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Nirao Shah decided in 1998 to study sex-based differences in the

brain using up-to-the-minute molecular tools, he didn’t have a ton
of competition. But he did have a good reason.

“I wanted to find and explore neural circuits that regulate specific

behaviors,” says Shah, then a newly minted Caltech PhD who was
beginning a postdoctoral fellowship at Columbia. So, he zeroed in
on sex-associated behavioral differences in mating, parenting and
aggression.

“These behaviors are essential for survival and propagation,” says

Shah, MD, PhD, now a Stanford professor of psychiatry and
behavioral sciences and of neurobiology. “They’re innate rather than
learned — at least in animals — so the circuitry involved ought to be
developmentally hard-wired into the brain. These circuits should
differ depending on which sex you’re looking at.”

His plan was to learn what he could about the activity of genes tied
to behaviors that differ between the sexes, then use that knowledge
to help identify the neuronal circuits — clusters of nerve cells in
close communication with one another — underlying those
behaviors.

At the time, this was not a universally popular idea. The

neuroscience community had largely considered any observed sex-
associated differences in cognition and behavior in humans to be
due to the effects of cultural influences. Animal researchers, for their
part, seldom even bothered to use female rodents in their
experiments, figuring that the cyclical variations in their reproductive
hormones would introduce confounding variability into the search for
fundamental neurological insights.

But over the past 15 years or so, there’s been a sea change as new
technologies have generated a growing pile of evidence that there
are inherent differences in how men’s and women’s brains are wired
and how they work.

Not how well they work, mind you. Our differences don’t mean one
sex or the other is better or smarter or more deserving. Some
researchers have grappled with charges of “neurosexism”: falling
prey to stereotypes or being too quick to interpret human sex
differences as biological rather than cultural. They counter,
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however, that data from animal research, cross-cultural surveys,

natural experiments and brain-imaging studies demonstrate real, if
not always earthshaking, brain differences, and that these
differences may contribute to differences in behavior and cognition.
Behavior differences

In 1991, just a few years before Shah launched his sex-differences

research, Diane Halpern, PhD, past president of the American
Psychological Association, began writing the first edition of her
acclaimed academic text, Sex Differences in Cognitive Abilities. She
found that the animal-research literature had been steadily accreting
reports of sex-associated neuroanatomical and behavioral
differences, but those studies were mainly gathering dust in
university libraries. Social psychologists and sociologists pooh-
poohed the notion of any fundamental cognitive differences
between male and female humans, notes Halpern, a professor
emerita of psychology at Claremont McKenna College.

In her preface to the first edition, Halpern wrote: “At the time, it
seemed clear to me that any between-sex differences in thinking
abilities were due to socialization practices, artifacts and mistakes in
the research, and bias and prejudice. … After reviewing a pile of
journal articles that stood several feet high and numerous books
and book chapters that dwarfed the stack of journal articles … I
changed my mind.”

Why? There was too much data pointing to the biological basis of
sex-based cognitive differences to ignore, Halpern says. For one
thing, the animal-research findings resonated with sex-based
differences ascribed to people. These findings continue to accrue. In
a study of 34 rhesus monkeys, for example, males strongly
preferred toys with wheels over plush toys, whereas females found
plush toys likable. It would be tough to argue that the monkeys’
parents bought them sex-typed toys or that simian society
encourages its male offspring to play more with trucks. A much
more recent study established that boys and girls 9 to 17 months old
— an age when children show few if any signs of recognizing either
their own or other children’s sex — nonetheless show marked
differences in their preference for stereotypically male versus
stereotypically female toys.
 Uvod u biološku psihologiju 2022./2023.

Halpern and others have cataloged plenty of human behavioral

differences. “These findings have all been replicated,” she says.
Women excel in several measures of verbal ability — pretty much
all of them, except for verbal analogies. Women’s reading
comprehension and writing ability consistently exceed that of men,
on average. They outperform men in tests of fine-motor coordination
and perceptual speed. They’re more adept at retrieving information
from long-term memory.

Men, on average, can more easily juggle items in working memory.

They have superior visuospatial skills: They’re better at visualizing
what happens when a complicated two- or three-dimensional shape
is rotated in space, at correctly determining angles from the
horizontal, at tracking moving objects and at aiming projectiles.

Navigation studies in both humans and rats show that females of

both species tend to rely on landmarks, while males more typically
rely on “dead reckoning”: calculating one’s position by estimating
the direction and distance traveled rather than using landmarks.
New technologies have generated a growing pile of evidence that
there are inherent differences in how men’s and women’s brains
are wired and how they work.

Many of these cognitive differences appear quite early in life. “You

see sex differences in spatial-visualization ability in 2- and 3-month-
old infants,” Halpern says. Infant girls respond more readily to faces
and begin talking earlier. Boys react earlier in infancy to
experimentally induced perceptual discrepancies in their visual
environment. In adulthood, women remain more oriented to faces,
men to things.

All these measured differences are averages derived from pooling

widely varying individual results. While statistically significant, the
differences tend not to be gigantic. They are most noticeable at the
extremes of a bell curve, rather than in the middle, where most
people cluster. Some argue that we may safely ignore them.

But the long list of behavioral tendencies in which male-female

ratios are unbalanced extends to cognitive and neuropsychiatric
disorders. Women are twice as likely as men to experience clinical
depression in their lifetimes; likewise for post-traumatic stress
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disorder. Men are twice as likely to become alcoholic or drug-

dependent, and 40 percent more likely to develop schizophrenia.
Boys’ dyslexia rate is perhaps 10 times that of girls, and they’re four
or five times as likely to get a diagnosis of autism spectrum disorder.

Could underlying biological differences — subtle though they may

be for most of us — help explain these gaping

between-sex imbalances in the prevalence of mental disorders and

account for the cognitive and behavioral differences observed
between men and women?
How our brains differ

The neuroscience literature shows that the human brain is a sex-

typed organ with distinct anatomical differences in neural structures
and accompanying physiological differences in function, says UC-
Irvine professor of neurobiology and behavior Larry Cahill, PhD.
Cahill edited the 70-article January/February 2017 issue of
the Journal of Neuroscience Research — the first-ever issue of any
neuroscience journal devoted entirely to the influence of sex
differences on nervous-system function.

Brain-imaging studies indicate that these differences extend well

beyond the strictly reproductive domain, Cahill says. Adjusted for
total brain size (men’s are bigger), a woman’s hippocampus, critical
to learning and memorization, is larger than a man’s and works
differently. Conversely, a man’s amygdala, associated with the
experiencing of emotions and the recollection of such experiences,
is bigger than a woman’s. It, too, works differently, as Cahill’s
research has demonstrated.

In 2000, Cahill scanned the brains of men and women viewing

either highly aversive films or emotionally neutral ones. The
aversive films were expected to trip off strong negative emotions
and concomitant imprinting in the amygdala, an almond-shaped
structure found in each brain hemisphere. Activity in the amygdala
during the viewing experience, as expected, predicted subjects’ later
ability to recall the viewed clips. But in women, this relationship was
observed only in the left amygdala. In men, it was only in the right
amygdala. Cahill and others have since confirmed these results.
 Uvod u biološku psihologiju 2022./2023.

Discoveries like this one should ring researchers’ alarm buzzers.

Women, it’s known, retain stronger, more vivid memories of
emotional events than men do. They recall emotional memories
more quickly, and the ones they recall are richer and more intense.
If, as is likely, the amygdala figures into depression or anxiety, any
failure to separately analyze men’s and women’s brains to
understand their different susceptibilities to either syndrome would
be as self-defeating as not knowing left from right.

The two hemispheres of a woman’s brain talk to each other more

than a man’s do. In a 2014 study, University of Pennsylvania
researchers imaged the brains of 428 male and 521 female youths
— an uncharacteristically huge sample — and found that the
females’ brains consistently showed more strongly coordinated
activity between hemispheres, while the males’ brain activity was
more tightly coordinated within local brain regions. This finding, a
confirmation of results in smaller studies published earlier, tracks
closely with others’ observations that the corpus callosum-— the
white-matter cable that crosses and connects the hemispheres — is
bigger in women than in men and that women’s brains tend to be
more bilaterally symmetrical than men’s.
Many of these cognitive differences appear quite early in life. ‘You
see sex differences in spatial-visualization ability in 2- and 3-
month-old infants.’

“To some appreciable degree, these brain differences have to

translate to behavioral differences,” says Cahill. Numerous studies
show that they do, sometimes with medically meaningful
implications.

A 2017 study in JAMA Psychiatry imaged the brains of 98

individuals ages 8 to 22 with autism spectrum disorder and 98
control subjects. Both groups contained roughly equal numbers of
male and female subjects. The study confirmed earlier research
showing that the pattern of variation in the thickness of the brain’s
cortex differed between males and females. But the great majority of
female subjects with ASD, the researchers found, had cortical-
thickness variation profiles similar to those of typical non-ASD
males.
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In other words, having a typical male brain structure, whether you’re

a boy or a girl, is a substantial risk factor for ASD. By definition,
more boys’ than girls’ brains have this profile, possibly helping
explain ASD’s four- to fivefold preponderance among boys
compared with girls.
Why our brains differ

But why are men’s and women’s brains different? One big reason is
that, for much of their lifetimes, women and men have different fuel
additives running through their tanks: the sex-steroid hormones. In
female mammals, the primary additives are a few members of the
set of molecules called estrogens, along with another molecule
called progesterone; and in males, testosterone and a few look-
alikes collectively deemed androgens. Importantly, males
developing normally in utero get hit with a big mid-gestation surge of
testosterone, permanently shaping not only their body parts and
proportions but also their brains. (Genetic defects disrupting
testosterone’s influence on a developing male human’s cells induce
a shift to a feminine body plan, our “default” condition.)

In general, brain regions that differ in size between men and women
(such as the amygdala and the hippocampus) tend to contain
especially high concentrations of receptors for sex hormones.

Another key variable in the composition of men versus women

stems from the sex chromosomes, which form one of the 23 pairs of
human chromosomes in each cell. Generally, females have two X
chromosomes in their pair, while males have one X and one Y
chromosome. A gene on the Y chromosome is responsible for the
cascade of developmental events that cause bodies and brains to
take on male characteristics. Some other genes on the Y
chromosome may be involved in brain physiology and cognition.

Scientists routinely acknowledge that the presence or absence of a

single DNA base pair can make a medically important difference.
What about an entire chromosome? While the genes hosted on the
X chromosome and the Y chromosome (about 1,500 on the X, 27
on the Y) may once have had counterparts on the other, that’s now
the case for only a few of them. Every cell in a man’s body
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(including his brain) has a slightly different set of functioning sex-

chromosome genes from those operating in a woman’s.

Sex-based differences in brain structure and physiology reflect the

alchemy of these hormone/receptor interactions, their effects within
the cells, and the intermediating influence of genetic variables —
particularly the possession of an XX versus an XY genotype, says
Cahill.
Zeroing in on neural circuits

Shah’s experiments in animals employ technologies enabling

scientists to boost or suppress the activity of individual nerve cells
— or even of single genes within those nerve cells — in a
conscious, active animal’s brain. These experiments have
pinpointed genes whose activity levels differ strongly at specific
sites in male versus female mice’s brains.

