What happens in the brain when we cry?
Final year undergrad coursework for Advanced cognitive neuroscience
100174576 What happens in the brain when we cry? An exploration into the neural substrates of crying. ABSTRACT Adult studies into crying divide their attention amongst an arbitrary list of complex emotional expressions which each deserve the full attention of independent neuroscientific research studies. Our understanding of the complex neuroanatomical processes that underlie infant and adult crying remains extremely limited. Neurological data supports the hypothesis that integrated brain networks involving motor, cingulated, limbic and paralimbic structures are involved in emotion processing and emotion-affect paradigms within the neurosciences have begun to illuminate a wide range of interconnected cerebral and sub-cortical structures that are consistently active during various emotional states. This study into the neuroanatomy of crying as a function of sadness, in adults and infants, using MRI methodologies, hopes to further our understanding of an emotion that has received little focus in recent years. INTRODUCTION “…emotions are part of a multi-tiered…mechanism aimed at maintaining organism homeostasis…based on structures that regulate…state by executing specific actions…from facial…expressions to complex behaviours, and by producing…neural responses aimed at the internal milieu, viscera and telencepahlic neural circuits…represented both in subcortical regulatory structures…[the] hypothalamus and brainstem tegmentum…and [in the] cerebral cortex…[the] insulu, SII and cingulated regions…[which] constitute a critical aspect of the neural basis of feelings…each emotion-feeling cycle engage brain regions in distinctive patterns…” Providing a succinct neuroanatomical and functional framework for the study of emotion and feeling. Damasio et al (2000) note that a complex pattern of movement, usually integral to the expression of sadness is what we â€˜knowâ€™ to be crying. Adolph et al., (1995) Study into brain activations during phenomenally experienced emotional states, as well as brain reactions to multimodal emotional stimuli have provided a strong foundation for a network of brain regions that are robustly activated during neuroimaging trials involving emotion detection and production (Schneider et al., 1997; Augustine 1996; Whalen et al 1998; Eblen and Graybiel 1995; Alexander et al 1986; Drevets et al., 1997; Damasio et al., 2000; Parvizi et al 2001). Kimbrell et al., (1999) found that the literature in this area reliably implicate anterior limbic and paralimbic regions and began delineating pathways of normal emotion recall and activation, establishing distinct topographies for anxiety and anger which had little in common with topographies of happiness or sadness. Supporting evidence from brain damaged patients adds weight to the network like nature of emotion processing and expression. The case of Pathological Laughing and Crying (PLC); damage to pathways arising in the motor areas of cerebral cortex and descending to the brainstem, suggests a putative centre for laughing and crying (Parvizi et al., 2001); lesions disinhibit this cortico-pontocerebellar centre, which is critically damaged in PLC. In their meta-analysis of brain mapping studies of cognitive and emotional tasks, the Anterior Cingulate Cortex (ACC), which connects deeper structures to the cortical areas of the brain, was segregated on the basis of cognitive vs affective functions, emphasising that it does not act in a vacuum, but as a component of several parallel networks. Damasio et al, (2000) discuss the commonalities of insula cortex, the secondary somatosensory (SII), Cingulate cortex and the nuclei in the brainstem tegmentum and hypothalamus, as all directly or indirectly receiving signals from the â€˜internal milieu, viscera and musculoskeletal frameâ€™, supporting the notion that emotion engages structures related to homesostasis. It is the goal of this investigation to study brain activity during crying states in adults and infants using 2 different neuroimaging techniques, in order to elucidate the emotion-feeling cycle of crying/sadness further and contribute to a clearer appreciation of which imaging techniques suit this sort of study best. METHODS The neuroanatomic pathways underlying normal emotional states can be imaged using PET, single photon emission computed tomography (SPECT) and fMRI. As this study involves infants, Near Infra-Red Spectrophotometry, a non-invasive methodology will be employed to register cortical activity in infants and also adults, to add to the fMRI time series from our crying experiment. Design: Using a categorical event related design; subtracting the activation from the neutral control condition, to discover which activations are specific to the process of crying in adults and infants using fMRI EPI BOLD measurements and EEG measurements with the NIRS system. The experimental condition was the crying phase of our study and the control condition was the neutral, not crying phase. With the independent variable being the condition (crying or not crying) and the dependent variable being the brain activation during those conditions. The variables of interest are the event-related activations during the categorical conditions and the differences between them. Confounding variables such as content of personal memory accessed for the self-induction sadness/crying task and potential differences in visualization or specific content of the â€˜sad- and neutral-valenceâ€™ phase are typically very difficult to control for. Participants: 15 2-6 month-old infants and 15 