk

Hannah Betts is a 2nd year Neuroscience Student

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Neuroplasticity-Based Interventions in Stroke Rehabilitation Rishi Ravishankar Bsc (Hons) Medicine

Laila Deen Bsc (Hons) Physics

Sushmhitah Sandanatavan Bsc (Hons) Medicine

Abstract—Stroke is a disease with high mortality and morbidity, carrying with it many debilitating and permanent impacts, such as motor, sensory, and cognitive impairments due to brain injury.

Neuroplasticity, the brain’s ability to form new connections, plays a crucial role in neural recovery as it’s driven by learning, behavior, and injury. While neuroplasticity is an ongoing process, the level of neuroplasticity that typically occurs throughout life is not very effective for neurological recovery post-stroke. This has led to the emergence of new technologies in the field of stroke medicine, aiming to tackle this issue. The idea is to promote neuroplasticity within the brain to enhance stroke recovery.

Among these innovations are brain-computer interfaces (BCIs), which translate brain activity into computer commands enabling the operation of diverse technological devices and virtual reality therapy (VR Therapy), the simulation of a virtual and interactable environment to restore function.

There is an ever-growing base of evidence to suggest that these approaches are effective in stroke rehabilitation and have the potential to be used in clinical practice. However, more research is needed to understand the specific mechanisms of each treatment and their adaptability.

N EUROPLASTICITY IS DEFINED AS THE NER VOUS SYSTEM ’ S CAPACITY to adapt and restructure its organization, function, and connections in response to internal or external stimuli. In simpler terms, it refers to the nervous system’s ability to bring about structural and functional changes (Cramer et al., 2011).

Learning (Galván, 2010) and meaningful behaviour (Kolb Whishaw, 1998) are key drivers that induce these changes. Much like learning and development, injury plays a significant role in driving neuroplasticity, acting as a huge driving force for neural changes on a cellular level, such as synaptic changes, axonal sprouting, dendritic remodelling etc (Zotey et al., 2023).

Neuroplasticity is defined as the nervous system’s capacity to adapt and restructure its organization, function, and connections in response to internal or external

stimuli. In simpler terms, it refers to the nervous system’s ability to bring about structural and functional changes (Cramer et al., 2011). Learning (Galván, 2010) and meaningful behaviour (Kolb Whishaw, 1998) are key drivers that induce these changes. Much like learning and development, injury plays a significant role in driving neuroplasticity, acting as a huge driving force for neural changes on a cellular level, such as synaptic changes, axonal sprouting, dendritic remodelling etc (Zotey et al., 2023).

Stroke is defined as a localized and acute neurological deficit/injury in the brain, which usually occurs due to injury of the brain’s vasculature and happens to be the second leading cause of death and disability globally. The resulting brain damage can lead to different aftereffects that can vary throughout a large spectrum of issues, including problems relating to

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motor movements, sensation, and cognition (Murphy Werring, 2020) — which can have a major effect on a patient’s quality of life. Over time, however, neuroplasticity within the brain occurs in response to the stroke-related injury to induce healing (Carey et al., 2019). That being said, the level of neuroplasticity that the brain undergoes throughout adult life is not sufficient to allow any form of major recovery following brain damage (Marı́n-Medina et al., 2023). This is substantiated by the fact that despite best post-stroke rehabilitation efforts, one-third of patients show poor recovery one year after the event (Lai et al., 2002). To tackle this issue, there have been many new emerging technologies in the field of stroke medicine to enhance these neuroplastic changes to aid rehabilitation.

Figure 1. Graphic showing the relationship between experience, neuroplasticity and stroke recovery as shown in Carey et al. (2019)

Brain-Computer Interfaces (BCIs) Brain-computer interfaces (BCIs) are one of the new technologies that have come to the forefront of neuroplasticity-based interventions to improve functional outcomes for stroke patients experiencing various degrees of neurological impairment. A BCI system offers a real-time view of brain activity, allowing interaction with the environment through control signals generated by brain activity alone (Mane et al., 2020). In simple terms, they work by converting brain signals into computer commands, allowing the control of various technological devices. This has been found to stimulate neuroplastic changes, indicating its useful wider implications in the field of stroke medicine (Marı́n-Medina et al., 2023). When it comes to rehabilitating the motor system specifically, BCI systems can interpret the intention to move the limb that’s been affected and use it to provide sensory-motor feedback in different forms, including actual movement, visual feedback, and touch feedback. There is increasing

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evidence that BCIs can promote functional recovery by bridging the gap between the desire for motor movement and the contingent sensory feedback that has been created by stroke (Mane et al., 2020).

BCIs function via three main stages: signal reception, signal processing, and machine response generation. The first step (signal reception) can be classified as being invasive or non-invasive. Although carrying surgical risk, the former produces a much clearer signal (e.g., ECOG, cortical penetrating electrodes, etc.). The latter is more commonly used and is more scientifically supported in terms of its efficacy (e.g., EEG). The second step (signal processing) involves sifting through and filtering brain signals to allow interpretation via various methods (sensorimotor rhythms, visual evoked potentials, event-related potentials, etc.). These signals are then further processed and analyzed to produce a specific command to be executed by the computer interface. The final step (response generation) involves translating the signal to allow the device to perform the coded function, such as producing a motor output to contribute towards stroke recovery. This entire process can lead to the reorganization of the motor cortex (neuroplasticity) on either the same or opposite side of the injury (Marı́n-Medina et al., 2023).

Virtual Reality Therapy (VR Therapy) VR therapy is another emerging therapy that has been useful in restoring motor function, contributing to an increased quality of life post-stroke. Much like BCIs, it involves an interface between a computer and the patient; however, it is used as a simulation to recreate an interactable virtual environment. The rationale is that through immersive sensory and motor simulation, new connections within the brain are created that closely mimic reality. This allows the patient to practice activities/exercises within the environment, after which the system provides sensory feedback.

This helps patients understand their movement and make necessary adjustments, improving the rehabilitation process (Marı́n-Medina et al., 2023). There are different levels/versions of immersion that patients can experience based on their requirements. Total immersion is the most engaging type, which allows the patient to fully interact with the virtual world, improving their cognitive and physical function. There is also strategic immersion, which aims to improve the patient’s cognition through problem-solving, and narrative immersion, which makes use of a storyline to give context for activities to increase patient en-

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gagement and uplift the patient psychologically and emotionally. VR therapy has particularly been proven to be very effective when it comes to restoring motor function (skilful immersion). Completing visual motor tasks virtually, such as grabbing a cup or ball, has been shown to stimulate mirror neurons and promote neuroplasticity, therefore leading to functional improvements (Marı́n-Medina et al., 2023).

Figure 2. VR setup, view and neuroplastic changes as shown in Marı́n-Medina et al. (2023)

In figure 1, image (a) shows the VR setup. This includes the headset along with two infrared cameras to track the patient’s position in the virtual setting.

The purple bands on the patient’s upper limbs act as controllers to track motor movements. Image (b) shows the patient’s view, which can be tracked by the healthcare professional to evaluate the patient’s movements and progress. Image (c) shows the activation of mirror neurons, contributing to the genesis of new synaptic connections that strengthen with continuous virtual repetition (Marı́n-Medina et al., 2023).

was found that connections across different areas of the brain were altered, substantiating the neuroplastic component of BCI interventions. Changes were also observed within the corticospinal tract in various regions, such as the corpus callosum, right cingulate, and left fronto-occipital tract, via diffusion tensor imaging, coinciding with an improvement in motor function as well (Yang et al., 2022). There have been many studies investigating the efficacy of Virtual Reality in stroke therapy, and the evidence suggests it is effective. A systematic review published in 2023 found that fullimmersion virtual reality (FIVR) has been shown to positively affect gait and balance regarding lower limb dysfunction post-stroke, according to various compiled studies. Another study within this review, however, found no statistically significant difference between FIVR and the control group. However, this treatment method is still considered beneficial due to its natural clinical applicability and its positive rating among patients with little risk involved, not to mention its customizability. There is also a plethora of evidence to vouch for its efficacy as an adjunctive therapy along with other forms of rehabilitation. One specific study combined virtual reality mirror therapy with occupational therapy in rehabilitating the upper extremities and found that its outcomes surpassed those achieved using occupational therapy alone. The positive effects of VR therapy are not only motor in nature but have also been found to improve a patient’s mental health. For example, another study within the review found that FIVR plays a role in improving depressive symptoms after stroke, which increases motivation and therefore adherence, yielding better outcomes overall.

Furthermore, the integration of sensory feedback can improve cortical neuroplasticity and contribute to improved motor function (Demeco et al., 2023).

EVALUATION In terms of efficacy, BCIs have been shown to be highly effective for stroke-related injuries. For example, a meta-analysis of randomized control trials was conducted to evaluate the effectiveness of BCIs for the rehabilitation of stroke-induced upper limb dysfunction, and it found that BCIs were indeed beneficial to recovery. This means that there is strong evidence that their induction into clinical practice on a wider scale could prove beneficial. Furthermore, further subgroup analysis of intervention time revealed significant improvements in upper limb function in chronic and subacute groups, with greater improvement within the subacute cohort. Within the same meta-analysis, it

DISCUSSION Although BCIs are effective in instigating and enhancing neuroplastic changes, there are some issues when it comes to their clinical application in stroke medicine. One of the main challenges is related to health infrastructure. BCI implementation can be seen as impractical due to the multitude of steps involved in its execution (setup, operation, and cleanup). This could impinge on the time meant for more traditional methods of rehabilitation. This suggests they may be better suited as adjunct therapies, which require additional time and resources and are often not covered by

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insurance in a privatized system (Rupp, 2014). There are also several limitations that come with VR therapy as well. This method of rehabilitation is very resourceheavy, requiring real-time motion sensing, head-mount displays, and sensors, which could present challenges in healthcare systems that are financially struggling.

