Cerebrum Spring 2020

EMERGING IDEAS IN BRAIN SCIENCE

The Mind of a

A Renaissance in Canine Cognitive Science Sheds Light on How They See the World and Bond with Humans

DOG

Gregory Berns, M.D., Ph.D.

Decoding the Canine Mind

Page 10

Lee Alan Dugatkin, Ph.D.

Jump-Starting Evolution

Page 16

Carl Sherman

Neurosteroids: A Major Step Forward

Page 22

Brenda Patoine

Tracking the Neural Footprints of Consciousness

Page 26

Gregory Berns, M.D., Ph.D., is the Distinguished Professor of Neuroeconomics at Emory University, where he directs the Center for Neuropolicy and Facility for Education & Research in Neuroscience. He is also a professor in the psychology department and a founding member of the Society for Neuroeconomics. His has penned two books about canine cognition, What It’s Like to Be a Dog (Basic Books, 2017), and How Dogs Love Us (New Harvest, 2013), a New York Times bestseller. Berns specializes in the use of brain imaging technologies to understand human and canine motivation and decision-making. He is the co-founder of Dog Star Technologies, a company using neuroscience to enhance the dog-human partnership.

Lee Alan Dugatkin, Ph.D., is a professor of biology and a College of Arts & Sciences Distinguished Scholar at the University of Louisville. He has studied the evolution of cooperation, the evolution of aggression, the interaction between genetic and cultural evolution, the evolution of antibiotic resistance, the evolution of senescence, and the evolution of risk-taking. He has been a contributing author to Slate Magazine, Scientific American, and The New Scientist, and author of The Altruism Equation (Princeton University Press, 2006), Mr. Jefferson and the Giant Moose (The University of Chicago Press, 2009) and co-author, with Lyudmila Trut, of How to Tame a Fox and Build a Dog (The University of Chicago Press, 2017).

Carl Sherman has written about neuroscience for the Dana Foundation for ten years. His articles on science, medicine, health, and mental health have appeared in national magazines including Psychology Today, Self, Playboy, and Us. He has been a columnist for GQ and Clinical Psychiatry News, and is the author of four books. He holds a doctorate in English literature and has taught at various universities. When not writing about the mind, the brain, and the interesting things people do with them, he enjoys travel, listening to music, looking at art, and copyediting. He lives and works in New York City.

Brenda Patoine is a freelance science writer, reporter, and blogger who has been covering neuroscience research for more than 30 years. Her specialty is translating complex scientific findings into writings for the general public that address the question of “what does this mean to me?” She has interviewed hundreds of leading neuroscientists over three decades, including six Nobel Laureates. She founded ScienceWRITE Medical Communications in 1989 and holds a degree in journalism from St. Michael’s College. Other areas of interest are holistic wellness, science and spirituality, and bhakti yoga. Brenda lives in Burlington, V.T., with her cat Shakti.

FEATURES

10 Decoding the Canine Mind

Curious about a dog’s perception of the world and how a pooch’s brain works?

Gregory S. Berns is using brain scanning and other strategies to find answers.

By Gregory Berns, M.D., Ph.D.

16 Jump-Starting Evolution

Three years after a best-selling book, a co-author explains how the silver foxdomestication experiment continues to help us better understand genetics and evolution.

By Lee Alan Dugatkin, Ph.D.

22 Neurosteroids: A Major Step Forward

Research that began three-quarters of a century ago has led to one of the first new drugs to treat depression in 60 years—and the potential to treat much more.

By Carl Sherman

26 Consciousness: A New Search for Answers

Two leading theories that are diametrically opposed are part of a new $20 million international research program to explore how consciousness arises and correlates in the brain.

By Brenda Patoine

SECTIONS

5 Advances

Notable brain science findings

6 Briefly Noted

Worry and Stress; Recommended Brain Science & Health Articles; Music and Preterm Babies; By the Numbers

7 Bookshelf

A few brain science books that have recently caught our eye

8 Neuroethics: Troubling Regulatory Standards

By Philip M. Boffey

2 Contributors | 4 From the Editor | 30 Advisory Board | 32 Editorial Staff

dana.org/cerebrum

POINTS

OF INTEREST NOTABLE FACTS IN THIS ISSUE

4 Serotonin and norepinephrine reuptake inhibitors, like fluoxetine (Prozac), are some of the most commonly prescribed drugs in veterinary behavioral medicine.

Decoding the Canine Mind, Page 10

4 2020 marks the start of the seventh decade of this experiment, making it one of the longest, continually running, controlled experiments ever undertaken.

Jump-Starting Evolution, Page 16

4 Researchers are considering therapeutic possibilities of neurosteroids for disorders ranging from schizophrenia and post-traumatic stress disorder to autism and Alzheimer’s disease.

Neurosteroids: A Major Step Forward, Page 22

4 The two models are in stark contrast to one another: their definitions of consciousness differ, their assumptions about what constitutes consciousness differ, and their whole approach to the subject is fundamentally different.

Consciousness: A New Search for Answers, Page 26

4 The case has raised a fierce debate in scientific journals over the ethics of conducting the trial and reporting the results through the media rather than a peerreviewed scientific paper.

Troubling Regulatory Standards, Page 8

It’s a Doggy Dog World

BY BILL GLOVIN Executive Editor, Dana Foundation

When we began putting together this issue, no one had ever heard the term “coronavirus.” But now, with physical distancing, businesses closed, and humans going stir-crazy in the house, dogs may be one of the pandemic’s main beneficiaries, as they are being showered with ample amounts of attention. What better way to get a change of scenery and some exercise than leashing up your pooch for a long walk?

In fact, a study by the Human Animal Bond Research Institute and Mars Petcare in 2019 revealed that 80 percent of people reported that pets reduced their loneliness, and 75 percent agreed that pets reduced feeling of social isolation.

This second issue comes to you as we explore new ways to reimagine and deliver content. We divide our feature well in half: two long-form articles on brain research by neuroscientists and two on brain research or policy issues by science journalists. My ten-person advisory board suggests both topics and specific neuroscientist authors to address those topics, and reviews submitted articles for scientific accuracy.

I’ve found that the board can be a tough nut to crack when it comes to article suggestions. All accomplished neuroscientists (see Page 30), they take into consideration recent advances, scientific merit, replication, and the potential of the research to change lives. So, to my great surprise—at the end of a conference call last fall—I told them I had been pitched the idea for an article about a fox domestication experiment.

One of my longtime advisers, Bruce McEwen, was the first to chime in: “I’ve read about this project and it was an absolutely fascinating book,” he told the group. Seconds later, another adviser suggested that we spotlight a neuroscientist who uses fMRI to gain insights into canine cognition. “Why don’t we publish companion pieces?” another suggested. Soon, there was unanimous agreement that half our feature well should focus on canine cognition and behavior.

My own research has since found at least 25 research centers throughout the world where canine cognition and behavior are studied—many of them forming in the last five years or so. In the U.S. alone, there are research centers at Duke, Yale, Arizona State, Barnard, and the University of Kentucky—just to name a few. The more we know about dogs, the more we help people—from service dogs for the disabled, to puppy training to make pet owners lives easier, to satisfying our curiosity about the behavior and intelligence of different breeds.

Bruce, who so enthusiastically endorsed the idea to focus on dogs, will never get to read our two articles. After a brief illness, he passed away early this year at the age of 81. Bruce touched so many lives in his legendary career, and clearly had a soft spot in his heart for man’s (and woman’s) best friend. He wouldn’t be surprised to hear that dogs are helping their owners through this terrible pandemic. l

EMERGING IDEAS IN BRAIN SCIENCE

Bill Glovin Executive Editor

Seimi Rurup Assitant Editor

Podcast

Brandon Barrera Editorial Assistant

Carl Sherman Copy Editor

Carolyn Asbury, Ph.D. Scientific Consultant

Bruce Hanson Art Director

Cerebrum is published by the Charles A. Dana Foundation, Incorporated. DANA is a federally registered trademark owned by the Foundation.

© 2020 by The Charles A. Dana Foundation, Incorporated. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher, except in the case of brief quotations embodied in articles.

Letters to the Editor

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Letters may be edited for length and clarity. We regret that we cannot answer each one.

ADVANCES

Notable brain science findings

BY NICKY PENTTILA

A 2019 Boston University study published in the Annals of Neurology found that for every 5.3 years tackle football players played the game, they doubled their risk of developing the worst forms of CTE (chronic traumatic encephalopathy), a degenerative brain disease linked to repeated head hits. Some NFL players have cited CTE in their decision to retire early, most recently Luke Kuechy, 28. The linebacker for the Carolina Panthers was one of only four defensive players who made all-pro NFL at least five times in the 2010s. l

A growing number of studies suggest that the gut MICROBIOME—all the genetic material in the many types of singlecelled organisms that live in your digestive system—may offer a rich target for treating mental health troubles. In one recent study in the Journal of Affective Disorders, researchers took repeated readings of the microbiomes of 111 people shortly after they were admitted into inpatient treatment for psychiatric disorders until they were released, and found a series of measurable differences. The more severe a person’s depression or anxiety was, the less variety of bacteria researchers found in their microbiome. Next question to answer: Does psychiatric illness lead to changes in gut health, or vice versa? l

ORGANOIDS—3-D clusters of cultured brain cells once optimistically called “mini-brains” or “brains in a dish”—might not be as directly or speedily helpful as once hoped. The cells appear to start developing similarly to normal brain cells, but the way they are grown in a culture dish itself puts them under unusual metabolic stress. This alters how the cells transport proteins, break down sugars, and differentiate into mature cell types, according to a new study in Nature Comparing the cells in organoids with cells collected from embryonic tissue, the researchers found some parts matched, including glia and some types of neurons, but not in the same proportions, and they could not match up some of the organoid cells with any type of naturally occurring cell. The researchers suggest finding new ways to grow these microtissues. l

More news that plenty of SLEEP is important for health: A recent Penn State cohort study (which follows people over a long stretch of time) suggests that middle-aged adults who have high blood pressure or type 2 diabetes were at greater risk of earlier death if they slept less than six hours a night. Other studies suggest sleep is when the body cleanses and restores itself; the brain washes away dead cells and toxins as well as consolidating the days’ memories. The Penn State researchers, writing in the Journal of the American Heart Association, suggest that people with diabetes or bloodpressure issues make sure they get help to get enough sleep as part of their treatment for those issues. l

Book snobs might not have cause to be so quick to discount AUDIOBOOK lovers as “nonreaders” or something other, researchers at University of California say. In a study published in the Journal of Neuroscience, they report that functional brain imaging of people who spent hours reading or listening to narrative stories showed the same patterns in the areas used for forming semantic meaning. If the finding holds that the same cognitive and emotional areas of the brain are stimulated whether we hear words or read them on a page, educators and others might consider offering audio as an alternative for some kids. l

Studies have shown a small but significant relationship between noticeable HEARING LOSS and dementia. Now, a study published late last year in the journal JAMA Otolaryngology—Head and Neck Surgery suggests that even small losses of hearing can translate to reduced scores on cognitive tests. Researchers examined data on hearing and cognitive performance from more than 6,400 people 50 and older and found those whose hearing was not as good as before but had not yet gone past the range of “normal hearing” had proportionally lower cognitive scores. While it’s not yet known what could be causing this—increased cognitive load on circuits? changes in brain structure over the years?—some researchers suggest that people who notice they’re starting to have problems might do better by getting hearing aids earlier, and not waiting for the loss to pass the currently accepted measure of at least 25 decibels. l

Worry, Stress, and Anxiety

“WORRY HAPPENS in your mind, stress happens in your body, and anxiety happens in your mind and your body. In small doses, they can be positive forces. But research shows that most of us are too worried, too stressed, and too anxious. The good news, according to Luana Marques, an associate professor of psychiatry at Harvard Medical School and president of the Anxiety and Depression Association of America, is that there are ways to regulate your symptoms: Get enough sleep; eat regular, nutritious meals, and move your body.” — Smarter Living, from the New York TImes l

MUSIC composed for preterm babies has been shown to strengthen the development of neural networks and may help counteract the neurodevelopment delays experienced by many who are born prematurely, according to an imaging study published in the Proceedings of the National Academy of Sciences. Composer Andreas Vollenweider tested many instruments and found infants most responsive to punji (a flute), harp, and bells. Researchers at the University Hospitals of Geneva then played the music he composed for some premature infants in their care and not for others nor for a control group of full-term infants. The brains of the babies who listened to the music showed patterns of connection that looked more like the full-term babies than the non-music preemies. These children are now six, and are undergoing cognitive and socio-emotional tests to see if this change has translated into reduced developmental delay. l

BY THE NUMBERS

$1.5 billion was raised in 2019 to find new drugs by artificial intelligence drug startups.

