Review ArticlesFrontostriatal deficits in unipolar major depression
Introduction
With an estimated life-time risk ranging from 5.2%–19% 95, 162, compared to a risk of approximately 1% for schizophrenia [85], major depression is a relatively common psychiatric disorder. The term “major” depression has historically been linked to endogenous etiology, as opposed to minor depression (i.e., that due to exogenous factors) [71]. Current systems of classification do not assume this, however, and neither DSM-IV [4] nor ICD10 [165] explicitly differentiate between endogenous and nonendogenous depression.
In addition to its effects on mood, major depression is associated with deficits in neuropsychological functioning. While patients with depression have been found to show deficits in a wide range of neuropsychological tests 54, 136, this review will focus on those deficits that are suggestive of prefrontal dysfunction. The prefrontal cortex is involved in so-called “executive function” or the capacity to organize cognitive-specific resources to allow development of contextually sensitive plans and flexible responses 8, 21. There is evidence that at least some patients with major depression show deficits in executive functions 19, 160.
The basal ganglia (BG) were originally believed to be involved exclusively in motor processes, but more recently have also come to be recognized as playing a role in executive functions. Reciprocal pathways connecting the BG and the prefrontal cortex, so-called “prefrontal-striatal loops” 2, 3, constitute a neural substrate for interaction between BG and prefrontal areas, and consequently for involvement of the BG in executive functions. There are five recognized prefrontal-striatal loops, or circuits, each with connections to distinct prefrontal regions. The five circuits are: 1) motor, 2) oculomotor, 3) dorsolateral prefrontal, 4) lateral orbitofrontal, and 5) anterior cingulate circuit. Each fiber tract projects from the cortex to the striatum, all then project to the globus pallidus and substantia nigra, then to the thalamus, and finally back to their respective cortical regions [3]. In the dorsolateral prefrontal circuit, fibers project from Brodman’s areas 9 and 10 and Walker’s area 12 of the prefrontal cortex and terminate in a region of the caudate extending from the dorsolateral head to the tail. Projections from the rostral caudate extend to the dorsomedial globus pallidus and the rostral substantia nigra. Fibers projecting from these locations extend to the parvocellular portions of the ventral anterior and medial dorsal thalamus, respectively. Projections from both these thalamic regions terminate in the dorsolateral prefrontal cortex (DLPFC) completing the circuit [3]. In the orbitofrontal circuit the relevant prefrontal regions are Brodman’s area 10 and Walker’s area 12, projecting to the ventromedial head of the caudate, then to the lateral dorsomedial globus pallidus interna, and rostromedial substantia nigra. Fibers from the substantia nigra project first to ventral anterior then medial dorsal magnocellular regions of the thalamus; thalamic projections to the orbitofrontal cortex (OFC) complete the circuit [3]. In the anterior cingulate circuit, fibers project from the anterior cingulate (Walker’s area 24) to the ventral striatum, then to the ventral pallidum, rostrodorsal substantia nigra, and rostrolateral globus pallidus interna. Fibers then return to the anterior cingulate via paramedial regions of the mediodorsal nucleus [3].
Although there appears to be some degree of overlap in the general regions traversed by these different circuits, anterograde transport studies indicate that at the cellular level they remain distinct [146]. Additional evidence of the parallel course of these circuits comes from the differential nature of the behavioral sequelae of focal damage to each of the circuits. The DLPFC circuit insult is associated with a dysexecutive syndrome, OFC circuit damage with a syndrome of dyscontrol, and anterior cingulate circuit insult with apathy and lack of spontaneous activity 21, 33, 34. These circuits represent a neural substrate for interaction between BG and prefrontal areas, and perhaps for BG involvement in the motor, executive, and emotional disturbances of major depression. In this review evidence for involvement of frontostriatal circuits in unipolar major depression will be examined from lesion, neuropsychological, structural, and functional imaging studies.
Section snippets
Prefrontal cortex
Lesions of the prefrontal cortex have been reported to be associated with depression 69, 142. This appears to be particularly true of left hemisphere lesions. Therefore, lesions that are specifically associated with depression (i.e., those that involve depressed mood) are located in the left frontal hemisphere significantly more often than in the right counterpart; the closer the site of the lesion to the left frontal pole, the greater the likelihood of accompanying depression 5, 107. Robinson
Prefrontal cortex
Numerous neuropsychological studies have reported frontal performance deficits in patients with major depression. Abrams and Taylor [1] compared healthy controls and patients with melancholic major depression on a battery of neuropsychological tests, which were chosen to sample bilateral functioning of all major divisions of the cortex 60, 79, 134. Depressed patients were impaired overall relative to controls, but with particular bilateral frontal and right parietal dysfunction, which was
Structural imaging studies
Computed tomography (CT) and nuclear magnetic resonance imaging (MRI) are the two main techniques used to generate structural images of living tissue that have been applied to the study of the brain. The latter technology represents a significant advance over the former with substantial improvements in resolution and ability to differentiate gray and white matter structures, allowing detection of more subtle structural changes [130].
Functional imaging studies
Functional imaging techniques provide measures of brain metabolism or blood flow that are believed to be closely correlated to levels of neural activity. Therefore, these methods provide an indirect indication of regional brain activity, and might allow identification of the functional correlates of major depression 7, 82.
Psychomotor retardation in major depression
Psychomotor retardation (PMR) has been defined as “generalized slowing of physical, mental, and emotional reactions” [8]. Although, as noted earlier, the association between PD and bradyphrenia is uncertain, similarities have been drawn between the motor slowness of PMR in some major depressed patients and bradykinesia in PD, and consequently to the possibility that the two phenomena may share some common underlying pathology. The BG constitute, therefore, a possible candidate as a site of
Conclusions
The findings from lesion studies and neuropsychological assessment implicate frontal involvement in depression, and perhaps left DLPFC in particular. The evidence from structural and functional imaging studies is less satisfactory. In the case of structural imaging this may indicate that major depression is primarily a functional disorder, except perhaps in some cases of LAO depression where structural abnormalities, particularly of subcortical white matter and the BG, are involved.
In the case
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