Furthermore, this technology is specialized, meaning specific training is required to use it to its full potential.

Its complex technological learning curve can present difficulties for patients who aren’t very tech-savvy.

There are also patient privacy issues that can arise with this technology (Aderinto et al., 2023).

Wider Implications and Future Work Overall, neuroplasticity-based interventions offer a comprehensive and adaptable approach towards stroke, possibly more so than traditional methods, and can also significantly improve outcomes relating to patients’ quality of life. Their customizable nature, along with their potential to be integrated with more advanced technologies make it an exciting scientific field that will no doubt continue to produce even more breakthroughs with dedicated resources and research. We know that BCIs are beneficial in stroke rehabilitation and that neuroplasticity plays a large role in stroke recovery relating to BCIs. However, the exact neurophysiological mechanisms that lead to recovery have not yet been fully identified. Despite plenty of neurological changes being observed upon various investigations (fMRI, EEG etc), further research is needed to understand the mechanics of these changes and how they can contribute towards creating a better outcome to further pave the way towards clinical integration (Marı́n-Medina et al., 2023). There is ample evidence that shows the potential that VR therapy has and the positive implications it could have in the field of stroke medicine - including furthering patient engagement and customizability. However, this technology is still in its infancy. More research is needed to further validate its efficacy, including larger patient-cohort studies to further understand its adaptability towards patients’ specific needs. Further research down the line can unmask this technology’s potential to reduce clinical burden through the possibility of remote assessment (Nath et al., 2022).

CONCLUSION In conclusion, the central role that the idea of neuroplasticity plays in stroke recovery is undeniable - as is the potential of interventions that leverage

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neuroplasticity. BCIs and VR therapy (among others) are only some of the many therapies at this field’s forefront. Moreover, its research base showing its clinical potential is only ever-expanding. All though there are some challenges to be overcome regarding their applicability - with further investigation – these methods can be properly adapted for use in hopes of decreasing the mortality and morbidity of this crippling disease.

REFERENCES Cramer SC, Sur M, Dobkin BH, O’Brien C, Sanger TD, Trojanowski JQ, et al. (2011) Harnessing neuroplasticity for clinical applications. Brain.1591–609.

Galván A. (2010) Neural plasticity of development and learning. Human Brain Mapping.879–90.

Kolb B, Whishaw IQ. (1998) BRAIN PLASTICITY AND BEHAVIOR. Annual Review of Psychology.43–64.

Zotey V, Andhale A, Shegekar T, Juganavar A. (2023) Adaptive Neuroplasticity in Brain Injury Recovery: Strategies and Insights. Cureus [Internet]. Available from: https://www.cureus.com/articles/189840-adaptiveneuroplasticity-in-brain-injury-recovery-strategiesand-insights Murphy SJX, Werring DJ. (2020) Stroke: Causes and clinical features.

Medicine [Internet]. 561–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7409792/ Carey L, Walsh A, Adikari A, Goodin P, Alahakoon D, De Silva D, et al. (2019) Finding the Intersection of Neuroplasticity, Stroke Recovery, and Learning: Scope and Contributions to Stroke Rehabilitation. Neural Plasticity [Internet]. 1–15. Available from: : https://www.hindawi.com/journals/np/2019/5232374/ Daniel Stiven Marı́n-Medina, Arenas-Vargas PA, Arias-Botero JC, Gómez-Vásquez M, Jaramillo-López MF, Jorge Mario Gaspar-Toro. (2023) New approaches to recovery after stroke. Neurological Sciences. 45.

Lai SM, Studenski S, Duncan PW, Perera S. (2002) Persisting Consequences of Stroke Measured by the Stroke Impact Scale. Stroke. 33(7):1840–4.

Mane R, Chouhan T, Guan C. (2020) BCI for stroke rehabilitation: motor and beyond.

Journal of Neural Engineering. Available from: https://www.ntu.edu.sg/home/ctguan/Publications /2020R aviJ N E.pdf

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Yang W, Zhang X, Li Z, Zhang Q, Xue C, Huai Y. (2022) The Effect of Brain-Computer Interface Training on Rehabilitation of Upper Limb Dysfunction After Stroke: A Meta-Analysis of Randomized Controlled Trials. Frontiers in Neuroscience. 15.

Demeco A, Zola L, Frizziero A, Martini C, Palumbo A, Foresti R, et al. (2023) Immersive Virtual Reality in Post-Stroke Rehabilitation: A Systematic Review. Sensors. 23(3):1712.

Rupp R. (2014) Challenges in clinical applications of brain-computer interfaces in individuals with spinal cord injury. Frontiers in Neuroengineering [Internet].

Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4174119/ Rishi Ravishankar is a 3rd year Medicine Student at the University of St Andrews, Contact at: rr219@standrews.ac.uk

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Bioengineering Breakthroughs: Transforming Clinical Psychology for the Future Thomas Burton Bsc (Hons) Mathematics

Leo Elliott Bsc (Hons) Neuroscience

Abstract—As technology continues to transform every aspect of the human condition, the medical world proves to be no exception. Throughout the recent past, technology has integrated itself within the A-Z of the medical world, revolutionising daily practice in all aspects of the healthcare system, including practices dealing with cognitive processing and psychological phenomena. One of the fastest evolving synergies seen between both worlds, technology and medicine, is the use of bioengineering in aiding clinical approaches in psychology-based fields, especially clinical psychology. Clinical psychology has been at the forefront of psychology research for decades since its introduction in 1907, following Lightner Witmer’s publication “The psychological clinic” [1]. Today, clinical psychology stands as one of the most prevalent forms of healthcare with an average of 22% of the UK population having been through mental health-orientated therapy or care [2]. As in other scientific fields, psychologists are continuously pushing themselves to innovate new treatment techniques, hoping to advance the field into revolutionary areas of research and development. As technology has advanced exponentially over the past decades, the drive for development in many areas of research now relies on tech advancements. Within the realm of healthcare this is predominantly in the form of biomedical engineering, utilising engineering principles to develop new therapies, instruments, medicines, and delivery methods [3]. Throughout this review, developments in clinical psychology using bioengineering techniques to overcome current limitations are investigated, with reference to historical elements and possible future outcomes. Conditions such as major depressive disorder, attention deficit hyperactivity disorder and post-traumatic stress disorder, will prove exemplary in how such illnesses may be treated more efficiently in future practices, supporting the notion that biotechnology aims to revolutionise daily practice in clinical approaches.

T HE RAPID EVOLUTION BIOTECHNOLOGY The rapid evolution biotechnology continuously faces, due to exponential advancements in both fields – biology and technology, renders it merely impossible to be encapsulated within a single review. Bioengineering, a relevant subsection of biotechnology, utilises the progressive and modern nature of engineering to address and aid biological concerns and research avenues. Described by Philip Kosky [4] bioengineering is “the application of engineering, life sciences,

and mathematics to define and solve problems in biology, medicine, healthcare, and other fields that deal with living systems”, capitalising on knowledge derived from engineering fields such as chemical, mechanical, and electrical. Bioengineering continuously demonstrates its relevance within biological research.

Within a matter of years, the way in which biologists interact and study certain processes have transformed completely, following discoveries unveiled utilising bioengineered technologies. The extremity of biotechnologies influence can be exemplified through Fire et al [5] where in the space of a decade the way in which

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geneticists studied and controlled genetic behaviour was completely altered once applied biotechnology revealed double stranded RNA’s inherent capability to block the expression of any gene if they possessed matching sequences [6].

More recent cutting-edge advancements within the realm of biology derived from bioengineering techniques include CRISPR-CAS9 genome modification (Figure 1) and nanotechnology (Figure 2), which have both revolutionised biologists’ capability to understand and control living systems. In the realm of cancer treatment CRISPR-CAS9 has proven to be essential, due to its ability to deactivate cancer causing genes and activate vital tumour suppressors, by directly altering the individual’s genome through targeting and cutting specific DNA sequences [9]. Secondly, nanotechnology has revolutionised the efficacy of drug delivery through the use of lipid based nanoparticles which encapsulate drugs and biomarkers. This newly formed unit is made to be specific towards certain cell types, increasing the specificity of drugs, in turn reducing side effects [10]. These Bioengineering techniques, along with a magnitude of others, have allowed for the generation of new focal points in research, inevitably changing the trajectory of multiple biological fields.

The advantageous nature of technological implementation in hopes to overcome biological concerns is actively redirecting the way in which research is approached and conducted, creating revolutionary breakthroughs in surrounding science based fields, including psychology.

An Introduction to Clinical Psychology Throughout the 18th and 19th century a pivotal shift in the physical treatment of the mentally ill within treatment institutions materialised, amid the pioneering guidance of psychologists such as William Luke, Philippe Pinel, Eli Todd and Dorothea Dix. Facilities began to stray from torturous designs towards more humane methods [11]. This transformative shift triggered a ripple effect, allowing for the evolution of treatment methods with rehabilitation at the forefront of design, thus leading to the creation of clinical psychology.