2 months is the time it took for multiple sclerosis patients to benefit from intermittent fasting Popular regimens range from ingesting few, if any, calories all day every other day or several times a week to fasting 16 hours or more every other day.

6 months of an aerobic training program helps improve brain glucose metabolism and executive function and has shown to help people with a genetic predisposition to Alzheimer’s disease.

300 Alzheimer’s drug trials have failed so far, including two recent trials for solanezumab (from Eli Lilly) and gantenerumab (from Roche).

60 is the number of chemical compounds (known as cannabinoids) found in a cannabis plant.

2,474 was the number of languages used to study cross-cultural emotional expression

60,000 people in the U.S. suffer from frontotemporal degeneration, the most common form of dementia for those under the age of 60.

PHOTO: DENNIS CONNORS

ILLUSTRATION:

SHUTTERSTOCK

BOOKSHELF

A few brain science books that have recently caught our eye

BY BRANDON BARRERA

The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine

by Donna Jackson Nakazawa

As recently as 2012, the medical world stood at the threshold of a new frontier. Microglia— tiny, non-neural cells oft-described as housekeepers of the brain—were revealed to be much, much more. In a series of groundbreaking discoveries, microglial cells graduated from humble removers of dead neurons and cells to the horticulturist of the brain, pruning its neuronal circuitry during development and, if triggered, ravaging the neural landscape into dysfunction. In The Angel and the Assassin (Random House/Ballantine) science journalist Donna Jackson Nakazawa, herself previously immobilized by a rare autoimmune disease, chronicles the breakthroughs, inviting readers into top research labs throughout the U.S. to speak with the neurobiologists furthering this knowledge and to hear directly from patients with autoimmune diseases who stand to benefit. Her work reveals that harnessing these tiny cells could help “those suffering with depression, anxiety, obsession, distraction, or forgetting … finally escape the thieves that can rob them of whole lifetimes.” l

Conscience: The Origins of Moral Intuition

by Patricia S. Churchland,

Evolutionary changes in the brain’s circuitry across millennia have made it likely that mothers will care for their vulnerable offspring. This bond—between mother and child—should be viewed as the platform for social and moral behavior, according to neurophilosophy pioneer and Dana Alliance member Patricia S. Churchland, Ph.D. In essence, the bond is a progression of selfcare extending to include my children, expanding to include my clan, and so on. This crude reconstruction of Churchland’s argument is only a pale imitation of the ideas found in Conscience (W. W. Norton), a work rife with the research and neuroscience of conscience. Besides the mother-child bond, she cites fascinating studies on psychopaths, sharing the knowledge gleaned from studying brains with “atypical wiring” and reveals the data from studies with twins, suggesting that political attitudes may well be hereditable traits. For Churchland, who argues that morality transcends “pure reason,” neurobiology is a promising path to ethical discovery. l

Sex in the Brain: How Seizures, Strokes, Dementia, Tumors, and Trauma Can Change Your Sex Life by Amee Baird

Although a rare phenomenon, it’s possible for sex to blow your mind. And that’s not speaking metaphorically. According to clinical neuropsychologist Amee Baird, Ph.D., the quality, location, and climactic (or anti-climactic) qualities of sex can trigger severe brain conditions: strokes, burst aneurysms, and even transient global amnesia (temporary memory loss). In Sex in the Brain (Columbia University Press), Baird explores the titillating subject without stepping into the salacious. Instead, she presents the personal accounts of patients (and their partners) who found themselves coping with radical changes in sexual behavior—sometimes humorous, at other times startling— and the knowledge gleaned from these fascinating case studies. The book is careful in explaining the science behind changes in sexual behavior and effective in diffusing the stigmas often associated with sexuality. (This is especially true of neurological changes affecting sexual behavior following neurosurgery, traumatic brain injuries, or brain disorders and their treatments.) l

Concentration: Staying Focused in Times of Distraction by Stefan Van der Stigchel; Translated by Danny Guinan

A fierce and relentless contest rages—the participants are legion, the ploys endless, and the prize dear to each of us: our attention. Social media, mobile devices, and advertisers all vie for our engagement. For Stefan Van der Stigchel, Ph.D., attention expert and Professor of Cognitive Psychology at Utrecht University, the “attention crisis” is a conflict that’s ours to win—we only have to make the right choices. Concentration: Staying Focused in Times of Distraction (MIT Press) is Van der Stigchel’s treatise on resisting distraction and reclaiming your ability to focus. In it, Van der Stigchel describes the intricacies of concentration, the precarious balancing act of multitasking (it’s not always a bad thing), and how to tame attention: your own and others’. If concentration is a muscle (and Van der Stigchel likens it so), then reading Concentration: Staying Focused in Times of Distraction will provide for you a fitness regimen to keep the skill deployment ready—no easy task in these content-saturated times. l

BOOKSHELF

A few brain science books that have recently caught our eye

The Deep History of Ourselves: The Four-Billion-Year Story of How We Got Conscious Brains by Joseph LeDoux

Behavioral scientists often compare the neurobiology of different animal groups (think rodents and flies, for example), searching for similarities and differences to further our understanding of human behavior. Certain ‘survival actions’—activities such as fluid balancing, reproduction, eating, drinking—are so universal, says neuroscientist and Dana Alliance member Joseph LeDoux, Ph.D., that they are exhibited by organisms predating nervous systems altogether, revealing just how early these behaviors manifested. Ambitious in scope, The Deep History of Ourselves (Penguin Random House) stretches back to protocells and the earliest microbial life, tracing behavior’s lineage from the simplest of origins in bacteria and protozoa. The content is grouped by theme, allowing readers direct access to the subject matter of their preference: survival and behavior, the dawn of complex organisms, vertebrates, neurons, cognition, consciousness, and emotion, just to name a few. An expansive work, The Deep History of Ourselves is a retrospective and welcoming journey for all seeking a better grasp on human behavior and self-awareness. l

Brain on the Web

A few brain-related articles we recommend:

> OCD and anxiety disorder treatment can be complicated by coronavirus fears

> COVID-19: dealing with social distancing

> A psychologist’s science-based tips for emotional resilience during the coronavirus crisis

> From a doctor, a reminder to keep pushing on

> Five years after a nasty crash, a symbolic layup for Josh Speidel

NEUROETHICS

Troubling Regulatory Standards

BY PHILIP M. BOFFEY

Ordinarily, I would not base a column about a new stem cell treatment on a single dramatic case, or even a dozen cases, of clinical improvement. But an announcement by scientists at a Japanese medical school claimed such miraculous results in largely curing one man of spinal cord paralysis, and restoring some functioning to others, that it begs for close analysis.

In 2015, a 47-year-old teacher who was high diving at a local pool hit his head on the bottom and damaged his spinal cord, leaving him mostly paralyzed. He was enrolled in a clinical trial of Stemirac, a new stem cell treatment for spinal cord injuries, at Sapporo Medical University. He showed immediate improvement the next day and seven months later left the hospital under his own power. Although he remains clumsy, he can cook, drive, and teach math online.

The stem cells used, known as mesenchymal stem cells, were isolated from his bone marrow, multiplied in the laboratory, and injected back into the bloodstream intravenously.

The case has raised a fierce debate in scientific journals over the ethics of conducting the trial and reporting the results through the media, rather than a peer-reviewed scientific paper. There is no question that the procedure was legal under Japan’s relatively lenient approach to drug and therapy approvals. The process—and the questions it raises—is ably described in a comprehensive overview by Amos

Zeeberg, a freelance journalist based in Phnom Penh, Cambodia, in Undark, a highly respected digital journalism site that examines issues raised by the sciences, and in a news report by David Cyranoski in Nature, based on interviews with ten independent experts.

Japan, which hopes to become a global leader in regenerative medicine, has set up a system to fast-track therapies based on hints of efficacy so long as researchers collect followup data to justify final approval. Last December, the Japanese health ministry gave conditional approval of Stemirac, which allows the inventors to market and sell the drug for the next seven years, as long as they collect data from the participants to show that it works. Most of the participants’ $140,000 cost will be paid by Japan’s National Health Insurance. The short-term clinical trials that claimed to show efficacy were based on only 13 participants, including the injured diver, and lacked a control group.

Critics of the fast-track approval cite a host of objections. Most important, the lack of a control group makes it impossible to be sure the therapy had any efficacy at all. It is possible the participants would have improved naturally, even without the stem cell treatment. Indeed, patients injected

In a worst-case scenario, if nations keep lowering the bars for approval, one expert warns that we could go back to the days when most medical products didn’t work and we didn’t know it.

with Stemirac did only as well as patients enrolled in the untreated control groups in previous trials testing other potential treatments for spinal cord injuries.

Some experts believe the small trial should have been double-blinded, with neither the doctors nor patients knowing who had received the stem cells and who got a placebo. That would have been easy to do. The stem cells were injected, and a placebo could have been injected, too; but the researchers did not do that since Japan’s regulations didn’t require it.

Critics also object that none of the data has been published, apparently because the Japanese Health Ministry believes such publications would amount to “promotional materials.” The university was allowed to promise great results from its therapy in an advertisement without any data, but it was forbidden to publish its data in a journal for experts to evaluate, a twisted logic which Nature’s article called “Kafkaesque.”

A final caveat: All of the work has been conducted by researchers at a single institution—Sapporo Medical University, on Japan’s northernmost island, Hokkaido—limiting the ability of other experts to detect and correct possible biases or errors.

The Sapporo researchers and their

The university was allowed to promise great results from its therapy in an advertisement without any data but it was forbidden to publish its data in a journal for experts to evaluate, a twisted logic which Nature’s article called “Kafkaesque.”

backers retort that the results achieved were “unprecedented” and amply justify making the product available on a conditional basis while further studies are conducted to support a full approval. They also note that other advanced countries, including the United States, have taken steps to speed drugs to patients suffering from devastating diseases based on preliminary evidence that the drugs appear safe and effective. There is a trend toward giving individuals a greater role in deciding what risks to take to improve their own health.

