By Eric J. Lerner
How does the brain integrate the work of billions of neurons
into a single conscious experience? In recent years, brain researchers
struggling towards an understanding of this profound question
have shifted from viewing the brain as a hierarchy of individual
cells to seeing it as a symphony of cooperating assemblies of
neurons. Thinking is thus seen as the shifting pattern in time
and space of the activity of these neuron assemblies.
At the University of Michigan's Mental Health Research Institute
(MHRI), a half dozen researchers, some collaborating with colleagues
in the Department of Psychology, have been using advanced mapping
technology to see how the various tasks that the mind carries
out are distributed within the brain. By analogy, where in the
brain's orchestra are the woodwinds, the brass and the string
sections? These studies have started to reveal how some of the
simplest mental tasks such as recognizing words, objects and
places are carried out, how we keep objects in short term memory,
and how diseases such as depression alter the way we experience
Efforts to map the brain have a long history and much is known
about the locations of certain very basic functions, such as
seeing, hearing and control over muscles. But how these basic
functions become integrated at higher levels, generally in the
frontal part of the brain, has remained mysterious. The development
of new mapping tech-nologies is now allowing researchers to
catch the brain in the act of thinking and, in the process,
is generating new insights that help in the diagnosis and treatment
of brain diseases, as well as in the fundamental effort to understand
the biological basis for mental activity.
While many brain mapping groups have focused on techniques
using the electroencephalogram (EEG) and the magnetoencephalogram
(MEG) that can capture fast brain actions but have poor spatial
resolution, most of the work at MHRI uses technologies that
have much finer spatial resolution, although they average brain
activity over periods of seconds. The different techniques are
complementary and, together, are beginning to form a much clearer
view of how the brain functions.
Photo: Martin Vloet
We feel as well as think with our brains, and our emotions
can be studied by brain mapping, including the way they become
abnormal in mental illnesses. Jon-Kar Zubieta, M.D., Ph.D.,
assistant professor of psychiatry and of radiology, is seeing
how the brain regulates emotional functioning, both in healthy
volunteers and in patients suffering from depression and substance
abuse. "We are focusing on chemicals called endorphins
and how they modulate the expression of emotions in the brain.
We know that these endorphins, which are brain chemical messengers
(so-called neurotransmitters), are involved in adaptation to
stressful situations, and that stress is involved in the development
of depression and substance abuse in predisposed individuals.
We are now capable of labeling the receptors for those endorphins,
using PET scans to examine how and where in the brain these
chemicals are able to regulate emotional reactions," Zubieta
says. Using the mapping technique of positron emission tomography,
small amounts of radioactive materials can be used to trace
neuronal activity, or the concentration of various proteins.
Radiation from these tracers can then be detected and used to
map the location of changes in neuronal function or in those
proteins. (See accompanying article, "Brain maps old and
In one of these studies, Zubieta asks subjects to think about
a sad experience in their life during the PET scan and to recall
that sad emotion. During that experience, there are changes
in the chemical responses of certain regions of the brain, especially
the amygdala and the anterior cingulate. In patients suffering
from severe, clinical depression, those chemical responses are
abnormal, with different patterns than those observed in healthy
volunteers. "We see in these patients large releases of
endorphins in certain areas of the brain, especially in the
anterial temporal lobe, that do not show up in healthy subjects.
However, there is a fair amount of variability in these responses,
with some depressed patients showing changes more similar to
those of non-depressed volunteers."
What is the difference between the two sets of depressed patients,
one with a normal or close-to-normal brain response and the
other with a very abnormal one? "We did not find any correlation
at all with the severity of the symptoms," points out Zubieta,
"but we are finding a relationship with responses to antidepressant
medication. Those with the more abnormal pattern did not respond
to medication, but those with the more normal pattern did."
These findings suggest that abnormalities in brain chemicals
associated with the brain's adaptation to stress may herald
poorer responses to antidepressant treatment. A considerable
number of patients diagnosed with severe depression do not respond
completely to available treatments. The study of these mechanisms
may ultimately improve current treatments for depression.
Photo: Martin Vloet
"Emotions are extremely complex and there is no clear
picture presented by the brain scans — there are no happy
or sad areas that show up consistently," cautions Stephan
Taylor, M.D. (Residency 1993), assistant professor of psychiatry.
Taylor, in collaboration with Israel Liberzon, M.D. (Residency
1992), associate professor of psychiatry, has used brain mapping
to study the relationship of emotions and working memory —
how emotional attachment can affect the ease with which something
is remembered. "What we and other researchers find is
that while specific areas are active in specific situations,
the same emotions will affect different areas in different
experimental contexts." He and his colleagues have been
trying to pull together work done by various groups using
different sets of mapping techniques, but the task is a difficult
as we get more data from brain scans, we will find new and
more subtle ways to characterize emotions that will be far
more accurate than our primitive categories like happiness
Measuring how our brains cope with
Endorphins are not only involved with emotions, they also have
a big effect on pain. Endorphins are also released by the brain
to reduce the sensations of pain. They are chemically related
to powerful drugs like opium and morphine, but are naturally
produced by the body.