The importance of this new wave field was wholefully acknowledged and introduced in Lightner Witmer’s publication, where he discusses how treatment using psychological principles as a basis in methodological framework proves beneficial in helping both morally and intellectually challenged school children

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Figure 1. Visual of Crispr-Cas-9 in action [7]

Figure 2. Lipid based nanoparticle containing drug [8]

[1]. Thought to be the father of clinical psychology Witmer then angled his career towards teaching others the beneficial nature his methods had, towards both the mentally ill and well. This one-of-a-kind clinic, founded in 1896, triggered the generation of hundreds alike. Alongside this emergent field, followed many psychologists who began to specialise in this new wave clinical method, helping individuals who otherwise would have been left helpless prior. Now one of the most prevalent forms of healthcare, clinical psychology continues to support a magnitude of diverse individuals globally.

Clinical psychology is now a broad field, under which multiple evidence-based treatment methods lay

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[12]. Arguably the most prominent practice within clinical psychology is psychotherapy, where personal growth and development is achieved through talking based techniques and interactive activities. Treated by renowned psychologists Breuer and Freud, patient Anna O coined the phrase “a talking cure” after experiencing alleviation of disturbing symptoms through verbal communication of circulating thoughts and emotions. This process, now termed abreaction, led to the innovation of psychoanalysis. Further established by Freud, psychoanalysis is thought to be the first form of psychotherapy, where talking based methods are used in attempts to target and change both conscious and unconscious processing. Stemming from Psychoanalytic principles numerous treatment techniques materialised, including the commonly used Cognitive Behavioural Therapy (CBT), which focuses on targeting conscious processing in hopes to generate more positive schemas revolving around oneself and the problems they may frequently face, thus developing effective coping mechanisms for their reoccurring issues [14, 15].

As this field grew in relevance, creativity grew also, with more abstract treatment techniques being introduced and tested. For example, eye movement desensitisation therapy (EMDT). Developed using frameworks based in PTSD, EMDT focuses on integrating two memory systems, the simultaneously accessible (SAM) and verbally accessible (VAM) systems, of which PTSD affected individuals cannot link together to inhibit trauma related triggers. This treatment style is thought to achieve successful integration of two memory types [16] through the introduction of a bilateral stimulus, typically a moving object, which the patient focuses on whilst discussing certain memories associated with their trauma [17]. The efficacy of this treatment being able to help the patient reprocess their traumatic memories can be exemplified through Silver, Rogers and Russells [18] case study where an exveteran was able to recall additional factors within the memory that triggered his PTSD response. This memory of him killing a shoulder was reprocessed using EMDT allowing for the recollection of additional factors like his friend calling for “help”, allowing the patient to further understand the scenario granting him closure and understanding, thus removing the negative schemas about himself that lead to maladaptive processing. This unique form of therapy proves innovation in clinical psychology is of utmost importance in developing new treatments, which are successful in

targeting alternative processing circuits and memory systems.

Talking based therapy proves beneficial in aiding psychological illness within many individuals, However, in some cases talking therapy alone lacks efficiency due to its inherent drawbacks and strategy.

Since communication-based treatments rely solely on verbal communication patients with severe psychological illness may struggle to effectively articulate and process their thoughts and feelings. They may also omit or alter certain aspects of their reports in hopes to avoid certain feelings and/or talking points.

Both hindrances shallow the depth of detail a session would be able to reach, rendering this method insufficient in achieving substantial change within the patient [15]. Alternative treatment routes, including the use of medication, can be useful in treating patients who are unable to achieve results from talking based therapies alone. Often used in synergy with talking based methods, medication helps to relieve symptoms on a biological level, allowing for more direct targeting of the problemed areas - in many cases accelerating the rate of success. This method is especially beneficial towards mental illnesses which have specific biological components, such as schizophrenia and depression, where specialised brain areas display abnormal activity [19, 20, 21]. The biopsychosocial model in clinical psychology includes the synchronous use of biomedicine and psychology-based treatments in providing personalised treatment routes for specific individuals [22]. It is this concept of drawing information from biology in hopes to create alternatives in psychological treatment which will be discussed in the latter part of this paper.

Intersection in action: Bridging biotechnology and Clinical Psychology The field of clinical psychology continues to evolve exponentially, with an expansive range of medicinal and talking based therapeutics being developed in hopes to effectively treat numerous illnesses.

Whilst the efficacy of these approaches is undoubtedly apparent, options orientated towards more extreme treatment methods remain lacklustre in treating individuals who do not respond adequately to conventional methods. As mentioned prior, talking based therapies hold unavoidable limitations, as do medications which can be ineffective in certain individuals despite their effectiveness in the majority. From these

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inherent drawback’s psychology has directed recent focus towards biotechnology as a possible solution in overcoming such problems. A clinical based scope will now be drawn over this paper with focus orientated towards biotechnology and its cross-disciplinary application in overcoming treatment limitations seen within mental disorders such as major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD).

Using techniques including Deep brain stimulation (DBS), Transcranial magnetic stimulation (TMS), and Vagus nerve stimulation (VNS), respectively. These innovative treatment routes will be introduced alongside relevant evidence supporting their use and potential for future development.

Using Deep Brain Stimulation in hopes to treat Major Depression Disorder Major Depressive Disorder (MDD) currently ranks as the most prevalent psychological condition, being the second top cause of disability worldwide - predicted to become first by the year 2030. With reoccurring symptoms including sadness, hopelessness, and lack of fulfilment within daily activity MDD continues to affect millions and is significantly correlated with an increase in mortality rates [23]. Although its dominance within today’s society cannot be undermined, little is known about this disease. Within most individuals’ symptoms can be effectively improved through talking based psychotherapies and/or medications, for example the use of serotonin reuptake inhibitors, which reduces presynaptic reuptake of mood boosting neurotransmitter serotonin [24], and communicative therapies such as Cognitive behavioural therapy which targets symptoms by discussing the negative thought patterns and behaviours which occur throughout the course of this illness, in turn fostering positive processing and coping strategies [25]. Although these ‘less severe’ treatment routes prove effective amongst many cases, around 20% do not respond to common treatment, so more extreme alternatives are used - including electroconvulsive therapy (ECT), where strong electronic impulses are externally delivered, triggering controlled seizures which are believed to alter the brain’s chemical environment increasing the efficacy of neuronal communication [26]. When alternative methods such as ECT are deemed ineffective, shortcomings in alternative options become apparent.

Depression’s high biological complexity is viewed as systems level, meaning one brain region isn’t fully

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responsible in causing this disease, alternatively multiple regions contribute towards symptomatology, where pathways linking areas such as the limbic, cortical, and subcortical regions become ineffective in normal processing. With contributions from the individual’s genome, environmental stressors and development, many aspects of one’s life contribute towards the likelihood of developing MDD. Bioengineered imaging technologies, such as functional magnetic resonance imaging (fMRI), has allowed researchers to develop an understanding on which brain regions are associated with MDD, leading to the development of highly specialised treatments.

Within fMRI imaging of individuals who responded positively to MDD treatment, a reduction in area 25 of the subgenual cingulate cortex (Cg25) was measured, implying hyperactivity in this region to be causal of depressive symptomatology. The Cg25 is the mood regulatory unit located within the Anterior Cingulate Cortex (ACC), controlling functions including error processing, automatic emotional response to physical experience and the controlling of behaviour in reference to punishment and reward. When these processes become dysregulated a cognitive shift in failure experience is caused. This shift causes the individual to become over sensitive to failure, inducing persistent feelings of guilt and negativity. Abnormal activation of the Cg25 is also thought to contribute towards other MDD symptoms, including mood dysregulation, fatigue, and insomnia. These additional symptoms are thought to be sourced via connections from the Cg25 to the medial prefrontal cortex, thalamus, brainstem, orbitofrontal cortex, and both anterior and posterior cingulate cortices [27].

In reference to the correlational link between Cg25 activity and MDD a clinical study conducted by Mayberg et al [28] was led in hopes to manually target the Cg25 using bioengineered technology, Deep Brain Stimulation (DBS), with aims to create an alternative treatment route in treatment resistant depressives. Deep brain stimulation is a result of advanced bioengineering, where brain activity is directly modulated by electrical stimulation through neurostimulatory nodes, of which are implanted into specific brain regions with the ability to be manually switched on/off affecting the specific neurons accordingly [29] (Figure 4). Within this trial inhibitory electrodes were implanted within 6 MDD affected individuals, targeting the Cg25 and its surrounding white matter. Upon initial activation all patients recorded immediate relief, including feelings

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of calmness and connectedness to their surrounding environment, also reporting an absence of the ‘void’, which in psychotherapy is used to describe feelings of persistent emptiness consequent to the feeling of destruction in aspects that once were within one’s mental psyche [31]. To quantify these findings a depression-based questionnaire “positive and negative affect schedule (PANAS)” was conducted before and after treatment, with all having an increase in positive scores and decrease in negative following initial stimulation. As treatment continued, increases in energy levels, psychomotor speed, empathy and interest developed, alongside reductions in anhedonia and apathy.

Of the 6 participants 4 achieved long term symptom relief, with 3 achieving almost complete remission of the illness.

In participants who reported long lasting benefits from DBS, PET scans obtained after 3 months of treatment showed successful reduction in Cg25 activity.