My own feeling is that if I were paralyzed by a spinal cord injury, I would take substantial risks to improve my motor function. True, there could be unexpected side effects in the future that the fast-track process failed to detect, but it is hard to believe those would be worse than near total paralysis.

The chief danger is to the regulatory system itself, which could be eroded to the point where no one really knows if a therapy is safe or effective, leaving patients prey to peddlers of dubious nostrums while wasting money that could be spent more productively. In an apocalyptic worst-case scenario, if nations keep lowering the bars for approval, one expert warns that we could go back to the days when most medical products didn’t work and we didn’t know it. l

Phil Boffey is former deputy editor of the New York Times Editorial Board and editorial page writer, primarily focusing on the impacts of science and health on society. He was also editor of Science Times and a member of two teams that won Pulitzer Prizes.

The views and opinions expressed are those of the author and do not imply endorsement by the Dana Foundation.

BY GREGORY BERNS, M.D., Ph.D.

ecoding Canine the Mind

ILLUSTRATION BY

ALEC KALTHOFF

ur author, the Distinguished Professor of Neuroeconomics at Emory University and co-founder of Dog Star Technologies—a company using neuroscience to enhance the dog-human partnership—has put more than 100 dogs through a brain scanner. His article addresses a dog’s perception of the world, social cognition findings, canine mental health, and more.

There is no official census for dogs and cats, but in 2016, the American Veterinary Medical Association estimated that 59 percent of households in the United States had a pet. Although the numbers of dogs and cats remains debatable, dogs continue to gain in popularity with 38 percent of households having at least one. Families with children are even more likely to have a dog (55 percent). With all due respect to cats, dogs have insinuated themselves into human society, forming deep emotional bonds with us and compelling us to feed and shelter them. Worldwide, the dog population is approaching one billion, the majority free-ranging.

Even though many people are convinced they know what their dog is thinking, little is actually known about what is going on in dogs’ heads. This may be surprising because the field of experimental psychology had its birth with Pavlov and his salivating dogs. But as dogs gained traction as household pets, in many cases achieving the status of family members, their use as research subjects fell out of favor. In large part, this was a result of the Animal Welfare Act of 1966, which set standards for the treatment of animals in research and put an end to the practice of stealing pets for experimentation.

How strange it is then that these creatures, whose nearest relatives are wolves, live with us and even share our beds, yet we know almost nothing about what they’re thinking. In the last decade or so, however, the situation has begun to change, and we are in the midst of a renaissance of canine cognitive science. Research labs have sprung up around the world, and dogs participate not as involuntary subjects, but as partners in scientific discovery. This new research is beginning to shed light on what it’s like to be a dog and the nature of the dog-human bond.

Instead of treating the dogs as research subjects, we treated them as voluntary participants, meaning they were afforded the same basic rights as human volunteers.

Dogs are Special

When scientists use animals in research, they often turn to species that are closely related to humans. “Close” is relative, as even chimpanzees and bonobos diverged from hominids at least 5 million years ago. Monkeys diverged about 25 million years ago, and to find a common ancestor with the dog—indeed with any carnivore—you have to go back 97 million years.

But this summary overlooks the very thing that makes dogs special: their evolution has been altered to make them more socially compatible with us than any other animal. They were, in fact, the first animal to have been domesticated. The milliondollar questions are when and where this happened. We know that dogs existed at the time of the first human settlements in the eastern Mediterranean. In the area known as the Fertile Crescent, their remains have been found buried alongside humans, and these have been dated to 11,000 years ago. Cats, for comparison, did not appear until 8,000 years ago and probably didn’t change into their modern form until 4,000 years later. It is fair to say that only dogs were present at the dawn of human civilization.

The world these early dogs and humans inhabited looked quite different from ours. Even though the last ice age was ending, the climate was still colder than now. This probably brought wolves (an ancestor of the dog) into more frequent contact with humans as the ice sheets retreated. One theory is that wolves and humans helped each other hunt. It seems increasingly likely, though, that the more social wolves began hanging around human settlements to scavenge for leftovers. It is not hard to imagine a curious wolf, probably a juvenile, approaching the edge of a tribe. A human, maybe a child who wouldn’t know any better, might

leave some food on the perimeter. And a friendship is born. Eventually wolfdogs, even if they didn’t hunt, could act as sentries, alerting humans to intruders.

The evolution of cooperation is what allowed humans to dominate the planet, and at the dawn of civilization, we extended our ability to cooperate with each other to another species: dogs. Although there is no fossil record of behavior, there is increasing genetic evidence for this sort of co-evolution. In 2017, a team of researchers found a correlation between sociality in dogs with variants of several genes that had previously been identified in WilliamsBeuren syndrome (WBS), a rare genetic disorder in humans. A core feature of WBS is hyper-sociality. When the team evaluated dogs and wolves on tasks that measured sociality, they found two canine genes in the WBS locus that are associated with this hyper-sociality in humans.

These results suggest that the key evolutionary event that turned wolves into dogs was an amplification of genes related to sociality. If that is true, dogs may hold the key to helping humans achieve what can often be a struggle: to be more social, more generous, more loving, more forgiving.

What It’s Like to Be a Dog

So what is going on in a dog’s head? The traditional approach, pioneered by Pavlov, is to measure a dog’s behavior under different circumstances and try to infer why they do what they do. But consider a common example: teaching a dog to fetch. Some dogs, like retrievers, may do this instinctively, but others do not. Is this because the non-performers don’t understand what is being asked of them? Or is it that they understand but would rather do something else? It is all too tempting to project a human explanation onto the

dog, to anthropomorphize. The fetch example also highlights an important point: dogs, like people, are individuals. We must be careful in generalizing about dog findings, as there is no such thing as a generic dog. Just like there isn’t a generic human.

Because of the limits of interpreting behavior, my colleagues and I turned to the use of brain imaging to figure out what dogs are really thinking. When we began ten years ago, our approach was different from most animal research. Instead of treating the dogs as research subjects, we treated them as if they were voluntary participants, affording them the same basic rights as human volunteers. We did not use sedation or restraints. Instead, we developed a training program that taught the dogs to walk into a functional magnetic resonance imaging (fMRI) scanner, place their heads in custom-designed chin rests, and lie comfortably while scanning their brains (music video). Since then, we have trained over 100 dogs for fMRI. Many of them have been participating for their entire lives and have become so used to the scanner that it is hard to get them to leave!

Before getting into how a dog’s brain works, it should be understood, if obvious, that dogs do not have the same amount of neural infrastructure that humans do. As a rule, larger animals have larger brains. The encephalization quotient (EQ) accounts for the relationship between brain and body size, such that an EQ=1 means an animal has an average brain size for its body weight. Humans have an exceptionally large EQ of about seven, while dogs are a bit better than your average mammal, with an EQ of 1.2. However, we can see from an MRI of a dog brain that even though it is smaller than a human brain, all of the same basic structures are present. This is

true for large regions like the cerebral cortex and the cerebellum, as well as for smaller, subcortical structures like the brainstem, hippocampus, amygdala, and basal ganglia, which have important roles in movement, memory, and emotion.

Dogs also have large olfactory systems, comprising about two percent of the total brain weight (compared to 0.03 percent in humans). Where dogs fall short is in the cortex. Apart from being smaller, there are fewer folds, which means less surface area and fewer neurons. The frontal lobe, which in humans occupies the front third of the brain, is relegated to a paltry ten percent in dogs.

The commonality of brain structures is true across all mammals. While there may be differences at a microscopic level, we all carry around the same basic hardware. Scientists and philosophers continue to debate whether a dog’s experience is the same as a human’s, but the commonality of brain structure suggests a certain commonality in function as well. Dogs have a hippocampus because they have to remember things, too. They have an

amygdala because they get aroused and excited and scared, just like we do. They may even suffer similar mental problems (more on that later).

We have discovered many things about dogs’ perceptual experience of the world, but the ones that are most interesting are in the domain of social cognition. The first question many people ask is, “Does my dog love me?” Without getting into the nuances of love, the question gets to the heart of the dog-human relationship, namely, what are a dog’s motives? Is it all about food, or can dogs experience positive emotions for purely social reasons? To answer the question, we used fMRI to measure activity in a structure at the heart of the brain’s reward system: the caudate nucleus.

Before scanning, we trained the dogs on a simple association between toys and rewards (video). Each toy was held in front of the dog for ten seconds and then followed by either a treat or by their owner popping into view and praising them with, “Good dog!” The toy set up a state of expectation, which we could measure in the caudate. We found that 13 of 15 dogs had equal or greater activation for praise than for

Dog brain (left) and human brain (right). Images are not to scale as the dog brain is approximately one-tenth the weight of the human brain. (Dog brain image courtesy of Thomas Fletcher, University of Minnesota.)

food. Is that love? We don’t know, but it does show that most dogs have brain systems highly tuned to social rewards, and some even respond more to their owner’s praise than food itself.

How does this social bond form?

Humans, like most primates, are born ready to bond with their parents and other members of their social group. Faces carry a wealth of social information and, in the 1990s, neuroscientists discovered that primates have an area of their visual systems dedicated to processing faces, called the fusiform face area. To see if dogs have equivalent areas, we showed pictures and videos to dogs while they were in the MRI scanner. We showed faces (dog and human), objects, scenes, and scrambled images. And just as in humans, we found an area of the dog visual system that is strongly and specifically activated by faces. We called it the “dog face area.” Like the praise experiment, this demonstrates that dogs have more in common with us than we realized, and that they have the basic tools to process human faces.

While we humans identify people by their appearance, dogs may rely on their sense of smell. In an early fMRI study, we presented dogs in the scanner with five scents: their owner, an unfamiliar person, another dog in the house, an unfamiliar dog, and their own scent. Human scents were obtained from underarm wipings and dog scents from the area that dogs like to smell—their butts. Although we expected to find the strongest response to the smell of other dogs, in fact we found that the scent of the owner elicited the greatest activation in the reward system of the dog’s brain. This means that dogs cannot only identify us by smell, they seem to like the smell of their human best (to the extent that reward system activation means they like something.)

Dogs may hold the key to helping humans achieve what can often be a struggle: to be more social, more generous, more loving, more forgiving.

Auditory Processing

What about dogs’ ability to understand human speech? Here, we have to be careful in what we mean by “understand.” Dogs seem to understand basic commands like “sit” and, to varying degrees, “come,” but that does not mean that they understand words the way humans do. We use words as symbolic placeholders. We are also very noun-centric. There are roughly ten times as many nouns as verbs, in part, because we label everything. A dog, however, may find actions more salient than names. Humans know that the word “ball” represents a whole class of objects, and its precise meaning derives from how it is used in a sentence. When a dog hears the word “ball,” do they conjure up an image in their mind’s eye like a human would? Maybe “ball” to a dog means the act of retrieving something, or maybe dogs pick up salient information by the tone of our voices when we say the word.

