Elsevier

Brain Research Bulletin

Volume 47, Issue 4, 1 November 1998, Pages 297-310
Brain Research Bulletin

Review Articles
Frontostriatal deficits in unipolar major depression

https://doi.org/10.1016/S0361-9230(98)00126-9Get rights and content

Abstract

Recent accounts of major depression have tended to focus on dysfunction of frontothalamic-striatal reentrant circuits as a possible source of the disorder. Evidence of frontostriatal involvement in unipolar major depression from lesion and neuropsychological studies, and functional and structural imaging studies is examined. The high incidence of depressive symptomatology following left frontal and basal ganglia lesions implicate these as possible sites of dysfunction. Neuropsychological evidence indicates similar deficits in patients with major depression, perhaps with dorsolateral prefrontal deficits most prominent. Structural imaging studies report frontal and basal ganglia (BG) abnormalities particularly in cases of late-age onset depression. Resting state functional imaging studies show deficits in dorsolateral, anterior cingulate (medial frontal), and BG structures. Activation imaging studies show less consistent evidence of dorsolateral deficit, while anterior cingulate deficit is more consistently demonstrated. Variability in findings across studies may reflect differences between subtypes of depression and differences in methodology. Possible involvement of the BG in the psychomotor retardation of depression is examined. It is concluded that, while there is evidence of frontostriatal deficit in major depression, the exact nature of such deficits is uncertain. Issues such as component vs. system dysfunction need to be addressed.

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

References (165)

  • D.A Gansler et al.

    Measures of prefrontal dysfunction after closed head injury

    Brain Cogn.

    (1996)
  • V Geller et al.

    Slow magnetic stimulation of prefrontal cortex in depression and schizophrenia

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1997)
  • M.S George et al.

    Gender differences in regional cerebral blood-flow during transient self-induced sadness or happiness

    Biol. Psychiatry

    (1996)
  • N Georgiou et al.

    The effects of Huntington’s disease and Gilles de la Tourette’s syndrome on the ability to hold and shift attention

    Neuropsychologia

    (1996)
  • G.M Goodwin et al.

    State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon emission tomography in major depression before and after treatment

    J. Affect. Dis.

    (1993)
  • K.R Hanes et al.

    A brief assessment of executive control dysfunction-discriminant validity and homogeneity of planning, set shift, and fluency measures

    Arch. Gen. Neuropsychol.

    (1996)
  • I Hickie et al.

    Subcortical hyperintensities on magnetic resonance imagingClinical correlates and prognostic significance in patients with severe depression

    Biol. Psychiatry

    (1995)
  • T.L Jernigan et al.

    Cerebral structure on MRI 1Localization of age-related changes

    Biol. Psychiatry

    (1991)
  • S Khanna et al.

    Bereitschaft-potential in melancholic depression

    Biol. Psychiatry

    (1989)
  • R Abrams et al.

    Cognitive dysfunction in melancholia

    Psychol. Med.

    (1987)
  • G.E Alexander et al.

    Basal ganglia-thalamocortical circuitsParallel substrates for motor, oculomotor, ‘frontal’ and ‘limbic’ functions

    Prog. Brain Res.

    (1990)
  • G.E Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Ann. Rev. Neurosci.

    (1986)
  • Diagnostic and statistical manual of mental disorders

    (1994)
  • J.R Ashber et al.

    Neurobehavioural examination of frontal lobe functions

    Aphasiology

    (1995)
  • M.-P Austin et al.

    Melancholia as a neurological disorder

  • M.-P Austin et al.

    Functional neuroimaging in affective disorders

  • F.J Ayd

    Lexicon of psychiatry neurology, and the neurosciences

    (1995)
  • S.C Baker et al.

    The interaction between mood and cognitive function studied with PET

    Psychol. Med.

    (1997)
  • L.R Baxter et al.

    Cerebral metabolic rates for glucose in mood disordersStudies with positron emission tomography and fluorodeoxyglucose F 18

    Arch. Gen. Psychiatry

    (1985)
  • L.H Baxter et al.

    Reduction of prefrontal cortex glucose metabolism common to three types of depression

    Arch. of Gen. Psychiatry

    (1989)
  • B.C Beats et al.

    Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly

    Psychol. Med.

    (1996)
  • C.J Bench et al.

    Regional cerebral blood flow in depressionThe relationship with clinical dimensions

    Psychol. Med.

    (1993)
  • C.J Bench et al.

    Changes in regional cerebral blood flow on recovery from depression

    Psychol. Med.

    (1995)
  • K.F Berman et al.

    Is the mechanism of prefrontal hypofunction in depression the same as in schizophrenia?Regional cerebral blood flow during cognitive activation

    Br. J. Psychiatry

    (1993)
  • D Blumer et al.

    Personality changes with frontal and temporal lobe lesions

  • K.B Boone et al.

    Cognitive functioning in older depressed out-patientsRelationships of presence and severity of depression to neuropsychological test scores

    Neuropsychology

    (1995)
  • J.L Bradshaw et al.

    Clinical neuropsychologyBehavioural and brain science

    (1995)
  • B.H Braffman et al.

    Brain MRPathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces

    Am. J. Roentgenology

    (1988)
  • B.H Braffman et al.

    Brain MRPathologic correlation with gross and histopathology. 2. Hyperintense white-matter foci in the elderly

    Am. J. Roentgenology

    (1988)
  • J Brant

    Cognitive impairments in Huntington’s diseaseInsights into the neuropsychology of the striatum

  • P Brotchie et al.

    A neural network model of neural activity in the monkey globus pallidus2. Cognitive aspects of movement and phasic neuronal activity

    Brain

    (1991)
  • S Channon et al.

    Working memory in clinical depressionAn experimental study

    Psychol. Med.

    (1993)
  • M.I Chimowitz et al.

    Perventricular lesions on MRIFacts and theories

    Stroke

    (1989)
  • C.E Coffey et al.

    Quantitative cerebral anatomy in depressionA controlled magnetic resonance imaging study

    Arch. Gen. Psychiatry

    (1993)
  • M Cope et al.

    The Simon effect and attention deficits in Parkinson’s diseaseA comparison with Huntington’s disease and Tourette’s syndrome

    J. Clin. Exp. Neuropsychol.

    (1996)
  • A.-M Cotham et al.

    Depression in Parkinson’s diseaseA quantitative and qualitative analysis

    J. Neurol. Neurosurg. Psychiatry

    (1986)
  • S.F Crowe

    The performance of schizophrenic and depressed subjects on tests of fluencySupport for a compromise in dorsolateral prefrontal functioning

    Aust. Psychologist

    (1996)
  • J.L Cummings

    Frontal-subcortical circuits and human behaviour

    Neurol. Rev.

    (1993)
  • J.L Cummings

    Anatomic and behavioural aspects of frontal-subcortical circuits

    Ann. N.Y. Acad. Sci.

    (1995)
  • R Cunnington et al.

    Movement-related potentials in Parkinson’s diseasePresence and predicability of temporal and spatial cues

    Brain

    (1995)
  • Cited by (146)

    View all citing articles on Scopus
    View full text