Pain management poses a major problem for physicians, because
pain is not objectively measurable. While physicians are aware
that patients with similar physical conditions perceive different
levels of pain, they have trouble taking these variations into
account when prescribing painkillers and other treatment. Is
a given patient really feeling more pain or just less tolerant
Zubieta and his colleagues have taken a step toward objectively
measuring with their PET mapping techniques how pain is regulated
by the brain. They injected the jaws of a group of volunteers
with a saline solution that temporarily produced pain resembling
that caused by temporo-mandibular joint disorder, or TMJ, a
common cause of chronic pain. As a control, they alternated
the saline with injections of a non-pain-causing solution, using
each in a 20-minute cycle. Neither the experimenters nor the
subjects knew if the control or the saline solution was being
used at a given time. The volunteers rated their pain level,
and a computer feedback mechanism adjusted the amount of saline
to maintain the intensity of the pain at a constant level.
In the meantime, Zubieta's team was mapping the release of
endorphins in the subjects' brains with a PET scanner. Says
Zubieta, "We saw an intense release of endorphins activating
their receptors in a number of brain areas, including the anterior
cingulate, frontal cortex, amygdala, thalamus and hypothalamus,"
which are brain regions involved in the processing of emotions
or sensations. The more endorphins that were released, the lesser
the experience of pain as rated by the volunteers.
When the team examined the responses of different volunteers,
they found that some subjects released far more endorphins than
others, and it was those volunteers that subjectively rated
the pain the least. "These differences may show why some
people react to pain differently than others," Zubieta
points out. It also could provide a way to objectively measure
individual subjective responses to pain and to anti-pain medications,
and perhaps help to explain why some chronic pain conditions
like TMJ and fibromyalgia become persistent in some but not
The specialized brain
Edward E. Smith
Photo: Martin Vloet
One of the key discoveries of brain mapping research is how
specialized certain areas of the brain can be, at least in a
given experimental context. Edward E. Smith, Ph.D., senior research
scientist at MHRI and a professor in the College of Literature,
Science and the Arts' Department of Psychology, has been looking
with his colleagues at the way brain regions cooperate to carry
out tasks using working memory. In such tasks, separate regions
appear to be responsible for verbal memory, spatial memory,
and executive functions like selectively attending to some sources
Patricia A. Reuter-Lorenz
Photo: D.C. Goings
Photo: Micheal Marsland
Working memory — the memory we use to keep things in mind
for a few seconds, like phone numbers — lends itself to experimental
studies of brain specialization because it can be tested rapidly
over and over again in short sessions and because it integrates
in simplified fashion some of the basic functions used in
memory generally. Beginning in the mid-1990s Smith and his
collaborators, including Patricia A. Reuter-Lorenz, Ph.D.,
associate professor of psychology, John Jonides, Ph.D., professor
of psychology, and Christy Marsheutz, Ph.D., began studying
working memory using PET scanning.
However, in the past two years, Smith and others have shifted
their work to a newer and more potent mapping technique, functional
magnetic resonance imaging (fMRI), a variant of the familiar
MRI scans. Unlike standard MRI which maps static structures
in the body, fMRI detects changes in blood flow, so it can,
like PET, trace increases in neuronal activity. "There
are many advantages of fMRI over PET," Smith explains.
"The spatial resolution is finer — down to a few millimeters.
Its time response is faster as well, dropping from several
seconds with PET to one or two seconds with fMRI. In addition,
it's entirely noninvasive, requiring no radioactive materials
— which also makes it cheaper to use."
The studies show that as different parts of simple tasks are
performed, different areas of the brain are activated, in varying
combinations. Most short-term memory tasks involve three steps
-memorizing an initial object; rehearsing the memory to retain
it, as when we repeat a phone number over and over until we
dial it; and retrieval, as when a memory is used to compare
the object with a stimulus. These steps can be distinguished
experimentally. For example, a test of pure rehearsal involves
asking subjects to repeat a letter over and over, while pure
recognition might involve matching test letters to a single
letter given at the beginning. A task involving all three steps
might be to look at a group of letters and then a few seconds
later, see if a new letter corresponded to any in the group.
"What we learn by subtracting the areas activated in these
different situations is that there are regions specializing
in each task," Smith says. A specific area called the dorsolateral
prefrontal cortex or DLPFC, is activated mainly when tasks involve
switching attention, such as alternating between recognizing
a letter and a number. Another region on the right side of the
brain is involved only in short-term memory of images, while
another on the left side is involved only in memory of words
and letters. Still others are active only during rehearsal or
recognize portions of the tasks.