As a first step toward answering these questions, we taught some of the MRI dogs the names of two new toys. To do this, the owner would point to a stuffed animal and say its name, for example, “monkey.” When the dog moved toward it, they would get a treat. Gradually, we removed the pointing. When the dog learned the name of one toy, we then introduced a second. After they learned that, they had to make the correct choice by name when both were present. Before they were deemed ready to scan, a dog had to demonstrate their knowledge by being 80 percent accurate in picking the correct toy on command, much like the famous dog, Chaser, who was reported to know the names of 1,000 toys. With the dog in the scanner, the owners spoke the names of the toys. As a control condition, they also spoke gibberish words that the dogs hadn’t heard before. When this type of experiment is done in humans,

real words activate language areas more than fake words, presumably because humans immediately recognize gibberish and stop trying to extract meaning from it. But in the dogs, we found the opposite. The gibberish words caused more activation in auditory areas than the real words. These areas extended beyond what is considered primary auditory cortex, and so we think they represent rudimentary language processing areas.

This tells us two important things. First, dogs can discriminate between words they have heard before and those they haven’t. Second, their reaction to novel words is different from humans’. Instead of immediately recognizing that they have no meaning, dogs pay close attention to novel words, perhaps to figure out what their human is trying to communicate. This response may derive from their hyper-sociality and desire to please. (However, you can be sure that a dog will learn to ignore you if you constantly speak gibberish).

What about complex emotions, like guilt? Although many people believe their dog knows when they have done something wrong, researchers continue to debate whether dogs have the capacity to experience emotions like shame or guilt. Unfortunately, we can’t use fMRI to look for a neural signature of guilt in a dog, in large part, because we haven’t found one in humans. (This may seem surprising, but it has been devilishly hard to find reliable neural markers of human emotional states in general.) However, we have found evidence for something like envy in the dog’s brain. In this experiment, the dog had to watch their owner feed a realistic statue of a dog. As a control condition, the owner placed food in a bucket. We found evidence for amygdala activation, which is a neural marker for arousal, when the fake dog was fed. Although not quite the same as envy, arousal

might be a response to envy. This wasn’t universal, though. Only the dogs who displayed aggressive traits toward other dogs had this amygdala response. Again, this highlights the individuality of dogs.

A complementary approach toward decoding emotional states uses machine learning to mine brain data obtained while a person (or dog) watches videos with different types of emotional content. Building on early results of decoding content of visual images from the brain, this new approach suggests a map of emotions in the human visual system, including states like anxiety, awe, fear, disgust, joy, and adoration. Machine learning techniques require a lot more data than conventional fMRI experiments provide—typically hours in the scanner

Research labs have sprung up around the world, and dogs participate not as involuntary subjects, but as partners in scientific discovery.

for each subject. This would seem impossible for a dog, but with each visit to the scanner, we have found that the MRI dogs get more and more comfortable with the environment. We have several dogs who are content to lie there, watching whatever content we create for them. Preliminary results suggest that it is possible to decode brain states in some dogs. In the language study, for example, we were able to decode which word was spoken from about half of the dogs’ brains. As we extend this approach to more complex stimuli, we may soon be able to decode emotional states and learn what makes them so hyper-social and lovable.

Dogs and Mental Health

If dogs have evolved to be man’s best friend, is it possible that they also suffer from some of the same mental disorders as people do? Growing evidence suggests the answer is yes, and this is all the more reason to take a closer look at what is going on in dogs’ heads.

Human mental illness is diagnosed largely by symptoms. According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), depression is characterized by depressed mood, diminished pleasure, slowed thinking, fatigue, feelings of worthlessness or guilt, and thoughts of death. The only objectively measurable symptom is weight change. Similarly, generalized anxiety disorder is associated with excessive anxiety and worry, restlessness, fatigue, decreased concentration, irritability, muscle aches, and sleep problems.

Dogs, of course, cannot speak, so they can’t report whether they’re feeling sad or anxious. Although neuroimaging may soon change things, we currently have to rely on dogs’ behavior to infer what they are feeling. For example, when dogs are scared, they behave in characteristic ways, which include trembling, hiding in closets or under furniture, chewing or scratching doors to escape, pacing, barking, whining, and defecating or urinating in the house. When these occur in the context of being left alone, they are often labeled “separation anxiety.” Aggression is another frequently misunderstood manifestation of emotional states in dogs. What humans label as aggression may be a normal part of a dog’s behavioral repertoire, which includes barking, growling, and biting. Any dog can bite, and most will do so if provoked sufficiently. However, when

Callie in the MRI scanner while watching pictures of faces.

they bite, dogs can cause serious injury, especially to children.

Interestingly, dogs with behavioral problems often improve when they are treated with human medications for depression and anxiety. Serotonin and norepinephrine reuptake inhibitors, like fluoxetine (Prozac), are some of the most commonly prescribed drugs in veterinary behavioral medicine. Others include benzodiazepines, tricyclic antidepressants, betablockers, and even lithium. Indeed, the psychopharmacopeia for dogs is nearly the same as for humans. The fact that these medications work in dogs speaks to common biological mechanisms of mood regulation. And unlike humans, dogs are not susceptible to placebo effects (although their owners might be, by expecting improved behavior.)

Notwithstanding their emotional quirks, dogs are used in a variety of capacities to help people with disabilities. Service dogs are trained for specific tasks that a person cannot do by themselves, which might include picking up items, opening doors, and alerting to sounds. A psychiatric service dog might be trained to detect the onset of psychiatric episodes, or to turn on lights for someone with post-traumatic stress disorder. In contrast, emotional support dogs are not trained for specific tasks, but used for companionship, to alleviate loneliness, and to aid in the treatment of depression and anxiety.

While service dogs are afforded certain protections under the Americans with Disabilities Act, emotional support animals are not (although they may be covered by other laws, like the Fair Housing Act and Air Carrier Access Act.) Because service dogs often require extensive training, the cost may be prohibitive for many people, up to $50,000. Most dogs are not cut out for

this kind of work, so there is a need to identify those that are and not waste resources training those who will not be good service dogs. Brain imaging may play a role here. In a study of 50 dogsin-training, we were able to predict with 91 percent accuracy whether a dog would or would not graduate service dog training. In particular, we found that amygdala activation was negatively correlated with success, suggesting that dogs that are prone to arousal—either because they are anxious or simply want to play—are not good candidates for service dogs.

It is worth keeping in mind, however, that dogs are not simply treatments to be prescribed for various conditions. Like people, dogs have a wide variety of skills and personalities. And while there are some differences between breeds in any particular personality trait, there seems to be as much variability within a breed. The key to a strong doghuman bond is in the match between dog and human, but this may be as hard to predict as the match between two people. Future research, both with brain imaging and other physiological measures, may soon shed light on the canine side of the equation. l

All good dogs? Yes, but which ones have what it takes to be a service dog?

Jump-StartingEvolutıon

BY LEE ALAN DUGATKIN, Ph.D.

ILLUSTRATION BY DANNY SCHWARTZ

Since How to Tame a Fox (and Build a Dog) was published in 2017, molecular genetics research connected to the silver fox domestication experiment has appeared in Nature and Proceedings of the National Academy of Sciences. Lee Alan Dugatkin writes about his connection to the project, the role of neural crest cells in domesticating foxes, and how dogs, bonobos, and humans fit into the picture.

Not long after arriving in Novosibirsk, Siberia, in January 2012, my 17-year-old son Aaron and I could barely see. We had come in the middle of winter, prepared for the -35-degree temperatures with ski masks, but our glasses iced up every time we stepped outside. Through the snow, ice, and wind, we soon learned the trick: pull down on the mask around the mouth to avoid the condensation that otherwise builds up there.

Each morning we’d meet our driver and begin the 45-minute drive to the Institute of Cytology and Genetics. This trip, the first of two that I would make to the institute, was focused on research for a book that I was coauthoring on the Russian silver fox domestication experiment, which had been going on since 1959.

The experiment first came to my attention in graduate school, where I studied evolutionary biology and behavior. When I became a professor of biology at the University of Louisville, my fascination with it continued, and I developed an email relationship with Lyudmila Trut, the Russian geneticist who had been leading the experiment since 1959. After the exchange of countless emails over two years, we had decided to collaborate on a book; now we would be meeting face-to-face for the first time.

At the institute and at the farm where the foxes lived, we interviewed everyone and anyone associated with the experiment, poking and probing, not just for information about the study, but what it was like to be part of the daily routine. Aaron, who had learned a little Cyrillic to help us navigate the streets of Novosibirsk (and Moscow before that), transcribed the interviews on his laptop, which were being translated into English in real time by our interpreter, Vladimir.

The people we talked to—ranging in age from their 20s to their 90s who had

After the exchange of countless emails over two years, we had decided to collaborate on a book; now we would be meeting face-to-face for the first time.

been devoted to the experiment—were gracious and thrilled that an American scientist thought enough of their work to not just collaborate, but to also spend time in Siberia in the dead of winter. After these interviews and my many days with the 78-year-old Trut, I came to see her as one of the most remarkable people I have ever had the pleasure of knowing.

History of the Experiment

Even before receiving her Ph.D. in 1966, Trut was already in charge of the day-to-day operations under her mentor, Dmitri Belyaev, the originator of the silver fox project. From Belyaev‘s reading of Charles Darwin’s book, The Variation of Animals and Plants Under Domestication, and his own work at the Institute for Fur Breeding Animals in Moscow in the 1940s and early 1950s, Belyaev knew that many domesticated mammals share similar traits: floppy ears, curly tails, reduced stress hormone levels, variation in fur/skin coloration, reduced skull size, juvenilized facial and body features, reduced sexual

dimorphism in facial and body features via feminization (domesticated males are more similar to females than were their wild ancestors), and relatively long reproductive periods. While there is some debate as to just how common such characteristics are across species, today this suite of traits is known as the domestication syndrome.

Belyaev was fascinated with these shared characteristics. He hypothesized that the early stages of animal domestication involved choosing the friendliest, most docile animals, because the one thing our ancestors always needed in a species they were domesticating—be it for food, transportation, protection, or companionship—was an animal that interacted relatively prosocially toward them. Belyaev also hypothesized that somehow, and he did not know how, many of the traits domesticated species share were linked to genes associated with tameness.

Working with a colleague who was in charge of a small population of foxes being bred for shiny (salable) furs near Tallinn, Estonia, in 1952, Belyaev initiated a pilot experiment testing these ideas in silver foxes (Vulpes vulpes). Each year, they selected a few of the friendliest foxes and preferentially bred those individuals. Within three breeding seasons, they were seeing promising results: the foxes were a little calmer than their parents, grandparents, and great-grandparents.

In 1959, Belyaev expanded this work into a large-scale study when he moved to the newly established Institute of Cytology and Genetics, located outside of Novosibirsk, the third largest city in Russia. He quickly recruited the 25-yearold Trut to work with him on this experiment. (Belyaev died in 1985.)

Within six generations (six years), intense selection for friendliness— by breeding the tamest ten percent

Lyudmila Trut, the Russian geneticist who has been leading the experiment in domesticating foxes since 1959.

of males and females—produced some foxes that licked the hands of experimenters, wagged their tails when humans approached, and whined when humans departed. These animals were never taught or trained; their prosociality toward humans was solely the result of genetic selection.

