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MAJOR DEPRESSION AND THE BASAL GANGLIA
NEUROPSYCHIATRY OF THE BASAL GANGLIA
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MAJOR DEPRESSION AND THE BASAL GANGLIA Beny Lafer, MD, Perry F. Renshaw, MD, PhD, and Gary S. Sachs, MD
The phenomenology of major depression is complex, involving abnormalities in several areas, such as mood, cognition, motor activity, and neurovegetative functions.61Clinical symptoms may be produced by a neurologic illness, induced by medical illness or drugs (secondary depression), or be idiopathic in etiology (primary depression). Depression also may occur in a single episode or be a recurrent illness.37Therefore, major depression is a heterogeneous disorder with various subtypes and it is unlikely that all the symptoms are mediated by one single brain area. Over the last decade, however, evidence suggesting that depressive disorders may be related to abnormalities in specific brain systems and networks has emerged. Data have pointed to decreased volume, hypometabolism, and reduced blood flow in the frontal lobes, basal ganglia, and medial temporal structures in patients with mood disorder.", 13, 23, 39, 54, 84 These observations have been facilitated by the use of structural and functional brain imaging techniques to evaluate subjects with primary and secondary mood disorders. Extensive functional and neuroanatomic connections exist between the basal ganglia, the frontal lobes, and the limbic system via fronto-subcortical networks, and the studies described in this article support a hypothesis pointing to abnormalities in the basal ganglia-thalamo-cortical circuits in major depressive disorder.*,25 We focus this article on the basal ganglia and, in particular, discuss the implications of recent research findings with regard to the pathogenesis and the clinical management of depressive disorders.
From the Mood Disorders Research Program, Institute of Psychiatry, University of S%o Paulo Medical School, S5o Paulo, Brazil (BL); Brain Imaging Center, McLean Hospital (PFR); Harvard Medical School (PFR, GSS); and Harvard Bipolar Research Program (GSS), Boston, Massachusetts
THE PSYCHIATRIC CLINICS OF NORTH AMERICA
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VOLUME 20 NUMBER 4 DECEMBER 1997
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DEPRESSION ASSOCIATED WITH NEUROLOGIC DISEASES AFFECTING THE BASAL GANGLIA
One line of investigation that has clarified the role of the basal ganglia in the pathophysiology of depression is the study of depression that occurs in the were context of illness that primarily affects the basal ganglia. Ross and among the first to suggest that the emergence of depression in patients with neurologic lesions might provide a database to generate initial hypotheses about the neuroanatomic basis of depression. They noticed that focal brain lesions in specific regions were more likely to produce depression than lesions in other brain areas. Therefore, if depression is highly prevalent in basal ganglia disorders then these structures may play a role in the modulation and production of depressive symptoms. In the 1980s, systematic studies evaluating mood changes in patients with brain injuries were undertaken, with a special focus on mood syndromes in stroke patient^.^^-^", 78, 80, 81 These studies demonstrated that depressive syndromes following stroke are not uncommon, affecting as many as 20% to 50% of patients in the acute postevent period.&,66 Depression may occur as a sequel to cortical infarcts (anterior more than posterior, left hemisphere more than right) and subcortical infarcts. The association between subcortical strokes and depression has been examined in two important studies: one showed that patients with left anterior subcortical strokes (mainly in the caudate) had a higher incidence of depression than did patients with posterior subcortical or right basal ganglia lesions,81and the second study noted that patients with left caudate lesions had a higher frequency of depression than did patients with either right basal ganglia or thalamic lesions.78,8o These findings demonstrate the importance of lesion location in post stroke depression and a specific vulnerability to depression in patients with basal ganglia disorder^.^" 66 Depression also has been examined in subcortical degenerative disorders. Cross-sectional studies in Parkinson’s disease (PD) show that 20% of patients may present with major depression and approximately 20% have minor forms of depression.”, 79 Longitudinally, however, more than 50% of patients with PD may present with a major depressive episode at some point of the illness.24PD also has been used as a putative model for the psychomotor inhibition and cognitive deficits seen in some patients with melancholic depression as there is an overlap between symptoms of depression and PD. Both disorders may be characterized in terms of psychomotor retardation (bradykhesia), diminished facial expression, and impaired cognition.’, n,79 Because there is a degeneration of nigrostriatal dopaminergic fibers in PD and some symptom overlap between both disorders, these findings may point to a role of the dopaminergic system in the pathophysiology of depre~sion.~, 44 Thus, PD may be used as a neurologic model to understand, in part, the phenomenology and neurochemistry of depressive disorder. One functional imaging study using fluorine-18 positron emission tomography (18F-PET) found that patients with PD and depression had significantly lower fluorodeoxyglucose uptake in the head of the caudate and the orbitofrontal cortex when compared with nondepressed PD patients and normal control This metabolic pattern is different from the one seen in patients with PD who have other behavioral deficits such as dementia, and suggests that a disruption of the basal ganglia circuits involving the inferior region of the frontal lobe may affect the regulation of mood. It is important to note that the presence and severity of depression in PD is only weakly related to patient di~ability.~~ Huntington’s disease (HD) also is associated with a high incidence of
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depressive syndromes and bipolar mood disorder in particular. In an important survey, Folstein and c011eagues~~ reported a lifetime prevalence of 38% for major affective disorders in patients with HD (22% with major depression). In a ~~ the separate study of 110 HD patients, Shiwach and L i n d e n b a ~ mreported prevalence of depression to be 39% in the prodrome or symptomatic phase of the illness. Depressive symptoms in HD often appear before the motor symptoms. The early occurrence of major depression in HD may have a neuropathologic correlate. In a neuropathologic study, Vonsattel et als7demonstrated that neuronal loss occurs first in the medial caudate, an area with prominent connections to the limbic cortex. This neuronal loss may mediate the high incidence of depression in the initial stages of the illness. There is also a disproportionately high incidence of suicide among patients with HD.18,75 Depression also occurs in 20% of patients with Wilson's disease, an autosomal recessive disorder of copper metabolism in which the lenticular nuclei specifically are affected by copper deposition.28 Taken together, the study of the prevalence, phenomenology, and metabolic abnormalities in depression affecting patients with organic basal ganglia disorders strongly suggests that these brain structures may mediate depressive syndromes. STRUCTURAL ABNORMALITIES OF THE BASAL GANGLIA IN PRIMARY MAJOR DEPRESSION Neuropathologic Studies