18-35 yr old adults, of mixed gender (approx 50% male) and Socio-economic status were selected from an opportunity sample of adults and infants attending a community centre where crying is encouraged during counseling sessions. Informed and written consent was obtained from the adults and parents of the infants involved, and there were no ethical problems with this study, as with many other self-induced sadness tasks, subjects volunteer to take part. Procedure: Structural MRI EPI time series were obtained as a baseline upon which we could overlay the functional scans from our experimental and control conditions. Within the categorical (crying or not crying) event-related design, scans were obtained in conjunction with the experimental and control condition, for 1 minute continuously in order to gather rich data sets into the neuroanatomy of crying. fMRI was chosen because of its high spatial resolution and the speed at which the slices of the brain are obtained. Data were first preprocessed within MATLAB and the SPM5 programme, which allows for realignment of the functional scans to adjust for the 6 regressors of head motion; spatial normalization of time-series into a common anatomical space, using the standard MNI template brain to assist in conventional reporting and finally smoothing with an 8mm kernel in order to retrieve BOLD signals from cortical and subcortical regions and to increase the signal-noise ratio. Once the model of the data had been created in SPM5, a General Linear Model multivariate analysis was done to establish how much of the data could be explained by the design matrix and reduce the error term within the GLM equation, thus identifying variables of interest that account for any outstanding activations. In order to find out about more specific regional changes a univariate Independent Components Analysis was computed within FSL, also in MATLAB on a Linux system. Subjects repeated the experiment using Near infrared spectrophotometry, which acquire EEG measurements via an emitting laser diode attached to the subjectâ€™s head via a fibre-optic cable. NIRS is a useful technique when changes in oxygenation occur spontaneously and work well in experiments that may involve gross movement because the head isnâ€™t retrained by the complex machinery of the MRI scanner. There are mixed opinions about the use of this technique, it is hoped that this experiment will shed some light on its usefulness for understanding cortical interactions during emotional states such as sadness. Data from the NIRS was digitalized and analysed with GLM and ICA on a similar system to the Echo Planar images. Spectrophotometry have been used on infants, benefiting from a small window of transparency in the young skull that allows near infra red topographies of activation and tomographic images of regional oxygenation to be mapped, this technique may also be useful in adult studies that involve more movement than typical MRI tasks, as the diodes are attached to the head, they move with the subject and therefore the signal is strong, but the signal-noise ratio of the detector system limits the resolution of measurable change in oxygenated and deoxygenated blood. MRI only provides information about changes in rCBF, which may result from several haemodynamic changes (Meek, 2002). Optical imaging is non-invasive and rarely raises any ethical problems and therefore may be a good choice for the study of infant crying. Ultimately BOLD MRI can be used to enhance the signal-noise ratio by identifying where the optode position is in the subjectsâ€™ brain. DISCUSSION: Based on previous research into this area, the discussion will address the major areas of likely activation and interest and show how these results reflect similarities to those expected from this investigation. AMYGDALA: Schneider et al (1997) used fMRI methodology to demonstrate rCBF increases in the left amygdala during sad mood induction compared to controls finding a significant increase in the BOLD response during sad mood induction in the left amygdala. It is expected that in the current adult/child self-induced sadness task, the amygdala will show early activation during the induction phase of the emotional expression of sadness through crying and that this activation would be significantly smaller and possible non-existent in the neutral/non crying phase of the experiment. INSULA: Augustine (1996) was interested in the circuitry and functional aspects of the insular lobe in primates including humans, reviewing over 20 years of research into this area. Connections were found between the insula and the orbital cortex, frontal operculum, lateral premotor cortex, ventral granular cortex and medial area 6 in the frontal lobe. Connections between the insula, SII and retroinsular area were documented. Intrainsular projections to subdivisions of the cingulate gyrus and connections with lateral, lateral basal, central, cortical and medial amygdaloid nuclei exist also. Confirming the insular as a sensori-motor, motor association area and a â€˜limbic integration cortexâ€™. With this connectivity, it is highly likely that the insula and its projections will show some activation, although knowing exactly what each pathway or network is doing is notoriously difficult to assess and requires comparisons to other studies focussing on single emotional expressions, but it is assumed, in line with previous research that crying will activate topographically and functionally distinct pathways similar to those found in Augustineâ€™s study which are known to interact with brain areas involved in emotion and memory for sadness/negative affect and