During the early years of the experiment, about two percent of the population showed such prosocial behaviors. Today, more than 75 percent of the experimental population displays these traits. What’s more, as Belyaev predicted, with selection for friendliness, a suite of other characteristics emerged in the experimental fox population. In less than ten generations, some of the animals had floppy ears and curly tails. Within 15 generations, baseline corticosteroid levels (a measure of stress) were about half those of typical foxes. Over the course of the experiment, Belyaev, Trut, and their team also found that the domesticated foxes exhibited significant variation in fur patterns and extended reproductive periods. They also displayed rounder and shorter, more juvenilized, dog-like snouts and shorter, thicker limbs

Social Cognition

The silver fox experiment has shed new light on the evolution of social cognition in nonhuman animals (similar characteristics to those of human persons). Work in this area began in 2002, when Brian Hare, at the time a Ph.D. student at Harvard University, began looking at the ability of nonhumans to follow human gaze and gestures. Prior work had shown that when researchers placed two opaque containers on a table and put food under one, chimpanzees did not use human gaze or gestures to determine where the food was, but Hare and his colleagues found that dogs easily solved the same sort of task using human gaze

In 1959, Belyaev expanded this work into a large-scale study when he moved to the Institute of Cytology and Genetics, located outside of Novosibirsk, the third largest city in Russia.

and gestures.

Why were dogs so good at this test of social cognition? Hare first examined whether it was because dogs spend their whole lives with humans, and so might learn how to do this. He tested dog pups of different ages, as well as dogs that had lots of interactions with humans and those that had few interactions, and in almost all cases, the dogs solved the task, suggesting it wasn’t experience with humans per se that made dogs good at this. Hare next considered the possibility that all canid species were adept at this, regardless of experience with humans. When he tested both wolves and dogs, dogs (again) solved the problem, but wolves did not. Being a canid per se was not the answer.

Hare next began to think that perhaps dogs were so good at this social cognition task because during the process of domestication, dogs that were astute at picking up on social cues emitted by humans were rewarded for doing so (likely with food and shelter). In a paper in Science, he and his colleagues hypothesized “that individual dogs that were able to use social cues more flexibly than could their last common wolf ancestor ... were at a selective advantage.”

Hare’s Ph.D. advisor, Richard Wrangham, suggested an alternative hypothesis. Perhaps the ability to follow human gaze and gestures was a byproduct of domestication: that is, during the process of domestication, instead of our ancestors having preferentially bred dogs that have this ability, selection had been for friendliness toward humans, and that the reason dogs follow gaze and touch today is because this ability is genetically correlated with friendliness. Selection for friendliness and following gaze and touch come along for the ride. Together, Hare and Wrangham

constructed a way to experimentally distinguish between these hypotheses using the silver foxes of the Novosibirsk project—the only domesticates where we know exactly what the selection pressures are and have been; Trut and her team select which individuals breed, based on friendliness and only friendliness, not on social cognition skills.

Hare knew that in addition to the domesticated foxes, the experiment has a control line of foxes that are selected randomly with respect to their friendliness to humans. If Hare’s hypothesis was correct, foxes in both the domesticated and control lines would fare poorly on the social cognition test, but if Wrangham was correct—that is, if social cognition was a byproduct of domestication—then the domesticated foxes would show social cognition skills on a par with dogs, but the control foxes would not.

Hare traveled to Novosibirsk and, working with Trut and others, tested these alternative hypotheses. They ran a series of experiments that involved gazing and then touching one of two objects placed in front of the foxes. Domesticated fox pups were significantly more likely than pups from the control group to follow human gazing at and touching cues. In a separate experiment, they found that domesticated pups were not only better than control pups, but just as good as dog pups, on this social cognition task. Together, these findings suggest that social cognition in domesticated species is indeed a byproduct of selection for friendliness, rather than direct selection for the ability to follow gaze or gestures.

Molecular Genetic and Neural Crest Cells

Much of the recent work on the domesticated foxes has probed deep into their genome for clues about the

process of domestication. In a 2018 paper published in Nature: Ecology and Evolution, Anna Kukekova, Trut, and their colleagues uncovered a cluster of genes associated with domestication on fox chromosome 15. SorCS, one of the genes associated with memory and learning functions, forms a bridge between molecular genetic work and the social cognition studies discussed earlier.

Right from the start of the silver fox study, Belyaev had hypothesized that some of the changes that occur during domestication were a consequence of changes in gene expression patterns: when genes “turn on” and “turn off,” and how much protein they produce. In a 2018 paper in Proceedings of the National Academy of Sciences, Kukekova, Trut, and Andrew Clark’s team at Cornell University followed up on earlier work on gene expression in domesticated foxes by comparing patterns in the domesticated animals versus another line of foxes from the Novosibirsk experiment that for the last 40-plus years have been selected for aggressive, rather than friendly, behavior toward humans. They found 146 genes in the prefrontal cortex and 33 genes in the basal forebrain that showed different patterns in domesticated and aggressive foxes, including genes associated with serotonin receptor pathways that modulate friendly and aggressive temperament.

Molecular genetic work on the silver foxes is also helping explain the domestication syndrome. Kukekova and her colleagues’ Proceedings of the

National Academy of Sciences paper describes changes in the frequency of alleles linked to neural crest cells. Adam Wilkins and his colleagues have hypothesized that changes in the behavior of such neural crest cells may be critical for many of the phenomena that characterize the domestication syndrome.

The argument goes like this: much work shows that very early in mammalian embryonic development, neural crest cells migrate to the brain, face, jaws, ears, tail, skin, and many other parts of the body. Wilkins and colleagues hypothesize that when our ancestors selected for calm, friendly behavior early in the process of domestication, they indirectly selected for a reduction in the number of migrating neural crest cells, and that, as a result, “most of the modified traits, both morphological and physiological [associated with the domestication syndrome], can be readily explained as direct consequences of such deficiencies [in neural crest cells]…”. For example, a decrease in neural crest cells that develop into cartilage might explain floppy ears and curly tails, both of which are in part due to reduced amounts of cartilage.

Self-Domestication in Bonobos and Humans

Around 1980, findings from the fox domestication experiment led Belyaev to propose an audacious idea about human evolution. In a keynote speech he gave in 1984 at the XV International Genetics Congress, he proposed that we

are the product of a process of selfdomestication. “The social environment created by man himself has become, for him, quite a new ecological milieu,” Belyaev told his audience.

This led to new natural selection pressures, and Belyaev came to think that “under these conditions, selection required from individuals some new properties: obedience to the requirements and traditions of the society, i.e., self-control in social behavior.” In particular, humans who were better able to cope with stress, to stay calm rather than strike out in aggression, had a selective advantage. “One can hardly doubt,” Belyaev noted in his speech, “that the word and its meaning has become for man an incomparably stronger stressful factor than a club blow for a Neanderthal man.” This in turn favored our ancestors selecting calmer, “tamer” mates and groupmates, setting the process of selfdomestication in motion.

Before delving a bit deeper into the possibility of human self-domestication, let’s examine some evidence that selfdomestication has occurred in another primate, the bonobo (Pan paniscus), a sister species to the chimpanzee, and its closest evolutionary relative.

Bonobos live in matriarchal societies, where females form alliances and voluntarily share food, even with strangers. Bonobos play often and sexual behavior is used as a greeting, a form of play, and a means of resolving conflicts. Chimp society, in contrast, is patriarchal. Males are dominant to females and fight with one another to

Domesticated silver foxes have a shorter, rounder, more dog-like snout.

rise up in the hierarchy. They sometimes form alliances, but unlike female coalitions in bonobos, chimp alliances sometimes raid and viciously attack individuals in other groups.

Contemporary populations of bonobos, but not chimpanzees, show behavioral, morphological, and endocrinological profiles that are strikingly similar to those seen in other domesticated species, including the domesticated foxes. Bonobos are far more cooperative and altruistic than chimpanzees. They have more juvenilized skeletal features and lower stress hormone levels. They display

Much of the recent work on the domesticated foxes has probed deep into their genome for clues about the process of domestication.

more variation in color (e.g., white color tufts and pink lips), and have smaller skulls (but have more gray matter in their brains devoted to areas linked with empathy). All of which is to say: bonobos act and look domesticated.

But if humans didn’t domesticate bonobos—and we didn’t—who (or what) did? Hare, Wrangham, and Victoria Wobber, who had just completed her Ph.D. with Wrangham at Harvard, suggested in a paper in 2012 that bonobos domesticated themselves. Here’s how: chimpanzees and bonobos began to diverge from a common ancestor approximately 2 million years

ago, at about the time the Congo River was forming in Africa. By chance, the formation of the Congo River split the population of the common ancestor of bonobos and chimpanzees into two groups, with the lineage that led to bonobos living in a small area to the south of the Congo River, and the chimpanzee lineage living north of the river, in a much larger area stretching across west and central Africa.

With this division, the bonobo lineage happened to find itself in an area with higher-quality foods than the chimpanzee lineage, and because there were no gorillas to the south of the Congo River, as there were to the north, the bonobo lineage had less competition for food with other large primates. Intense competition with gorillas would likely have favored more aggressive individuals in the chimpanzee lineage, while reduced competition and more reliable sources of food may have provided protobonobos with more time for play and cooperation.

Hare (who is now an associate professor in evolutionary anthropology at the Center for Cognitive Neuroscience at Duke University and founder of the Duke Canine Cognition Center) and his colleagues hypothesize that bonobos who played and cooperated with one another to obtain food, shelter, and sexual partners fared better than aggressive intolerant types. At this stage of bonobo evolutionary history, the argument goes, females may have selected the least aggressive, most friendly males as mates, selfdomesticating themselves in a process similar to that outlined by Belyaev for humans. This preference may have been specific to the early stages of bonobo self-domestication; indeed, recent work in modern female bonobos has found that they are no more likely than chimpanzees to choose the calmest, friendliest males as mates.

Professor and book co-author Lee Alan Dugatkin snuggles with one of his furry friends on one of two trips he made to Siberia.

Circling back to our own species, comparisons between humans and domesticated animals, as well as between humans and other primates, suggest that we display the morphological, endocrinological, and behavioral signs of a self-domesticated species. Anatomical studies have found that modern humans show feminization of facial features compared to ancestral Homo species (as well as other closely-related species), and a recent molecular genetic study of neural crest cells (published in Science) suggests a possible mechanism for such changes.

Compared with other primate species, modern humans also have a prolonged juvenile stage, wherein young are reliant for long periods on their parents, and we generally display relatively juvenilized traits for longer periods of time. Hormone profiles, especially those associated with androgens, suggest reduced aggressive tendencies in modern humans, and behavioral comparisons of aggression between humans and other closelyrelated species find that we in fact display much less aggressive behavior, particularly reactive aggressive behavior (more on that below). In addition, broadscale genomic comparisons suggest natural selection has operated on Homo sapiens in a manner similar to the “selective sweeps” (in which many traits increase in frequency simultaneously) that we see in domesticated species like dogs, cats, horses, and cattle.

The fullest treatment to date of human self-domestication can be found in Richard Wrangham’s 2019 book, The Goodness Paradox: The Strange Relationship Between Virtue and Violence in Human Evolution. In his book, Wrangham turns to the silver fox domestication experiment as a base from which to explore all discussions of domestication; indeed, he refers to the

Selective breeding for docility in foxes led to offspring with floppy ears, curly tails, reduced stress hormone levels, variation in fur/skin coloration, reduced skull size, and juvenilized facial and body features.

process of human self-domestication, as a case of what he calls “Belyaev’s Law.”

Wrangham hypothesizes that the process of human self-domestication began about 300,000 years ago. But how and why? The answer, he suggests, centers on an evolutionary shift from reliance on reactive aggression toward reliance on proactive aggression. Wrangham defines reactive aggression as “a response to a threat or frustrating event … that it is always associated with anger, as well as with a sudden increase in sympathetic activation, a failure of cortical regulation, and an easy switching among targets.”