There are very few neuropathologic data in major depression. Jeste et a143 reviewed studies on the neuropathology of primary affective disorders and found a total of only eight studies that described results obtained from more than four brains. These studies often included heterogeneous groups of affective disorder patients, which were diagnosed using unspecified criteria, and generally used qualitative (rather than quantitative) methods of neuropathologic analysis. None of these studies focused primarily on the neuropathology of mood disorders, as manic and depressive patients were included as controls in studies of schizophrenia. Jeste et a1 concluded that it is "difficult to draw even tentative conclusions about cerebral lesions in primary affective disorders" from these data. A related approach to this problem would be to study the brains of suicide victims, but this method also has limitations, as clinical information often is lacking and it is difficult to confirm the diagnosis of clinical depression. Studies with suicide victims mostly have examined the neurochemistry of the frontal lobes and the hippocampus.6To our knowledge there are no postmortem neuropathologic studies of the basal ganglia in patients with primary unipolar depression as opposed to several studies in patients with schizophrenia.4l Therefore, only limited conclusions can be drawn from the postmortem studies that have been reported to date. Future postmortem studies, however, may help investigators by identifying brain regions and neurotransmitter systems that may be characterized by in vivo neuroimaging studies. Structural Neuroirnaging Studies Computed Tomography Brain CT scans do not provide good definition of gray and white matter, which makes it difficult to examine subcortical gray matter structures, such as
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the basal ganglia. Most research studies of patients with affective disorders have focused on the measurement of ventricular size and cortical atrophy. The results suggest that ventricular size is increased in at least some populations with both unipolar and bipolar affective illnes~.~, 58, 63, 85 Elkis et a132 performed metaanalyses of studies of ventricular enlargement and sulcal prominence in mood disorders and found that patients with mood disorders have larger ventricles and increased sulcal prominence when compared with normal controls. Magnetic Resonance Imaging
For the evaluation of brain structure and volumetric measurements of the basal ganglia, MR imaging offers at least two major advantages over CT scanning. In particular, no ionizing radiation is used, and brain substructures are defined with very distinct gray/white matter contrast? Early brain MR imaging studies of patients with affective disorder replicated some of the CT findings on ventricular volume and sulcal enla~gement.~~, 83 Recent work has focused on the measurement of specific brain substructures. Two important studies have examined specifically the volumes of basal ganglia nuclei in patients with unipolar depression. Husain et a142compared 41 depressed subjects with 44 normal age-matched controls and found significantly smaller putamen volumes in depressed patients. Krishnan et a149compared caudate volumes of 50 unipolar depressed subjects with 50 age-matched controls and observed significantly smaller caudate nuclei. Krishnan et a1 also reported diminished caudate and putamen volumes in a controlled study with elderly unipolar Dupont et a13" found smaller, but not statistically significant, caudate and lenticular volumes in a sample of unipolar and bipolar subjects. Aylward et all0 were not able to replicate the findings of Krishnan et a1 with a bipolar patient sample but found a trend toward reduced caudate and putamen volumes among female bipolar patients. The volumes frontal and temporal lobes of patients with primary mood disorder (unipolar and bipolar) also have been examined in depressed 82 subjects and appear to be smaller than those of age-matched Subcortical signal hyperintensities, which are compatible with a range of pathologic etiologies, occur with a higher prevalence in older unipolar patients when these were compared with age-matched normal controls.21,23 The subcortical hyperintensities appear as areas of increased signal intensity in T2-weighted images. These hyperintensities most commonly involve the periventricular white matter, but also affect subcortical gray matter nuclei such as the basal ganglia. These abnormalities have been referred to as leukoencephalopathy, leukoaraiosis, unidentified bright objects (UBOs), and encephalomalacia. In an important prospective study, subcortical hyperintensities were noted in a consecutive series of 51 elderly depressed patients referred to ECT (51% showing lesions of subcortical gray matter). Therefore, it has been suggested that patients with late onset of illness and resistance to antidepressant pharmacotherapy are more likely to present with evidence for subcortical encephalomalacia.22, 23 Brown et all5 evaluated 229 patients with a range of psychiatric disorders and reported that only in depressed subjects over the age of 45 years is the incidence of white matter hyperintensities higher than in age-matched normal controls. In some studies with bipolar patients, the presence of these signal abnormalities has been associated with neuropsychological impairment and a greater number of hospitalization^.'^, 31 The neuropathologic correlates of these white matter hyperintensities in mood disorders is unknown, but studies suggest they may be a result of ischemic vascular insult, increased water content in perivascular space, or axon and myelin 2o In some cases, these lesions also
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may represent pathologic changes associated with multiple sclerosis.5oThus, subcortical white and gray matter hyperintensities may be markers of conditions that predispose individuals, especially older people, to the expression of depressive disorder. It is possible that these white matter hyperintensities represent lesions that disrupt the basal ganglia-thalamo-cortical circuits increasing the vulnerability to depressive illness. FUNCTIONAL NEUROIMAGING STUDIES OF REGIONAL METABOLISM AND BLOOD FLOW IMPLICATES BASAL GANGLIA ABNORMALITIES IN DEPRESSIVE DISORDERS Functional Neuroimaging Studies
Functional brain imaging describes those techniques that allow in vivo measurements of regional cerebral blood flow (rCBF) and metabolism. At least four modalities currently are being used for studies of brain function in people: (1)single photon emission tomography (SPECT); (2) positron emission tomography (PET); (3) MR spectroscopy, and (4) functional MR imaging (fMRI). To our knowledge, NRI has not been used to investigate the pathogenesis of depressive disorders. We describe the SPECT, PET and MR spectroscopy results that point to basal ganglia dysfunction in depression. Single Photon Emission Computed Tomography
The use of 133 Xe to measure rCBF is determined by the rate of gas washout; consequently, spatial resolution tends to be poor (> 10 mm) and only cortical areas can be studied. Although 133 Xe techniques are easy to use and quite reliable, the emitted radiation is only detected from the outer 2 to 3 cm of brain. Thus, it is difficult to obtain information regarding rCBF in subcortical structures. Using this technique, the majority of studies noted a global reduction in rCBF in major depression.” 73 More recently, SPECT blood flow imaging has been performed using stable injectable tracers, most commonly HMPAO (technetium-99m-d,l-hexamethylpropyleneamine oxime). The introduction of Tc-99m-containing ligands represents a fundamental advance because the uptake of these agents is proportional to CBF, and brain SPECT images permit the analysis of subcortical and limbic structures. The majority of studies using HMPAO have noted a decrease in total cortical blood flow, hemispheric asymmetries, and hypofrontality in depression.8,54 Using HMPAO SPECT, Mayberg et a153 detected a left-sided decrease in CBF in patients with refractory unipolar depression. Positron Emission Tomography