that these significant affective activations will be distinguishable from those present in the control task. ANTERIOR CINGULATE CORTEX Whalen et al 1998 demonstrated that the ventral AC region activated more to emotional stimuli in contrast to the dorsal AC, which activated more during cognitive tasks. Eblen and Graybiel (1995) note that the AC has efferent excitatory input to the head of the caudate in macaque monkeys and Alexander et al., (1986) found that the modulatory caudate inputs back to the AC have intervening connections via the globus pallidus and thalamus. This structural connectivity suggests a cortical-subcortical system, endorsed by Drevets et al., (1997) who reported increased activity in the basal ganglia in mania. These findings suggest the AC is â€œ a vulnerable part of an important final common pathway of emotional regulationâ€? (Blumberg et al 1995) and it is expected that during crying, the ventral and rostral AC, as the regions implicated in affect processing and expression, will be active with decreased left dorsal AC activity, as our task has very low cognitive demands as contrasted with the expectation of very low activity in these areas during the neutral condition. With the fMRI scans, subcortical activations may be picked up around the caudate and hypothalamus during crying states but it is unlikely the Optical imaging will show activation in structures so deep, due to the low spatial resolution of that technique. However cortical activations from NIRS should match those discovered with fMRI and add weight to the findings that crying involves an integrated network of segregated cerebral and subcortical brain regions. NETWORKS/LESIONS: Damasio et al (2000) hypothesised that the process of feeling emotions implies the activation of the somatosensory cortices and the upper brainstem nuclei, which are known to be critical for homeostasis. They found activation in these areas, concluding that: â€œthe subjective process of feeling emotions is partly grounded in dynamic neural maps, which represent several aspects of the organismâ€™s continuously changing internal state.â€? Sadness decreased activity in right SII and there were increases and decreases in right posterior cingulated. Sadness resulted in negative peaks in the SII, active peaks with the orbitofrontal region and basal forebrain activation. Post hoc analysis found significant positive peaks in the anterior pons for sadness, as well as both sides of the midline cerebellum, the caudate nucleus and left thalamus. Decreases were prominent in the left and right frontal pole for sadness as with the right and left DLPF cortices and right premotor regions. Inferior parietal lobule showed bilateral and significant decrease for sadness as did the parietooccipital region as well as the inferotemporal (IT) and temporal polar (TP) regions, along with the occipital lobe bilaterally. This work gives a very neat example of the activations expected during this sadness induction task, reflecting the cortico-subcortical nature of the networks subserving emotional expression of sadness. We also expect the see more activity in the motor areas of the brain connected to the facial muscles, as crying involves gross facial movements. Damasio et al., (2000) underscore the close topographic affinity and physiologic connectivity between homeostasis and emotion; the neural patterns depicted constitute a â€˜perceptual landscapeâ€™ of the internal state of sadness. It is likely that the lateralization of activation in these areas will contribute to a clear focus on either the valence or lateralization model of brain-emotion relations, finding either a left or right hemispherical bias, respectively (Fox, 1994) Studies of pathological crying in humans suggest the brainstem nuclei and related cerebellar circuitry are involved in emotional processing, including the acute induction of sadness with high frequency stimulation of the substantia nigra. Bejjani et al., (1999) noted an increased activity in anterior pontine nuclei for sadness and anger, and a decrease for happiness/fear. These nuclei receive projections from the cerebral cortex (cingulated cortices and insula) and project to the cerebellum so activation in these deeper structures is fully expected in our crying data and support the prior observations that sadness involves the ventral and medial frontal cortices and the insula in concert with more limbic and paralimbic networks, reflecting a cortico-limbic-subcortico-thalamic-pontocerebellar network as a significant pathway in the expression of human emotions. Parvizi et al (2001) suggest that PLC is caused by dysfunction in circuits that involve the cerebellum and exert influence over brainstem nuclei as well as cerebral cortex itself. Revealing lesions to brainstem and cerebellum affecting the lateral segment of the left cerebral peduncle and the midline basis pontis at the level of mid-to-upper pons, and the right middle cerebellar peduncle from its brainstem root to the superior semilunar lobule and the middle cerebellar peduncle and white matter beneath the inferior semilunar lobule. Lesions along pathways from telencephalic structures to the nuclei of the basis pontis and from these nuclei to the cerebellum disrupted the cerebro-ponto-cerebellar projections; the route through which the telencephalic structures communicate with the cerebellum. They conclude that the cerebellum is â€˜partially deafferentedâ€™ from anatomically organized, descending telencephalic inputs most severely with respect to connections from the left telencephalic structures to the right cerebellar hemisphere. PLC in this case was believed