What would happen, Shah’s team wondered, if you knocked out of

commission one or another of these genes whose activity level
differed between male and female brains? They tried it with one of
their candidate genes, turning off one that was normally more active
in females.

Doing this, they found, totally shredded mouse moms’ willingness to

defend their nests from intruders and to retrieve pups who had
wandered away — maternal mandates that normal female mice
unfailingly observe — yet had no observable effect on their sexual
behavior. Torpedoing a different gene radically reduced a female
mouse’s mating mood, but males in which the gene has been
trashed appear completely normal.

All this points to a picture of at least parts of the brain as consisting

of modules. Each module consists of a neural or genetic pathway in
charge of one piece of a complicated behavior, and responds to
genetic and hormonal signals. These modules — or at least some of
them — are masculinized or feminized, respectively, by the early
testosterone rush or its absence. The mammalian brain features
myriad modules of this sort, giving rise to complex combinations of
behavioral traits.
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Which is not to say every man’s or woman’s brain looks the same.
Our multitudinous genetic variations interact with some of our
genes’ differential responsiveness to estrogens versus androgens.
This complicated pinball game affects goings-on in at least some of
the brain’s neural circuits and in whatever little piece of behavior
each of these neural circuits manages.

“We think gender-specific behavior is a composite of all these

modules, which, added up, give you your overall degree of
maleness and femaleness,” says Shah.

Consider the genes Shah has isolated whose activity levels differ
significantly in the brains of male and female mice. “Almost all of
these genes have human analogues,” he says. “We still don’t
completely understand their function in human social behavior. But
when we looked at publicly available databases to find out what we
do know about them, we found a surprising number that in humans
have been linked with autism, alcoholism and other conditions.”

Bigger imaging studies and imaginative animal research now in the

works promise to reveal much more about humanity’s inherent —
although by no means uniform, and often not substantial — sex-
associated cognitive differences and vulnerability to diseases.

Trying to assign exact percentages to the relative contributions of

“culture” versus “biology” to the behavior of free-living human
individuals in a complex social environment is tough at best.
Halpern offers a succinct assessment: “The role of culture is not
zero. The role of biology is not zero.”

MULTIDISCPLINARNOST

Izvori: https://sm.stanford.edu/archive/stanmed/2012spring/article2.html

https://stanmed.stanford.edu/issue/2021issue2/

1. Brains on brains

At the founding of the Wu Tsai Neurosciences Institute in 2013, director Bill Newsome, PhD, invited
faculty members from across Stanford to a series of dinners where he would pose the same
question: “What can we do together to solve fundamental questions in brain science that are too big
to tackle alone? Assume funding is no object.”
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After only a moment’s hesitation, the gathered scientists, clinicians, engineers, educators and
ethicists began talking all at once, in conversations that set the tone for priorities for the institute
that stand to this day.

“Understanding how the 3 pounds of matter in our skulls generates our mental life and behavior is
among humanity’s biggest questions, and developing new treatments for brain diseases is one of
society’s most urgent priorities,” said Newsome, the Vincent V.C. Woo Director of the institute and
Harman Family Provostial Professor of neurobiology.

“These are questions we can solve only by coming together as one neuroscience community to share
ideas and technologies that will reveal the workings of the brain in health and disease.”

The institute — renamed in 2018 after donors Clara Wu Tsai and Joe Tsai — promotes collaborative,
interdisciplinary research with three broad goals: discovering fundamental principles of brain
function, engineering new tools to probe and connect with brain circuits, and advancing brain health
by translating neuroscience discoveries into treatments.

“In the next decade, I’d love to see us expand our impact — not only in the realm of brain health, but
also in education, economics, health policy and all the realms where unraveling the mysteries of
human behavior could help lead us to a more just and equitable world.”

Bill Newsome, Wu Tsai Neurosciences Institute director

The institute has grown to encompass more than 400 Stanford faculty with backgrounds in
neuroscience, medicine, engineering, psychology, education, law and other fields, including six
scholars the institute has hired whose work transcends traditional disciplinary boundaries.

The institute has committed more than $26 million in targeted grants to support cross-disciplinary
teams advancing new ideas and technologies in brain science, including its ambitious Big Ideas in
Neuroscience initiatives, which are aimed at fundamentally transforming the field.

The institute also supports the next generation of neuroscience leaders through interdisciplinary
fellowships for graduate students and postdoctoral scholars as well as summer research
opportunities for undergraduates. It is dedicated to diversity, inclusion and equity as essential to the
advancement of science and the development of a vibrant intellectual community.
 Uvod u biološku psihologiju 2022./2023.

In February 2020, the institute moved into the new Stanford Neurosciences Building. Designed to
maximize collaborative research between experimentalists, engineers and theorists, the building
houses 24 neuroscience labs, a theory center dedicated to computational neuroscience, and
community laboratories where researchers from different disciplines can share access to
technologies and expertise.

“The collaborative community we’ve nurtured over the years has been incredibly fruitful in advancing
our knowledge,” said Newsome.

“In the next decade, I’d love to see us expand our impact — not only in the realm of brain health, but
also in education, economics, health policy and all the realms where unraveling the mysteries of
human behavior could help lead us to a more just and equitable world.”

Author headshot

Nicholas Weiler
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2. Same injury, different brain

Five years ago, Odette Harris, MD, professor of neurosurgery and a brain trauma expert, began to
weave an age-old question into her research: What are the differences between men and women?

Harris had not intended to bring sex differences into her work, but while analyzing brain trauma data
from the Department of Veterans Affairs, she realized there’s a big gender difference in the
aftermath of traumatic brain injuries, and no one was talking about it.

In fact, in her analysis, Harris, director of the Traumatic Brain Injury Center of Excellence at the VA
Palo Alto Health Care System, found several unexpected trends: Women with brain injury trauma
and other severe injuries typically saw higher rates of depression, substance abuse, memory
problems and homelessness, among other troubles, than men with brain trauma.

Initially, Harris was wary of widely sharing her findings. “I was concerned that this information could
be weaponized or misconstrued. We’re not saying women don’t do as well as men, or women aren’t
as strong as men. That’s not it at all,” she said.

“We’re saying that women and men experience brain injuries differently, and we need to treat them
as such. This is a challenge in our field that deserves attention.”

To better understand the nature of brain trauma in women — physiologically, psychologically and
socially — Harris teamed up with colleagues, including Maheen Adamson, PhD, a clinical scientific
research director for Rehabilitation Services at the VA Palo Alto and a clinical associate professor of
neurosurgery at Stanford School of Medicine.

Using data from surveys, neuropsychological testing and brain imaging, they have conducted
matched analyses comparing male and female patients, meaning that, sex aside, the comparison
groups’ specifics — age, severity of injury and time since the injury — were equal.

Their work has so far revealed some big differences in the brains and behavior of men and women
with post-trauma injuries — insights that could guide treatment for women who have suffered
debilitating injuries to the head.
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Lisette Meylan is grateful for the new direction. In 2004, her daughter, Mariela, who was on duty in
Kuwait, suffered severe head and other injuries when a car hit her and four other soldiers as they
changed a flat on their truck.

She survived the accident but ended up in a coma, receiving care in a nursing home for veterans in
Washington, D.C. “Her doctors told me I needed to be prepared for my daughter to never wake up,”
Meylan said.

But Meylan could not give up on her daughter, so she moved her closer to home, in Livermore,
California, to the VA’s Livermore division. There, Meylan and her daughter’s care team tried different
therapies to wake her from a vegetative state.

It seemed all but hopeless. Two years passed. Then, one day, Meylan saw a light blinking on her
phone’s message machine, indicating a new voicemail.

She played the recording: “This is Mariela, I’m your daughter, and I love you.”

“Those were the first words she’d spoken in two years,” said Meylan. Since then, her daughter’s
recovery has been challenged by physical and mental hurdles, such as learning to walk again, but she
has progressed immensely.

“My biggest challenge is my memory,” said Mariela Meylan. That’s more common for women who
have experienced multiple traumatic injuries, compared with men, according to Adamson.

“My short-term memory has been affected the most. But through the support of my family and my
team of practitioners, I’m able to continue to heal and show up for my life.”

In 2014, she participated in a storytelling workshop run by Harris for women who’ve experienced
traumatic brain injury to share their stories with other women who have the diagnosis and health
care professionals.

“Patients like Mariela are the reason we do this. The stories of their strength, perseverance and
motivation give my research a purpose and motivate me to never stop discovering.”

Maheen Adamson, PhD, a clinical associate professor of neurosurgery

Through intensive physical therapy at the Livermore VA, she now regularly practices yoga, rides
horses and swims. She lives with her mother, who helps her navigate other day-to-day activities, like
making meals.
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“Patients like Mariela are the reason we do this,” said Adamson. “The stories of their strength,
perseverance and motivation give my research a purpose and motivate me to never stop
discovering.”

Surveys and analysis of health record data by the Stanford researchers and others continue to find
stark differences in how men and women experience severe brain injury.

But there’s also a physical clue: The imaging research suggests a link between a physical trait of
women’s brains — a thinning of part of the cortex — and the tendency to experience a different
array of post-brain injury symptoms than men do.

Their analysis will help fill in research gaps. “Females account for 15% of the traumatic brain cases we
see, yet the studies investigating TBI comprise data almost exclusively from men,” said Adamson.

Photo of neuroscientists Odette Harris, left, and Maheen Adamson by Leslie Williamson

Studies by neuroscientists Odette Harris, left, and Maheen Adamson reveal key differences in how
brain trauma affects women when compared with men who have similar injuries. The neurosurgery
professors hope their insights lead to better treatment and recovery for female patients. (Photo by
Leslie Williamson)

Setting women up to succeed

In her deep dive into the Armed Forces Health Surveillance Center data from 2000 to 2010, Harris
found several key differences in the aftermath of severe head trauma for men and women, including
that women are four times more likely to abuse drugs, seven times more likely to be homeless and
about three times more likely to be unemployed.

Women with traumatic brain injury are also 30% more likely than males to suffer from post-traumatic
stress disorder. And they experience higher rates of vertigo — the feeling that the environment is
moving (often spinning) around you.

Part of the research goal is to figure out how best to set women up for success after brain trauma.
It’s not always the same as what’s best for men. “For instance, when we see unemployment in males
with traumatic brain injury, our approach is to assist in education and skills training,” said Harris.

“So the knee-jerk reaction is to find ways to increase education and training when we see
unemployment in women with traumatic brain injury. But we found that female veterans were
better educated and more likely to have a college degree than their male counterparts.”
 Uvod u biološku psihologiju 2022./2023.

So education and skills training might not be as helpful for women as it is for men.

Bringing it back to the brain

What’s causing the differences in the impact of brain injury trauma on women and men?

In 2016, Adamson began investigating, using neuropsychological testing and brain imaging. The tests
gauged general brain function and memory, among other abilities. The imaging portion of the study,
which comprised 70 veterans (28 women and 42 men) used MRI to measure the thickness of the
cortex, the thin outer layer of the brain’s cerebrum.