PET provides a means to construct brain images of positron emitting nuclei with in-plane spatial resolution on the order of 2 to 5 mm. A limited number of studies involving patients with affective disorders have been conducted. The PET methodology that has been used most frequently to study patients with affective disorders is fluorodeoxyglucose (FDG) PET, which allows the study of regional glucose metabolism. Using FDG PET, two initial studies have documented relatively lower glucose metabolic rates in the basal ganglia of depressed
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patients compared with normal controls.ll, l6 Other studies have noted mood stateedependent, diminished metabolic rates in the left anterolateral prefrontal cortex in depressed patients.lz,52 Subsequent studies using 150xygen-PETto examine regional cerebral blood flow have been able to replicate the decrease in CBF in the left anterolateral prefrontal cortex and also show that cognitive impairment in severely depressed patients may be associated with decreased activity in the left anteromedial prefrontal cortex and increased activity in the cerebellar c o r t e ~ . ’This ~ same group of investigators also has reported correlations between psychomotor retardation and decreased blood flow in the left dorsolateral prefrontal cortex.14 Conversely, Drevets et alZ9used 150-PETand detected an increased rCBF in the left prefrontal cortex, the left amygdala, and the left medial thalamus and decreased rCBF in the left medial caudate in patients with familial pure de90 Diagnostic criteria and pressive disorder, a subtype of major depre~sion.~~, different PET methodologies may explain differences across studies. Activation Studies
Most of the studies described previously have examined subjects ”at rest.” Another way to approach the neuroanatomy of depression has been through activation and symptom provocation studies. It is proposed in these studies that CBF and metabolism may change when patients perform certain tasks or have specific thoughts that make their symptoms worsen. Pathologic regions may appear only under these conditions. Pardo and c011eagues~~ studied normal subjects and have detected transient increased CBF in the left orbital and prefrontal cortex when subjects were asked to imagine or recall a situation that would make them feel very sad (“transient ~ a d n e s s ” )Activation .~~ studies have shown decreased brain activation of limbic and paralimbic areas in tasks (e.g., emotional facial recognition) that involve the limbic system.= These results are in contrast to the observation that there are no differences between depressed and normal controls in tasks that rely on cortical structures (memory and spatial matching tasks).34,35 Treatment Response Effects on Regional Cerebral Blood Flow and Metabolism
Some investigators have assessed the effects of treatment on functional brain images in an attempt to clarify whether the abnormalities observed in these patients are reversed by treatment and clinical remission. In particular, Baxter et all2 and MartinoP have been able to show a normalization of the dorsolateral prefrontal hypometabolism seen in depressed patients after antidepressant treatment using 18FDG-PET.12,52 Conversely, Drevets et al” detected a decrease in CBF in the left prefrontal cortex following treatment with desipramine. In the same study, increased blood flow in the left amygdala detected in the depressed state persisted in remitted patients, suggesting that increased perfusion of the amygdala may represent a trait marker. This finding must be replicated in future studies to clarify state versus trait biologic markers in depression. Some patients with clinical depression respond to sleep deprivation. Wu et a191used ‘*FDG-PETscanning to document a higher rate of metabolic activity in the cingulum of responders relative to nonresponders to sleep deprivation.
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These data suggest that some of the metabolic derangements normalize with treatment. Future studies should clarify this issue by looking more closely at responders versus nonresponders, and by using more homogeneous samples of patients with mood disorders. IN VlVO NEUROCHEMICAL STUDIES: RECENT MAGNETIC RESONANCE SPECTROSCOPY FINDINGS Magnetic Resonance Spectroscopy in Depressive Disorders
MR spectroscopy is a noninvasive method to investigate the brain neuro~ , is possible through the use of MR spectroscopy to chemistry in v ~ v o .76~ It determine cerebral levels of a number of metabolites. Using phosphorus MR spectroscopy (31P-MRS)it is possible to detect high-energy phosphates (phosphocreatine and nucleoside triphosphates), inorganic phosphate, phosphomonoesters, and phosphodiesters. Using proton MR spectroscopy ('H-MRS), we can determine cerebral levels of choline, myo-inositol, N-acetyl-aspartate, and creatine. MR spectroscopy allows also the determination of brain levels of psychotropic drugs like lithium, fluoxetine, and fluorinated antipsychotic medications.26 Most MR spectroscopy studies in mood disorders have focused on metabolism of the frontal lobes in bipolar disorder.4547These investigations have suggested the presence of changes in high-energy phosphate and membrane metabolism. Focusing specifically in the basal ganglia of unipolar patients, initial studies have reported decreased basal ganglia choline levels in depression, which may reflect altered membrane metabolism within the basal ganglia.@A recently published study using 31P-MRS reported lower levels of nucleoside triphosphate in the basal ganglia of unmedicated unipolar depressed patients, possibly reflecting hypometabolism in this brain region.57This finding is consistent with the PET results showing diminished rCBF and glucose metabolism at the level of the basal ganglia. UNDERSTANDING THE PATHOPHYSIOLOGY OF MOOD DISORDERS: INTEGRATING BIOCHEMICAL HYPOTHESES WITH BASAL GANGLIA ABNORMALITIES
Taken together, data from structural and functional neuroimaging studies in primary and secondary depressive disorders strongly suggest that abnormalities in a number of the functional circuits proposed by Alexander et a13 are involved in the pathophysiology of depression?, 6o Two interrelated basal ganglia-thalamocortical circuits may be of particular relevance: (1) the "limbic" circuit, connecting limbic structures (amygdala and anterior cingulate, ventral striatum) with medial and ventrolateral prefrontal cortex; and (2) the "prefrontal" circuit, connecting the basal ganglia (more specifically the head of the caudate) and thalamus with the dorsolateral prefrontal cortex. Accumulating evidence implicates the neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in the pathophysiology of depression. This evidence is derived from what we know about the mechanisms of action of antidepressant medications, and also from animal studies; studies of metabolites in plasma, urine, and CSF; precursors (e.g., tryptophan) depletion studies; platelet studies; receptor-binding studies, and neuroendocrine studies