Patients who experienced prolonged benefits at the 6th month interval also exhibited a reduction in activation within their hypothalamus, anterior insula, and medial frontal cortex. Alongside increased activation within the dorsolateral prefrontal cortex, posterior cingulate, anterior cingulate, parietal and premotor regions - exemplifying the downstream effects of Cg25 stimulation in relation to MDD symptom alleviation.

Although this method shows evidenced based DBS benefits in MDD treatment, viability in its application within other depression subdivisions such as bipolar and unipolar depressives remain unexplored. This exposes the inherent drawbacks of this technique’s replicability, as each patient needs individually tailored electrode placement and voltage strength [28].

Although DBS isn’t without drawbacks, widening its therapeutic capability is the recent adaptation of delivery nodes known as directional leads. Now frequently used within recent DBS trials, these stimulatory nodes grant higher precision and directionality with their electrical impulses, achieving greater specificity towards brain regions, negating precision drawbacks critiqued throughout past trials. Due to its unidirectional capabilities (meaning stimulation can be delivered in specific orientations) this superior method grants researchers the ability to shape the electrical field around the node - a manipulation deemed impossible using previous omnidirectional methods [32]. The neurological complexity of depression makes this disease an ideal candidate for directional lead stimulation, potentially leading this treatment style

Figure 3. Using Vagus Nerve Stimulation in hopes to treat post-traumatic stress disorder. [39]

towards an increasingly advanced space, where finite precision, specific to the individual, could be delivered more effectively, reducing MDD symptomology on an unprecedented level.

Using Transcranial Magnetic Stimulation in hopes to treat Attention Deficit Hyperactivity Disorder Described as the most common neurobehavioral disorder, attention deficit hyperactivity disorder (ADHD) is characterised by persistent hyperactivity, impulsivity and inattentiveness, and is most prevalent within children, with a small percentage of individuals carrying it through into adulthood. Due to diverse cultural and socio-economic factors, as well as surrounding elements including comorbid disorders which induce symptoms similar to those seen within ADHD, diagnosis varies widely and is less defined in comparison to other psychiatric disorders – occurring in 2-18% of school aged children [33]. A hallmark indicator of ADHD is the dysregulation of dopamine throughout the individual’s dopaminergic system. With a substantial genetic component, this dysregulation contributes towards increasing the risk of ADHD, alongside external contributions from factors including upbringing, social life and home life. Comorbid disorders are also seen within 50-80% of ADHD cases, including depression of which dopamine dysregulation and inattentiveness is assessed also – accentuating the complex nature of ADHD diagnosis and aetiology

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[34].

Multiple therapeutic approaches based in clinical psychology have been developed in hopes to provide the individual with effective coping mechanisms and thinking strategies. An expansive list of diverse therapeutic approaches has materialised in the past decade, resultant of this disorder gaining recent traction amongst fellow psychologists. However, a select few have proven more effective than others, including Cognitive behavioural therapy (CBT) which focuses on the generation of compensatory processing which negates the neurological deficits caused by the disorder, and helps the individual to develop alternative thinking routes in response to symptoms occurrence. Cognitive training (CT) which is used to strengthen cognitive abilities including executive function, of which ADHD individuals possess deficits in. and Dialect behavioural therapy (DBT) which aims to validate and acknowledge ADHD induced symptoms and subsequently provide them with efficient self-management skills. Although these communicative therapeutics prove beneficial amongst a large proportion of ADHD affected individuals, progress is not achieved in every case. The lack of reliable, positive, long-term benefits from talking based therapies in treating ADHD also highlights the implicit limitations this approach possesses, with beneficial effects of CBT on average only lasting up to 12 months post treatment [35]. Suggested to be a result of this method’s inability to directly target neurobiological irregularities seen within ADHD [36] limitations in communicative treatment methods persists. A systematic limitation in Lambez et al [37] meta-analysis also exposes how potential treatment avenues remain unexplored due to methods being developed solely based upon psychological constructs, hinting towards a new wave of promising treatments which place other scientific fields centre within their framework of design.

Proposed by Acosta and Leon-Sarmiento [38]a promising alternative to communicative and medicinal based therapeutics was introduced in the form of transcranial magnetic stimulation (TMS). Transcranial magnetic stimulation is a non-invasive bioengineered technology used to induce change within cortical brain regions, via triggering or inhibiting neuronal activation through localised magnetic field projection, delivered using a small handheld device (Figure 5). Transcranial magnetic stimulation possesses the ability to directly modify neurotransmitter activity, including dopamine and its metabolites [40, 41]. Within ADHD the dysreg-

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ulation of dopamine, particularly within the right hemisphere fronto-striatum, triggers ADHD symptomatology by affecting behavioural processing circuits, including the reward system. It was hypothesised that targeting this region using TMS may prove beneficial in negating dopamine induced symptoms, by treating the dopaminergic dysregulation within the patient’s right hemisphere. Following Acosta and Leon-Sarmiento’s [38] proposal a pilot study by Bloch et al [40] was conducted to test the viability of this technology in ADHD treatment. A group of 13 adult individuals, all diagnosed with ADHD underwent repeated TMS within their dorsolateral prefrontal cortex, the area of which the dopamine dysregulation is thought to occur. Following initial stimulation, in comparison to pre-stimulation attention scores, all participants scored significantly higher just minutes post treatment, providing researchers with an evidence-based report showing the positive effects which follow TMS in ADHD treatment. This advantageous result implies modification of dopaminergic activity has taken place within each subject, echoing previous studies which show such changes in dopamine signalling in response to dorsolateral TMS [41]. This positive result highlights the cutting-edge potentiality of TMS in relation to behavioural illnesses, potentially developing selftreatment routes, giving the individual the choice to manually override neurological abnormalities which lead to ADHD symptomatology at the click of a button. This option provides a more preferable treatment method, alternative to lengthy communicative based methods which prove lacklustre in long term efficacy as well as potentially harmful psychostimulant medications.

As mentioned prior, ADHD is most common within children, however criticism in using neurostimulatory technology in treating children is widely debated with scepticism revolving around long term safety. The underdeveloped infant brain is considered to be more plastic, making neuromodulation more effective and capable in altering brain activity. Although seen as a positive in many regards this increased susceptibility may lead to an increased risk of abnormal development, potentially materialising into long term deficits and/or disability in adulthood [42]. Although risks are apparent, it is important we continue to lean into these technology-based trials in search for ADHD treatments, as current ADHD treatment methods appear elementary in comparison to current treatments aimed towards different psychiatric illnesses. Finding

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effective ways to treat this disorder should be at upmost importance, as within child ADHD cases 3060% of them will develop a variety of psychiatric and behavioural problems into adult hood [34], alongside significant increases in suicide rates and harmful behaviours [35].

Using Vagus Nerve Stimulation in hopes to treat post-traumatic stress disorder.

Categorised by the recurrence of four symptom clusters; re-experiencing, cognitive alterations, hyperarousal and avoidance, post-traumatic stress disorder (PTSD) affects 7-12% of individuals following the exposure of a traumatic event. Symptoms derived from these clusters consist of flashbacks, nightmares, hypervigilance, social avoidance, intrusive memories and social deficits. These symptoms are thought to be partially caused through abnormal autonomic nervous system activity, increasing levels of stress and sensitivity, inducing prolonged states of flight or flight [43, 44]. Since all individuals who experience traumatic events do not contract PTSD, a genetic component is believed to influence susceptibility to this illness.

Known as the gene x environment interaction [45], this complex synergy of environmental and genetic contributions leading to PTSD symptomatology has synthesised a more biological approach within PTSD research. Genetic influences which impact the individual’s Cognitive ability and autonomic physiological response, as well as environmental factors including trauma severity, duration and type, all partake in determining whether PTSD follows a traumatic experience. A hallmark neurological irregularity assessed in PTSD is the dysregulation of the hypothalamus pituitary adrenal (HPA) axis, a part of the stressinducing sympathetic nervous system. The HPA axis is central in regulating the body’s stress response, triggering a cascade of biological processes beginning in the amygdala. Danger detection processed in the amygdala will send cautionary signals to the hypothalamus, leading to increased secretion of stress-inducing hormone cortisol, proportional to the severity of the evaluated stressor. Within PTSD the HPA axis becomes insufficient in stress regulation following traumatic exposure. Regulated by two receptor groups, mineralocorticoid (MR) and glucocorticoid (GR), cortisol levels in healthy individuals remain balanced. Mineralocorticoid Receptors have high affinity to cortisol hormones, increasing stress levels in response to the onset of increased cortisol release. As cortisol levels increase,

low affinity GR receptors begin to bind to these molecules, triggering a negative feedback loop, which returns cortisol levels back to baseline. However, in PTSD this regulatory system becomes ineffective in balancing cortisol levels, due to a decrease in cortisol release rates and hypersensitivity within GR receptors [44], The results of these irregularities are consistent with PTSD symptomology, including hypersensitivity to stressful stimuli, increased hypervigilance, startle, and irregulated physiological (autonomic nervous system) arousal [46] rendering the individual less adapt in the processing of stressful scenarios. Memory based deficits, of which are suggested to be responsible for symptoms including flashbacks and false memories, are largely correlated with decreased hippocampal, amygdala and prefrontal cortex activity [47]. The CA3 region of the hippocampus is responsible for the initial encoding of memories and appropriate retrieval of specific memories in response to correlational ques [48]. In mammals damage to the CA3 region is caused in response to trauma and stress inducing experiences, lowering hippocampal functionality, volume, and inhibiting the synthesis of new neurons. It is this neurodegenerative response to traumatic events which is believed to leave the individual sensitive to external cues triggering sporadic re-experiencing [47].