“Scientists have looked at how cortical thickness changes in a variety of neurological diseases, such
as schizophrenia, and we thought it made sense to start there for this research, too,” said Adamson.

Under healthy conditions, women’s cortex is about 6% thicker than men’s. In the MRI study, injured
brains of all veterans exhibited signs of cortical thinning, only for women it was significantly worse.

“We’re seeing a shift toward looking at differences between male and female traumatic brain injury
more deeply, and my hope is that that trend will extend to other groups within the traumatic brain
injury patient population.”

The brains of the women she studied had more patches of cortical thinning, especially in regions that
regulate emotion and decision-making. Scientists know cortical thinning is not good, but it’s too early
to say how the condition impacts behavior or overall health of the brain.

Researchers are recruiting more participants to further explore how cortical thinning impacts
symptoms and post-brain injury outcomes for women, said Adamson. “We’re just hitting the tip of
the iceberg here.”

She and Harris are also considering other populations of brain trauma survivors and how their
experiences differ.

“I see our research as aligning well with a shift we’re seeing at the national level — incorporating
gender, race, ability and other differences into science and patient health,” said Harris.

“We’re seeing a shift toward looking at differences between male and female traumatic brain injury
more deeply, and my hope is that that trend will extend to other groups within the traumatic brain
injury patient population. That’s what will enable us to improve outcomes and ensure equitable care
for all people, not just women.”

— Contact Hanae Armitage at [email protected]

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3. The man who couldn’t cry

Why am I here tonight?” Mateo asked. He took his glasses off and set them carefully on the
gurney. “Because I don’t know why I can’t cry.” Looking at his hands, open in his lap, he considered
each palm in turn, seemingly puzzled by its emptiness. Then his eyes came back up to mine, and his
story began to slowly drain out, passively, by force of gravity.

He had been brought to the ER by his three brothers, who were surging about in the tiny waiting
room down the hall; I was the psychiatrist summoned to evaluate him. My first impression, on
stepping into the room, was that he seemed childlike — just 26 but appearing much younger, with
smooth skin and rich brown eyes framed by thick black glasses; he looked as though he had lost his
backpack, or perhaps was worried about his homework. And yet that impression lasted only an
eyeblink.

Eight weeks earlier, he told me, his wife of a year — his pregnant bride — had been crushed and
killed in their car. She was stolen from beside him late one night, as they drove in darkness on a
country highway. They were returning from a weekend bed-and-breakfast getaway in Mendocino,
when a white-panel van cut across their lane. Mateo jerked the wheel hard left, and their little car
flipped into the median, finding a small tree stooped there that had been waiting quietly 50 years for
this moment. They hung upside down for an hour, Mateo trapped beside his wife’s broken body, the
young family swinging quietly in their seat belts — along with the little one too, deep within her,
cooling slowly along with her, unsafe in her soft embrace.

He stared at the wall now, arms empty. Two months later, there was still visceral horror in his heart
— but also a relentless dry isolation. As we talked, I learned this was a man whose inner self, his
emotions, had been projecting out into the world — tears had come before, in his adult life, in many
moments of joy as well as sadness — but this dimensionality was now reduced, his expressions flat
and colorless. He seemed set aside, set apart in time, sighted in one direction only. When I asked
about his plans, there was only nothingness. Mateo could not see even a few minutes into the future,
which was invisible, impossible, a featureless white wall.

Crying is significant in psychiatry; our patients experience extreme emotions, and we work with the
expression of these emotions. But the reason for tears is a mystery; pure emotional tears are not
clearly present elsewhere in the great ape lineage, and with all the risks of revealing true feelings in
complex social environments, the poor controllability of this emotional signal seems a handicap
rather than an advantage. Yet value may lie in a signal remaining largely involuntary, and thus mostly
true.

When I asked about his plans, there was only nothingness. Mateo could not see even a few
minutes into the future, which was invisible, impossible, a featureless white wall.

Every innovation in evolution is accidental at first. Our neurons are guided during brain development
by a vast diversity of path-setting molecules as strong as thread-guides on a loom — tiny signposts
that send a slowly growing bundle of nerve fibers, called axons, on to the next brain region, or turn it
back if it has come too far. Mutation in genes governing any of these steps, redirecting axons from
emotion-regulation regions of the brain, would be enough to bring into the world a new way of being
human, with a new way of expressing feeling.

The new target here, for tears, would have been deep in the brainstem: the cells of the seventh
cranial nerve, grandmaster of facial expressions but also of the lacrimal gland — the storehouse of
 Uvod u biološku psihologiju 2022./2023.

tears. The lacrimal system likely evolved for flushing irritants from the eye, washing away particulate
nuisances. With an almost-trivial rewiring, seventh-nerve control of tears would have become
accessible by floods of emotion — with a tweaking of fibers already present, already projecting from
emotion-control regions in the upper forebrain down to the brainstem parabrachial cells that
regulate emotional changes in breathing (next-door neighbors of the seventh-nerve lacrimal cells) —
and so finally wrenching, from within, the full cathartic, diaphragmatic contraction of the sob.

Mateo never did cry for his family — not that I saw, nor that he could ever tell me. In considering
this, and the reasons we have for crying, it seemed to me that an odd unity links tears of sadness,
when they happen, and the more mysterious tears of joy. Tears come when we feel hope and frailty
together, as one. I managed to keep myself from writing this in the medical chart — and that Mateo
had no hope left to cry for.

Mild improvements in material outcome that do not require a new model of self and circumstance —
as with just making a bit more money in accord with known probabilities of the world — will not
cause most people to cry. But when we do cry for joy — as when we feel the sudden warmth and
promise of human connection, or when we see an unexpected depth of empathy in a young child —
we seem to signal a flickering of hope, for the future of a vulnerable community, for humanity
against the cold. We can cry at a wedding or a birth, seeing heartfelt aspiration but knowing deeply
the fragility of life and love: I hope that the joy I see here will never die, I hope that the world will be
kind enough to let this last forever, I hope that these feelings will survive — but I know very well they
may not.

Tears come when we feel hope and frailty together, as one. I managed to keep myself from writing
this in the medical chart — and that Mateo had no hope left to cry for.

At the other, truly negative, pole of value, tears of sadness in adults also come not with mild losses
from known risks but with sudden adverse personal realizations that must be addressed, and
signaled (recruiting support from the self as well as from others) — like a shock of betrayal, when the
hope we had for the future is shaken and our model of the world, our map of possible paths in life,
must be redrawn. Large brains can contemplate many such possible actions and outcomes,
ruminating and worrying, mapping out decision trees thickly ramified with possibilities projecting far
into the future. But in situations where no positive outcome is possible, a passivity not only of body
but also of mind can be adaptive — a deep discounting of hope, which would otherwise drain
resources from our attentional and emotional budgets. Perhaps it is best to save the striving and the
struggle, and to spare the trouble of tears when hope is gone.

Mateo was not suicidal, but among other symptoms of depression he had prominent hopelessness,
an inability to look forward in time. Without hope for the future, Mateo could only look back. There
was no point in signaling for help; his arms held nothing.

After talking it all over with Mateo and his brothers, we ended up sending him home with them —
and with an appointment for follow-up care and medication — but not before I took the time to carry
out an hour of predawn psychotherapy with him, right there in the ER, laying groundwork. When we
can, we often steal the time to do this in psychiatry, almost instinctively, even during the besieged
rush of an on-call shift. It can be hard to hold us back, as hard as it is to hold back surgeons from
cutting to heal. We do this even knowing we will never see the patient again. I was discharging
Mateo to the care of his family, and to outpatient treatment; in all likelihood our paths would never
intersect again.
 Uvod u biološku psihologiju 2022./2023.

But that night, I had thought I could do something — not much, but something. And that matters —
realizing at a place and moment you have been called to be whatever it is that humanity can be for a
person. That is not nothing.
 Uvod u biološku psihologiju 2022./2023.

4. Good vibrations

On June 17, 2018, Kanwarjit Bhutani stepped out of an elevator with his wife, unaware his life was
about to change. A woman followed the couple from the elevator to the door of their
condominium in New York City. Out of the blue, she recommended that Bhutani see Stanford
Medicine researcher Peter Tass, MD, PhD, about his promising treatment for Parkinson’s — a
vibrating glove.

Bhutani was still processing what had happened when he realized the mystery woman was gone. He
had been diagnosed with Parkinson’s disease nearly a decade before, but only his close family and
friends knew.

“I felt that Parkinson’s was something old people had. I don’t want to be associated with that. I’m not
old, and I was very young — only 39 — when I got the disease,” he said.

For years he’d been managing Parkinson’s while juggling a career as president of several companies,
including Tupperware U.S., Avon and Jeunesse. Then, the disease worsened without warning.

“All of a sudden, I couldn’t work,” Bhutani said. “I basically went into hiding.”

Bhutani scoured the internet for information on Tass’ research and introduced himself over email.
Within minutes, Tass replied. In August 2018 Bhutani and his wife flew to the Stanford campus in
Palo Alto, California, to meet Tass, who assessed Bhutani’s condition and explained the concept
behind the glove.

“Most of it went over my head,” Bhutani said. “It was all la la land, to be honest with you. I didn’t
understand much, but he said, ‘It’s noninvasive.’”

“It was noninvasive and it couldn’t hurt him,” added Bhutani’s wife, Suhkpreet Bhutani. “We had
nothing to lose.”

Parkinson’s disease attacks brain cells that make dopamine, a chemical that is key to nerve
communication for functions like movement, mood and behavior. Drugs that mimic dopamine are
common treatments for the condition.

If the symptoms stop responding to drugs, deep brain stimulation is the gold standard treatment.
The technique targets abnormal brain patterns with electrodes that are implanted into the brain and
linked to a pacemaker-like device. Because of the risks of brain surgery, not all patients are eligible
for or choose the treatment.

Yet, neither therapy is perfect. Drugs and deep brain stimulation are expensive and both can have
serious side effects. They also don’t always work and, even when they do, their benefits can wane. So
it might be hard to imagine that a vibrating glove could be much help.

But a recent study of a small group of patients found that wearing the glove for two hours, twice a
day does just that, alleviating the tremor, stiffness, abnormal walking, slow body movement and
balance problems associated with Parkinson’s.

Although the researchers didn’t set out to study other symptoms, they were surprised to find
patients reported the glove also alleviated mood swings, behavior changes, depression and the loss
of smell and taste.
 Uvod u biološku psihologiju 2022./2023.

“It seemed like magic,” said Stanford Medicine neurobiologist Bill Newsome, PhD, recalling the first
time he saw videos showing improvements for Parkinson’s patients before and after using the glove.

“But Tass’ modeling studies suggest a plausible mechanism whereby fingertip stimulation could alter
abnormally synchronous activity in the central nervous system.”

Convincing the research community the seemingly “magic” vibrating glove has real therapeutic
effects will require further testing, explained Newsome, who holds the Harman Family Provostial
Professorship and directs Stanford’s Wu Tsai Neurosciences Institute.