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among others. Additionally, recent reports indicate that stress promotes profound and complex alterations involving DA release, metabolism, and receptors densities in the mesolimbic system.', 17, 27, 51 There are extensive dopaminergic, noradrenergic, serotonergic, and cholinergic projections into the basal ganglia-and they likely contribute to the overall modulation of basal ganglia thalamocortical Although somatic antidepressant therapies influence each of these systems, their therapeutic mechanisms may be associated with enhancing dopaminergic and serotonergic activity (especially 5-HT1, relative to 5-HT2).Both effects would be predicted to inhibit the 36, 51* 86, 89 A recent hypothesis links depression to a strong interaclimbic circ~it.'~, tion between the NE and DA systems in depression. We also know that the NE and 5-HT systems strongly interact with each Although we are proposing a putative anatomic localization for depression where important neurochemical dysfunctions may occur, we suspect that depression is associated with both functional and structural disruption of the relevant described circuits. A functional or anatomic disruption at different sites of the basal ganglia-thalamocortical circuits may be associated with different forms of depression and explain, in part, why depression appears to be such a heterogeneous disorder. CLINICAL AND TREATMENT PERSPECTIVES
Although these findings have helped researchers in identifying neuroanatomic circuits that may be involved in clinical depression, a critical shortcoming is that neuroimaging has yet to provide much help for the clinician. The findings described, however, may help us to understand, in part, the heterogeneity of depressive disorders. Additionally, a better understanding of the pathophysiology of depressive disorders may open new possibilities for the development of better treatments we can offer to our patients. This is especially true for those who are refractory to conventional pharmacotherapy. Over time, continued research in this field may provide important insights into early detection, diagnosis, and prevention of depressive disorders. References 1. Abercrombie ED, Keefe KA, Di Frischia DF, et al: Differential effects of stress on in vivo dopamine release in striatum, nucleus accumbens and medial frontal cortex. J Neurochem 521665-1658, 1989 2. Alexander GE, De Long MR, Strick P: Parallel organization of functionally segragated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357-381, 1986 3. Alexander GE, Grutcher MD, DeLong MR Basal ganglia thalamocortical circuits: Parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. Prog Brain Res 85:119-146, 1990 4. Andreasen NC: Nuclear magnetic resonance imaging. In Andreasen NC (eds): Brain Imaging: Applications in Psychiatry. Washington, DC, American Psychiatric Press, Inc., 1989, p 67-121 5. Andreasen NC, Swayze 11, V, Flaum M, et al: Ventricular abnormalities in affective disorder: Clinical and demographic correlates. Am J Psychiatry 147893-900, 1990 6. Arango V, Emsberger P, Sved AF, et a1 Quantitative autoradiography of alpha 1- and alpha 2-adrenergic receptors in the cerebral cortex of controls and suicide victims. Brain Res 630:271-282, 1993 7. Austin MP, Mitchell P: The anatomy of melancholia: Does frontal-subcortical patho-
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with refractory unipolar depression measured with Tc-99m HMPAO SPECT. J Nucl Med 32:951, 1991 54. Mayberg HS, Lewis PJ, Regenold W, et al: Paralimbic hypoperfusion in unipolar depression. J Nucl Med 35:929-934, 1994 55. Mayberg HS, Starkstein SE, Sadzot B, et al: Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson’s disease. Ann Neurol28:57-64, 1990 56. Mendez MF, Adams NL, Lewandowski KS: Neurobehavioral changes associated with caudate lesions. Neurology 39:349-354, 1989 57. Moore CM, Christensen JD, Lafer B, et al: Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: A phosphorous-31 magnetic resonance spectroscopy study. Am J Psychiatry 154:116-118, 1997 58. Nasrallah HA, McCalley-Whitters M, Jacoby C : Cerebral ventricular enlargement in young manic males: A controlled study. J Affect Disord 4:15-19, 1982 59. Pardo JV,Pardo PJ, Raichle ME: Neural correlates of self-induced dysphoria. Am J Psychiatry 150:713-719, 1993 60. Parent A, Hazrati LN: Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev 20:91-127, 1995 61. Paykel ES Handbook of Affective Disorders, ed 2. New York, Guilford Press, 1992 62. Pearlson GD, Veroff AE: Computerised tomographic scan changes in manic-depressive illness. Lancet 2470-471, 1981 63. Pearlson GD, Garbacz DJ, Breakey WR, et al: Lateral ventricular enlargement associated with persistent unemployment and negative symptoms in both schizophrenia and bipolar disorder. Psychiatry Res 121-9, 1984 64. Renshaw PF, Lafer B, Babb SM, et al: Basal ganglia choline levels in depression and response to fluoxetine treatment: An in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 41S37-843, 1997 65. Robinson RG, Price TR Post-stroke depressive disorders: A follow-up study of 103 patients. Stroke 13:635-641, 1982 66. Robinson RG, Starkstein SE: Current research in affective disorders following stroke. J Neuropsychiatry Clin Neurosci 21-14, 1990 67. Robinson RG, Boston JD, Starkstein SE, et al: Comparison of mania and depression after brain injury: Causal factors. Am J Psychiatry 145:172-178, 1988 68. Robinson RG, Kubos KL, Starr LB, et al: Mood changes in stroke patients: Relationship to lesion location. Compr Psychiatry 24:555-566, 1983 69. Robinson RG, Kubos KL, Starr LB, et al: Mood disorders in stroke patients-Importance of location of lesion. Brain 10781-93, 1984 70. Robinson RG, Lipsey JR, Bolla-Wilson K, et al: Mood disorders in left-handed stroke patients. Am J Psychiatry 142314241429,1985 71. Ross ED, Rush JA: Diagnosis and neuroanatomical correlates of depression in braindamaged patients: Implications for a neurology of depression. Arch Gen Psychiatry 3831344-1354, 1981 72. Sackeim HA, Prohovnik I: Brain imaging studies of depressive disorders. In Mann J, Kupfer D (eds): Biology of Depressive Disorders. New York, Plenum Press, 1993, pp 205-272 73. Sackeim HA, Prohovnik I, Moeller JR, et al: Regional cerebral blood flow in mood disorders: I. Comparison of major depressives and normal controls at rest. Arch Gen Psychiatry 4760-70, 1990 74. Shiwach RS, Lindenbaum RH: Prevalence of Huntington’s disease among UK immigrants from the Indian subcontinent. Br J Psychiatry 157598-599, 1990 75. Shoulson I Huntington’s disease: Cognitive and psychiatric features. Neuropsychiatry Neuropsychol Behav Neurol3:15-22, 1990 76. Soares JC, Krishnan KR, Keshavan MS: Nuclear magnetic resonance spectroscopy: New insights into the pathophysiology of mood disorders. Depression 494-30, 1996 77. Sobin C, Sackeim H: Psychomotor symptoms of depression. Am J Psychiatry 154:417, 1997 78. Starkstein SE, Robinson RG: Affective disorders and cerebral vascular disease. Br J Psychiatry 154:170-182, 1989