A recent region of interest in PTSD treatment is the therapeutic effects of Vagus Nerve stimulation (VNS) in relation to targeting neurological deficits seen within PTSD affected individuals. Being the largest nerve within the body’s parasympathetic nervous system the vagus nerve reduces sympathetic (autonomic stress inducing) input and contributes towards the control of multiple bodily functions, including immunity, digestion, cardiovascular regulation and mood [43]. Once stimulated, either through invasive (Figure 6) or noninvasive (Figure 7) methods, the vagus nerve also modulates fear circuits, encourages neural plasticity, and enhances cognitive functioning and memory [51].

Its strengthening effects on cognitive ability, and connections to stress controlling regions including the hypothalamus, amygdala and HPA axis [43], has proved effective in treating multiple stress related illnesses, including depression, panic disorder and obsessivecompulsive disorder [52]. The vagus nerve’s capability to manipulate stress related processing as well as strengthening memory function has inevitably placed it forefront within PTSD research, alongside the discovery that VNS has an inhibitory effect on the reduction of cortisol release [53], which is a neurological deficit

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Figure 4. Example of invasive Vagus nerve stimulation [49]

Figure 5. Example of Non-Invasive Vagus nerve stimulation [50]

correlated with PTSD as mentioned prior.

Initial testing of VNS in hopes to treat fear related PTSD symptoms was conducted using rats, where VNS and its impact on memory extinction was assessed. Memory extinction takes place when a response to a certain stimulus deteriorates or vanishes as time progresses due to repeated future exposure to the stimulus without the following predicted negative outcome. This process does not erase the past memory of which the response is derived from, however consolidates new memories which suppresses the previous response taking place upon future exposure.

Memory extinction is a key feature of behavioural adaptation allowing for individuals to change their reactions based on more recent experiences. In relation

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to PTSD efficient memory extinction is impaired, rendering the individual incapable of overriding their traumatic memories with new trauma related memories which do not need such adverse reactions, resulting in consistent fear responses being triggered in reaction to stimuli that correlates with their traumatic memory.

Within this study fear was conditioned using a tone shock experimental design, where fear was learned in acquisition trials where an electric shock followed the presentation of an audible stimuli, thereafter extinction trials were constructed by shocks no longer being administered in consequent to auditory stimuli.

Results found a significant decrease in conditioned fear responses (CFR) and freezing rates in rats who received VNS in extinction trials compared to nonstimulatory control groups, who consistently displayed high levels of CFR and freezing behaviours in multiple extinction trials following the conditioned fear learning [54]. This relationship between VNS and enhanced memory extinction exemplifies the potential VNS has within memory-based therapeutics in affecting memory extinction allowing the individual to increasingly adapt to new experience learning. A recent pilot study conducted by Wittbrodt et al [55] tested VNS in human application to assess the potential neurological influence VNS may achieve in relation to the exposure of personalised trauma scripts (Passages which accurately correlated/described past personal traumatic events).

Although all participants were not diagnosed with PTSD, each of them had experienced traumatic life events - of which were represented in the personalised scripts. Results showed VNS lessened visualisation and re-experiencing behaviours in reaction to script exposure, consequent to a VNS induced upregulation in their ventral visual stream. Individuals who received VNS also exhibited altered activity levels in stress inducing brain areas, including the amygdala and anterior cingulate cortex, blunting the individual’s trauma response on both emotional and neurological levels, highlighting VNS’s ability in lessening trauma induced processing upon exposure to stimuli which correlates with the traumatic memory. A recent surge in interest within PTSD research has emerged following the aforementioned rodent and human VNS studies, showing VNS ability in improving memory extinction, stress regulation and trauma-related response. Such pilot studies and advancements in VNS techniques, like electrical earpiece stimulation [56], contribute to the development of VNS as a viable treatment for PTSD. This progress positions VNS as a potential

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method in future PTSD therapy, helping individuals who are unable to respond to current PTSD treatment.

CONCLUSION As we stand on the verge of this new era in psychological treatment, recent integration of clinical methodologies and biotechnology echoes the now frequent synergy seen amongst technology and numerous scientific disciplines. Through the use of innovative biotechnologies including Deep Brain Stimulation, Transcranial Magnetic Stimulation, and Vagus Nerve Stimulation we are witnessing the development of more precise, personalised treatment methods which are becoming unparallel in efficiency, hinting towards the future norm in mental health management. The use of biotechnology in clinical treatment most importantly provides promising alternatives to individuals who do not respond adequately to current treatment methods, usually rooted in talking/medication-based practices.

This interdisciplinary approach also enhances our current knowledge towards the neurobiology of several psychiatric/psychological illnesses, positively impacting surrounding areas of research. Resultant from this, it is imperative that research continues to promote and invest their time and money into the testing and development of new technologies in relation to psychiatric treatment, as outcomes possess the potential to change the lives of millions. Overall, this exciting new wave approach cannot be reduced to a mere extension of existing methods seen within clinical psychology, instead this interdisciplinary approach is a completely distinct field – which may hold the key to overcoming the biggest challenges seen within clinical psychology today, through the redefinition of possibility and limitless room for improvement.

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51. Bremner, J.D., Gurel, N.Z., Wittbrodt, M.T., Shandhi, M.H., Rapaport, M.H., Nye, J.A., Pearce, B.D., Vaccarino, V., Shah, A.J., Park, J., Bikson, M. and Inan, O.T. (2020). Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders. Journal of Personalized Medicine, [online] 10(3). doi:https://doi.org/10.3390/jpm10030119.

52. George, M.S., Ward, H.E., Ninan, P.T., Pollack, M., Nahas, Z., Anderson, B., Kose, S., Howland, R.H., Goodman, W.K. and Ballenger, J.C. (2008). A pilot

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study of vagus nerve stimulation ( 53. George, M.S., Ward, H.E., Ninan, P.T., Pollack, M., Nahas, Z., Anderson, B., Kose, S., Howland, R.H., Goodman, W.K. and Ballenger, J.C. (2008). A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders. Brain Stimulation, [online] 1(2), pp.112–121. doi:https://doi.org/10.1016/j.brs.2008.02.001.

54. Warren, C.M., Tona, K.D., Ouwerkerk, L., van Paridon, J., Poletiek, F., van Steenbergen, H., Bosch, J.A. and Nieuwenhuis, S. (2019). The neuromodulatory and hormonal effects of transcutaneous vagus nerve stimulation as evidenced by salivary alpha amylase, salivary cortisol, pupil diameter, and the P3 event-related potential. Brain Stimulation, 12(3), pp.635–642. doi:https://doi.org/10.1016/j.brs.2018.12.224.

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56. Wittbrodt, M.T., Gurel, N.Z., Nye, J.A., Ladd, S., Shandhi, M.M.H., Huang, M., Shah, A.J., Pearce, B.D., Alam, Z.S., Rapaport, M.H., Murrah, N., Ko, Y.-A., Haffer, A.A., Shallenberger, L.H., Vaccarino, V., Inan, O.T. and Bremner, J.D. (2020). Non-invasive vagal nerve stimulation decreases brain activity during trauma scripts. Brain Stimulation, 13(5), pp.1333–1348. doi:https://doi.org/10.1016/j.brs.2020.07.002.

Leo Elliott is a 3rd year Biology and Psychology Student at the University of St Andrews, Contact at: le42@st-andrews.ac.uk

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Exploring the Complexities and Innovations within Electric Vehicle Battery Technology Violet Melcher Bsc (Hons) Environmental & Earth Sciences

Sushmhitah Sandanatavan Bsc (Hons) Medicine

Laila Deen Bsc (Hons) Physics

Abstract—This report explores the complexities associated with the electrification revolution of the global automotive industry. Though electric cars promise fewer emissions over their lifetimes compared to their petrol-reliant alternatives, the battery production process required for such vehicles is both resource and energy-intensive. By examining current mineral requirements for electric vehicles (EVs) and the projected market growth, this work suggests a two-fold solution to meet future demand for electric cars. Sodium-ion batteries must continue to advance to reduce calculated greenhouse gas emissions. However, this battery technology has the potential to relieve the demand stress currently surrounding typical lithium-ion batteries due to the crustal abundance of sodium and its relative cost. As innovations are developed to mitigate environmental detriments within the production of sodium-ion batteries, ‘Direct Lithium Extraction’ can act as a short-term solution to relieve the stressors created by current lithium harvesting techniques. Electric cars are a promising technique for reducing emissions, but battery innovations are required to make a truly beneficial impact in the years to come.