An old idea refined

The idea of using vibrations to treat Parkinson’s is not new, Tass explained. In the 19th century,
neurologist Jean-Martin Charcot created a vibrating chair after learning that his patients’ symptoms
briefly improved after long, jostling carriage and horseback rides.

Charcot’s vibrating chair, and the vibrating platforms and therapies developed by researchers who
followed, alleviated some symptoms of Parkinson’s, but the results were inconclusive and temporary.

When Tass was a medical student, he became intrigued with self-organization — the seemingly
spontaneous assembly of patterns and structures, such as clouds and snowflakes. He went on to earn
a doctorate in physics and a master’s in mathematics for his research on self-organization, which
revealed potential applications for neurological diseases, including Parkinson’s.

“My goal is to create treatments that are more effective and less brutal on the body by simply
utilizing the self-organization power within the body,” Tass said.

How a buzzing glove could treat Parkinson’s

The symptoms of Parkinson’s arise when large groups of neurons abnormally fire in unison. Using
computer simulations, Tass and his team discovered that a patterned stimulus that vibrates at a
frequency of 100 to 300 hertz (cycles per second) can desynchronize neuron-firing. They called this
coordinated reset stimulation.

Further, Tass discovered how to make the benefits of vibratory stimulus last, something that eluded
Charcot and others who used vibrations to treat Parkinson’s: Pauses are crucial between treatments
and within stimulus patterns.

The body needs to unlearn abnormal neural connectivity patterns, Tass explained. Just as taking
small breaks increases the effectiveness of study or exercise, pauses improve the treatment’s
effectiveness.

Tass explored possible therapeutic effects of the treatment by applying it directly to the brain with
electrical stimuli via deep brain electrodes in studies in monkeys with Parkinson’s symptoms (Annals
of Neurology, 2012) and later in a study of six Parkinson’s patients (Movement Disorders, 2014).

In the 2014 study in humans, coordinated reset stimulation was applied for three consecutive days in
two daily sessions of up to two hours. The researchers found that the stimulation reduced the neural
synchrony associated with Parkinson’s and this correlated with improvement of motor function.

“My goal is to create treatments that are more effective and less brutal on the body by simply
utilizing the self-organization power within the body.”

Peter Tass, MD, PhD, professor or neurosurgery

 Uvod u biološku psihologiju 2022./2023.

Next, Tass and his team set out to find a way to deliver the stimulation without implanting electrodes
in the brain. The solution was to replace electrical bursts delivered through electrodes embedded in
the brain with vibratory bursts delivered through mechanical stimulators to the fingertips.

Fingertips have many sensory neurons, which means a large portion of the sensory cortex of the
brain is dedicated to receiving signals from them. This is important because a noninvasive therapy
must act on a sufficiently large portion of the brain to have similar benefits as deep brain stimulation.
(This is also why fingertips are ideal for Braille, but not tattoos.)

The outcome of this research is a strappy, skin-exposing glove that looks like something out of a sci-fi
film. The glove is lightweight and can be worn while performing regular daily activities. It’s attached
to a device that delivers bursts of 250 hertz (a buzz slightly stronger than a cat’s purr) through pin-
sized openings on plastic pads strapped to the index, middle, ring and pinky fingertips.

Each glove collectively stimulates a patch of skin smaller than a dime.

What’s next for the research?

In April 2021, Tass and his team published the results of pilot studies of patients — including Bhutani
— with mild to moderate Parkinson’s disease in Frontiers in Physiology. In these studies, eight
Parkinson’s patients received vibrotactile coordinated reset stimulation daily for at least three
months (three of those patients received the therapy for six or more months).

The researchers assessed patients’ motor function and obtained at-rest electroencephalographs
before and after the three months of glove therapy using four subcategories — tremor, rigidity,
bradykinesia (slow body movement) and axial (balance). They used EEGs, which measure brain
activity, to investigate the therapy’s possible effects on the abnormal, synchronous neural patterns
associated with Parkinson’s.

The researchers assessed the patients’ movements and brain activity off medication at the start of
the study, at three months, and during follow-up visits approximately every three months thereafter.

These pilot studies revealed that the vibrations were well-tolerated, produced no side effects,
improved the patient’s motor performance and reduced Parkinson-related neuronal synchrony in the
brain.

“There’s currently no middle ground between drugs and invasive treatments for Parkinson’s
patients,” said Leila Montaser Kouhsari, MD, PhD, a movement disorders neurologist at Stanford
Medicine.

“Parkinson’s patients are often really suffering, but symptoms, such as tremor, can vary with stress
and medication fluctuations, so they may not be ready to go all in with invasive procedures. Or,
because of other health problems, they may not be able to get surgery,” said Montaser Kouhsari,
clinical assistant professor of neurology and neurological sciences.

“Depending on how the clinical trial goes, the glove could expand what we have to offer patients. It
could be huge if it helps a lot of patients with no side effects.”

For now, the glove treatment is available only to Parkinson’s patients participating in a clinical trial of
the device that started Aug. 1. Tass is also working with an industry partner to gain U.S. Food and
Drug Administration clearance for the treatment, which he hopes to have by summer 2023.

“Depending on how the clinical trial goes, the glove could expand what we have to offer patients.
It could be huge if it helps a lot of patients with no side effects.”
 Uvod u biološku psihologiju 2022./2023.

Leila Montaser Kouhsari, MD, PhD, clinical assistant professor of neurology and neurological
sciences

Newsome said the new trial is one of many important next steps: “The therapeutic effects need to be
documented in a larger group of patients.” More research will be needed to identify which
Parkinson’s patients are likely to benefit from the therapy, he said.

“Although much painstaking research remains to be done, this therapy is potentially game-changing
because it is completely noninvasive,” Newsome said.

Before Bhutani used the glove as part of the study published this year in Frontiers, his Parkinson’s
symptoms included muscle contractions, loss of taste and smell, inability to speak above a whisper,
mood swings, and obsessive-compulsive buying behaviors. Each day he took 25 medications — some
to treat Parkinson’s and others to alleviate the side effects of the other drugs.

At the beginning of his treatment, Bhutani wore the glove for two hours every morning, and two
hours in the afternoon or evening.

Within three weeks, he said, his sense of taste and smell returned, and he was able to work in the
garden again. Bhutani also reduced the drugs he was taking to 10 medications a day, and his muscles
became less rigid and stiff, which restored his ability to show emotion with his face.

Bhutani still uses the vibrating glove, but not as often as he did initially because the benefits are
lasting longer.

“In November 2018, I ran my first marathon,” Bhutani said. “It was a dream come true.”

His mood has also improved. “I feel my quality of life has come back. And I’ve got a very strong
caregiver,” Bhutani said, smiling at his wife. “She has been by my side … I’m grateful to her.”

He’s also grateful to the mystery woman who suggested he contact Tass in the first place. Bhutani
tried to discover her identity to thank her, but he never saw or heard from her again.

“I don’t know who she was, but she changed my life,” Bhutani said.
 Uvod u biološku psihologiju 2022./2023.

5. Sounding the mental health alarm

For many Americans, aspects of ordinary life — working in an office, going to school, eating inside a
restaurant, hugging a friend — still feel impossibly unsafe.

Amid continued uncertainty about when the COVID-19 pandemic will be brought under control,
Stanford mental health experts are planning for the psychological fallout of having an entire
population under prolonged stress.

“We’ve all been talking about virus surges. What we’ve been preparing for in psychiatry is a surge in
mental health problems,” said child and adolescent psychiatrist Victor Carrion, MD, director
of Stanford Early Life Stress and Resilience Program.

Such a surge was well underway as early as March and continues today. In late March, the Kaiser
Family Foundation conducted a poll asking American adults whether pandemic-related worries were
harming their mental health; 45% said they were. By the end of July, that figure had risen to 53%.

Other indicators, such as more phone calls to hotlines designed for reporting child and domestic
abuse, worry experts, too.

The emotional consequences of the pandemic will vary, said Carrion, the John A. Turner, MD,
Endowed Professor for Child and Adolescent Psychiatry. Some people are discovering strengths,
including the capacity to adapt to the strange circumstances and support their loved ones.

But others are finding their coping skills overwhelmed. This group could experience increases in post-
traumatic stress disorder, anxiety and depression, as well as greater rates of substance abuse and
domestic violence.

Although the pandemic affects everyone, certain groups are more vulnerable, including the young,
older adults, people with pre-existing mental health conditions, individuals adversely affected by
racism or gender discrimination, frontline health care workers, and people experiencing economic
losses. Stanford psychologists and psychiatrists are using a variety of tactics to help.

How do disasters affect us?

Previous research on the mental health status of those who survive wars, natural disasters and other
catastrophes shows that, although they might feel distressed, the majority of people recover without
long-term psychological problems. The Stanford experts are seeing this in their day-to-day
interactions during the pandemic.

“I’ve been pleasantly surprised by how resourceful people have been,” said Shaili Jain, MD, clinical
associate professor of psychiatry and behavioral sciences. “I’ve had conversations with people who I
was concerned about, but they are doing well.”

Still, she knows that losses during the pandemic will tip some people from successfully coping into
being unable to adapt, with mental health consequences that include PTSD, which is characterized by
flashbacks, avoidance of circumstances that resemble the original trauma and emotional numbing.

“I think people have experienced micro-traumas: loss of a way of life, perhaps a job, maybe their
perception of how safe and predictable the world is,” she said. “And it happened suddenly. The
sudden bit is what I, as a PTSD specialist, associate with a traumatic response.”
 Uvod u biološku psihologiju 2022./2023.

Depending on their proximity to a disaster — whether they’re a victim, rescue worker or member of
the general population — 5% to 40% of people will experience PTSD. The number rises to nearly
100% in certain situations, such as among children who witness random acts of extreme violence.
Incidences of major depression and substance abuse also increase after a disaster, especially in
people who have a history of these conditions.

“PTSD correlates closely with economic adversity and unemployment,” Jain said. “We know trauma
trickles down in financial hardship. Intimate partner violence and family violence go up. We’ll see the
downstream consequences in the weeks, months and years ahead.”

Historically, for every 1% increase in unemployment among adults, there is a 25% increase in child
neglect and a 12% increase in physical abuse of children, Carrion said. Unemployment reached its
highest level since the Great Depression, jumping from 3.5% in February to 14.7% in April before
declining to 8.4% in September.

After an initial decline in calls to trauma hotlines during the earliest days of shelter-in-place orders,
child abuse reports rose 22% by the end of March with 70% of reporters identifying abuse
perpetrators as family members. Reports of child-abuse injuries in emergency departments also rose.

For people in more stable and safe situations, pandemic-related isolation is still likely to tax their
emotional health.

This is especially true for people at vulnerable life stages, such as young children, who need
interaction to build social skills; teens, who thrive on feeling valued by their peers; new parents, who
need in-person help from friends and family during the exhausting newborn days; family members
caring for vulnerable adults; and older adults, who are more likely than other age groups to live alone
and are more medically susceptible to the novel coronavirus.

“Isolation is very much related to depression, which has significant impacts on health and can lead to
suicide,” Carrion said.