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79. Starkstein SE, Preziosi TJ, Bolduc P: Depression in Parkinson's disease. J Nerv Ment Dis 178:27-31, 1990 80. Starkstein SE, Robinson RG, Berthier ML, et al: Differential mood changes following basal ganglia vs. thalamic lesions. Arch Neurol 45:725-730, 1988 81. Starkstein SE, Robinson RG, Price T R Comparison of cortical and subcortical lesions in the production of post-stroke mood disorders. Brain 110:1045-1059, 1987 82. Steingard RJ, Renshaw PF, Yurgelun-Todd DA, et al: Structural abnormalities in brain magnetic resonance images of depressed children. J Am Acad Child Adolesc Psychiatry 35:307-311, 1996 83. Swayze I1 VW, Andreasen NC, Alliger RJ, et al: Structural brain abnormalities in bipolar affective disorder. Arch Gen Psychiatry 47310541059, 1990 84. Swayze I1 VW, Andreasen NC, Alliger RJ, et al: Subcortical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging study. Biol Psychiatry 31:221-240, 1992 85. Targum SD, Rosen LN, DeLisi LE, et al: Cerebral ventricular size in major depressive disorder: Association with delusional symptoms. Biol Psychiatry 18:329-336, 1983 86. Thierry AM, Mantz J, Milla C, et al: Influence of the mesocortical/prefrontal dopamine neurons on their target cells. In Kalivas PW, Nemeroff CB (eds): The Mesocorticolimbic Dopamine System. New York, The New York Academy of Sciences, 1988, pp 101-111 87. Vonsattel JP, Meyers RH, Stevens TJ, et al: Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44:559-577, 1985 88. Weiss JM, Demitrikopoulos MK, West CH, et al: Hypothesis linking the noradrenergic and dopaminergic systems in depression. Depression 3225-245, 1995 89. Willner P: Dopaminergic mechanism in depression and mania. In Bloom FE, Kupfer DJ (eds): Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, 1995, pp 921-932 90. Winokur G: The development and validity of familial subtypes in primary unipolar depression. Pharmacopsychiatry 15:142-146, 1982 91. Wu JC: Effect of sleep dreprivation on brain metabolism of depressed patients. Am J Psychiatry 149:538-543, 1992
Address reprint requests to Beny Lafer, MD Mood Disorders Research Program (GRUDA) University of Sao Paulo Medical School Rua Ovidio Pires de Campos s/n", sala 4045 S%oPaulo, SP 05403-010 Brazil
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MAJOR DEPRESSION AND THE BASAL GANGLIA Beny Lafer, MD, Perry F. Renshaw, MD, PhD, and Gary S. Sachs, MD
The phenomenology of major depression is complex, involving abnormalities in several areas, such as mood, cognition, motor activity, and neurovegetative functions.61Clinical symptoms may be produced by a neurologic illness, induced by medical illness or drugs (secondary depression), or be idiopathic in etiology (primary depression). Depression also may occur in a single episode or be a recurrent illness.37Therefore, major depression is a heterogeneous disorder with various subtypes and it is unlikely that all the symptoms are mediated by one single brain area. Over the last decade, however, evidence suggesting that depressive disorders may be related to abnormalities in specific brain systems and networks has emerged. Data have pointed to decreased volume, hypometabolism, and reduced blood flow in the frontal lobes, basal ganglia, and medial temporal structures in patients with mood disorder.", 13, 23, 39, 54, 84 These observations have been facilitated by the use of structural and functional brain imaging techniques to evaluate subjects with primary and secondary mood disorders. Extensive functional and neuroanatomic connections exist between the basal ganglia, the frontal lobes, and the limbic system via fronto-subcortical networks, and the studies described in this article support a hypothesis pointing to abnormalities in the basal ganglia-thalamo-cortical circuits in major depressive disorder.*,25 We focus this article on the basal ganglia and, in particular, discuss the implications of recent research findings with regard to the pathogenesis and the clinical management of depressive disorders.
From the Mood Disorders Research Program, Institute of Psychiatry, University of S%o Paulo Medical School, S5o Paulo, Brazil (BL); Brain Imaging Center, McLean Hospital (PFR); Harvard Medical School (PFR, GSS); and Harvard Bipolar Research Program (GSS), Boston, Massachusetts
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DEPRESSION ASSOCIATED WITH NEUROLOGIC DISEASES AFFECTING THE BASAL GANGLIA
One line of investigation that has clarified the role of the basal ganglia in the pathophysiology of depression is the study of depression that occurs in the were context of illness that primarily affects the basal ganglia. Ross and among the first to suggest that the emergence of depression in patients with neurologic lesions might provide a database to generate initial hypotheses about the neuroanatomic basis of depression. They noticed that focal brain lesions in specific regions were more likely to produce depression than lesions in other brain areas. Therefore, if depression is highly prevalent in basal ganglia disorders then these structures may play a role in the modulation and production of depressive symptoms. In the 1980s, systematic studies evaluating mood changes in patients with brain injuries were undertaken, with a special focus on mood syndromes in stroke patient^.^^-^", 78, 80, 81 These studies demonstrated that depressive syndromes following stroke are not uncommon, affecting as many as 20% to 50% of patients in the acute postevent period.&,66 Depression may occur as a sequel to cortical infarcts (anterior more than posterior, left hemisphere more than right) and subcortical infarcts. The association between subcortical strokes and depression has been examined in two important studies: one showed that patients with left anterior subcortical strokes (mainly in the caudate) had a higher incidence of depression than did patients with posterior subcortical or right basal ganglia lesions,81and the second study noted that patients with left caudate lesions had a higher frequency of depression than did patients with either right basal ganglia or thalamic lesions.78,8o These findings demonstrate the importance of lesion location in post stroke depression and a specific vulnerability to depression in patients with basal ganglia disorder^.^" 66 Depression also has been examined in subcortical degenerative disorders. Cross-sectional studies in Parkinson’s disease (PD) show that 20% of patients may present with major depression and approximately 20% have minor forms of depression.”, 79 Longitudinally, however, more than 50% of patients with PD may present with a major depressive episode at some point of the illness.24PD also has been used as a putative model for the psychomotor inhibition and cognitive deficits seen in some patients with melancholic depression as there is an overlap between symptoms of depression and PD. Both disorders may be characterized in terms of psychomotor retardation (bradykhesia), diminished facial expression, and impaired cognition.’, n,79 Because there is a degeneration of nigrostriatal dopaminergic fibers in PD and some symptom overlap between both disorders, these findings may point to a role of the dopaminergic system in the pathophysiology of depre~sion.~, 44 Thus, PD may be used as a neurologic model to understand, in part, the phenomenology and neurochemistry of depressive disorder. One functional imaging study using fluorine-18 positron emission tomography (18F-PET) found that patients with PD and depression had significantly lower fluorodeoxyglucose uptake in the head of the caudate and the orbitofrontal cortex when compared with nondepressed PD patients and normal control This metabolic pattern is different from the one seen in patients with PD who have other behavioral deficits such as dementia, and suggests that a disruption of the basal ganglia circuits involving the inferior region of the frontal lobe may affect the regulation of mood. It is important to note that the presence and severity of depression in PD is only weakly related to patient di~ability.~~ Huntington’s disease (HD) also is associated with a high incidence of