T HE GLOBAL SALE OF E LECTRIC V EHICLES (EV S ) has been growing consistently year after year at a rapid rate, with projections for the years to come showing no sign of halting (Rocky Mountain Institute, 2022). Projections for 2024 indicate that global sales of plug-in electric vehicles are anticipated to grow by more than 21 percent, totaling 16.7 million vehicles worldwide by the end of this year (McKerracher, 2024). Many sources and a variety of publications, including the International Energy Association, emphasise that the electrification of the automotive industry is a vital component in reaching net zero emissions by 2050 (IEA, 2023). However, electric vehicles require critical minerals and energy-intensive practices to be produced, averaging 173kg more minerals than the petrol alternative (IEA, 2023). Minerals

such as lithium, nickel, and copper are finite and require practices such as mining for extraction, which are detrimental to the surrounding human and natural environments (Beales et al., 2021). Though electric vehicle batteries range in exact composition, all require similar materials and critical minerals (Beales et al., 2021). In the past decade, CO2 emissions from the manufacturing of electric vehicles have expanded threefold because of past market growth (Lakshmi, 2023). Even so, it has been shown that over the lifetime of an EV, emissions still do not reach those of petrol vehicles (USEPA, 2021). However, solutions must be constructed and developed if EVs are meant to be a pathway towards net zero emissions. Sodium-ion batteries have been proposed and researched as an alternative to current battery technology with techniques such as Direct Lithium Extraction as a possible adaptation to

Published by STATIC Student Journal

LAILA DEEN, 2024

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current practices. Though electric vehicles consistently emit less than petrol-reliant alternatives, the resourceheavy production of EV batteries lessens pollutant reduction. As the EV market continues its rapid expansion with no signs of slowing, advancements in battery technology are crucial to reduce reliance on harmful mineral extraction practices. However, the technological breakthroughs necessary for this progress are still in their early stages.

EVs produce fewer emissions post-manufacturing compared to traditional vehicles (Moseman, 2022).

Though the main opposition to EVs comes from critics who propose that since critical minerals and energy-intensive processes are required for the battery production of EVs, they are far less sustainable than their conventional counterparts, Figure 1, produced

by The Greenhouse gases, Regulated Emissions, and Energy use in Technologies Model, illustrates the stark difference between the two vehicle types (USEPA, 2021).

Figure 1. Lifecycle GHGs for an Electric Vehicle vs a Gasoline Reliant Car from the United States Environmental Protection Agency (2021)

EVs are, and remain, the greenest option to date when finding the most sustainable avenue for personal transportation. However, when considering the role that EVs are meant to play in the upcoming years, as the goal of net zero carbon emissions by 2050 is emphasised, the resources required to produce such vehicles must be considered. Though EVs are the best option, this statement is relative to the options currently available. As of this year, a single lithium battery-powered electric vehicle requires, on average, 53.2 kg of copper, 8.9 kg of lithium, 39.9 kg of nickel, 24.5 kg of manganese, 13.3 kg of cobalt, 66.3 kg of graphite, and .5 kg of rare earths (IEA, 2023). EVs are resource heavy and global demand for such vehicles grow daily (EPA, 2023). Figure 2 shows the growth of the global electric vehicle market in recent years.

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Figure 2. Growth of the Chinese, European, and American Electric Vehicle Market from the International Energy Agency (2023)

By 2032, 30% of all passenger cars worldwide will be electric (Lieven and Rietmann, 2020). Additionally, by 2050, this percentage is predicted to grow to over 80% of all global car sales (Carlier, 2022). Because of the proposed demand for EVs between 2022-2050, this transition could require over 6.5 billion tons of enduse materials such as copper (Mazzanti, 2023). Mining is often utilised to harvest the minerals required for EV production (Agusdinata, Eakin, and Liu, 2022).

Currently, the mining and refining process required for EVs accounts for roughly a quarter of all production emissions, with lithium and nickel making up approximately half of the mined resources (McKinsey & Company, 2023). Lithium extraction requires large amounts of water, creating mineral waste, impacting surrounding communities, and being associated with over 1.3 million tons of emitted carbon annually (Ukpanah, 2024). The MIT Climate Portal calculates that for every ton of lithium mined, an estimated 15 tons of CO2 is emitted into the atmosphere (Crawford, ShaoHorn, and Keith, 2022). Alongside this, a 2022 report highlights that harvesting practices often occur in the Global South, while many end-products are utilised and consumed in countries such as the US and Canada (Agusdinata, Eakin, and Liu, 2022).

Given the imminent market growth, it is urgent to revolutionise the harmful extraction practices of essential minerals used in EVs. If electric vehicles

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could be associated with less polluting practices and have a reduced impact on global communities, a future dominated by electric cars would be significantly less harmful. This is where the innovation of battery alternatives and extraction practices becomes crucial.

A 2017 article published by the Royal Society of Chemistry suggests that sodium-ion batteries may hold promise in satisfying increasing demand and limiting the negative impacts of lithium extraction (Hwang, Myung, and Sun, 2017). Sodium is widely available globally and has a similar chemistry to lithium-ion batteries (Hwang, Myung, and Sun, 2017). Another proposed improvement in current EV technologies is changing current lithium harvesting techniques to the more direct and environmentally sound technique of Direct Lithium Extraction (Vera et al., 2023). This technique recycles the resources utilised, significantly reducing the need for additional mining when accessing the initial lithium brines (Vera et al., 2023).

2023). Within South America, Argentina, Bolivia, and Chile comprise the Lithium Triangle region, producing more than half the global lithium supply (Institute for Energy Research, 2023). Lithium extraction through brine uses over 65% of the region’s water, harming the natural environment and the surrounding communities (Institute for Energy Research, 2023). Many recent innovations regarding battery technology have been proposed. Sodium-ion batteries are a leading contender in this debate. Unlike lithium, sodium is one of the most abundant minerals in the Earth’s crust (Yabuuchi et al., 2014). Sodium is also the second lightest and smallest alkali metal, behind lithium (Yabuuchi et al., 2014), in addition to being significantly cheaper than other minerals used in battery manufacturing (Rudola et al., 2023).

DISCUSSION Though currently utilised lithium-ion batteries have been meeting demands and reducing global fossil fuel dependency compared to prior levels, lithium is not regarded as an abundant element within Earth systems (Yabuuchi et al., 2014).

Figure 4. Price of Carbonate, Sodium, Cobalt, and Nickel Over the Last Five Years from Rudola et al (2023)

Figure 3. Crustal Abundance of Common Elements from Yabuuchi et al (2014)

Figure 3 expresses this relationship, illustrating the relative abundance of lithium compared to other elements in the Earth’s crust, showing a calculated abundance of 20 ppm (Yabuuchi et al., 2014). Additionally, lithium production is tied to specific countries, relying on significant exports from regions such as South America as global demand increases (Berg, 2021). Lithium extraction is resource-heavy and environmentally harmful (Institute for Energy Research,

Figure 4 articulates the relationship between mineral prices, enforcing the increased availability of sodium resources compared to its counterparts (Rudola et al., 2023). Recent studies also show that alongside sodium-ion batteries’ promising per kWh storage capacity, the cycle life nears that of Li-ion batteries (Peters et al., 2016). However, comparison studies between lithium and sodium-ion-based batteries show that when considering raw materials, energy carriers, manufacturing requirements, and supply chains, the greenhouse gas emissions associated with sodium-ion batteries outrank those of lithium batteries (Schneider et al., 2019).

Figure 5 exemplifies this, notating sodium-ion batteries as NIB and lithium-ion batteries as LIB. This research suggests that though sodium-ion batteries may solve future supply and demand issues presented by

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from the extracted brine while replacing the previously lithium-bearing brine into basins, recycling the water resources instead of losing them through evaporation (Nicolaci et al., 2023).

Figure 6. Lithium Brine Extraction Compared to DLE from Nicolaci et al (2023)

Figure 5. GHG Emissions of Sodium-Ion Batteries and Lithium-Ion Batteries from Schneider et al (2019).

lithium-ion batteries, they do not yet solve the environmental impact problems associated with lithium-ion batteries (Schneider et al., 2019).

As sodium-ion batteries do not currently present a worthwhile alternative to lithium-ion batteries, other innovations must be considered. An innovation that has received recent media attention is a change in lithium extraction mechanisms, switching to a process called Direct Lithium Extraction (DLE). Current lithium extraction for EV batteries relies on hard rock mining.

This process is not only associated with emissions and large amounts of generated waste but also can pollute surface waters, degrade wetlands and other nearby natural habitats, as well as disrupting surrounding communities (USEPA, 2019). Lithium extraction through the brine method is another form of extraction that has become more common in recent years.

However, this process requires 2 million tons of water usage through evaporation per ton of lithium harvested while jeopardising massive quantities of underground freshwater water reserves through contamination with the utilised brine (Wetlands International, 2023). DLE minimises the negative impacts of alternative extraction techniques, extracting lithium brine from basins and using a processing unit to extract and concentrate the available lithium (Vera et al., 2023). Instead of evaporating vast amounts of water, this mechanism uses a processing unit to remove only the lithium

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Figure 6 provides a visual for the comparison between these processes. This approach minimizes waste, using 50 times less water than the currently used brine technique, and shortens the processing times of typical lithium extraction from months to years to days or months (Cleantech, 2022). This process minimizes the current environmental impact of lithium extraction while curbing some of the demand issues. That said, the crustal abundance of lithium is still an issue on the horizon (Yabuuchi et al., 2014). Environmental degradation and meeting ever-growing demand remain the fundamental problems. Though sodium-ion batteries have yet to curb negative environmental impacts, multiple publications, including the Argonne National Laboratory, a group supported by the US Department of Energy, continue to research promised innovations and changes to current proposals (Harmon, 2024). As this battery technology has yet to be produced at scale and changes must still be made, DLE acts as a possible short-term solution to current degradation caused by lithium-ion batteries, reducing waste and impact while increasing the ability to meet demand.

A single solution has yet to be established, but the future is still promising.