With kids, he added, stress doesn’t need to rise to the level of trauma to harm well-being. “We worry
about developmental milestones that may be delayed because play and other social interactions are
limited.”

Even people with social phobias, who might initially have felt relieved to stay home, can be hurt by
isolation, Carrion added: “If people have intense, persistent fear of being embarrassed by others,
isolation maintains that anxiety and strengthens the association between anxiety and socializing.”

How to get through

With a resolution to the COVID-19 pandemic still distant, Carrion, Jain and their colleagues are
helping others cope.

“Humans can cope with incredibly stressful situations when they feel they’re empowered to deal
with it,” Jain said, noting that good social support is a key protective factor during and in the
aftermath of stressful events.

Jain worries about frontline health workers because they’re especially likely to show delayed
psychological responses; there have even been high-profile instances of health care workers dying by
suicide during the pandemic.
 Uvod u biološku psihologiju 2022./2023.

Not only are they under extraordinary strain from the uncertainties of treating an infectious disease
but health care professionals are also accustomed to temporarily sidelining their emotions to focus
on patients’ distress, she said.

“It’s normal, in the moment, to leave the processing to later, but I think the processing has to
happen,” Jain said. “When they’re ready to do it, it’s really good if people are met with a spirit of
openness and compassion from whomever they want to share with.”

One early effort to provide such support was led by Debra Kaysen, PhD, professor of psychiatry and
behavioral sciences, and Ryan Matlow, PhD, clinical assistant professor of psychiatry and behavioral
sciences.

Using principles of psychological first aid, a concept developed by the National Child Traumatic Stress
Network in response to disasters, Kaysen and Matlow trained a few dozen colleagues to lead one-
hour “connect and recharge” groups online. The groups were offered from March to June for all staff
at Stanford Healthcare and Stanford Children’s Health.

“We started each session by offering some psychoeducation — ‘Here are the expected responses to
a global crisis’ — to normalize what was happening, and really just give people a space to talk about
what was going on,” Matlow said. Participants then discussed their specific concerns and planned
strategies they could use to manage stress and meet their own emotional needs.

“Children are not resilient just by nature of being children.”

Session facilitators encouraged them to find time for their favorite healthy modes of coping, such as
exercise, meditating, improving sleep or making time for a phone call with a supportive friend.

The sessions also included opportunities to problem-solve about common challenges, such as how to
manage conflict at work or at home when everyone around you is stressed out. Session leaders
connected participants to other mental health services if necessary.

Evidence suggests that we can all benefit from emotional support, and that we should keep up with
phone calls, video chats and other connections to the people we care about. There may even be
hidden social benefits to the pandemic because, unlike previous disasters, it affects everyone. Jain
hopes that the shared experience will boost empathy for people in difficult circumstances.

Social support is especially important for kids and teens, Carrion said. “Children are not resilient just
by nature of being children,” he said, noting the common misconception that children automatically
bounce back from bad experiences.

Although a consistent predictor of children’s resilience is having at least one adult in their lives whom
they can count on, other factors also foster resilience, such as perseverance, the ability to think
about multiple things at once and consciously regulating emotional responses. Adults can encourage
and facilitate these skills by modeling them and by engaging with the children in their lives.

Right now, parents can set their children up for a healthy reaction to the pandemic by giving age-
appropriate answers to their questions about the COVID-19 crisis, listening to and helping assuage
their fears, helping them maintain virtual connections to friends, and giving them a sense of agency
— even if it’s simply letting them pick a new ice cream flavor for dessert.

“I have been surprised to see how well many children coped with the early phase,” Carrion said.
“During the first phase of our shelter in place, they may have enjoyed being home and having their
 Uvod u biološku psihologiju 2022./2023.

parents around a bit more. But as our crisis continues and this is now becoming a chronic stressor,
we need to be vigilant of children’s reactions.”

For teens, maintaining some normal social markers of healthy adolescent development is important,
too. Carrion recommends giving them space to interact with their peers without parents around,
such as leaving them alone to video chat with friends.

It is also important to recognize their opinions and thoughts about current events by including them
in conversation and encouraging them to record or write about their experience.

“Many healthy ways of coping have been taken away. Things like support groups, Alcoholics
Anonymous meetings, going to the gym for a workout: People really rely on those.”

To help support people across California, Carrion is rolling out a statewide program to teach
psychological first aid and skills for psychological recovery to counties’ mental health staffers.

Tailored to address pandemic-related stressors, this psychological training is intended for

psychologists, psychiatrists, social workers, people who answer calls to crisis hotlines and anyone
interacting with clients, including receptionists and clinic managers at county behavioral health
clinics. The sessions began in September.

“The staff are being equipped to do a basic stress and resilience intervention so they can treat their
clients and communities,” Carrion said.

Carrion also helps disseminate information for parents about how to look after themselves and their
kids, and how to communicate with children on challenging subjects, such as the pandemic and racial
injustice.

He’s been a key source for local and national media stories on the topic, and is conducting online
seminars for a variety of audiences.

It’s also important that people who already have mental health diagnoses continue receiving
treatment during the pandemic, he said.

Many mental health providers have been able to transition to phone or videoconference
appointments, though Carrion noted that barriers to treatment accessibility are far from over. (Pre-
pandemic, two-thirds of the children in America who needed mental health services did not get
them.)

And self-care is more important than ever, experts say, including getting enough sleep and exercise
and eating well; moderating screen time; and engaging in restorative experiences such as meditating,
praying or spending quiet time in nature.

“Many healthy ways of coping have been taken away,” Jain said. “Things like support groups,
Alcoholics Anonymous meetings, going to the gym for a workout: People really rely on those. And
little organic opportunities for social interaction that lift up your day are no longer there.”

In light of all this, Jain stressed the importance of being kind to yourself. In a phone call this spring,
Jain’s elderly mother was lamenting the cancellation of their family’s summer plans and Jain gently
reminded her to acknowledge what she had achieved: “I said, ‘Mom, you’ve kept yourself alive, kept
Dad alive, and neither of you has gotten sick. That’s a huge accomplishment.’”
 Uvod u biološku psihologiju 2022./2023.

6. NEUROSCIENCE OF NEED

IN THE PAST 10 OR 15 YEARS, there’s been a shift in thinking about addiction, to a new appreciation
that it is, at its root, a maladaptive form of learning. And like learning to ride a bike, addiction is not
quickly unlearned.

If you think quitting is a simple matter of willpower, you’re in good company. More than a third of
the general public agrees, according to a 2008 survey by the federal Substance Abuse and Mental
Health Services Administration. But it’s tougher than that.

“It’s kind of like putting on a lot of weight,” says Keith Humphreys, PhD, a Stanford professor of
psychiatry and behavioral sciences who has served as a senior White House drug-policy advisor.
“Your body changes, and from then on losing weight is way harder than it ever was before you got
fat in the first place. Because addiction-associated brain changes are so enduring, a lot of people are
going to relapse. So the course of treatment has got to be longer-term than it often is.”

Some of the key biological insights were made by Stanford neuroscientist Rob Malenka, MD, PhD,
who continues his studies using animal models to extrapolate to humans. And now others, like brain
imaging expert Sam McClure, PhD, are finding that changes Malenka sees in rats take place in
humans as well.

This new understanding of addiction’s long-term grip has policy implications: A short-term detox stint
to rid the body of the unwanted chemical just won’t cut it. Authorities have to be prepared to treat
addiction as they would any chronic disease, even though that implies long-haul and therefore
costlier treatment (it’s still a lot cheaper than imprisonment). An equally important implication: They
must also try their best — from both health and cost standpoints — to prevent people from starting
down that lonely, dangerous road in the first place.

UNFORGETTABLE

There are things you don’t forget, and there are things you can’t. For people who become drug
addicts, the drug experience — the substance, but the entire “scene” too — is not only unforgettable
but indelibly etched into the physiological brain circuitry that drives us onward through the obstacle
course of existence.

And much of that memory is false. Because all addictive drugs appear to share a rather mysterious
property: They’re “better than the real thing.” Better, that is, than the real things our reward circuitry
was designed by evolution to reward: food, sleep, sex, friendship, novelty, etc. And better, even, than
they were the last time around. At least, it sure seems that way to the addict.

About 25 million Americans are addicted to drugs (including alcohol but excluding nicotine), about
the same number as those who have diabetes. But wanting a drug — really, seriously craving it —
doesn’t mean you have to like it. “That’s a big part of the problem of addiction,” says Malenka, the
Nancy Friend Pritzker Professor in the Department of Psychiatry and Behavioral Sciences. Malenka
was among the first investigators to home in on the molecular details of just how the mechanisms
involved in memory and learning are hijacked by drugs of abuse.

Addictive drugs mimic natural rewards such as food and sex by kindling a network of brain areas
collectively called the reward circuitry, which is responsible for enjoyment — which if you think
 Uvod u biološku psihologiju 2022./2023.

about it, is an important survival response. It gets us to do more of the kinds of things that keep us
alive and lead to our having more offspring: food-seeking and ingestion, hunting and hoarding,
selecting a mate and actually mating.

Moreover, addictive drugs fire up the reward circuitry in a way that natural rewards can’t — by, in a
sense, pressing a heavy thumb down on the scale of pleasure. Over time, the desire for the drug
becomes more important than the pleasure the addict gets from it. By the time the thrill is gone,
long-lasting changes may have occurred within key regions of the brain.

The brain is a little bit like the big snarl of tangled wires snaking their way out of that six-outlet surge
protector behind your bed. They know where they’re going, even if you don’t. Nerve cells (or
neurons, as scientists call them) can be seen as hollow wires transmitting electrical currents down
long cables called axons to other neurons.

Addiction was once defined in terms of physical symptoms of withdrawal, such as nausea and cramps
in the case of heroin or delirium tremens in the case of alcohol, which reflect physiological changes
within cells of an addict’s body. It’s now seen as changes in brain circuits, or combinations of
neurons; in other words, the very neurophysiological changes that result from learning and
experience. You crave, seek and use a pernicious drug again and again because you have a memory
of it being more wonderful than anything else, and because your brain has been rewired so that,
when exposed to anything that reminds you of the drug, you will feel rotten if you don’t get some.

“These are symptoms of a brain disease, not a mere weakness of will,” Malenka says. He and other
researchers are working to understand addiction as a sum of behavioral consequences of changes
within nerve cells that occur with repeated drug use. Over time, these subcellular changes alter the
strength of connections in the circuit, essentially hardwiring the yen for drugs into a habitual craving
that is easily reignited not only by the drugs but also by environmental cues — people, places, things
and situations associated with past drug use — even when the addict hasn’t been anywhere near the
drug or the drug scene for months or years.

SERENDIPITY STRIKES

In the 1950s James Olds, PhD, a postdoctoral researcher working with psychologist Peter Milner,
PhD, at McGill University in Montreal, was conducting experiments to try to assemble a wiring
diagram for some of this complicated brain circuitry. They were using a then-new technique, based
on the understanding that neurons are at heart electrical critters, that came down to sticking
electrodes (painlessly) into a rat’s brain, running an electric current and seeing what happened.