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depressive syndromes and bipolar mood disorder in particular. In an important survey, Folstein and c011eagues~~ reported a lifetime prevalence of 38% for major affective disorders in patients with HD (22% with major depression). In a ~~ the separate study of 110 HD patients, Shiwach and L i n d e n b a ~ mreported prevalence of depression to be 39% in the prodrome or symptomatic phase of the illness. Depressive symptoms in HD often appear before the motor symptoms. The early occurrence of major depression in HD may have a neuropathologic correlate. In a neuropathologic study, Vonsattel et als7demonstrated that neuronal loss occurs first in the medial caudate, an area with prominent connections to the limbic cortex. This neuronal loss may mediate the high incidence of depression in the initial stages of the illness. There is also a disproportionately high incidence of suicide among patients with HD.18,75 Depression also occurs in 20% of patients with Wilson's disease, an autosomal recessive disorder of copper metabolism in which the lenticular nuclei specifically are affected by copper deposition.28 Taken together, the study of the prevalence, phenomenology, and metabolic abnormalities in depression affecting patients with organic basal ganglia disorders strongly suggests that these brain structures may mediate depressive syndromes. STRUCTURAL ABNORMALITIES OF THE BASAL GANGLIA IN PRIMARY MAJOR DEPRESSION Neuropathologic Studies
There are very few neuropathologic data in major depression. Jeste et a143 reviewed studies on the neuropathology of primary affective disorders and found a total of only eight studies that described results obtained from more than four brains. These studies often included heterogeneous groups of affective disorder patients, which were diagnosed using unspecified criteria, and generally used qualitative (rather than quantitative) methods of neuropathologic analysis. None of these studies focused primarily on the neuropathology of mood disorders, as manic and depressive patients were included as controls in studies of schizophrenia. Jeste et a1 concluded that it is "difficult to draw even tentative conclusions about cerebral lesions in primary affective disorders" from these data. A related approach to this problem would be to study the brains of suicide victims, but this method also has limitations, as clinical information often is lacking and it is difficult to confirm the diagnosis of clinical depression. Studies with suicide victims mostly have examined the neurochemistry of the frontal lobes and the hippocampus.6To our knowledge there are no postmortem neuropathologic studies of the basal ganglia in patients with primary unipolar depression as opposed to several studies in patients with schizophrenia.4l Therefore, only limited conclusions can be drawn from the postmortem studies that have been reported to date. Future postmortem studies, however, may help investigators by identifying brain regions and neurotransmitter systems that may be characterized by in vivo neuroimaging studies. Structural Neuroirnaging Studies Computed Tomography Brain CT scans do not provide good definition of gray and white matter, which makes it difficult to examine subcortical gray matter structures, such as
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the basal ganglia. Most research studies of patients with affective disorders have focused on the measurement of ventricular size and cortical atrophy. The results suggest that ventricular size is increased in at least some populations with both unipolar and bipolar affective illnes~.~, 58, 63, 85 Elkis et a132 performed metaanalyses of studies of ventricular enlargement and sulcal prominence in mood disorders and found that patients with mood disorders have larger ventricles and increased sulcal prominence when compared with normal controls. Magnetic Resonance Imaging
For the evaluation of brain structure and volumetric measurements of the basal ganglia, MR imaging offers at least two major advantages over CT scanning. In particular, no ionizing radiation is used, and brain substructures are defined with very distinct gray/white matter contrast? Early brain MR imaging studies of patients with affective disorder replicated some of the CT findings on ventricular volume and sulcal enla~gement.~~, 83 Recent work has focused on the measurement of specific brain substructures. Two important studies have examined specifically the volumes of basal ganglia nuclei in patients with unipolar depression. Husain et a142compared 41 depressed subjects with 44 normal age-matched controls and found significantly smaller putamen volumes in depressed patients. Krishnan et a149compared caudate volumes of 50 unipolar depressed subjects with 50 age-matched controls and observed significantly smaller caudate nuclei. Krishnan et a1 also reported diminished caudate and putamen volumes in a controlled study with elderly unipolar Dupont et a13" found smaller, but not statistically significant, caudate and lenticular volumes in a sample of unipolar and bipolar subjects. Aylward et all0 were not able to replicate the findings of Krishnan et a1 with a bipolar patient sample but found a trend toward reduced caudate and putamen volumes among female bipolar patients. The volumes frontal and temporal lobes of patients with primary mood disorder (unipolar and bipolar) also have been examined in depressed 82 subjects and appear to be smaller than those of age-matched Subcortical signal hyperintensities, which are compatible with a range of pathologic etiologies, occur with a higher prevalence in older unipolar patients when these were compared with age-matched normal controls.21,23 The subcortical hyperintensities appear as areas of increased signal intensity in T2-weighted images. These hyperintensities most commonly involve the periventricular white matter, but also affect subcortical gray matter nuclei such as the basal ganglia. These abnormalities have been referred to as leukoencephalopathy, leukoaraiosis, unidentified bright objects (UBOs), and encephalomalacia. In an important prospective study, subcortical hyperintensities were noted in a consecutive series of 51 elderly depressed patients referred to ECT (51% showing lesions of subcortical gray matter). Therefore, it has been suggested that patients with late onset of illness and resistance to antidepressant pharmacotherapy are more likely to present with evidence for subcortical encephalomalacia.22, 23 Brown et all5 evaluated 229 patients with a range of psychiatric disorders and reported that only in depressed subjects over the age of 45 years is the incidence of white matter hyperintensities higher than in age-matched normal controls. In some studies with bipolar patients, the presence of these signal abnormalities has been associated with neuropsychological impairment and a greater number of hospitalization^.'^, 31 The neuropathologic correlates of these white matter hyperintensities in mood disorders is unknown, but studies suggest they may be a result of ischemic vascular insult, increased water content in perivascular space, or axon and myelin 2o In some cases, these lesions also
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may represent pathologic changes associated with multiple sclerosis.5oThus, subcortical white and gray matter hyperintensities may be markers of conditions that predispose individuals, especially older people, to the expression of depressive disorder. It is possible that these white matter hyperintensities represent lesions that disrupt the basal ganglia-thalamo-cortical circuits increasing the vulnerability to depressive illness. FUNCTIONAL NEUROIMAGING STUDIES OF REGIONAL METABOLISM AND BLOOD FLOW IMPLICATES BASAL GANGLIA ABNORMALITIES IN DEPRESSIVE DISORDERS Functional Neuroimaging Studies
Functional brain imaging describes those techniques that allow in vivo measurements of regional cerebral blood flow (rCBF) and metabolism. At least four modalities currently are being used for studies of brain function in people: (1)single photon emission tomography (SPECT); (2) positron emission tomography (PET); (3) MR spectroscopy, and (4) functional MR imaging (fMRI). To our knowledge, NRI has not been used to investigate the pathogenesis of depressive disorders. We describe the SPECT, PET and MR spectroscopy results that point to basal ganglia dysfunction in depression. Single Photon Emission Computed Tomography
