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Despite a dazzling display of the latest knowledge made possible by sophisticated brain-imaging techniques and new genetic knowledge, it took only a single anecdote to remind participants at the two-day symposium "The Science of Emotion" last month at the Library of Congress in Washington, D.C., that humans are, after all, far more than the sum of their separate neurochemical parts.
In a discussion of post-traumatic stress disorder (PTSD), panelist Susan Mineka, Ph.D., a professor of psychology at Northwestern University, described one striking variable that may influence whether someone tortured is likely to develop PTSD. That variable is political activism.
Political activists in Turkey who were tortured developed PTSD at a much lower rate than nonpolitically active citizens subjected to virtually identical torture, said Mineka. The apparent explanation is that the political activists were partially immunized against the most dire psychological consequences of torture both by having expected such treatment if captured and by their belief that this was part of the price paid to advance their political goals. In slightly different terms, the political activists were psychologically prepared for the experience of torture and capable of imbuing that experience with meaning. For nonpolitically oriented prisoners, torture lacked context and was experienced as meaningless brutality.
Although human experience will never be reduced to molecular neurochemistry, molecular neurochemistry has a great deal to say about why things go wrong and what paths may prove fruitful in devising pharmacological and psychodynamic remedies to help people cope with their environment. This was the message of panelists and invited guest Tipper Gore, who gave a keynote address for the symposium.
Dennis Charney, M.D., deputy chair of academic and scientific affairs at Yale University, also discussed PTSD. Sixteen percent of women are exposed to some form of sexual trauma in their lives, and half of them develop PTSD, said Charney. Men suffer sexual trauma and PTSD at about half the rate of women. But whatever the trauma, "once you've been traumatized, you are sensitive to further trauma in your life," said Charney. Those traumatized are neurochemically altered, and the issue for clinicians is whether this change can be reversed or mitigated by treatment.
The amygdala is one key brain structure implicated in PTSD, said Charney. Research has shown that traumatic stimuli activate the amygdala, but that the orbital-frontal cortex exerts an inhibiting effect on this activation. In people who develop PTSD, however, the orbital-frontal cortex appears less capable of inhibiting activation of the amygdala than in trauma survivors who do not develop PTSD, according to Charney.
Research points to other neurobiological differences between those who develop PTSD and those who do not. In monkeys exposed to stress, for example, there are reduced numbers of hippocampal neurons, and in humans with PTSD, magnetic resonance imaging reveals reduced hippocampal volume.
The neurotransmitter norepinephrine facilitates the formation of long-term memory and may preferentially facilitate the encoding of traumatic memory, according to Charney. Propranalol, an antihypertensive that blocks release of norepinephrine, may help prevent PTSD if administered immediately after exposure to trauma, said Charney. The excitatory amino acid neurotransmitter glutamate also appears to play a role in the encoding of traumatic memory, and Charney speculated that it may ultimately prove feasible to reverse or mitigate the impact of stress on the hippocampus by pharmacologically blocking gluta-mate production.
Twin studies and studies of family histories of bipolar disorder suggest a significant genetic component in the disorder, but the complexity of the variables involved have made conclusive findings elusive, observed panelist Raymond DePaulo Jr., M.D., a professor of psychiatry and director of the Affective Disorders Clinic at the Johns Hopkins University School of Medicine. In some cases it has been difficult to replicate earlier findings; further, research on the genetics of bipolar disorder has been complicated by changes in the standard for what is considered "statistically significant," DePaulo said. Scientists "may have to intuit the genetic subtypes" before they will be able to more precisely pinpoint the primary genes contributing to this and other mood disorders, he added. Despite the proliferation of new medications for affective disorders, drug research remains largely empirical, as the state of knowledge in the field is inadequate to the task of rational, theory-based drug development.
Although stress is most often conceived as negative, our capacity to experience events as stressful is "literally essential for survival," observed panelist Philip Gold, M.D., chief of clinical neuroendocrinology at the National Institute of Mental Health (NIMH). If, however, this normally adaptive mechanism becomes "disregulated, if it doesn't turn off when it turns on," it can be disease-producing, said Gold.
When a cat chases a rat, the rat's noradrenergic nervous system is activated, cranking out cortisol and noradrenaline, the latter the precursor to adrenaline, overall producing the classic "fight or flight" response, Gold explained. Hence the capacity to experience fear, in rat or man, is "utterly essential for survival just as [the capacity to experience] pain is essential to survival." While this evolutionary adaptation works well all the way up the animal kingdom, for human beings it can be "a tragedy of evolution," said Gold.
For man, this evolutionary response reinforces the tendency not to "stop and smell the flowers," said Gold, and as such may detract from mankind's capacity to interact harmoniously with the environment. When, under chronic stress, the human stress response becomes inflexible, it becomes harmful.
Gold, who has studied the relationship between depression and heart disease, describes depression as "a particularly cruel disorder in that it deprives those afflicted of the most gratifying aspects of their past and present." It also has a profound adverse effect on biological function, he added.
Melancholic depression, that subtype of depression in which the sufferer focuses on hopeless, anxious thoughts about his or her self-deficiencies, is characterized by insomnia, loss of appetite, loss of libido, and early awakening, said Gold. Physiologically, the individual is experiencing unremitting activation of the sympathetic nervous system, said Gold. "It looks like a stress response that has gotten turned on and has lost its flexibility," he said.
Brain scans of depressed people show increased activity on the left side of the amygdala, a structure in the brain that normally plays a central role in the experience of fear and anger. "We think that the mood and cognitive changes are but the tip of the iceberg of a syndrome," said Gold.
Research has revealed, for example, that depression correlates with significant bone loss in premenopausal women. The death rate for the clinically depressed is double that for age-matched nondepressed people. And as an increasing number of researchers have discovered, the depressed are at increased risk for cardiovascular disease as well as having a poorer prognosis for survival if they develop cardiovascular disease.
Schizophrenia is "a clinical syndrome that represents a number of complex abnormalities of human perception, cognition, and comportment," observed Daniel Weinberger, M.D., chief of NIMH's Clinical Brain Disorders Branch. In addition to suffering from auditory, and often, visual hallucinations, people with schizophrenia fail to grasp context or respond appropriately to routine environmental stimuli.
Neuroscientists are still in a rudimentary state of understanding what goes wrong in the brain of someone with schizophrenia, said Weinberger. Frontal lobe injury replicates some aspects of schizophrenia, including "failure to appreciate the complexities of context." The capacity for integrating context "has been shown to be particularly relevant to frontal lobe cortex brain systems," he observed. Brain scans of those with schizophrenia "suggest the frontal lobes are functionally out of service in some way," Weinberger added.
In a normal person, the frontal lobes respond selectively to stimuli. But in someone with schizophrenia, the hippocampus appears overactive, generating neurophysiological "noise." If someone with schizophrenia engages in a simple activity such as moving the fingers of one hand, there is bilateral activation of the brain, whereas in a normal person, there is only unilateral activation, with the noninvolved hemisphere remaining silent. This observation suggests a "noisy, inefficient" system in schizophrenia in which "cortical cross-talk" creates some of the commonly observed symptomatology of the disorder.
Aided by more sophisticated brain-imaging technology, scientists are now peering within cells at specific molecules to see if the expression of specific molecules correlates with the populations of neurons in specific brain systems, Weinberger said. This may ultimately provide further insight into how both normal and abnormal brains work. -R.B.K.