YOUR BRAIN HAS BEEN REWIRED SO THAT, WHEN EXPOSED TO ANYTHING THAT REMINDS YOU OF
THE DRUG, YOU WILL FEEL ROTTEN IF YOU DON’T GET SOME.

At one point Olds and Milner were shooting for an area of the brain called the reticular formation, an
archipelago of interconnected clusters dispersed throughout the brain and involved in arousal and
attention. But they missed and hit another circuit by accident. They discovered that when they
stimulated this circuit, the animals loved it.

So the investigators tried something new. They taught the rats to press a lever in order to deliver
shocks to their own brains, and recorded the points in the brain that rats liked to electrically
stimulate over and over again by pressing that lever — and press it they would, sometimes for hours
on end, to the exclusion of just about anything including eating or drinking. (Of course, the rats
couldn’t move the electrodes from one part of their brain to another. So Olds and Milner did that for
them.)
 Uvod u biološku psihologiju 2022./2023.

Point by point, Olds and Milner were able to map the network of brain regions, interconnected as
they are by bundles of axons running from one region to the next, that became known as the reward
circuit. To oversimplify things a great deal, this circuit includes nerve bundles that run from deep
inside the brain to spots such as the nucleus accumbens (associated with pleasure), the more
recently evolved prefrontal cortex (involved in decision-making, planning and so forth), and other
places of more ancient evolutionary vintage that control habitual movements and are sometimes
referred to as the “lizard brain.”

A brain, viewed from behind in two planes, showing the pathways implicated in addiction. The
pathway travels from dopamine neurons (central) to areas in the striatum.

But what flips on the reward circuit in regular life, when electrical zaps to the brain are blessedly few
and far between? The same chemical that’s triggered by dope. It’s called dopamine.

DOPE FIRES UP YOUR DOPAMINE

Dopamine is one of a growing number of known neurotransmitters, substances neurons produce for
the purpose of relaying information from one neuron to the next. Different groups of neurons
manufacture different neurotransmitters, which all work pretty much the same way but in different
nerve bundles and with a spectrum of different results. These substances are stored inside numerous
tiny bulbs budding from points along a neuron’s long, electricity-conducting axon at key contact
points the neuron shares with other neurons.

When an electrical signal roaring down the axon’s surface rumbles past one of these little bulbs,
myriad molecules of neurotransmitters get squirted into the surrounding space. They diffuse across
that space (called a synapse) to specialized receptors on the abutting neuron, where the interaction
can either set off (enhance) or shut down (impede) a new electrical current in the downstream
neuron.

These dopamine-squirting neurons constitute a tiny fraction of all neurons. But each of them can
network with up to 10,000 or more other neurons stretching to the far corners of the brain. A dollop
of dopamine in your tank can really boost your reward mileage, so to speak.
 Uvod u biološku psihologiju 2022./2023.

Once dopamine’s centrality to the neurons constituting the reward circuit was worked out, people
started wondering whether drugs might activate the reward circuits. It turned out that they do.

“One reason that the advances in our study of the neurophysiology of addiction so far exceed our
understanding of other psychiatric disorders is because the animal models for addiction are
extremely good,” says Malenka. Teach a rat to press a lever for an infusion of a drug of abuse, and
you will see the same compulsive behavior in the rat that you would in a person. “A rat will work very
hard to get drugs,” he says. “It will press that lever hundreds, even thousands, of times and endure
pain and suffering to get drugs.”

In this rear view of the brain, the colored areas show the origin of the dopamine neurons in the
midbrain.

As these animal studies have shown, virtually all abused drugs — for instance, heroin and other
opiates; cocaine, amphetamines and other psychostimulants; nicotine; and alcohol — operate by
interfering with the reward circuitry. They cause the release of dopamine in target structures such as
the nucleus accumbens, that key structure in the experience of pleasure.

Different drugs do this in different ways. Cocaine and amphetamines prolong the effect of dopamine
on its target neurons. Heroin inhibits other neurons that inhibit these dopamine neurons. (In the
logic circuitry that is the brain, a double negative roughly equals a positive.)

HIJACKING THE REWARD SYSTEM

You might think that the more you eat, or the more sex you have, or the more good vibrations you
get, the more dopamine your reward-circuit neurons will squirt at their target structures in the brain.
But it’s not so simple.

A seminal 1997 Science paper by P. Read Montague, PhD, at Baylor postulated that what really gets
the reward circuitry jazzed up isn’t so much the good vibes as it is the extent to which the goodness
of the vibes exceed expectations.

The newer theory was based on animal studies involving lever pressing, with a twist. In this case, the
test animal learns that if it presses a lever after it receives an environmental cue — to wit, a light
goes on — it will get a reward: say, a nice slice of apple or a drop of juice, both of which rats love. Of
course, the animal soon learns to reach for the lever the instant the light goes on. With repeated
 Uvod u biološku psihologiju 2022./2023.

exposure, the rat gets the hang of it, and a few interesting things happen inside its brain. First of all,
the reward itself (the food) no longer produces the dopamine surge associated with reward-circuit
activation.

Second of all, it is now the light, not the food, that triggers the activity in the reward circuit. The
timing of the reward-circuitry’s dopamine squirts has shifted from the time of reward delivery to the
time of the cue (the essence of the so-called “conditioned response” familiar to anyone who has ever
taken Psychology 101).

It’s not that the juice or apple slice no longer tastes good. It’s that the reward circuitry is responding
to the difference between what we expect and what we get. How much dopamine gets secreted
depends not on how great the reward is, but on the degree to which it meets expectations. The juice
still tastes great, but it’s no longer a surprise; it’s predictable. However, the light’s timing can’t be
predicted. It’s always a surprise, and (as the animal now knows) it’s always a prelude to something
good.

The reward circuitry is always secreting dribs and drabs of dopamine. If an experimental animal gets
a bigger-than-expected reward, the frequency and amount of dopamine secretion increases; if it’s
smaller than anticipated (or if the light goes on but the animal’s frantic lever-pressing brings no juice
at all), dopamine secretion drops below baseline levels. Moreover, this depression in firing rates of
dopamine-secreting neurons occurs precisely when the anticipated reward should have come, but
didn’t. Thus, the brain seems to interpret the absence of the expected reward not merely as a lack of
enjoyment but as a punishment. (How does a rat spell “disappointed”?)

Sam McClure, an assistant professor of psychology at Stanford who studied under Montague, has
been imaging human brains to visualize connections between the regions that constitute the reward
circuit. “Variations in dopamine levels tell all kinds of structures in your brain when something you
want is within reach, getting closer, slipping away or not working for you anymore,” he says.

At least that’s the way it’s supposed to work. Cocaine, heroin and other abused substances usurp this
system. And they do it in a really creepy, pernicious way: by short-circuiting it.

With normally rewarding things like food and sex, we usually have a pretty good idea of how good it
will be. It’s when the reward exceeds our expectations that the dopamine circuitry really lights up big
time. Conversely, if our expectations aren’t met, dopamine activity drops off.

But cocaine, heroin, alcohol and nicotine directly activate the circuit — they goose dopamine
secretion — regardless of how high the expectation was. “Every time you take it, you activate that
dopamine activity, so you’re getting a readout that says, ‘Wow, this was even better than I thought it
would be,’” McClure says. “It’s always better than you expected. Every single time.” The experience is
remembered as always getting better — even if, paradoxically, it’s actually not so great anymore.
(“Tolerance mechanisms” within the brain can cause a drug’s pleasant effect to diminish with
repeated use.)

THE NEEDLE AND THE DAMAGE DONE

In susceptible individuals, repeated drug use creates the same kind of lasting changes in the
connections among neurons that we get from learning to ride a bike.

One important way our brains snap an experience into long-term memory is by strengthening the
synaptic contacts between neurons in the network that encodes this experience. This involves a
number of biochemical changes in both the bulb protruding from a neuron’s axon and the brush-like
 Uvod u biološku psihologiju 2022./2023.

extension of a nearby neuron. Drug abuse can also cause neurons to sprout brand-new synapses —
for example in the nucleus accumbens, the hotspot for positive emotions. It can weaken synapses,
too. Nora Volkow, MD, of the National Institute on Drug Abuse has shown that the plan-oriented
prefrontal cortex functions poorly in cocaine addicts.

The long-term strengthening of drug-associated memory circuits, combined with that “even better
than expected” illusion addictive drugs foist on users, goes a long way toward explaining what is
probably the biggest problem addicts and those who treat them face: a pronounced tendency to
slide back into the habit. It’s why former White House drug-policy advisor Humphreys believes long-
term treatment is vital.

If you are an addict, not just the drug but also all the associated physical, geographical and social
cues exert a powerful effect, even decades after the last time you were anywhere near the drug: You
walk past the bar you used to get drunk in and see your buddies in there, or you smell cigarette
smoke — or, if you used to inject cocaine or heroin, all it may take is seeing a spoon — and you
experience a craving and risk a relapse. Stress — you lose your job, suffer a divorce, undergo a
financial crisis — can mimic drugs’ influence on the reward circuitry, and is therefore another major
cause of relapse.

WHO’S SUSCEPTIBLE? (WHO KNOWS?)

Only a fraction of people who experiment with drug use get addicted. But virtually all of us have an
intact, functional reward system. So why wouldn’t we all be subject to the tyranny of drug-induced
illusions of “better-than-expected-ness?”

The short answer is that nobody knows enough to be able to single out a potential addict with any
certainty. “There’s no such thing as an ‘addictive personality,’” says Humphreys. “Those 25 million
addicts in the United States have wildly different personalities.” There are, however, obvious risk
factors: genetics, poor social support networks, a sense of having nothing to lose and stress.

One big risk factor, says Humphreys, is the age at which you start using. “We’re the most vulnerable
to addiction in our early teenage years, when our brains are most plastic. So it’s not an accident that
almost every single adult smoker started smoking when they were teenagers. If you start smoking
when you’re 30, you are almost certainly not going to get addicted. But the younger you start, the
more likely you are to keep smoking.

“There are two groups of people who really understand that: prevention professionals, and the
tobacco companies. You want to make addictive substances as inaccessible as possible in the
environment, particularly for young people.”

The biggest risk factor of all, of course, is the initial use of an addictive substance, says Malenka. “It’s
impossible to get addicted if you never take the drug.”
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7. SLEUTH OF THE MIND

OLIVER SACKS HAS OPENED THE EYES OF THE WORLD TO NEUROLOGICAL MALADIES THAT DEFY
EASY MEDICAL EXPLANATIONS. IN HIS PRACTICE AS A GENERAL NEUROLOGIST, PATIENTS MISTAKE
THEIR WIVES FOR HATS, LONG- DORMANT MINDS INEXPLICABLY RECOVER CONSCIOUSNESS AND
RARE BRAIN DISORDERS AFFLICT INDIVIDUALS OUT OF NOWHERE.

