Figure 4 Scattergram showing the correlation between severity of depression based on total Present State Exam (PSE) scores and proximity of the anterior border of the lesion from the frontal pole. Patients all had subcortical lesions restricted to the basal ganglia, thalamus, or internal capsule (data from Starkstein, 1987, with the permission of Cambridge University Press).
Another phenomenon that has emerged from studies of patients with secondary mood disorders is the significant correlation between proximity of the anterior border of the lesion to the frontal pole and severity of associated depressive symptoms (Fig. 4). Eleven studies have found significant correlations between the proximity of a stroke lesion to the front of the brain and severity of depression as measured by a depression rating scale (Fig. 5). There is only one published study that has failed to identify this clinical pathological correlation, and it did so because patients with very large posterior lesions were included in the study. Some studies have found that this correlation holds for both left and right hemisphere lesions, whereas other studies have found that it is significant only among left hemisphere lesion patients or only among patients with lesions of the anterior portion of the left hemisphere. A recent study demonstrated that the clinical pathological correlation between proximity of the lesion to the frontal pole and severity of poststroke depression is also a time-related phenomenon. During the first few months following stroke, the correlation was significant only among patients with left hemisphere lesions. At 3-6 months poststroke, however, the correlation between severity of depression and proximity of the lesion to the frontal lobe was significant in both the right and left hemisphere.
Although the structural or physiological basis for this clinical-pathological correlation has not been identified, it nevertheless constitutes an intriguing phenomenon perhaps related to mechanisms of
Correlation Coefficient/A-P Distance & Depression
Figure 5 Magnitude of correlation coefficients between severity of depression and proximity of the anterior border of the brain lesion to the frontal pole (left hemisphere or combined left and right hemispheres) for all studies that have examined this correlation. All correlations were statistically significant and the magnitude ranged from relationships that would explain 8% to those that would explain 80% of the variance in depression severity. From Robinson (1998); reprinted with the permission of Cambridge University Press.
depressive disorder. It has been suggested that the pathophysiological basis for this linear correlation between severity of depression and proximity of the lesion to the frontal pole may be a consequence of frontal lesions producing more proximal injury to the norepinephrine- or serotonin-containing neurons and therefore greater depletions of these biogenic amine transmitters. Although other explanations might also be proposed to explain this phenomenon, the fact that multiple investigators have replicated this finding suggests that it may reflect some fundamental mechanism of mood regulation.
In summary, neuroimaging of structural changes in both primary and secondary depression has led to a number of intriguing clinical-pathological findings. Structural abnormalities of brain in primary depression and structural lesions in secondary depression have generally implicated dysfunction of the frontal cortex and basal ganglia in mood disorders. In addition, there may be a laterality effect on depression, with left hemisphere dysfunction associated with depression and right hemisphere dysfunction associated with mania. Alexander and De Long described five frontal-subcortical circuits that appear to play an important role in brain-behavior relationships: Each of these circuits involves the frontal lobe, striatum, globus pallidus, substantia nigra, and thalamus. Findings of abnormalities in primary and secondary mood disorders have suggested abnormalities in the function of one or more of these circuits (Fig. 1). These frontal brain areas associated with mood disorders also contain axonal projections from the biogenic amine-containing neurons located in the brain stem. Thus, frontal or basal ganglia lesions could disrupt function and release of noradrenergic, serotoninergic, or dopaminergic transmissions in the cortex. This combination of basal ganglia and cortical dysfunction associated with disruption of neurotransmitter mediation within the frontal and temporal cortex may provide a common mechanism for both primary and secondary depressive disorder.
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