singleCerebrumSpring2020v7spreads fx22 (singlepage)

SPRING 2020

EMERGING IDEAS IN BRAIN SCIENCE

The Mind of a

DOG

A Renaissance in Canine

Cognitive Science Sheds Light

on How They See the World

and Bond with Humans

CONTRIBUTORS

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

Decoding the Canine Mind

Page 10

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.

Jump-Starting Evolution

Page 16

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

Neurosteroids:

A Major Step Forward

Page 22

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

Tracking the Neural

Footprints of Consciousness

Page 26

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.

COVER ILLUSTRATION: DANNY SCHWARTZ

2 DANA FOUNDATION CEREBRUM | SPRING 2020

SPRING 2020 | VOLUME 1, ISSUE 2

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

DANA FOUNDATION CEREBRUM | SPRING 2020 3

FROM THE EDITOR

It’s a Doggy Dog World

BY BILL GLOVIN

Executive Editor, Dana Foundation

EMERGING IDEAS IN BRAIN SCIENCE

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

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

Cerebrum magazine

505 Fifth Avenue, 6th Floor

New York, NY 10017

or cerebrum@dana.org

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


BRIEFLY NOTED

ILLUSTRATION: SHUTTERSTOCK

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

PHOTO: DENNIS CONNORS

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.


BOOKSHELF


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 / BRIEFLY NOTED CONTINUED ON PAGE 8


BOOKSHELF

NEUROETHICS


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

ILLUSTRATION: ISTOCK

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


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.

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

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.


ecoding

Canine

BY GREGORY

BERNS,

M.D., Ph.D.

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.


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.

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.

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 Williams-

Beuren 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

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.)

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


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.

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.)

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


Research labs have sprung up around the world, and dogs

participate not as involuntary subjects, but as partners in

scientific discovery.

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

Callie in the MRI scanner while watching pictures of faces.

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


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

> Financial disclosure

All good dogs?

Yes, but which

ones have what

it takes to be a

service dog?


ump-Starting

Evolutıon

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.


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.

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

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

Lyudmila Trut, the Russian geneticist

who has been leading the experiment

in domesticating foxes since 1959.

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


SECTION TITLE

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.

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

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


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

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


SECTION TITLE

Much of the recent work on the domesticated foxes has probed

deep into their genome for clues about the process

of domestication.

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

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

Professor and book co-author Lee

Alan Dugatkin snuggles with one

of his furry friends on one of two

trips he made to Siberia.

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.


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

Financial Disclosure: The author has no

conflicts of interest to report.


EUROSTEROID S

A MAJOR STEP FORWARD

BY CARL SHERMAN

ILLUSTRATION BY WILLIAM HOGAN


“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.”

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

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?


SECTION TITLE

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.

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,

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


Looking further, Roberta Diaz Brinton and her colleagues found

evidence that allopregnanolone also improves mitochondrial

function redressing the “bioenergetics crisis of Alzheimer’s disease.”

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, 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


Tracking the Neural Footprints of

Consciousness

BY BRENDA PATOINE

ILLUSTRATION BY JEAN-FRANCOIS PODEVIN


“We see consciousness as a big concept that needs to

be solved before one can expect to solve other big

problems in society.”

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

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


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.

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

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

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

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.

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


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.


EDITORIAL STAFF

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.

WANT MORE CEREBRUM?

Join us as we talk to our Cerebrum

neuroscientist authors about their

research, personal stories, and

how their work has the potential to

make a difference in people’s lives.

dana.org/cerebrum-podcast


singleCerebrumSpring2020v7spreads fx22 (singlepage)

Create successful ePaper yourself

Delete template?

Save as template?