In his latest book, The Mind’s Eye, Sacks writes of a variety of visual abnormalities that stem from
neurological accidents. Besides detailing the unusual nature of these disorders, Sacks unveils the
miraculous ways that human beings often adapt and compensate for their illness. He also writes of
confronting his own neurological malady, a condition known as prosopagnosia or face blindness. And
he describes how he has coped since experiencing a radical change in his vision seven years ago.

Diagnosed with ocular melanoma in 2005, Sacks has lost vision in his right eye along with the ability
to see in three dimensions, a sad irony for someone who has long been a member of the New York
Stereoscopic Society. He works surrounded by blown-up copies of documents and magnifying
glasses, putting the final touches on his next book, which will be about hallucinations. The Columbia
University Medical Center physician continues to see patients and still swims every day. He spoke
with Paul Costello, chief communications officer for the School of Medicine, who gets the sense from
talking with him that he’s always swimming upstream.

COSTELLO: In The Mind’s Eye, people surmount incredible challenges: an art dealer whose strokes
leave her without language but is still able to communicate, a novelist who loses his ability to read
but not to write. They seem almost superhuman, with great courage and unusual perceptual skills.
Does coping with neurological problems hone survival instincts?

SACKS: Well, it can. I think any disadvantage can. What do they say, what doesn’t kill one
strengthens one? But I may be guilty of some selection in writing about people who have one way or
another dealt with or transcended their conditions, rather than being beaten down by them.
Obviously, in real life, one sees both.

COSTELLO: The people you write about compensate in many ways. What do we know about the
biological basis of compensation?

SACKS: Living organisms will find ways of accommodating to adverse circumstances. With bacteria,
it’s sort of genetic. In a few generations, you’ll find bacteria that can get nourished by an antibiotic
that would have killed them 20 generations earlier. But in the individual, there’s this tremendous
power to go on regardless, even if you break a leg on a mountain and no one else is there.

But in particular, the brain is enormously resourceful and has all sorts of tricks up its sleeve. For
example, the Canadian novelist who became unable to read: He started to read again and wondered
if his brain was healing. It turned out he was still visually totally unable to read, but unconsciously he
had started to move a finger and then his tongue [on the roof of his mouth], copying what he read.
Since, in this condition, one can write even though one can’t read, he was in effect reading by writing
with his tongue. That sounds weird and wild, but...
 Uvod u biološku psihologiju 2022./2023.

COSTELLO: It does. It sounds so wild.

SACKS: But it worked. There was one point at which he bit his tongue and it got sore and swollen and
he said he couldn’t read for two weeks because of his tongue.

COSTELLO: Would you talk more about the plasticity of the brain?

SACKS: First, one needs to say that the brain and nervous system in general has more ability to
recover and even generate new nerve cells than some of us realized. But also there’s this capacity to
develop new paths in the existing machinery. I encourage patients to explore this and to try to do
things a different way — although, they often discover this for themselves. I will say to patients, “I’m
not sure that I can cure you or I can help this directly. But let’s think about other ways of living, other
ways of doing things, and think positive.”

COSTELLO: When you lost vision in your eye, you began having hallucinations. Do you still have
them?

SACKS: Oh, I do. If I sit here and look up at the ceiling, it is covered with what look like runes or
hieroglyphics. They vaguely resemble English letters or numbers or Greek letters. But I’m used to
that, as I’m used to my tinnitus hissing in my ears, and I pay no attention to it.

COSTELLO: I read that your vision loss also led to a loss of stereovision. How are you coping with
everything looking two-dimensional instead of 3D now?

SACKS: I was rather dangerous pouring wine or tea for some people because I would miss the glass
and pour it into their lap. Sometimes, when shaking hands, my hand would miss their hand by a foot
or so. I think I’ve become more skillful at making judgments with one eye. I mean, people who lose
an eye early can become ball players and aviators. In one’s late 70s, you don’t adapt so easily. I’ve
had particular dangers going down stairs, and I will hold a rail or I will count, I will feel for the next
step with my toe. But even so, I may have an overwhelming sense that there isn’t another step, so I
have to learn to disbelieve my eyes.

COSTELLO: You also write about your face blindness. How did you come to realize that was a
disorder?

SACKS: I don’t think that was until I was an adult and met my brother in Australia whom I hadn’t seen
for 35 years. He was also quite unable to recognize faces, including his own, and places. Then, after I
published The Man Who Mistook His Wife for a Hat, I got many, many letters from people saying
they’d had this sort of thing all their lives and it was often in the family. At that point I realized that
this must be something quite common, but almost never discussed. I think one of my reasons for
writing is to open up a subject so it can be discussed.

COSTELLO: When I read reviews of your new book, critics wrote first and foremost about survival and
compensation and less so about the individual disorders. Is facing adversity what you want people to
focus on?
 Uvod u biološku psihologiju 2022./2023.

SACKS: Well, yes, I think survival is my theme, but I can only explore the theme in a highly specific
way. I think both impulses are there. There’s a great physician, William Osler, who once said, “To talk
of diseases is a sort of Arabian Nights entertainment,” which sounds like a hideous thing to say. But
there is something very interesting about what happens to people, and that’s also very frightening.
It’s also inspiring to know how people deal with it.

This interview was condensed and edited by Rosanne Spector.

 Uvod u biološku psihologiju 2022./2023.

8. POSITIVE CHARGE

Neurologist and psychiatrist Mark George, MD, was studying brain imaging and depression in 1990 at
London’s Queen Square Hospital, a center for neurological diseases renowned for a century as a
hotbed of discovery, when he bumped into a man in an elevator with an astonishing report.

“He said, ‘You’ll never believe it, but this person put a magnet to my head, and it made my thumb
move,’” recalls George, who was fresh from South Carolina, where he’d just finished residencies in
neurology and psychology. In fact, the man was part of a study in which researchers were
experimenting with magnets to treat malfunctions of the brain’s motor cortex — the part of the
brain that controls voluntary movements.

The encounter left George, then in his early 30s, with the “crazy idea” that it might be possible to use
magnets to influence the brain in other ways and perhaps alter an individual’s mood. After all, he
thought, if a magnet could stimulate the brain enough to cause movement, might it be possible to
position it over a spot where it might affect feelings and emotions?

Back in the United States, George took a research position at the National Institutes of Health and
persuaded his boss to let him test the theory in healthy people, aiming magnets through their skulls
to the area just behind their foreheads — the site of the prefrontal cortex, the brain’s planning and
decision-making center. Scientists then were just learning about the brain’s interconnectedness, so
he speculated that in stimulating the cortex, he could reach deeper structures involved in depression
and other mood disorders. It was a risky move, in that scientists were concerned that if magnets
were powerful enough to move a thumb, they could be powerful enough to cause a seizure.

But, notes George, “It could be a window to the cortex and it could make people better.” Now a
professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina,
George became the first U.S. psychiatrist to use the technique, known as transcranial magnetic
stimulation, to treat depression. About 3,000 patients received TMS in the past year, not including
those in research studies, according to estimates from Neurostar, manufacturer of the only TMS
device used for depression.

Psychiatrists are turning to TMS and other forms of brain stimulation as alternatives to drug
treatment, which is often ineffective. Some 20 to 30 percent of people with severe depression fail to
get relief from currently available medications; about 0.5 percent of adults in the United States suffer
severe depression unaided.

“These patients can’t work. They’re not functioning. Their lives are pretty miserable,” says Charles
DeBattista, MD, professor of psychiatry and behavioral sciences at Stanford.

“It cuts across the economic spectrum,” he adds. “We have former CEOs, doctors and university
professors who become debilitated — they can’t think or can’t get out of bed. Sometimes they’ve
lost the will to eat. I have seen patients wither away and die. So we need some options for those who
don’t respond to standard treatments.”

Drugs, together with psychotherapy, have been the mainstay of treatment since the advent of the
first antidepressants in the 1950s and 1960s, followed by the ever-popular SSRIs — medications like
Prozac, Zoloft and Lexapro. But drugs are not foolproof, and some patients either don’t respond or
become resistant to them over time. Moreover, there are few new drugs in the pipeline, says Alan
Schatzberg, MD, professor of psychiatry and behavioral sciences.
 Uvod u biološku psihologiju 2022./2023.

“It’s relatively quiet, and that’s unfortunate. Some companies are pulling out, and a lot of people are
very worried about that,” Schatzberg says. “Some people feel we need better animal models or a
better sense of biology. We need to come up with innovative targets. The bottom line is companies
are investing less, and we’re looking at a potential shortage of new drug options over the next
decade.”

So attention has turned to such techniques as TMS and deep brain stimulation, which involves
placing an electrode in deep brain structures and has long been used to reduce tremors and other
symptoms of Parkinson’s disease. Radiosurgery, used to treat tumors, is also being explored at
Stanford as a treatment for depression.

The stimulation methods rely on the brain’s design as an exquisite piece of electrochemical
machinery. When a nerve cell is exposed to electricity during normal function or as part of
treatment, it opens its gates to a rush of ions, mostly sodium and calcium. This triggers an electrical
impulse that travels down the length of the cell and activates connections with other cells.

With each movement or thought, that process is repeated thousands of times with neurons
communicating via electrical signals in a complex system of circuitry. In depressed patients, the
circuits involved in regulating mood don’t function normally; connections are faulty or lost
altogether. In theory, electrical stimulation may be able to jump-start the process and repair some of
these broken circuits, thus relieving sufferers of their overwhelming despair. It would be something
akin to rebooting an errant computer.

ELECTROSHOCK AND BEYOND

The principle was first applied in the 1930s in the form of electroshock treatment, which delivers a
jolt of electricity directly to the brain. The treatment, known today as electroconvulsive therapy or
ECT, is used in 100,000 Americans annually and remains unquestionably the most effective therapy
for major depression, freeing as many as 80 percent of patients from their symptoms. In the early
days, however, it was crudely applied and subject to abuse, becoming the bête noire of the
psychiatric field. Though it has evolved into a sophisticated therapy, with rigorous patient
safeguards, it has never completely shed its early reputation (immortalized in the 1975 film One Flew
over the Cuckoo’s Nest). Moreover, the treatment can cause some disquieting side effects, including
memory loss and effects on cognition. The fear of side effects and stigma around the treatment are a
deterrent for some physicians and would-be patients.

“So there has been a major effort to develop therapies that can help people with treatment-resistant
disease without significant side effects,” says Brent Solvason, MD, PhD, medical director of
psychiatric interventional therapy at Stanford.

In transcranial magnetic stimulation, a magnetic field passes unimpeded and uncharged through the
skull, creating an electrical spark only when it bumps against neural tissues. As a result, the side
effects — scalp discomfort, pain at the site and temporary headache — are minimal in comparison
with ECT.

Amit Etkin, MD, PhD, a psychiatrist who comes to the field from the perspective of a neuroscientist,
says he was drawn to TMS because he could apply it to manipulate small sections of the brain and
then use brain imaging technology to see the response. That makes it very useful for understanding
brain networks, as well as for treating mood and anxiety disorders.

He sees TMS as the ultimate replacement for ECT, which distributes electricity widely through the
brain, inducing a seizure in patients, and thus requiring anesthesia and muscle relaxers. TMS, on the
 Uvod u biološku psihologiju 2022./2023.

other hand, precisely targets a specific area of about a square centimeter, or the size of a fingertip,
Etkin says. The procedure is done without anesthesia, while the patient is fully awake.

