FULL TEXT OF SLIDES, Below
31. The hippocampus is vulnerable to ishchemic damage and to damage from kainic acid induced seizures (Sapolsky and Pulsinelli, 1985;Roozendaal et al., 2001). The former involves the CA1 and subiculum to a greater extent and the latter, the CA3 region, as discussed above. Glucocorticoids exacerbate both forms of damage.
32. Whether or not there is brain damage in depressive illness of long duration, there are other changes in the body and brain that are slow in developing and cumulative in time and cause wear and tear to the individual. However, we must first consider the systems that are responsible for this wear and tear.
33. Depressive illness is associated with an hyperactivation of the amygdala (Drevets and Raichle, 1992;Frodl et al., 2002), and more recently, with an actual enlargement of the amygdala in the first episode of major depression . Since the amygdala integrates information related to fear and strong emotions and also sends outputs via the central nucleus for autonomic arousal and via the basal nucleus for more active aspects of coping, the elevation of amygdala activity may be a first step that leads to overactivation of systems involved in physiological and behavioral coping. The long-term consequences of this may well be a wear and tear on the body that results in a number of pathophysiological consequences.
34. Increased activity of autonomic and HPA axis responses that are characteristic of major depressive illness have a number of cumulative consequences when the conditions of over-activity persist over long times. Cumulative, long-term effects include not only atrophy of brain structures, but also bone mineral loss and abdominal fat deposition. Sleep disruption may be a key feature that lead to these consequences, since even short periods of sleep deprivation in otherwise normal individuals elevate evening cortisol and glucose levels and increase insulin levels and insulin resistance. The combination of long term changes, together with disregulation of the autonomic nervous system, is associated with increased risk for cardiovascular disease.
It should also be noted that this sequence of events may not be unique to major depressive illness but shared to some degree in other long-term psychiatric illnesses. In additon, Cushing's disease, not normally recognized as involving psychiatric complications, shares many of the features in common, In addition, there is evidence that hippocampal atrophy in Cushing's is at least partially reversible over a year or more after correction of the hypercortisolemia (Starkman et al., 1999;Bourdeau et al., 2002).
35. Does stress actually damage the brain? Yes, perhaps it does, but the brain has a huge capacity for adaptive plasticity. This slide presents a summary of the main points of the lecture.
First, glucocorticoids have an important role in normal brain function:
o -We have seen that they facilitate as well as inhibit memory; and they also have biphasic effects on excitability
o -Moreover, excitatory amino acids play a major role in these aspects of adaptive plasticity.
Second, there is extensive structural remodeling of the hippocampus involving neurogenesis & remodeling of dendrites:
o -We must wonder if these are a normal part of brain function as well as action of pharmaceuticals?
o -We must also find out if other brain regions are capable of some degree of adaptive plasticity.
Third, we have seen that stress causes reversible structural remodeling:
o -This involves excitatory amino acids aided by glucocorticoids
o - Given the reversibilty we can speculate that the plasticity may be a protective strategy designed to prevent permanent damage.
36. We have also seen that there is atrophy of a number of brain structures in depressive illness and a number of other disorders. The results of the animal studies raise the question whether the atrophy is reversible.
o We have also seen that there is damage to the brain in stroke and seizures that is caused by excessive excitatory amino acids, aided by glucocorticoids. Insofar as the same combination operates in long-term depressive illness and other psychiatric disorders of long-duration, the question is when and how to intervene to prevent such damage.
o Finally, we have seen a possible sequence of changes in depressive illness :
- Amygdala hyperactivity
- HPA disregulation resuling, at least in part, from disrupation of normal sleep patterns
- Delayed atrophy of hippocampus, bone mineral loss, abdominal obesity
- Increased risk of cardiovascular disease
37. Finally, I am indebted to a wonderful group of colleagues and collaborators for their input and contributions to many of these topics.
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