The use of 133 Xe to measure rCBF is determined by the rate of gas washout; consequently, spatial resolution tends to be poor (> 10 mm) and only cortical areas can be studied. Although 133 Xe techniques are easy to use and quite reliable, the emitted radiation is only detected from the outer 2 to 3 cm of brain. Thus, it is difficult to obtain information regarding rCBF in subcortical structures. Using this technique, the majority of studies noted a global reduction in rCBF in major depression.” 73 More recently, SPECT blood flow imaging has been performed using stable injectable tracers, most commonly HMPAO (technetium-99m-d,l-hexamethylpropyleneamine oxime). The introduction of Tc-99m-containing ligands represents a fundamental advance because the uptake of these agents is proportional to CBF, and brain SPECT images permit the analysis of subcortical and limbic structures. The majority of studies using HMPAO have noted a decrease in total cortical blood flow, hemispheric asymmetries, and hypofrontality in depression.8,54 Using HMPAO SPECT, Mayberg et a153 detected a left-sided decrease in CBF in patients with refractory unipolar depression. Positron Emission Tomography
PET provides a means to construct brain images of positron emitting nuclei with in-plane spatial resolution on the order of 2 to 5 mm. A limited number of studies involving patients with affective disorders have been conducted. The PET methodology that has been used most frequently to study patients with affective disorders is fluorodeoxyglucose (FDG) PET, which allows the study of regional glucose metabolism. Using FDG PET, two initial studies have documented relatively lower glucose metabolic rates in the basal ganglia of depressed
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patients compared with normal controls.ll, l6 Other studies have noted mood stateedependent, diminished metabolic rates in the left anterolateral prefrontal cortex in depressed patients.lz,52 Subsequent studies using 150xygen-PETto examine regional cerebral blood flow have been able to replicate the decrease in CBF in the left anterolateral prefrontal cortex and also show that cognitive impairment in severely depressed patients may be associated with decreased activity in the left anteromedial prefrontal cortex and increased activity in the cerebellar c o r t e ~ . ’This ~ same group of investigators also has reported correlations between psychomotor retardation and decreased blood flow in the left dorsolateral prefrontal cortex.14 Conversely, Drevets et alZ9used 150-PETand detected an increased rCBF in the left prefrontal cortex, the left amygdala, and the left medial thalamus and decreased rCBF in the left medial caudate in patients with familial pure de90 Diagnostic criteria and pressive disorder, a subtype of major depre~sion.~~, different PET methodologies may explain differences across studies. Activation Studies
Most of the studies described previously have examined subjects ”at rest.” Another way to approach the neuroanatomy of depression has been through activation and symptom provocation studies. It is proposed in these studies that CBF and metabolism may change when patients perform certain tasks or have specific thoughts that make their symptoms worsen. Pathologic regions may appear only under these conditions. Pardo and c011eagues~~ studied normal subjects and have detected transient increased CBF in the left orbital and prefrontal cortex when subjects were asked to imagine or recall a situation that would make them feel very sad (“transient ~ a d n e s s ” )Activation .~~ studies have shown decreased brain activation of limbic and paralimbic areas in tasks (e.g., emotional facial recognition) that involve the limbic system.= These results are in contrast to the observation that there are no differences between depressed and normal controls in tasks that rely on cortical structures (memory and spatial matching tasks).34,35 Treatment Response Effects on Regional Cerebral Blood Flow and Metabolism
Some investigators have assessed the effects of treatment on functional brain images in an attempt to clarify whether the abnormalities observed in these patients are reversed by treatment and clinical remission. In particular, Baxter et all2 and MartinoP have been able to show a normalization of the dorsolateral prefrontal hypometabolism seen in depressed patients after antidepressant treatment using 18FDG-PET.12,52 Conversely, Drevets et al” detected a decrease in CBF in the left prefrontal cortex following treatment with desipramine. In the same study, increased blood flow in the left amygdala detected in the depressed state persisted in remitted patients, suggesting that increased perfusion of the amygdala may represent a trait marker. This finding must be replicated in future studies to clarify state versus trait biologic markers in depression. Some patients with clinical depression respond to sleep deprivation. Wu et a191used ‘*FDG-PETscanning to document a higher rate of metabolic activity in the cingulum of responders relative to nonresponders to sleep deprivation.
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These data suggest that some of the metabolic derangements normalize with treatment. Future studies should clarify this issue by looking more closely at responders versus nonresponders, and by using more homogeneous samples of patients with mood disorders. IN VlVO NEUROCHEMICAL STUDIES: RECENT MAGNETIC RESONANCE SPECTROSCOPY FINDINGS Magnetic Resonance Spectroscopy in Depressive Disorders
MR spectroscopy is a noninvasive method to investigate the brain neuro~ , is possible through the use of MR spectroscopy to chemistry in v ~ v o .76~ It determine cerebral levels of a number of metabolites. Using phosphorus MR spectroscopy (31P-MRS)it is possible to detect high-energy phosphates (phosphocreatine and nucleoside triphosphates), inorganic phosphate, phosphomonoesters, and phosphodiesters. Using proton MR spectroscopy ('H-MRS), we can determine cerebral levels of choline, myo-inositol, N-acetyl-aspartate, and creatine. MR spectroscopy allows also the determination of brain levels of psychotropic drugs like lithium, fluoxetine, and fluorinated antipsychotic medications.26 Most MR spectroscopy studies in mood disorders have focused on metabolism of the frontal lobes in bipolar disorder.4547These investigations have suggested the presence of changes in high-energy phosphate and membrane metabolism. Focusing specifically in the basal ganglia of unipolar patients, initial studies have reported decreased basal ganglia choline levels in depression, which may reflect altered membrane metabolism within the basal ganglia.@A recently published study using 31P-MRS reported lower levels of nucleoside triphosphate in the basal ganglia of unmedicated unipolar depressed patients, possibly reflecting hypometabolism in this brain region.57This finding is consistent with the PET results showing diminished rCBF and glucose metabolism at the level of the basal ganglia. UNDERSTANDING THE PATHOPHYSIOLOGY OF MOOD DISORDERS: INTEGRATING BIOCHEMICAL HYPOTHESES WITH BASAL GANGLIA ABNORMALITIES