‘IT FEELS LIKE A WOODPECKER TAPPING ON THE SIDE OF MY HEAD. IT DOESN’T HURT. WHEN YOU
GET USED TO IT, IT KIND OF FEELS GOOD.’

The magnetic field quickly loses its potency, so it penetrates only a few centimeters into the skull. But
because the brain is so interconnected, it can have an indirect impact on deeper structures like the
amygdala, two almond-sized nerve bundles that process emotion, memory and fear.

“So you’re stimulating one area, but it has wide effects,” says Solvason, associate professor of
psychiatry and behavioral sciences. Solvason, who has a background in cell and molecular biology,
began experimenting with TMS in 1998 because existing treatments had been of little help to his
patients, he says. He has used the technique in about 100 patients and, together with DeBattista, was
involved in one of the TMS trials that led to Food and Drug Administration approval.

ONE WOMAN’S EXPERIENCE

Like many patients, Myrl, a 58-year-old Pacifica, Calif., resident, turned to TMS out of desperation.
Haunted by depression for more than two decades, she had tried at least 10 different drugs, virtually
everything on the market. Some gave her brief relief, in which she felt like a veil on the world had
been lifted, and she could enjoy a simple walk outside. But then the curtain would fall again.

“It’s paralyzing. There is no motivation there, even though I have lots of interests,” she says. “And
there is the isolation. Sometimes I find it hard to talk. Everything takes energy. It’s just swimming
upstream. Just getting up and taking a shower to get ready is overwhelming. I feel like I’m not really
living — I’m just existing.”

She learned about TMS from a friend and thought it was worth a try. She already had rejected ECT
because of the possible cognitive side effects, including memory loss.

“I didn’t feel I could afford to lose any more brainpower,” she says, as there are days when her mind
feels foggy. “So when I heard about this, I thought, ‘Boy, this sounds really good.’ There wasn’t any
radiation involved. It was pretty benign, and I was willing to try it because I had run out of other
options.”

At the Stanford Mood Disorders Clinic, Myrl, a spare, gray-haired woman in blue jeans, reclined in a
light blue leather dentist’s chair, hands resting on a magazine in her lap. DeBattista attached a 1-inch,
T-shaped plastic strip to her forehead, which helped define the anatomy so he could properly
position the magnet — heavy, figure-eight-shaped coils about the size of two fists. The insulated
magnet has the strength of 1.5 Tesla, similar to those used in a standard MRI, and is placed against
the left side of the head. A wire connects it to a computer, which DeBattista programmed to emit a
series of pulses. Then the magnet began its rat-a-tat-tat, sounding like mini-jackhammer against the
head without actually striking it.

“It feels like a woodpecker tapping on the side of my head,” Myrl reported. “It doesn’t hurt. When
you get used to it, it kind of feels good.”

Her forehead twitched with the pulsing of the magnet. Because of the muscle spasms, some patients
complain of headache or pain at the site, but these typically resolve within a day, physicians say.

Myrl lay there calmly for the 37-minute session, submitting to the treatment without complaint.
When she spoke, it was in a flat tone; her expression rarely changed. As she did crossword puzzles or
 Uvod u biološku psihologiju 2022./2023.

tried to read her Architectural Digest, she received the standard 3,000 pulses, with short breaks in
between. She returned daily for six weeks, as the therapy has to be repeated to achieve any long-
lasting effect.

At the end of her sixth week, she noticed an improvement. Her husband told her she was joking and
laughing more. And an incident with a family member that normally would have plunged her into
depression has left her feeling unruffled. “There is definitely more resilience there,” she says with a
lift in her voice.

She’s also begun thinking about returning to some creative hobbies she’d abandoned, like jewelry
making and decorating. “I just feel excited about doing things that I’d put aside because I couldn’t
enjoy them like I once did.”

The FDA approved the therapy in 2008 on the basis of a trial in 301 patients, including 30 at Stanford,
who had tried all else and failed. Those patients who received TMS were twice as likely (24 percent
versus 12 percent) to get better as those who got a sham treatment, in which a shield prevented the
magnet from penetrating the brain. DeBattista says in daily clinical practice results are even better,
with about half of patients responding. He notes clinic patients are typically on medication (not
allowed during the controlled study), which might magnify the effects of TMS.

“Firing those neurons may help the medication work better,” he says.

One of the limitations of TMS, which is available at most academic medical centers and some
community hospitals, is its cost — $8,000 to $12,000 for a course of treatment — which is just
beginning to be covered by insurance.

Moreover, the treatment is still very much evolving, as clinicians are trying to figure out which brain
area to target for best results. Currently, they aim for the prefrontal cortex, as depressed patients
appear to have reduced activity there, says Etkin, an assistant professor of psychiatry and behavioral
sciences. But clinicians now use a very hit-or-miss approach to locate that spot, and about a third of
the time, they miss, he says.

So Etkin has begun a study aimed at making the procedure more exact. For the study, patients lie in a
standard MRI machine while undergoing TMS so Etkin and his colleagues can simultaneously expose
the patients to TMS and obtain real-time data on what’s happening in the brain. Stanford radiologists
have created a special set-up for this purpose, one of the few in the country. This way they can see
which regions of the brain are active during TMS and use that to develop new, more precise targets
and, they hope, improve treatment results.

“One of the things that is shocking about the field is not only do we not know how to target it but we
don’t know how to personalize it,” Etkin says. “We’re really groping at straws in our current method,
which I think will be revolutionized by the combined TMS/fMRI.”

He also hopes the TMS/fMRI study will give clinicians a better understanding of the underlying
mechanisms of TMS. Though it’s believed to act on abnormal circuitry, either suppressing or
stimulating activity there, it could in fact be working through an altogether different mechanism to
relieve patient symptoms, he says.

Etkin is also testing the technique in patients with post-traumatic stress disorder. He’s enrolling 64
PTSD sufferers in a new trial in which he and his colleagues will map brain activity associated with
psychotherapy treatment and with pre-treatment TMS stimulation in various areas in the prefrontal
cortex. He and his colleagues then will look to see where brain activity in response to TMS matches
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brain activity associated with eventual response to psychotherapy. As with depression treatment,
many PTSD patients are helped by psychotherapy — now the most effective treatment — but many
are not, and in the case of PTSD, even fewer alternatives exist. “We can look at our scans subject by
subject and see what’s going on,” he says. He hopes this work will form the basis for either a novel
TMS treatment or a combined, new approach to PTSD, taking advantage of the strengths of both. At
Stanford and other institutions, scientists are exploring TMS for treating other psychiatric disorders,
including obsessive-compulsive disorder and schizophrenia, as well as non-psychiatric disorders, such
as pain, Parkinson’s disease, stroke and tinnitus.

DEEPER TREATMENT

For depressed patients unreachable through TMS, Stanford investigators are looking at another
option: deep brain stimulation. Jaimie Henderson, MD, associate professor of neurosurgery, has used
DBS in some 600 patients with Parkinson’s disease since 1996, when he was involved in the early
trials. Now he’s launching a study with Solvason and DeBattista, part of a multicenter trial in which
they will test the stimulation technique in 10 patients with debilitating depression.

It is in many ways a last-resort option: “You don’t get more invasive than opening up the skull and
putting a probe in the brain,” DeBattista notes. But if it works, it could be a godsend for those who
are simply not able to function otherwise.

The approach is based on work by neurologist Helen Mayberg, MD, at Emory University, and
neurosurgeon Andres Lozano, MD, PhD, at the University of Toronto, whose imaging studies showed
that severely depressed patients had hyperactivity in a region of the cortex known as the subgenual
cingulate, also called Brodmann Area 25. This thumbnail-sized structure, labeled in 1909 by German
neurologist Korbinian Brodmann (who first conceived the idea of mapping and numbering sections of
the brain), is a bit like the brain’s Grand Central station, connecting networks involved in mood,
anxiety, memory and cognition.

In 2005, Mayberg and Lozano began zeroing in on that target, implanting electrodes in five patients.
Later they expanded their testing to 20 patients, with 60 percent of them responding gradually over
six months. Some of the results were striking, with patients doing so well that they were able to
return to work and re-engage in family and social activities.

“Patients described it like the release of a block, the removal of a veil,” Henderson says. “Colors seem
brighter. Things seem more interesting. This all-encompassing feeling of despair is relieved.”

In the Stanford trial, he will implant two electrodes into the target area, one on each side, then
connect these by wire to a battery pack buried in the patient’s chest wall. Patients will be able to turn
the device on and off, making the treatment reversible.

“I’m optimistic,” DeBattista says. But, he notes, “It would be nice to have something less invasive. If
we have a target, we might be able to get to that target without opening up someone’s skull.”

That’s the goal of another small study at Stanford using the Cyberknife, a noninvasive form of
precision radiotherapy used for more than a decade in cancer patients. The therapy, invented by
Stanford neurosurgeon John Adler, MD, uses high-dose precision radiation on a particular target with
sub-millimeter accuracy without harming nearby cells.

Since the spring of 2010, he and Solvason have treated three severely depressed patients with the
Cyberknife in a safety trial, using it to slow down areas of the brain that are too active in the
depressed state. Like the deep brain stimulation trial, this one targets Brodmann 25.
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One of the challenges is finding the right radiation dose to disable the cells, but not kill them, while
maintaining a sustained antidepressant effect, Solvason says.

Yet another option for those resistant to standard therapy is vagus nerve stimulation, in which
clinicians install a stimulator in the armpit and snake the wire to one of the vagus nerves, a major
pair of nerves that run from the brainstem through the neck and down to each side of the chest and
abdomen. These nerves carry messages between the body’s major organs and areas of the brain that
control mood, sleep and other functions. The stimulator is programmed to send out signals along the
nerve, in the form of short bursts of energy, to the brain’s mood centers to help relieve depression
symptoms.

The FDA-approved technique is commonly used in patients with epilepsy, and has been found to be
moderately effective in patients with intractable depression, says John Barry, MD, a professor of
psychiatry and behavioral science who was involved in a major trial on the treatment. But he says the
therapy hasn’t caught on in the psychiatric community, in part because of its high cost — more than
$33,000 for the device alone, not including implantation — which is not typically covered by
insurance.

“It’s probably useful, but I don’t think it’s found its place yet,” Barry says.

Scientists say these techniques still need refinement before they can be counted on for wider use.

“We have a lot to learn,” DeBattista says. “We don’t know what will work in the long term. We have a
lot of brave patients who are desperate and for whom there are no alternatives.”

Etkin says he envisions a time when these patients, rather than spending years on a hopeless quest
of drug after drug, would be referred early on to a specialty TMS diagnosis and treatment center
where they would undergo brain imaging and receive a tailored, personalized treatment using one or
multiple magnets simultaneously targeting superficial structures in the cortex, as well as deep brain
structures. Treatment times would be reduced and side effects minimal. “That would certainly be a
triumph for neuroscience in the clinic,” he says.

E-mail Ruthann Richter