In contrast, proactive aggression involves “a purposeful planned attack with an external or internal reward as a goal. It is characterized by attention to a consistent target, and often by a lack of emotional arousal.” When our ancestors began to rely more on proactive aggression, Wrangham proposes, we began to domesticate ourselves, as we moved away from a more typical primate social system, where a few strong, hyper-aggressive, reactive individuals dominated and secured most of the mating within a group.

Language, Wrangham proposes, facilitated proactive aggression, leading to a social system where proactive individuals could plan and work together to threaten, and if need be, punish hyper-aggressive, reactive

individuals, dramatically reducing the total amount of aggression in early human societies. Once a shift toward proactive aggression—and selfdomestication—was under way, other traits in the domestication syndrome began to appear, perhaps because the evolution from reactive to proactive aggression caused a reduction in the number of neural crest cells migrating during early stages of development. Tests of the human self-domestication hypothesis are in their early stages and it will be fascinating to see how this idea fares with time.

As they have from the initiation of the experiment, the now 86-year-old Trut and her colleagues in Novosibirsk continue to test hundreds of foxes each year, preferentially breeding the friendliest individuals. While much of the work today centers on molecular genetics, changes in behavior, morphology, neurobiology, and endocrinology continue to be recorded. 2020 marks the start of the seventh decade of this experiment, making it one of the longest, continually running, controlled experiments ever undertaken. That said, 60 years is but the blink of an eye in terms of evolutionary time. Who knows what new discoveries might emerge if this experiment continues for 100 years, or 200? Time will tell. l

NEUROSTEROIDS

A MAJOR STEP FORWARD

BY CARL SHERMAN

ILLUSTRATION BY WILLIAM HOGAN

The world of neuroscience and psychiatry sat up and took notice last March when the Food and Drug Administration (FDA) approved brexanolone (Zulresso) for postpartum depression. It was the first drug specifically approved for the condition, which afflicts some 15 percent of women just before or shortly after childbirth.

The event was a pivotal chapter in a neuroscience story that began threequarters of a century ago with the 1941 discovery by Hans Selye (best known for his pioneering research into the nature of stress) that hormones including progesterone could affect the brain to induce deep anesthesia.

Fast-forward 40 years to the discovery that a number of hormones—termed “neurosteroids” by the neuroscientist/endocrinologist Étienne-Émile Baulieu, a key figure in this work—are synthesized within the nervous system itself. In their National Institutes of Mental Health (NIMH) lab, Steven Paul and colleagues showed that several of these compounds work by binding to receptors on brain cells that are activated by GABA, the most plentiful inhibitory neurotransmitter in the brain. The GABA-A receptor is the site of action of several sedating central nervous system (CNS) drugs, including benzodiazepines (Valium, Librium), barbiturates, and many anesthetics.

Neurosteroids can also bind to receptors for glutamate, the brain’s principal excitatory neurotransmitter. Paul and Robert Purdy proposed that, with its effect on both GABAergic and glutaminergic systems, neuroactive steroids (a term they coined to include synthetic analogues as well as the naturally-occurring hormones themselves) help regulate excitation throughout the brain. Excitation is a major factor in conditions such as epilepsy. Although there are many neuroactive steroids, the lion’s

“In all these clinical studies, the drugs reduce anxiety as much as depression. Clinically, they are not only antidepressants but anxiolytics and sleep-promoting agents as well.”

share of research has focused on allopregnanolone, a progesterone derivative.

Michael Rogawski, who then headed the epilepsy research division at the National Institute of Neurological Disorders and Stroke, noted with interest his colleagues’ discovery. In subsequent work at the University of California, Davis, where he is now professor of neurology and pharmacology, he developed an injectable synthetic formulation of allopregnanolone (also known as brexanolone), which was licensed for clinical development to Sage Therapeutics, a biotechnology company co-founded by Paul.

Targeting Depression

After first investigating brexanolone as a treatment for epilepsy, Sage concentrated on depression. “A lot of parallel research comes together,” says Paul, professor of psychiatry and neurology at Washington University of St. Louis. “There’s a lot of evidence, some direct, some indirect, that GABA receptors and the inhibition system are altered and dysregulated in patients with major depression...With successful [antidepressant] treatment, levels normalize.” Although neurosteroids’ antidepressant mechanism—which circuits are involved, and how—is unknown, some research suggests that boosting inhibitory GABA activity corrects dysfunction in the hypothalamus-pituitary-adrenal axis and spurs production of hippocampal cells, which are reduced in depression.

Postpartum depression was a natural first target. “There’s a very decent hypothesis that during pregnancy, especially the third term, levels of progesterone, the precursor of allopregnanolone, rise very high and then drop rapidly when the baby and placenta are delivered,” says Charles Zorumski, professor and head of

psychiatry at Washington University (Zorumski is also a member of the Sage board of scientific advisors). “People wondered if that drop in allopregnanolone could be a trigger for postpartum depression.”

For whatever reason, the drug was a success. Two pivotal multicenter trials found that a 60-hour IV infusion of brexanolone reduced post-partum depression symptoms significantly more than placebo. The difference became apparent within 24 hours and remained, when measured 30 days later.

This rapid effect contrasts sharply to the four-plus weeks needed for conventional antidepressants to take hold.

The approval of brexanolone is “a nice shot in the arm for the field of depression research, which went five, six decades without a new mechanism of medication,” says Eric Nestler, director of the Friedman Brain Institute at the Icahn School of Medicine at Mt. Sinai, New York. All prior antidepressants— MAOIs, SSRIs, SNRIs, and tricyclics— increase activity of one or more of the same neurotransmitters—serotonin, norepinephrine, and dopamine, he pointed out. Brexanolone, in contrast, works through its action on GABA receptors and the inhibition system.

Another new antidepressant, ketamine, which affects glutamate receptors, was approved just two weeks before brexanolone. “All of a sudden, we have two new medications that have fundamentally novel mechanisms of action,” he says. (Nestler has not been involved in neurosteroid research but has done basic science work with ketamine).

Research into allopregnanolone continues. Could it be effective for postpartum depression in an oral form, rather than the current 60-hour infusion that requires hospitalization? And might this work for major depressive disorder (MDD), a far more widespread condition?

Studies in progress (both by Sage) are investigating these possibilities.

Early reports on the postpartum depression study are promising.

According to a presentation at the 2019 conference of the European College of Neuropharmacology, results with zuranolone (SAGE-217)—a synthetic analogue of allopregnanolone, modified to be available when taken orally—were comparable to those with brexanolone (and significantly superior to placebo), two and four weeks after initiation of two-week therapy. Improvements were observed from the third day of treatment.

Results with SAGE-217 for MDD have been more equivocal. Although the drug was more effective than placebo in a phase II trial enrolling 89 patients with moderate to severe depression, a much larger phase III trial failed to show its superiority at 15 days, the primary endpoint. There were indications, however, that the drug may work here as well: a post-hoc analysis of the study that excluded data from non-compliant patients found a statistically significant improvement with zuranolone, as did analysis of patients with severe MDD only.

Wider Horizons

Allopregnanolone’s success against depression suggests that neurosteroids may work for related disorders, too. “In all these clinical studies, the drugs reduce anxiety as much as depression. Clinically, they are not only antidepressants but anxiolytics and sleep-promoting agents as well,” says Paul. “They promote slow wave without disrupting REM sleep.”

Studies of PH94B, a synthetic version of the pheromone androstadienol, which like allopregnanolone—and tranquilizers like Valium that stimulates GABAA receptors—suggest this neuroactive steroid may be effective for social anxiety. A phase II trial of an intranasal formulation of PH94B,

In the National Institutes of Mental Health lab, Steven Paul and colleagues showed that several of these compounds work by binding to receptors on brain cells that are activated by GABA.

developed by the biopharmaceutical company VistaGen, found that women with the disorder felt significantly less distressed during experimental public speaking and personal interaction situations when they had taken the drug 15 minutes earlier, than when they hadn’t taken it.

The treatment was effective within minutes, suggesting it would be particularly adaptable for short-term use when stressful situations arose, the study authors wrote.

PH94B has been granted fast-track status by the FDA, a designation to speed up the development and review of drugs to address unmet medical needs, and VistaGen is conducting phase III trials of the drug, according to the company.

From a broader perspective, researchers are considering therapeutic possibilities of neurosteroids for disorders ranging from schizophrenia and post-traumatic stress disorder to autism and Alzheimer’s disease. “In 2020, almost none of these things are off the table,” says Zorumski. “The reason, I think, is that these agents are affecting the two most major neurotransmitter systems, GABA and NMDA [a type of glutamate] receptors. The idea is that alterations in the balance of excitation and inhibition occur across a range of neuropsychiatric illnesses, and these compounds give you a powerful way to control excitation under conditions of stress.”

Although most of the research has focused on GABA receptors and the inhibition/excitation balance, neurosteroids appear to affect intracellular targets as well, such as processes regulating neurogenesis and mitochondria function, Zorumski says. Inflammation is believed to be a factor in a number of neuropsychiatric disorders, and there is evidence that neurosteroids have anti-inflammatory effects. One recent study identified a molecular pathway that may underlie

this effect in allopregnanolone. [It should be kept in mind that the mechanistic underpinnings of neuropsychiatric disorders as a whole are imperfectly understood, and neurosteroids are unlikely to be more than part of the story.]

Targeting Epilepsy

Researchers have explored therapeutic applications for epilepsy since the 1980s. Seizures are the result of excessive excitation in areas of the brain, which the GABAmediated inhibition induced by these compounds would predictably counter. “There’s absolutely no question that neurosteroids stop seizures, and are prophylactic for them,” says Rogawski. But as yet, no neurosteroid-based drug has been approved for these purposes.

They would seem to have a particular role in catamenial epilepsy, a fluctuation of seizure frequency around the menstrual cycle. “Most commonly, seizures increase at menstruation,” Rogawski says: “Progesterone and estrogen rise during the second half of the cycle and drop rapidly at the time of menstruation. We demonstrated in animal models that seizure exacerbation is likely triggered by the drop in progesterone, and in corresponding levels of allopregnanolone.”

Although an allopregnanolone-based drug might be expected to address the deficiency and reduce perimenstrual seizures in women, there are only animal models and limited anecdotal evidence to support this hypothesis

“In my opinion, there is a need for a rigorous study with a neurosteroid or neurosteroid analog,” says Rogawski.

There have been no such studies as yet, he conjectured, because of technical difficulties—the natural variability in both menstrual cycles and seizure frequency would make it hard to demonstrate efficacy—and the limited potential market for this application. Negative findings in a recent

NIH-sponsored trial of progesterone, the precursor of allopregnanolone, “has probably dampened enthusiasm for another trial,” he added.

Investigators have devoted considerable attention to status epilepticus, a medical emergency in which a seizure that normally last two to three minutes, persists, often despite high doses of conventional anticonvulsants. In many cases, such events can only be terminated by IV anesthetics.