to be caused by partial deafferentation of the cerebellum and forwards yet more evidence that crying implicates many brain regions that function within complex networks, providing a sound base of expected activity in the current study of crying versus a neutral control. METHODOLOGICAL ISSUES This investigation has lagged because of the subjective nature of feeling-states and because infant crying may involve vastly different imaginative processes than adult self-induced crying as well as individual differences in cognition/visualization/habituation between adult and infant subjects. However this study is a first step toward a theory driven systematic investigation of the neurobiology of feelings and highlights the need for more concentrated focus on individual as well as combinations of emotional states and their opposites, although the polarities of emotionality are difficult to pin down. The signal-to-noise ratio of the detector system in the NIRS system limits the resolution of measurable concentration changes and spatial resolution is also low, but these draw backs were thought not to outweigh the benefits of backing up fMRI data with similar results from the cortical activations using Optical imaging. NIRS is also vulnerable to motion artifact, and secure fixation of the optodes on the infant or childâ€™s head can be difficult, but the unrestrained nature of this technique lent itself well to our study of crying, and indeed results from NIRS did support data from EPI time-series, and in some cases helped establish significant activations where fMRI alone may not have found after analysis. The reliability of the preprocessing steps for the fMRI data, also has its drawbacks, as interesting signal can be lost and signals of no interest may also be enhanced with the normalization and smoothing steps, but conventional reporting takes precedence over finite details of mathematical validity and as yet, these are the best methods for discovering results from notoriously noisy data sets that show us something meaningful. Despite the confounds; methodological flaws; contextual differences in individual states, it is believed that this study has illuminated the basis of a vast array of syncronised and connected substrates for the emotion-feeling cycle of crying as a function of sadness, and that NIRS combined with fMRI has potential for strengthening our findings and in some cases, providing new areas of interest. Thus far, few researchers have probed the intricate details of the crying brain, and indeed, comparisons to other emotional states are necessary but not at the expense of a thorough appreciation of the complex workings of some of the complicated processes within the brain, such as crying. The homeostatic rationale for emotion-feeling processes is also little understood, but it is clear that we have a long way to go before we truly know why we cry, or for what purposes it serves neurologically, socially, personally and cognitively, these areas are suggested as issues to consider in future work. Adolph, R., Tranel, D., Damasio, H. & Damasio, A. R. (1995). Fear and the human amygdala. Journal of Neuroscience, 15, 5879-5891 Alexander, G. E., Delong, M, R. & Strick, P .L. (1986). Parallel organisation of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357-381. Augustine, J. R. (1996) Circuitry and functional aspects of the insular lobe in primates including humans. Brain Research Reviews, 3, 229-244 Bejjani, B. P., Damier, P., Arnulf, I., thivard, L., Bonnet, A. M., Didier, D., Cornu, P., Pidoux, B., Samson, Y. & Agid, Y. (1999). Transient acute depression induced by high-frequency deep-brain stimulation. The New England Journal of Medicine, 340, 1476-1480 Blumberg, H. D., Stern, E., Martinez, D.. Ricketts, S., de Asis, J., White, T., , Epstein, J., McBride, P. A., Eidelberg D., Kocsis, J. H. & Silbersweig D. A. (2000). Increased anterior cingulated and caudate activity in bipolar mania. Biological Psychiatry, 11, 1045-1052 Damasio, A. R., Grabowski, T. J., Bechara, A., Damasio, H., Ponto, L. L. B., Parvizi, J. & Hichwa, R .D. (2000) Subcortical and cortical brain activity during the feeling of self-generated emotions. Nature America, 3, 10491056 Drevets, W. C., Price, J. L., Simpson, R. Todd, R. D., Reich, T., Vannier, M. & Raicle, M. E. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 385, 824-827 Eblen, F. & Graybiel, A. M., (1995). Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. Journal of Neuroscience, 15, 5999-6013. Fox, N., A. (1994). Dynamic Cerebral processes underlying emotion regulation. Monographs of the Society for Research in Child Development, 59, 152-166 Kimbrell, T. A., George, M. S., Parekh, P. I., Ketter, T. A., Podell, D. M., Danielson, A. L., Repella, J. D., Benson, B. E., Willis, M. W., Herscovitch, P. & Post, R. M (1999). Regional brain activity during transient self-induced anxiety and anger in healthy adults. Biological Psychiatry, 46, 454-465 Meek, J. (2002). Basic principles of optical imaging and application to the study of infant development. Developmental Science, 3, 371-380 Parvizi, J., Anderson, S. W., Martin, C. O., Damasio H. & Damasio A. R (2001). Pathological laughter and crying: A link to the cerebellum. Brain, 124, 1708-1719 Schneider, F., Weiss, U., Kessler, J.B., Salloum, J. B., Posse, S., Grodd, W., Muller-Gartner, H. W. (1997). Differential amygdala activation in schizophrenia during sadness. Schizophrenia Research, 3, 113-142 Whalen, P. J., Rauch, S. L., Etcoff, N. L., McInerney, S. C., Lee, M. B. & Jenike, M. A. (1998). Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. The Journal of Neuroscience, 18, 411-418