But what is still more interesting is the way that the tasks
performed by certain regions changed depending on circumstances,
giving clues to how the tasks were being carried out. In one
test, researchers looked at the areas that were activated in
a test that required subjects to remember the order in which
letters were shown, and specifically how far apart certain letters
were in the order. The work, performed by Marshuetz and colleagues,
showed that the area that became more and more active as the
difference in order increased was the same one that was involved
in numerical calculations. It thus seems that in the brain there
is a close relation between quantity and order, a result that
makes sense, since our basic ideas of numbers seems to have
emerged from counting, an ordering process.
regions indicate the areas of younger and older brains activated
during verbal working memory tasks, demonstrating a higher
degree of left lateralization in younger adults compared
with more bilateral activity in older adults.
from the Primer of Cognitive Aging, D. Park and N. Schwarz,
eds. Reproduced by permission of Taylor & Francis, Inc.
The studies also showed that the harder the task, the larger
the neuronal assemblies that worked on it, and the larger
the flow of blood. For example, when subjects were asked to
compare letters with those that had been seen two or three
tests before, more activity was observed than for the simple
comparison of letters with the immediately previous test.
In accord with our subjective perception, when we are "thinking
our brain is actually burning more energy — perhaps by 10-15
percent — than when we are just resting.
The generalized brain
The specialization of brain function is not the only story that
brain mapping studies tell. As the brain ages, the high degree
of specialization evident in young adult subjects becomes replaced
with a more complex pattern: the older brain seems to be more
of a generalist. One of Smith's colleagues in the Department
of Psychology, Patricia Reuter-Lorenz, has concentrated on understanding
how normal, healthy human brains change with age.
"In one recent series of studies, we looked at short term
memory tasks that involved inhibition," explains Reuter-Lorenz,
"both in a group of adults in their 20s and another group
in their 60s and 70s." Subjects were supposed to respond
to letters they had just seen as part of a group. But to complicate
the tasks, a letter that had been seen in a recent previous
test was shown. Since the letter was familiar, there was a tendency
to respond to it, but this impulse had to be inhibited to provide
the correct answer. For all subjects, response times were a
bit longer for the confusing letters, and delays and inaccuracies
were somewhat greater for older subjects than for younger ones.
(Older subjects' response times increased by about seven percent,
compared with four percent for younger subjects.)
"The interesting result was shown in the brain scans,"
says Reuter-Lorenz. "When the younger subjects were dealing
with the inhibition task, a specific area in the brain was
activated that was not used in the other cases. But in the
older adults, this did not happen — the areas activated in
the inhibition case were just the same as the other cases.
It seems as if the younger brains are using a higher degree
of specialization to get a somewhat faster response time."
Other studies by Reuter-Lorenz and Smith confirm the idea that
human brains become less specialized with normal aging. For
example, the tendency for the left hemisphere to be involved
in verbal tasks and the right in spatial ones breaks down with
increasing age, and areas in both hemispheres become involved
in both types of tasks. "Only certain parts of the brain
are involved in a given task, but there is much more overlap
between the areas involved in one task and those in another
in older adults, and there are more areas involved in each task,"
Reuter-Lornez points out. "We don't yet know the reason
for this. The brain might be compensating for the lower efficiency
of neurons by bringing more of them into a task, or more positively,
the older brain, with a richer base of experience, is using
a richer combination of experiences and skills to perform a
task, even at the expense of doing it slightly slower."
Sick brains and well
The more that brain mapping shows how the normal brain functions,
the more useful it becomes for diagnosing disease as well. Kirk
Frey (M.D., Ph.D. 1984), professor of radiology and neurology
and senior research scientist at MHRI, has shown that PET scans
indicating the uptake of specific neurochemicals can be used
to measure the progression of both Parkinson's and Alzheimer's
diseases and indicate how patients are responding to medications.
"The advantage of PET scanning is that you can see the
very uneven distribution of labeled neurochemicals, a distribution
that is sensitive to brain damage in these two diseases."
By carefully selecting the neurochemical to label, Frey has
been able to distinguish the level of damage in the brain, despite
the brain's attempts to compensate chemically for the damage.
Such studies can provide a test of medication efficiency that
is more objective and accurate than tests of patients' performance.
While brain mapping is being applied for diagnosis, to a large
extent the field remains in its early stages. "We are just
starting to pull together the information from different types
of mapping, such as fMRI, EEG, MEG and PET," Taylor emphasizes.
"It's only in the past few years that we have started to
have good time-and-space resolution and we still have not achieved
both at once." In the next few years, as the growing mass
of brain mapping data is integrated together, a far clearer
picture will develop of how huge assemblies of neurons in different
parts of the brain work together to produce our thoughts and
Two models of the brain
Brain maps old and new