“There is strong evidence neurosteroids would be useful for status epilepticus,” Rogawski says; work in his laboratory has shown endogenous allopregnanolone to be effective in animal models. Clinical trials of a synthetic allopregnanolone derivative, ganaxolone, are being conducted by Marinus Pharmaceuticals, a company that Rogawski co-founded. A small phase II trial suggested the drug could shorten seizures and obviate the need for anesthetics, the company recently reported

Targeting Alzheimer’s

Roberta Diaz Brinton, director of the Center for Innovation in Brain Science at the University of Arizona, became interested in neurosteroids in the 1980s, as a graduate student at Rockefeller University. As a postdoctoral fellow at Rockefeller, working with patients kindled an interest in Alzheimer’s disease (AD).

When she had her own lab, Brinton focused on the failure, early in AD, to encode new information, a process in which neuron regeneration is essential. Her research a few years later “brought me full circle, to the discovery that allopregnanolone promotes the generation of new neurons by stimulating neural stem cells. Where the new neurons go is the dentate gyrus of the hippocampus—which is responsible for encoding and processing new information.”

Looking further, Roberta Diaz Brinton and her colleagues found evidence that allopregnanolone also improves mitochondrial function redressing the “bioenergetics crisis of Alzheimer’s disease.”

Looking further, Brinton and her colleagues found evidence that allopregnanolone also improves mitochondrial function, redressing the “bioenergetic crisis of AD. We also think it reduces the hallmark pathologies of AD—beta amyloid deposition and phosphorylation of tau.”

Neuroinflammation is another pathophysiological mechanism in AD`, and she noted that allopregnanolone “is a very effective anti-inflammatory drug.”

Given their multiple modes of action, a role for neurosteroids in other neurodegenerative disorders seems worth pursuing, she says. “Thus far, we only have preclinical evidence in a Parkinson’s model; allopregnanolone promotes regeneration of dopaminergic fibers [which are vastly depleted in Parkinson’s]. We have to pursue that more deeply. We’re focusing on common mechanisms across agerelated neurodegenerative diseases; we know, for example, that there is a bioenergetic crisis in Parkinson’s, ALS (amyotrophic lateral sclerosis), and multiple sclerosis, as well as AD. There’s also evidence allopregnanolone promotes the regeneration of white matter,” the nerve fibers that connect brain regions.

AD research has gone past animal models. A phase I trial of allopregnanolone for patients with mild disease showed the drug to be safe and well-tolerated, and a multicenter

phase II trial is starting up to assess its effectiveness in delaying cognitive decline and maintaining the ability to function, and to explore its effects on the brain. “Based on results of the first study, we are targeting individuals who carry the ApoE4 gene [an established risk factor for AD]. We’re beginning to apply precision medicine principles,” Brinton says.

In a separate in vitro study, Brinton’s research team is exploring the feasibility of transdermal administration of allopregnanolone for AD. While current therapies require weekly intravenous injections, this would make it possible to apply a patch—a far simpler and more patient-friendly business.

Taking an overview of neurosteroid research, Nestler sees a broad lesson. The development of allopregnanolone is “exciting… it represents a mechanism based on rational drug discovery, not serendipity.”

At the same time, he says, “the initial work on [the compound] as an antidepressant goes back three decades. Why did it take so long to get to this point? This says something about the challenges in the development of psychiatric medications.

“There are likely other mechanisms that the basic science field has talked about for years, waiting on the shelf for effective human translation, if we only have the will and resources to focus on them,” he says. l

ILLUSTRATION: SHUTTERSTOCK

kcarT i n g

the Neural Footprints of

Consciousness

BY BRENDA PATOINE

ILLUSTRATION BY JEAN-FRANCOIS PODEVIN

Can the key to consciousness be found in the folds of the cerebrum? Can the simple unfettered state of “being conscious” be localized in the brain, its properties deconstructed to precisely timed patterns of neural firing? Finding the answers is the goal of a $20 million international research program to search for the neural footprints of consciousness.

The broad, multi-year initiative— termed Accelerating Research in Consciousness (ARC)—is being funded by the Templeton World Charity Foundation. In the first phase, representing $5 million, two leading brain theories of consciousness with diametrically opposed assumptions will face off to test their hypotheses. ARC pits the Integrated Information Theory (IIT) and the Global Neuronal Workplace (GNW) theory directly against one another, in what Templeton calls “adversarial collaboration,” to settle some fundamental questions about how, when, and where the brain processes subjective awareness of ourselves and the world around us.

The two theoretical models are in stark contrast to one another: their definitions and assumptions of what constitutes consciousness differ and their whole approach to the subject is fundamentally different. What they have in common is that they both study the neural correlates of consciousness.

IIT is the brainchild of Giulio Tononi, a professor and director of the Wisconsin Institute for Sleep and Consciousness at the University of Wisconsin. GNW has been elaborated by Stanislas Dehaene of INSERM/Unicog, in concert with Lionel Naccache of Sorbonne/ INSERM, Jean-Pierre Changeux of Institut Pasteur, and others. These two theories were selected by Christof Koch, a leading consciousness researcher who is serving as an advisor to the

“We see consciousness as a big concept that needs to be solved before one can expect to solve other big problems in society.”

Templeton project, because each has an established following among scientists and a “preponderance of evidence” backing them, says Koch, who now heads the Allen Institute for Brain Science.

Why This Approach?

ARC is audacious not only in its approach and its subject matter, but also in its commitment to model best practices in open science. The underlying premise is that meaningful progress on big questions like consciousness requires focused, structured collaboration beyond what any isolated research group can do.

“The days of the lone genius scientist, the chap in the lab who solves the big problem, are pretty much over,” says Dawid Potgieter, senior program director at Templeton, which is bankrolling the project on the premise that siloed science is the enemy of progress. “There’s a need to do science differently,” notes Potgieter.

“What’s happened over the last 50 years, in biomedical sciences in general, is that you never have a single experiment that tests two competing theories,” says Koch. “[Adversarial collaboration] requires people to work together in a productive way so disagreements can be tested.” He points to the experiments of 1919 that directly tested Einstein’s then recently introduced Theory of General Relativity against the prevailing Newtonian view of the universe, largely settling the argument in favor of Einstein. In contemporary science, Koch says: “This is very rarely done.”

Naccache, a French neurologist and neuroscientist who is a coarchitect of GNW, says the nature of the consciousness question calls for a bold approach. “We don’t yet have a full theory of consciousness. We have only sketches—‘esquisses’ in French,”

he says. “The best way to go beyond our current knowledge is to provoke collisions between these theories in order to test their respective core ideas, and to go forward with new ideas,” he adds.

ARC provokes collisions by bringing the leaders of opposing views to the same table—literally, over the course of a multi-day workshop—to hash out and agree to “killer ideas” that could disprove the other’s theory. Then it turns to six top-notch independent laboratories to empirically test the predictions and find out who’s got it right—or at least, who might be closer to right. The scientific protocol is designed to ensure scientific objectivity and rigor with maximal transparency, with an eye toward moving the field forward. A team of independent investigators will direct the scientific program, led by principal investigator Lucia Melloni of Max Planck Institute and New York University and coprincipal investigators Liad Mudrik of Tel Aviv University and Michael Pitts of Reed College.

Why Now?

The Templeton initiative reflects the level of maturity of a field that used to be a no-go for young scientists. Tononi, who became intrigued by the topic as an adolescent contemplating ethical dilemmas, recalls that young people were strongly dissuaded from going into this area of investigation. “I asked neuroscientists at the time, and I was literally told ‘Shut up. Don’t even ask. Hush. Go away.’” It was considered an occupation, he says, “for aging Nobel prize winners,” a reference to Francis Crick and Gerald Edelman, who both took on consciousness only as senior, world-recognized scientists.

“Crick could do it because he was a half-god,” deadpans Koch, who collaborated with Crick on a seminal

1990 paper proposing a roadmap for rigorous investigation of the neural correlates of consciousness. “Retired people could do it, but reasonable working scientists didn’t work on consciousness. It was career-killing,” says Koch.

Melloni came to the field as a Ph.D. a decade after Koch and Crick’s influential paper, which she said re-energized thinking about consciousness and laid out concrete steps for its investigation. “From that moment on, somehow consciousness went back to business,” she says.

Scientific theories about consciousness are now ubiquitous and proliferating. “We’ve gone from ‘you couldn’t talk about it’ to ‘everyone can talk about it,’” Tononi says, pointing to the plethora of books on the subject before adding wryly: “It’s not necessarily making things easier.”

Different Approaches

IIT and GNW take fundamentally different approaches to trying to understand consciousness. GNW, according to Naccache, is inspired by knowledge of the psychological properties of being conscious. It says that as soon as you are conscious of

This split is of particular interest because there is no universal agreement as to whether the essential wiring for being conscious is—roughly speaking—in the back of the cortex or the front.

something—a face, a sound, a memory, a feeling—you can not only self-report it (e.g., I see X, I hear X, I remember X, I feel X) but you can also apply all your cognitive abilities to it – you can think about it, you can remember something related to it, or make some plan of action as a result of it. This “cognitive availability,” a term coined by psychologist Bernard Baars, who proposed the Global Workplace theory, is at the core of the model. As such, GNW takes a functionalist approach. It says consciousness is a function of the brain, so let’s look for where in the brain this function is orchestrated.

In contrast, IIT starts from consciousness itself, the subjective experience of being as opposed to doing. Rather than viewing consciousness as a particular brain function and searching for the neural correlates, it describes the essential properties of consciousness, including the core concept of how information is integrated to engender awareness of the world and self. Then, IIT theory postulates that the physical substrate of consciousness will share those essential properties, providing a sort of treasure map to the kind of neural environment likely to support conscious being.

Back or Front?

The IIT approach has led Tononi and others to look at cortical tissue in the back of the brain, where primary sensory areas form a dense “supergrid” of neuronal connections that are integrated both vertically and laterally. This particular part of the brain, marked by extraordinary complexity, [fits] the essential properties of consciousness as enumerated in IIT.

“If we could unfold the structure of the back of the brain, the complexity there is astronomical,” Tononi says. “It boggles the mind, and fills you with a certain humility and awe…,” he notes.

In contrast, GNW theory postulates that a network engaging both the front and the back of the brain is where the action is. According to Naccache, the cognitive availability that characterizes consciousness should be associated with a neural availability, a particular functional architecture in the brain. GNW theory predicts this neural signature is long-distance, coherent, and complex, a kind of sustained, complex conversation between brain regions engaged in high-level neural processing, located mostly in frontal and parietal regions of the neocortex, he says.

“This is where the theories disagree,” Koch says. This split is of particular interest because there is no universal agreement as to whether the essential wiring for being conscious is—roughly speaking—in the back of the cortex or the front.

The models also diverge in how they envision the timing of neural processing. IIT says as long as one remains conscious of something, a neural correlate representing that “something” will be evident in the brain. GNW postulates that the moment of “conscious access” will be associated with a particular neural representation that is separate and distinct from activity surrounding that moment. A central question of GNW is how to

disentangle the actual neural signature of conscious access from events just before and after.

The experimental protocols and methods selected by the investigative teams are designed to tease out these two issues of localization and timing. Study participants will perform tasks designed to pinpoint the moment of conscious recognition and researchers will look at the data for the corresponding neural signatures. Three different neuroscience techniques will be used: functional magnetic resonance imaging (fMRI), which tracks patterns of activity in the brain with high spatial resolution; magnetoelectroencephalopathy (MEG/EEG), a method for recording electrical activity in groups of neurons noninvasively and with high temporal resolution; and electrocorticography (ECoG), direct recordings from implanted electrodes. The latter procedure, which offers the best spatial and temporal resolution, is done in patients with intractable epilepsy as part of treatment to localize seizure initiation to determine where to intervene.

