Fear and Anxiety: The Benefits of Translational Research by Jack M. Gorman (American Psychiatric Association) Animals, like people, experience fear and avoidance, which can be reliably observed, quantified, and manipulated in almost all species.
Remarkably, as this volume demonstrates, the neural circuits responsible for the acquisition and expression of fear are conserved throughout phylogeny from rodents through nonhuman primates to humans. Thus, what is discovered about the neuroanatomy and physiology of fear in a mouse can be usefully "translated" to a hu-man with an anxiety disorder.
This breakthrough in both neuroscience and mental health re-search is detailed in 14 fascinating chapters that address conditioned fear in animals, showing the essential role of the amygdala in conditioned fear and of the hippocampus in contextual memory of conditioned fear; the importance of the amygdala in fear responses of nonhuman and human primates, including studies that show that patients with fear and anxiety disorders have lower thresholds for amygdala activation than do control subjects; and the possibility that chronic exposure to fear may have deleterious effects on the brain's structural integrity.
The results of translational research—in which both psychosocial and psychopharmacological approaches have proven effective in reversing not only anxiety disorders but even some changes in the brain—suggest beneficial interventions. Use of these scientific models of brain function allows us to view psychotherapy and medi-cation as complementary rather than antagonistic, with each ad-dressing different parts of the same fear circuitry.
The synthesis of knowledge in this groundbreaking work justifies the optimism of its distinguished contributors that psychiatric re-search is at last in an era in which unprecedented insights will be gained and progress made toward better treatments for fear and anxiety disorders.
Perhaps scientists always believe that theirs is an age of never-before-realized promise and progress, and the unbridled enthusiasm of those of us who work in the area of mental health and illness re-search may one day seem like another of history's examples of wishful thinking. Nonetheless, there are many reasons to assert that the large field encompassed by brain science is indeed undergoing an era of unprecedented developments. That sense was wonderfully reinforced at the 92nd annual meeting of the American Psychopathological Association in March 2002. The topic was fear and anxiety, emotions and behaviors ubiquitous to human and nonhuman life. Three types of evidence were presented: basic neuroscience, neuroimaging of both animals and humans, and careful clinical observation. The result was a true ability to "translate" the work of basic, preclinical, and clinical investigators into common themes, hypotheses, and even concrete conclusions. From this derives our current state of optimism: Never before in the history of psychiatry and psychology have we been able to call on a basic science relevant to the clinical illnesses we are charged with treating. Finally, as occurs in all other specialties of medicine, laboratory and clinical scientists can work together to solve an over-riding problem and make headway toward understanding disorders of emotion, behavior, and cognition.
To be sure, the study of fear and anxiety lends itself to this kind of translational approach. It is difficult (although by no means impossible) to conceive of convincing animal models for depression or psychosis. Animals by and large do not commit suicide, starve themselves, or attend to imaginary voices. Fear and avoidance, on the other hand, can reliably be observed, quantified, and manipulated in almost all species. What is remarkable, as the chapters in this volume reveal, is that the neural circuits responsible for the acquisition and expression of fear appear to be conserved throughout phylogeny, at least from rodents through nonhuman primates to humans. Hence, what is discovered about the neuroanatomy and physiology of fear in a mouse can be usefully translated to a human with an anxiety disorder. Such knowledge surely represents a breakthrough in both neuroscience and mental health research.
At the basic level, we have several papers that focus on a particular type of fear: conditioned fear. This example of classical or Pavlovian conditioning has been elegantly studied in laboratories such as those of Joseph LeDoux of New York University. He and others have convincingly documented that the amygdala is the essential brain structure necessary for an animal to exhibit conditioned fear, and the hippocampus is required for contextual memory of conditioned fear. Two objections have been raised with respect to the relevance of this research to human fear. First, it focuses on only one particular type of fear, the conditioned type. As LeDoux has often made clear, this type of fear was chosen because it is tractable to lab-oratory study. There is much debate about the extent to which fears in humans are learned and whether pathological fear states, such as panic at-tacks and phobias, represent conditioned phenomena. Nevertheless, as other studies show, the applicability of anatomical and physiological findings from studies of conditioned fear to other forms of fear is actually quite robust. Second, the present model of "fear circuitry" has been called unduly "amygdalocentric." I find this criticism unfair. The data clearly show that the amygdala is essential for the acquisition and expression of conditioned fear, but most investigators in the field have pointed to multiple other brain structures involved, including (but not limited to) the hippo-campus, brainstem, prefrontal cortex, and ventral striatum. Once again, the validity lies to some degree in the applicability. Human neuroimaging studies persistently show that although many areas of the brain are activated when an individual experiences fear, the amygdala is the area most consistently energized.
Several of the papers in this volume do indeed add to the mounting literature that the amygdala is an area of the brain that is important in fear responses of nonhuman and human primates. When nonanxious volunteers are shown masked fearful faces, for example, most studies show amygdala activation. It appears that patients with anxiety disorders such as posttraumatic stress disorder (PTSD), social anxiety disorder, and panic disorder have a lower threshold for amygdala activation than control subjects, so that fear cues apparently not capable of registering an amygdala response in most individuals do so in anxious patients.
As if anxiety and fear were not sufficient cause for concern among patients with anxiety disorders, several papers in this volume present the possibility, based on both animal studies and clinical studies in children and adults, that chronic exposure to fear may have deleterious effects on the structural integrity of the brain. The hippocampus appears to be particularly vulnerable to this stress effect, and reports of smaller hippocampal volume in patients with depression and PTSD, although controversial, suggest that this is a matter of concern. Furthermore, animal and clinical studies suggest that damage from stress may not be limited to the hippo-campus but may also occur in regions of the prefrontal cortex, such as the anterior cingulate.
Just as translational research can give rise to concerns that observed negative changes in animal brains might apply to humans, the same strategy can suggest advantageous interventions. Thus, both psychosocial and psychopharmacological approaches are effective in reversing anxiety disorders and may even reverse some of the brain changes. What is perhaps of greatest interest is the way in which the mutually beneficial approaches to treatment—psychotherapy and medication—can be understood as complementary when one refers to the basic scientists' models of brain function underlying fear and anxiety. Rather than being antagonistic, as they once appeared to be, the cognitive-behavioral and pharmacological approaches to treating anxiety are now understood as addressing different parts of the same fear circuitry. For psychopharmacologists like me, this means that cognitive-behavioral psychotherapy can be viewed as a very effective drug.
insert content here