Scientists Find Connections in the Brain Between Physical and Emotional
290 No.18, November 12, 2003
Poets muse about the agony of a broken heart. Losing a friend hurts,
and rejection can feel like a kick in the gut.
It turns out that
these expressions are more than metaphorical. When
Wake Forest University psychologist Mark Leary, PhD, investigated
the linguistics of pain, he discovered that the overlap
is not a coincidence of English. Each of the 15 languages
he analyzed likened emotional pain to physical harm.
studies have revealed that the emotional
pain of social rejection activates two
brain regions that are also important
in the response to physical pain. Pain
activates the anterior cingulate
cortex, which signals higher brain regions
that impel an individual to act to stop
the pain; social rejection similarly
triggers activity in this region. Activation
of the right ventral prefrontal cortex
appears to help dampen the distress of
both physical pain and social exclusion.
beginning to understand why. It turns out that the
brain processes both experiences in much the same way. While
a large part of how the brain responds to physical pain
remains mysterious, a series of recent discoveries
has unveiled an evolutionary efficiency: the brain
circuits and structures that respond to a twisted
ankle also recognize a stinging rebuke.
For decades, physicians
have known that physical pain and depression are
intertwined. Chronic pain can cause depression, while depression
can heighten pain. In fact, up to 80% of patients with
depression present with mainly physical symptoms
(Am J Psychiatry. 1993;150:734-741).
Thirty years ago,
the first empirical evidence of a neurochemical overlap
between pain and depression appeared when physicians discovered
that small doses of tricyclic antidepressants can ease
chronic pain. The phenomenon is so well-known that tricyclics
are considered a first-line therapy for fibromyalgia and
other poorly understood pain syndromes (Curr Opin
Investig Drugs. 2002;3:454-458). The latest research
continues to bear out the benefit of these older
antidepressants. One recent study found that in patients
with chronic tension headaches, tricyclics work better
than relaxation strategies; combined, the two approaches
proved synergistic (JAMA. 2001;285:2208-2215).
show promise, too. A few clinical studies have found
that drugs that work on serotonin and norepinephrinetwo
neurotransmitters that help regulate moodcan relieve
some chronic pain, including migraine headaches. One review
found that venlafaxine, the best studied of the newer
antidepressants, is just as efficacious against neuropathic
pain as the tricyclic antidepressants, with fewer
adverse effects (Minerva Anestesiol. 2002;68:105-114).
However, a paucity of data led those authors and
others to call for randomized clinical trials of newer antidepressants
for chronic pain.
between mood and chronic pain, then, lies with the
so-called monoamine neurotransmitters, serotonin and norepinephrine.
Cells heavy with these signaling molecules sow axons into
essential mood-regulating areas of the brain. But
these cells also send fibers down the spinal cord,
where they help regulate external and internal sensation,
according to research from Stephan Stahl, MD, PhD,
a psychopharmacologist at the University of California,
When the body
is functioning normally, serotonin and norepinephrine circuits
suppress routine autonomic input, like that from the stomach
during digestion, and somatic input, like that from the
musculoskeletal system. This prevents the brain from wasting
energy on irrelevant details. But in depressed people,
these routinely ignored sensations may reach the
possible that a malfunctioning of these descending serotonergic
and noradrenergic pathways allows routine sensory input
to be felt as uncomfortable or even painful," said Stahl.
"When depressed patients complain of headache, abdominal
pain, or musculoskeletal pain in the lower back,
joints, and neck . . . these sensations have escaped
up the spinal cord and into the brain where they
are interpreted as pain." Stahl recommends antidepressants
with serotonin and norepinephrine action for depressed
patients with pain.
the National Institute of Alcoholism and Alcohol Abuse
(NIAAA) recently published a genetic finding that also
implicates norepinephrine (Science. 2003;299:1240-1246).
In a search for individual differences in response
to pain, the team came across an enzyme, catechol-O-methyltransferase
(COMT), that metabolizes both norepinephrine and
dopamine. Individuals carry one of three versions
of the COMT gene that produces enzymes with
low, medium, or high efficiency.