CONCLUSION With the future holding many years of continued projected growth for electric vehicles, innovations must be made in terms of battery technology. Current lithium battery options are environmentally detrimental and are not sustainable for the calculated market increase. From CO2 emissions to massive amounts of water loss, various methods of harvesting lithium negatively impact both natural and human life. With that in mind, technological innovations would be massively beneficial in many ways. However, proposed solutions have yet to have the infrastructure needed to meet supply and demand requirements without further harming the environment. Because of this, a twophased approach is suggested in this report. Starting with switching to Direct Lithium Extraction in current

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lithium harvesting practices, an improvement could be made in terms of the environmental impacts, making the process more sustainable, reducing water waste, land use, time required, and overall impact. Following this, as sodium-ion battery technology advances and solutions are established to solve the current calculated emissions for battery creation, a switch could ultimately be made to a battery source that does not have as strict resource limits. If this option becomes more environmentally viable, current complications could be curbed.

REFERENCES Agusdinata, D.B., Eakin, H. and Liu, W. (2022). Critical minerals for electric vehicles: a telecoupling review. Environmental Research Letters, 17(1), p.013005. doi:https://doi.org/10.1088/17489326/ac4763.

Beales, E.J., Brøske Danielsen, J., Grytli, T. and Simas, M. (2021). Environmental and social consequences of mineral extraction for low-carbon technologies: Cobalt, lithium and nickel extraction, impacts and relation to the SDGs. [online] sintef.brage.unit.no. SINTEF AS. Available at: https://sintef.brage.unit.no/sintefxmlui/handle/11250/3047770 [Accessed 24 May 2023].

Berg, R. (2021).

South America’s Lithium Triangle: Opportunities for the Biden Administration. [online] www.csis.org. Available at: https://www.csis.org/analysis/south-americas-lithiumtriangle-opportunities-biden-administration.

Carlier, M. (2022). Global market share of electric vehicles 2050. [online] Statista. Available at: https://www.statista.com/statistics/1202364/evglobal-market-share/.

CleanTech (2022). Direct Lithium Extraction • Cleantech Lithium. [online] ctlithium.com. Available at: https://ctlithium.com/about/direct-lithiumextraction/::̃text=The%20DLE%20process%20and% 20reinjection.

Crawford, I., Shao-Horn, Y. and Keith, D. (2022). How much CO2 is emitted by manufacturing batteries? [online] MIT Climate Portal. Available at: https://climate.mit.edu/ask-mit/how-much-co2emitted-manufacturing-batteries.

Harmon, J. (2024). Cathode innovation makes sodium-ion battery an attractive option for electric vehicles — Argonne National Laboratory. [online] www.anl.gov. Available at:

https://www.anl.gov/article/cathode-innovation-makessodiumion-battery-an-attractive-option-for-electricvehicles.

Hwang, J.-Y., Myung, S.-T. and Sun, Y.-K. (2017).

Sodium-ion batteries: present and future. Chemical Society Reviews, [online] 46(12), pp.3529–3614. doi:https://doi.org/10.1039/c6cs00776g.

IEA (2023a). Critical minerals – Topics. [online] IEA. Available at: https://www.iea.org/topics/criticalminerals.

IEA (2023b).

Prospects for electric vehicle deployment – Global EV Outlook 2023 – Analysis. [online] IEA. Available at: https://www.iea.org/reports/global-ev-outlook2023/prospects-for-electric-vehicle-deployment.

Institute for Energy Research (2023).

Environmental Impacts of Lithium-Ion Batteries. [online] Institute for Energy Research. Available at: https://www.instituteforenergyresearch.org/renewable/ environmental-impacts-of-lithium-ion-batteries/.

International Energy Agency (2023).

Electric vehicles. [online] IEA. Available at: https://www.iea.org/energy-system/transport/electricvehicles.

Lakshmi, R.B. (2023). The Environmental Impact of Battery Production for Electrical Vehicles. [online] Earth.org.

Available at: https://earth.org/environmental-impact-of-batteryproduction/.

Lieven, T. and Rietmann, N. (2020). Forecasting the trajectory of electric vehicle sales and the consequences for worldwide CO2 emissions. Journal of Cleaner Production, 261(121038), p.121038. doi:https://doi.org/10.1016/j.jclepro.2020.121038.

Manoharan, Y., Hosseini, S.E., Butler, B., Alzhahrani, H., Senior, B.T.F., Ashuri, T. and Krohn, J. (2019). Hydrogen Fuel Cell Vehicles; Current Status and Future Prospect. Applied Sciences, 9(11), p.2296. doi:https://doi.org/10.3390/app9112296.

Mazzanti, T. (2023). Scale-up of critical materials and resources for energy transition. [online] Energy Transitions Commission. Available at: https://www.energy-transitions.org/new-report-scaleup-of-critical-materials-and-resources-requiredfor-energy-transition/::̃text=Between%202022 %E2%80%932050%2C%20the%20energy [Accessed 5 Apr. 2024].

McKerracher, C. (2024). Electric Vehicle Market Looks Headed for 22% Growth This Year. Bloomberg.com. [online] 9 Jan. Available at:

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https://www.bloomberg.com/news/newsletters/202401-09/electric-vehicle-market-looks-headed-for-22growth-this-year?embedded-checkout=true.

McKinsey & Company (2023). The Race to Decarbonize electric-vehicle Batteries — McKinsey. [online] www.mckinsey.com. Available at: https://www.mckinsey.com/industries/automotiveand-assembly/our-insights/the-race-to-decarbonizeelectric-vehicle-batteries.

Moseman, A. (2022). Are Electric Vehicles Definitely Better for the Climate than gas-powered cars? [online] MIT Climate Portal. Available at: https://climate.mit.edu/ask-mit/are-electric-vehiclesdefinitely-better-climate-gas-powered-cars.

Nicolaci, H., Sachs, G., Young, P., Bailey, E., Chen, T., Lin, Y., Snowdon, L., Goldman, S., International, J., Zhang, Rai, L., Zheng, N. and Shi, R. (2023). Global Metals & Mining Di rect Li thi um Extracti on: A potenti al game changi ng technol ogy. [online] Available at: https://www.goldmansachs.com/intelligence/pages/gsresearch/direct-lithium-extraction/report.pdf.

Peters, J., Buchholz, D., Passerini, S. and Weil, M. (2016). Life cycle assessment of sodium-ion batteries. Energy & Environmental Science, [online] 9(5), pp.1744–1751. doi:https://doi.org/10.1039/C6EE00640J. Rocky Mountain Institute (2022). EVs to surpass two-thirds of global car sales by 2030, putting at risk nearly half of oil demand, new research finds. [online] RMI. Available at: https://rmi.org/pressrelease/evs-to-surpass-two-thirds-of-global-car-salesby-2030-putting-at-risk-nearly-half-of-oil-demandnew-research-finds/.

Rudola, A., Sayers, R., Wright, C.J. and Barker, J. (2023). Opportunities for moderaterange electric vehicles using sustainable sodiumion batteries. Nature Energy, [online] pp.1–4. doi:https://doi.org/10.1038/s41560-023-01215-w.

Schneider, S.F., Bauer, C., Novák, P. and Berg, E.J. (2019). A modeling framework to assess specific energy, costs and environmental impacts of Li-ion and Na-ion batteries. Sustainable Energy & Fuels, 3(11), pp.3061–3070. doi:https://doi.org/10.1039/c9se00427k.

Ukpanah, I. (2024). Is Lithium Mining Bad For The Environment? Stats And Facts. [online] GreenMatch.co.uk.

Available at: https://www.greenmatch.co.uk/blog/is-lithium-miningbad-for-the-environment.

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United States Environmental Protection Agency (2021). Electric Vehicle Myths. [online] United States Environmental Protection Agency. Available at: https://www.epa.gov/greenvehicles/electric-vehiclemyths.

USEPA (2019).

Office of Wastewater Management - Hardrock Mining: Environmental Impacts. [online] www3.epa.gov.

Available at: https://www3.epa.gov/npdes/pubs/env.htm: :̃text=likely%20to%20erode.- [Accessed 5 Apr. 2024].

Vera, M.L., Torres, W.R., Galli, C.I., Chagnes, A. and Flexer, V. (2023). Environmental impact of direct lithium extraction from brines. Nature Reviews Earth & Environment, [online] 4(4), pp.149–165. doi:https://doi.org/10.1038/s43017-022-00387-5.

Wetlands International (2023). World Water Day: The water impacts of lithium extraction. [online] Wetlands International Europe. Available at: https://europe.wetlands.org/blog/worldwater-day-the-water-impacts-of-lithiumextraction/::̃text=Each%20tonne%20of%20lithium%20 requires.

Yabuuchi, N., Kubota, K., Dahbi, M. and Komaba, S. (2014). Research Development on Sodium-Ion Batteries. Chemical Reviews, 114(23), pp.11636–11682. doi:https://doi.org/10.1021/cr500192f.

Violet Melcher is a 2nd year Environmental & Earth Sciences Student at the University of St Andrews, Contact at: vvrm1@st-andrews.ac.uk

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Improving Crop Resilience to Climate Change Teddy Henderson Bsc (Hons) Biology

Thomas Burton Bsc (Hons) Mathematics

Laila Deen Bsc (Hons) Physics

Abstract—Enhancing the resilience of crops to climate change is critical for future food security, and scientists are developing many different approaches to this issue. Technological advances such as RNA sequencing and CRISPR-Cas9 are among many of the tools helping researchers to create crops with enhanced tolerance to environmental stresses. In addition, the agricultural system must find ways to increase its sustainability, with a reduction in nitrogen fertiliser usage of particular importance. The beneficial symbiosis between crops and arbuscular mycorrhizal fungi (AMF) could help reach both aims. The transfer of water and nutrients from AMF to host plants means that crops have higher tolerance to abiotic stress, such as drought, as well as increased nutrient use efficiency, minimizing the need for environmentally harmful fertilisers.