Taken together, data from structural and functional neuroimaging studies in primary and secondary depressive disorders strongly suggest that abnormalities in a number of the functional circuits proposed by Alexander et a13 are involved in the pathophysiology of depression?, 6o Two interrelated basal ganglia-thalamocortical circuits may be of particular relevance: (1) the "limbic" circuit, connecting limbic structures (amygdala and anterior cingulate, ventral striatum) with medial and ventrolateral prefrontal cortex; and (2) the "prefrontal" circuit, connecting the basal ganglia (more specifically the head of the caudate) and thalamus with the dorsolateral prefrontal cortex. Accumulating evidence implicates the neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in the pathophysiology of depression. This evidence is derived from what we know about the mechanisms of action of antidepressant medications, and also from animal studies; studies of metabolites in plasma, urine, and CSF; precursors (e.g., tryptophan) depletion studies; platelet studies; receptor-binding studies, and neuroendocrine studies
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among others. Additionally, recent reports indicate that stress promotes profound and complex alterations involving DA release, metabolism, and receptors densities in the mesolimbic system.', 17, 27, 51 There are extensive dopaminergic, noradrenergic, serotonergic, and cholinergic projections into the basal ganglia-and they likely contribute to the overall modulation of basal ganglia thalamocortical Although somatic antidepressant therapies influence each of these systems, their therapeutic mechanisms may be associated with enhancing dopaminergic and serotonergic activity (especially 5-HT1, relative to 5-HT2).Both effects would be predicted to inhibit the 36, 51* 86, 89 A recent hypothesis links depression to a strong interaclimbic circ~it.'~, tion between the NE and DA systems in depression. We also know that the NE and 5-HT systems strongly interact with each Although we are proposing a putative anatomic localization for depression where important neurochemical dysfunctions may occur, we suspect that depression is associated with both functional and structural disruption of the relevant described circuits. A functional or anatomic disruption at different sites of the basal ganglia-thalamocortical circuits may be associated with different forms of depression and explain, in part, why depression appears to be such a heterogeneous disorder. CLINICAL AND TREATMENT PERSPECTIVES
Although these findings have helped researchers in identifying neuroanatomic circuits that may be involved in clinical depression, a critical shortcoming is that neuroimaging has yet to provide much help for the clinician. The findings described, however, may help us to understand, in part, the heterogeneity of depressive disorders. Additionally, a better understanding of the pathophysiology of depressive disorders may open new possibilities for the development of better treatments we can offer to our patients. This is especially true for those who are refractory to conventional pharmacotherapy. Over time, continued research in this field may provide important insights into early detection, diagnosis, and prevention of depressive disorders. References 1. Abercrombie ED, Keefe KA, Di Frischia DF, et al: Differential effects of stress on in vivo dopamine release in striatum, nucleus accumbens and medial frontal cortex. J Neurochem 521665-1658, 1989 2. Alexander GE, De Long MR, Strick P: Parallel organization of functionally segragated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357-381, 1986 3. Alexander GE, Grutcher MD, DeLong MR Basal ganglia thalamocortical circuits: Parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. Prog Brain Res 85:119-146, 1990 4. Andreasen NC: Nuclear magnetic resonance imaging. In Andreasen NC (eds): Brain Imaging: Applications in Psychiatry. Washington, DC, American Psychiatric Press, Inc., 1989, p 67-121 5. Andreasen NC, Swayze 11, V, Flaum M, et al: Ventricular abnormalities in affective disorder: Clinical and demographic correlates. Am J Psychiatry 147893-900, 1990 6. Arango V, Emsberger P, Sved AF, et a1 Quantitative autoradiography of alpha 1- and alpha 2-adrenergic receptors in the cerebral cortex of controls and suicide victims. Brain Res 630:271-282, 1993 7. Austin MP, Mitchell P: The anatomy of melancholia: Does frontal-subcortical patho-
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physiology underpin its psychomotor and cognitive manifestations? Psychol Med 25665-672,1995 8. Austin MP, Dougall N, Ross M, et al: Single photon emission tomography with 99m Tc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum. J Affect Disord 26:3144, 1992 9. Awad lA,Spetzler RF, Hodak JA, et al: Incidental subcortical lesions identified on magnetic resonance imaging in the elderly: I. Correlation with age and cerebrovascular risk factors. Stroke 171084-1097, 1986 10. Aylward EH, Roberts-Twillie J, Barta P, et al: Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry 151:687-693, 1994 11. Baxter LR, Phelps M, Mazziotta JC, et al: Cerebral metabolic rates for glucose in mood disorders. Arch Gen Psychiatry 42411447, 1985 12. Baxter LR, Schwartz J, Phelps M, et al: Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46:243-250, 1989 13. Bench CJ, Friston K, Brown R, et al: The anatomy of melancholia-Focal abnormalities of cerebral blood flow in major depression. Psychol Med 22:607-615, 1992 14. Bench CJ, Friston KJ, Brown RG, et al: Regional cerebral blood flow in depression measured by positron emission tomography: The relationship with clinical dimensions. Psychol Med 23:579-590, 1993 15. Brown FW, Lewine R, Hudgins P, et al: White matter hyperintensity signals in psychiatric and nonpsychiatric subjects. Am J Psychiatry 149:620-625, 1992 16. Buchsbaum MS, Wu J, DeLisi L, et a1 Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with 118 F]2-deoxyglucose in affective illness. J Affect Disord 10:137-152, 1986 17. Cabib S, Puglisi-Allegra S Stress, depression and the mesolimbic dopamine system. Psychopharmacology 128331-342,1996 18. Caine ED, Shoulson I: Psychiatric syndromes in Huntington’s disease. Am J Psychiatry 140~728-733,1983 19. Charney DS, Woods SW, Krystal JH, et a1 Hypotheses relating serotonergic dysfunction to the etiology and treatment of panic and generalized anxiety disorders. In Coccaro EF, Murphy DL (eds): Serotonin in Major Psychiatric Disorders. Washington, DC, American Psychiatric Association, 1990, pp 129-152 20. Chimowitz MI, Estes M, Furlan A, et al: Further observations on the pathology of subcortical lesions identified on magnetic resonance imaging. Arch Neurol 49:747752, 1992 21. Coffey CE, Figiel G, q a n g W, et al: Subcortical hyperintensity on magnetic resonance imaging: A comparison of normal and depressed elderly subjects. Am J Psychiatry 147187-189, 1990 22. Coffey CE, Figiel G, Qang W, et al: White matter hyperintensity on magnetic resonance imaging: Clinical and neuroanatomic correlates in the depressed elderly. J Neuropsychiatry Clin Neurosci 1:135-144, 1989 23. Coffey CE, Wilkinson W, Weiner R, et a1 Quantitative cerebral anatomy in depression: A controlled magnetic resonance imaging study. Arch Gen Psychiatry 50:7-16, 1993 24. Cummings JL: Depression and Parkinson’s disease: A review. Am J Psychiatry 149:443454, 1992 25. Cummings JL: Frontal-subcortical circuits and human behavior. Neurol Rev 50:873880, 1993 26. Dager SR, Grant Steen RG: Applications of magnetic resonance spectroscopy to the investigation of neuropsychiatric disorders. Neuropsychopharmacology 6:249-266, 1992 27. Delgado PL, Price LH, Heninger GR, et al: Neurochemistry. In Paykel ES (eds): Handbook of Affective Disorders, ed 2. New York, Guilford Press, 1992, pp 219-253 28. Dening TR, Berrios GE: Wilson’s disease: Psychiatric symptoms in 195 cases. Arch Gen Psychiatry 46:1126-1134, 1989 29. Drevets WC, Videen TO, Price JL, et al: A functional anatomical study of unipolar depression. J Neurosci 123628-3641, 1992 30. Dupont RM, Jemigan TL, Heindel W: Magnetic resonance imaging and mood disor-
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