During their most
recent work, the researchers, led by NIAAA's David
Goldman, MD, subjected 29 people to painful saline solution
injections. Those with the high-efficiency COMT experienced
less subjective pain than those with the low-efficiency
enzyme. Positron emission tomography scans confirmed
the phenomenon: subjects with high-efficiency COMT
displayed more activation of pain-relieving opioid
receptors in certain brain structures than those
with low-efficiency COMT. These differences were largest
in the thalamus, a key sensory relay station, and the amygdala,
which sends out fear and distress signals to other parts
of the brain. Recent animal research also supports the
idea that soothing the amygdala will inhibit pain (Nature.
Perhaps the most
striking example of the brain's parallel processing of
emotional and physical pain comes from a group at the University
of California at Los Angeles (UCLA). Using functional
magnetic resonance imaging (MRI) scans, which produce
real-time maps of blood flow, the researchers found
that social rejection lights up two brain regions
key in the response to physical pain (Science. 2003;302:290-292).
KEY BRAIN REGIONS
The first area,
the anterior cingulate cortex, acts as a neural alarm
system, said Matthew Lieberman, PhD, assistant professor
of psychology at UCLA. Pain, as the most primitive "something
is wrong" signal, strongly activates this area, which
then sends signals to higher brain regions that prompt
the individual to act to stop the pain.
The second area,
the right ventral prefrontal cortex, helps dampen
the emotional distress caused by pain. Activation of this
area lessens pain response in rats, and also appears to
improve pain symptoms in humans given placebo, said Lieberman,
citing his team's own unpublished work.
It turns out that
these two regions also activate during social rejection.
To test this idea, the UCLA team recruited subjects to
play a game of "cyberball" while inside a functional MRI
scanner. Participants were told that they would be throwing
a virtual ball to two other study subjects. They were
then scanned as the other playerscomputer simulations,
reallystopped throwing the ball to them.
The results were
dramatic. As a participant felt more excluded, the
anterior cingulate cortex became more active.
"This was a powerful
response," said Lieberman. "Anything that looked
like exclusion triggered it."
the person felt less excluded when the ball was thrown
to them, the right ventral prefrontal cortex displayed
more activity. In other words, said Lieberman, the prefrontal
cortex area dampens the distress signal sent from the
anterior cingulate cortex.
He said that the
study provides compelling evidence of the evolutionary
piggybacking of social attachment to pain response. Because
young mammals need to be near their caregivers to survive,
it makes sense that their brains register painlike
alarm in response to rejection or exclusion. The
area of the anterior cingulate cortex most activated
by rejection, said Lieberman, overlaps with the area
activated by internal, rather than external pain. That
means rejection "feels more like a punch in the stomach
than a broken arm," he said.
PhD, a neuroscientist at Bowling Green University in
Bowling Green, Ohio, said that the study by Lieberman and
colleagues marks the first attempt to map emotions onto
pain centers in the human brain. Since the 1970s,
Panksepp has studied the neurochemistry of emotion
in rats and other laboratory animals. His most robust
finding is that small doses of opioids diminish the
cry response in young animals separated from their parents.
Again and again, "trickle doses" of opioids soothe the
frightened animals. "The animals are not simply being
drugged," he said, because the animals do not act
like to see the UCLA group explore similar research; he
thinks that opioids may well dampen the anterior cingulate
cortex during the cyberball challenge.
of years, sensitive physicians have known that opioids
ease social pain," said Panksepp, who wrote a commentary
that accompanied the UCLA report (Science. 2003;302:237-238).
abuse opioids may simply be searching for an ersatz
social balm, a replacement for human warmth. In the same
vein, those suffering from depression and other emotional
pain could conceivably benefit from small doses of
opioids. Although the idea is controversial, Panksepp
is among a group of researchers who believe this
line of research could bear fruit.
"We might just
discover a whole new type of antidepressant," he