Data collection and analysis for this initial phase of the broader Templetonfunded program is expected to take three years. Subsequent phases, which have already been initiated, will match up other theories to face off and run complementary animal studies in rodents and nonhuman primates to examine questions that cannot be answered with human subjects. At the conclusion of each phase, all data will be made publicly available in an open-science protocol intended to propel progress toward a more comprehensive view of how the brain does consciousness.

Why Bother?

The search for the neural underpinnings of consciousness is more than

academic; the implications are broad and diverse if not immediately obvious. Improving the detection of conscious awareness in unresponsive patients is one clear application for this type of research, and Tononi’s work has already yielded promising results in developing an objective measure of consciousness. More far-fetched but entirely plausible applications include managing chronic pain or treating mental illness such as depression; the idea being that if we understand how the brain processes subjective awareness, it may be possible to tweak the system to alter one’s experience of pain or illness. Outside the realms of medicine, a current hot topic is when and whether sophisticated machine learning systems

that mimic brain processing might actually be “conscious” to some degree, and what that means for the burgeoning field of Artificial Intelligence.

“We see consciousness as a big concept that needs to be solved before one can expect to solve other big problems in society,” says Templeton’s Potgieter.

For his part, Koch sees consciousness as a question that science cannot afford to ignore. “If science cannot explain how my conscious mind comes into the world, then it’s leaving a gigantic hole in the center of our everyday existence,” he says. He goes on to note that “It’s a simple challenge for science. Science so far has not done it. It’s time that we do.” l

Giulio Tononi (above), a professor and director of the Wisconsin Institute for Sleep and Consciousness at the University of Wisconsin, and author of the Integrated Information Theory (IIT). Stanislas Dehaene (below) of INSERM/ Unicog, a proponent of the Global Neuronal Workplace (GNW) theory.

PHOTOS: TONONI © JOHN MANCINI/STONY BROOK MEDICINE; DEHEANE © P. DELAPIERRE/INSERM

ADVISORY BOARD

JOSEPH T. COYLE, M.D.

Joseph T. Coyle is the Eben S. Draper Chair of Psychiatry and Neuroscience at Harvard Medical School. A graduate of the Johns Hopkins School of Medicine in 1969, he was a research fellow at the National Institute of Mental Health with Nobel Laureate, Julius Axelrod. After psychiatric residency at Hopkins, he joined the faculty in 1975. In 1982, he became the director of the Division of Child and Adolescent Psychiatry. From 1991 to 2001, he was chairman of the Department of Psychiatry at Harvard Medical School. His research interests concern the causes of neuropsychiatric disorders. He is the past-president of the Society for Neuroscience (1991), a member of the National Academy of Medicine (1990), a fellow of the American Academy of Arts and Sciences (1993), a fellow of the American Association for the Advancement of Science (2005), and the former editor of JAMA Psychiatry

MARTHA J. FARAH, Ph.D.

Martha J. Farah is the Walter H. Annenberg Professor of Natural Sciences at the Center for Neuroscience & Society, University of Pennsylvania. She is a cognitive neuroscientist who works on problems at the interface of neuroscience and society. Her recent research has focused on socioeconomic status and brain development. Farah grew up in New York City, was educated at MIT and Harvard, and taught at Carnegie-Mellon University before joining the University of Pennsylvania. She is a fellow of the American Academy of Arts and Sciences, a former Guggenheim Fellow and recipient of honors including the National Academy of Science’s Troland Research Award and the Association for Psychological Science’s lifetime achievement award. She is a founding and current board member of the International Society for Neuroethics.

PIERRE MAGISTRETTI, M.D., Ph.D.

Pierre Magistretti is the dean of the Division of Biological and Environmental Science and Engineering at King Abdullah University of Science and Technology and professor emeritus in the Brain Mind Institute, EPFL and Center for Psychiatric Neuroscience, Department of Psychiatry–CHUV/UNIL, Switzerland. Magistretti received his M.D. from the University of Geneva and his Ph.D. from the University of California at San Diego. Magistretti’s research team has made significant contributions in the field of brain energy metabolism. His group has discovered some of the cellular and molecular mechanisms that underlie the coupling between neuronal activity and energy consumption by the brain. This work has considerable ramifications for the understanding of the origin of the signals detected with the current functional brain imaging techniques used in neurologic and psychiatric research.

HELEN S. MAYBERG, M.D.

Helen S. Mayberg is a neurologist renowned for her study of brain circuits in depression and for her pioneering deep brain stimulation research, which has been heralded as one of the first hypothesis-driven treatment strategies for a major mental illness. She is the founding director of Mount Sinai Health System’s The Nash Family Center for Advanced Circuit Therapeutics Mayberg received an M.D. from the University of Southern California, trained at the Neurological Institute of New York at Columbia University, and was a post-doctoral fellow in nuclear medicine at Johns Hopkins Medicine. Immediately prior to joining Mount Sinai, Mayberg was Professor of Psychiatry, Neurology, and Radiology and held the inaugural Dorothy C. Fuqua Chair in Psychiatric Neuroimaging and Therapeutics at Emory University School of Medicine. She is a member of the National Academy of Medicine, The American Academy of Arts and Sciences, and the National Academy of Inventors. She is on the board of the International Society for Neuroethics and won the society’s Steven E. Hyman for Distinguished Service to Neuroethics (2018).

JOHN H. MORRISON, Ph.D.

John H. Morrison is UC Davis Distinguished Professor, director of the California National Primate Research Center (CNPRC), Professor of Neurology in the School of Medicine, and professor in the Center for Neuroscience at UC Davis. Morrison earned his bachelor’s degree and Ph.D. from Johns Hopkins University and completed postdoctoral studies in the laboratory of Dr. Floyd E. Bloom at the Salk Institute for Biological Studies. Morrison’s research program focuses primarily on the neurobiology of aging and neurodegenerative disorders. His laboratory is particularly interested in age-related synaptic alterations that compromise synaptic health, lead to cognitive decline, and potentially leave the brain vulnerable to Alzheimer’s Disease. Morrison is a member of the National Academy of Medicine.

ADVISORY BOARD

RICHARD M. RESTAK, M.D.

Richard Restak is clinical professor of neurology at George Washington Hospital University School of Medicine and Health Sciences, a member of the clinical faculty at St. Elizabeth’s Hospital in Washington, DC, and also maintains a private practice in neurology and neuropsychiatry. A graduate of Georgetown University School of Medicine, Restak has written over 24 books on the human brain and has penned articles for the Washington Post, The New York Times, the Los Angeles Times, and USA Today; and presented commentaries for both Morning Edition and All Things Considered on National Public Radio. He is a past recipient of the Claude Bernard Science Journalism Award, given by the National Society for Medical Research.

HARALD SONTHEIMER, Ph.D.

Harald Sontheimer is I. D. Wilson Chair and professor and founder and executive director of the Virginia Tech School of Neuroscience. He is also Commonwealth Eminent Scholar in cancer research and director of the Center for Glial Biology in Health, Disease & Cancer and the Fralin Biomedical Research Institute. A native of Germany, Sontheimer obtained a master’s degree in evolutionary comparative neuroscience, where he worked on the development of occulomotor reflexes. In 1989, he obtained a doctorate in Biophysics and Cellular & Molecular Neuroscience form the University of Heidelberg. He moved to Yale University for post-doctoral studies and later founded Transmolecular Inc., which was acquired by Morphotec Pharmaceuticals. He is the author of Diseases of the Nervous System (Elsevier, 2015).

STEPHEN WAXMAN, M.D., Ph.D.

Stephen Waxman is the Bridget Flaherty Professor of Neurology, Neurobiology, and Pharmacology at Yale University, and served as chairman of neurology at Yale from 1986 until 2009.  His research uses tools from the “molecular revolution” to find new therapies that will promote recovery of function after injury to the brain, spinal cord, and peripheral nerves.  A member of the National Academy of Medicine, Waxman has been honored in Great Britain with the Physiological Society’s annual prize, an accolade that he shares with Nobel Prize laureates Andrew Huxley, John Eccles, and Alan Hodgkin. In 2018, Waxman received the Julius Axelrod Prize from the Society for Neuroscience.

CHARLES F. ZORUMSKI, M.D.

Charles Zorumski is the Samuel B. Guze Professor and head of the Department of Psychiatry and Professor of Neuroscience at Washington University School of Medicine in St. Louis. Zorumski is also Psychiatrist-in-Chief at Barnes-Jewish Hospital and founding director of the Taylor Family Institute for Innovative Psychiatric Research. Zorumski’s laboratory studies synaptic transmission in the hippocampus. Since 1997, he has served on the steering committees of the McDonnell Center for Cellular and Molecular Neurobiology and the McDonnell Center for Systems Neuroscience and was director of the Center for Cellular and Molecular Neurobiology from 2002 to 2013. Zorumski has also served on the editorial boards of JAMA Psychiatry, Neurobiology of Disease, and served on the board of Scientific Counselors for the NIMH Intramural Research Program from 2009 to 2013. Since 2011, he has also served on the scientific advisory board of Sage Therapeutics, a publicly-traded company developing neurosteroids and oxysterols as treatments for neuropsychiatric illnesses.

CAROLYN ASBURY, Ph.D.

In-House advisor

Carolyn Asbury has worked in health philanthropy for more than two decades, directing neuroscience-related health programs at the Robert Wood Johnson Foundation and directing the Pew Charitable Trusts’ Health and Human Services Program prior to consulting with the Dana Foundation. Her own research, through the University of Pennsylvania’s Leonard Davis Institute, concerns policies to facilitate development and market availability of drugs and biologics for “orphan” (rare) diseases. She undertook pro bono research and helped to design the Orphan Drug Act; authored “Orphan Drugs: Medical vs Market Value,” and has authored several journal articles and book chapters on these topics. She has served on the boards of several nonprofit health-related organizations, including the National Organization for Rare Disorders, U.S. Pharmacopeia, College of Physicians of Philadelphia, and Treatment Research Institute.

Bill Glovin Executive Editor

Glovin has been a working journalist for more than 30 years. He is executive editor at the Dana Foundation and hosts a regular podcast on brain science. He has served as editor of Cerebrum since 2012. Previously, he was senior editor at Rutgers Magazine, managing editor of New Jersey Success, editor for New Jersey Business and a staff writer for The Bergen Record. Glovin graduated from George Washington University with a degree in journalism. He sometimes escapes from in front of the monitor to enjoy basketball, biking, and guitar.

Seimi Rurup Assistant Editor

Rurup oversees the production of all digital and print content at the Dana Foundation. She previously served as editor of Brain in the News, which was the Foundation’s longest running print publication, and utilizes her background in fine arts to contribute to current publications and social media. She also contributes to the Foundation’s Neuro News section. Rurup graduated from Sarah Lawrence College with a degree in writing. When she is not in the office, she can be found in one of NYC’s many museums, Brooklyn cafés, or at home cooking with friends.

Brandon Barrera Editorial Assistant

Barrera is a New York City journalist, born and raised in Queens, N.Y. Barrera was a contributor to the Dana Foundation blog and Bronx Net. He is currently a public affairs assistant at the Dana Foundation and, when not enthralled by all things sci-fi, is fond of cycling, film, and arguing the finer points of tabletop gaming.