A N INCREASINGLY UNPREDICTABLE AND MORE EXTREME CLIMATE threatens the stability of life on our planet; therefore, we must take action to minimize the consequences. Climate change may have potentially disastrous impacts on our agricultural system, due to an increased risk of flooding, extreme temperatures, drought, pests, and pathogens, which threaten the food security of many. The United Nations Sustainable Development Goal 2 is to “End hunger, achieve food security and improve nutrition, and promote sustainable agriculture” (Nations, 2024).

To address these targets, with future climate conditions in mind, scientists are endeavoring to improve crop resilience to climate change, and farmers are adapting their crop management practices to help farmland better withstand weather challenges. In addition, the agricultural system is continuously innovating to improve sustainability and lessen its contribution to global warming and climate change. In this review, I will investigate how collaborations between scientists and industry are hoping to enhance crop resilience.

Understanding Plant Responses to Environmental Stress Firstly, to enhance crop resilience, we must understand plant responses to environmental stress. A plant’s stress response involves changes to many physiological, morphological, and molecular processes, which may result in limited growth and reduced yields. These include changes in signaling, grain formation, water use efficiency, root and shoot growth, and the symbiotic microbiome (Benitez-Alfonso et al., 2023). While many of these stress response phenotypes are easily observable, the underlying molecular mechanism of these changes is more challenging to uncover.

Advances in technology allow these plant stress responses to be measured holistically, from genotype to phenotype, helping to elucidate the origin of specific resilience traits. In particular, the ability to measure changes in gene expression through RNA sequencing has been revolutionary (Stark et al., 2019). It is now possible to map the “transcriptome” of an organism, tissue, or cell, which is the overall level of different RNA transcripts. RNA transcripts are created by the cell when a gene is expressed (switched “on”) and are the templates for protein synthesis. This means

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that when two plants are subjected to different environmental conditions, we can see how the plant responds on a molecular level: the variation in gene expression and, therefore, protein production (Stark et al., 2019). This information may then give clues about the mechanism of a specific plant response, and if we can identify resilience pathways, we can breed or engineer crops to take advantage of these responses. There are many different approaches to improving crop resilience to environmental stresses.

During the development of improved crop lines, these resilience traits can then be selected for and enhanced through genetic engineering or breeding programs.

Some of the traits which provide plants with enhanced resilience to environmental stresses include water use efficiency, root morphology, age of maturity, and the soil microbiome (Benitez-Alfonso et al., 2023).

DISCUSSION CRISPR-Cas9 and Genetically Modified Plants There is still an ongoing debate about the ethics and dangers of genetically modified (GM) plants and their consumption, and variation worldwide in the technology’s acceptance and legal status. While humans have been selectively breeding crop plants over thousands of years, it is only recently that researchers have been able to genetically engineer plants for desired characteristics. CRISPR-Cas9 has advanced many areas of research, with plant science experiments benefitting from this novel method for precisely altering and removing genes (Belhaj et al., 2015). The “knockout” of a gene is a common application of CRISPR-Cas9 and provides an effective way to study the function of a gene if you can link it to changes in the phenotype of the mutant plant. Furthermore, CRISPR-Cas9 has been used to successfully improve crop resilience and yields in a variety of crop plants by altering the genome to include optimum genes for desired traits (Yuan et al., 2023). This method of genome engineering is promising due to its rapid results compared to traditional breeding and selection methods.

The Role of AM Symbiosis in Improving Drought Tolerance Recent studies on drought resilience have been investigating a widely beneficial soil fungus, arbuscular mycorrhizal fungi (AMF), and its symbiotic relationship with around 80% of land plants. AMF

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infects plant roots, initiating a mutually beneficial relationship where AMF provides nutrients and water to the plant and receives carbon fixed by the plant through photosynthesis in return. There is evidence for this symbiosis with AMF increasing plant tolerance to drought by helping the plant adapt to water deficiency and increasing its access to water and nutrients (Cheng et al., 2021). While water deficit conditions can limit the diversity and development of AMF symbiosis, some AMF species have developed adaptations to these conditions and are still able to thrive.

Inoculation of plants with AMF has been shown to increase drought tolerance through a complex mix of mechanisms (Cheng et al., 2021). Under drought conditions, the air spaces in soil increase, making water transfer uptake more challenging. AMF aids the plant in overcoming this challenge by facilitating the passage of water from the soil through the AMF and to the roots through aquaporins (AQP), thereby improving water uptake. Furthermore, AMF is able to induce changes in root morphology, which improve soil water retention and nutrient acquisition. AMF induces changes in gene expression of nutrient and water transporters to promote water and nutrient acquisition. Another way that AMF contributes to drought tolerance is through the formation of soil aggregates due to the secretion of glomalin, which is able to bind soil particles together and improve soil structure and water retention. AMF also reduces the air gap between soil and plant root, which allows more efficient transfer of nutrients and water. AMF symbiosis also enhances drought tolerance through improved photosynthetic capacity, enhanced defense against antioxidants, osmotic regulation, polyamine and fatty acid metabolism, as well as regulation of endogenous hormones (Cheng et al., 2021).

Nutrient Use Efficiency and Reducing Reliance on Nitrogen Fertiliser Furthermore, harnessing AMF symbiosis has the potential to reduce reliance on nitrogen fertiliser, which causes harm to the environment due to associated greenhouse gas emissions from production, as well as pollution after application (Robertson & Vitousek, 2009). The use of nitrogen fertiliser is vital to produce the high yields seen across the globe in our current agricultural system. However, with a shift toward sustainability, there are increasing efforts to reduce its application. Instead, researchers are hoping to improve the nutrient use efficiency of crops, so they

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make the most of the nitrogen already available in the soil or require less nitrogen fertiliser to achieve the same yields (Anas et al., 2020). It is thought that AMF could also be helpful in improving the nitrogen use efficiency of plants due to its role in supplying the host plant with nutrients (Xie et al., 2022).

The symbiosis between AMF and plants is an example of one of many different interactions at play between microorganisms in the soil and plants, which together form the plants’ microbiome (phytomicrobiome). One way in which industry is translating this research into innovation to improve crop resilience and agricultural sustainability is the development of biostimulants which promote the growth of beneficial microorganisms in the soil (Alahmad et al., 2023).

Inoculation of plants with AMF has been shown to act as a biostimulant and is a promising alternative to nitrogen fertilisers (Rouphael et al., 2015).

CONCLUSION In summary, technological advances in RNA sequencing are allowing us to investigate the genetic basis for environmental stress responses and resilience.

With this knowledge of key genes in mind, CRISPRCas9 allows us to rapidly develop plants with precise mutations, either to investigate a phenotype further or to create a crop with increased resilience due to the insertion of an optimized gene into the genome.

If we are to achieve the United Nations Sustainable Development Goals, there may need to be wider acceptance of the use of technology like CRISPR-Cas9 to create crops able to withstand the challenges of climate change. However, the ethics behind genome editing and consumption must be discussed with care and clear public communication.

This report also outlined the potential advance in crop resilience that comes from optimizing crop plants’ symbiosis with AMF, due to its role in water and nutrient uptake. To achieve this, the agricultural industry is developing biostimulants that harness the benefits of the soil microbiome for crops by creating products that promote the growth of microorganisms

Belhaj, K. et al. (2015) Editing plant genomes with CRISPR/Cas9. Curr Opin Biotechnol 32, 76-84.

Yuan, Y. et al. (2023) Supporting crop plant resilience during climate change. Crop Sci 63, 18161828.

Cheng, S. et al. (2021) Elucidating the mechanisms underlying enhanced drought tolerance in plants mediated by arbuscular mycorrhizal fungi. Frontiers in Microbiology 12, 809473.

Robertson, G.P. and Vitousek, P.M. (2009) Nitrogen in agriculture: balancing the cost of an essential resource. Annual review of environment and resources 34, 97-125.

Anas, M. et al. (2020) Fate of nitrogen in agriculture and environment: agronomic, eco-physiological and molecular approaches to improve nitrogen use efficiency. Biological research 53, 1-20.

Xie, K. et al. (2022) Plant nitrogen nutrition: The roles of arbuscular mycorrhizal fungi. J Plant Physiol 269, 153591.

Alahmad, A. et al. (2023) Prebiotics: a solution for improving plant growth, soil health, and carbon sequestration? Journal of Soil Science and Plant Nutrition 23, 6647-6669.

Rouphael, Y. et al. (2015) Arbuscular mycorrhizal fungi act as biostimulants in horticultural crops. Scientia Horticulturae 196, 91-108.

Teddy Henderson is a 3rd year Biology Student at the University of St Andrews, Contact at: teh8@standrews.ac.uk

REFERENCES Nations, U. (2024). THE 17 GOALS. Benitez-Alfonso, Y. et al. (2023) Enhancing climate change resilience in agricultural crops. Curr Biol 33, R1246-R1261.

Stark, R. et al. (2019) RNA sequencing: the teenage years. Nature Reviews Genetics 20, 631-656.

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