Structural Abnormalities

Neurological Depressions. Lesion deficit correlation studies demonstrate that certain disorders are more likely to be associated with a major depression than others: (a) discrete brain lesions, as seen with trauma, surgery, stroke, tumors, and certain types of epilepsy; (b) neurodegenerative diseases with regionally confined pathologies such as Parkinson's, Huntington's, and Alzheimer's diseases; (c) disorders affecting diffuse or multiple random locations such as multiple sclerosis; and (d) system illness with known central nervous system effects such as thyroid disease, cancer, and acquired immunodeficiency syndrome (AIDS) (Table 7.1).

Computed tomography (CT) and magnetic resonance imagining (MRI) studies in stroke patients have demonstrated a high association of mood changes with infarctions of the frontal lobe and basal ganglia, particularly those occurring in close proximity to the frontal pole or involving the caudate nucleus (Robinson et al., 1984; Starkstein et al., 1987). Studies of patients with head trauma or brain tumors or who have undergone neurosurgery (Grafman et al., 1986) further suggest that dorsolateral rather than ventral-frontal lesions are more commonly associated with depression and depressive-like symptoms such as apathy and psychomotor slowing. As might be expected, more precise localization of "depression-specific regions" is hampered by the heterogeneity of these types of lesions.

These limitations shifted focus to those diseases in which the neurochemical or neurodegenerative changes are reasonably well localized, as in many of the basal ganglia disorders. Notable is the high association of depression with Parkinson's disease (Mayberg and Solomon, 1995), Huntington's disease (Folstein et al., 1983), and others. These observations directly complement the findings described in studies of discrete brain lesions and further suggest the potential importance of functional circuits linking these regions (Alexander et al., 1990; Haber, 2000).

TABLE 7.1. Disorders Associated with Depressive Symptoms

Primary Psychiatric

Primary Neurological

Systemic Disorders


Focal lesions


Major depressive disorder



Bipolar disorder

Trauma/surgical ablation


Schizoaffective disorder

Complex partial seizures

Adrenal disease


Multiple sclerosis

(Cushing's, Addison's)

Panic disorder

Degenerative diseases

Parathyroid disorders

Generalized anxiety

Parkinson's disease


Posttraumatic stress

Huntington's disease



Diffuse Lewy body disease



Progressive supranuclear





Eating disorders

Fahr's disease, Wilson's


Anorexia nervosa


Vitamin deficiencies

Bulimia nervosa

Alzheimer's disease


Substance abuse

Frontal-temporal dementia

Systemic lupus

Alcohol and

Pick's disease



Other CNS

Sjogren's syndrome

Cocaine, amphetamines,



other stimulants

AIDS (limbic involvement)


Carbon monoxide exposure

AIDS (also medication

Paraneoplastic (limbic

side effects)



Migraine, chronic pain


Ischemic heart disease

Medication side effects

Chronic fatigue syndrome

Obstructive sleep apnea

Studies of systemic disorders, such as lupus erythematosus, Sjogren's syndrome, thyroid and adrenal disease, AIDS, and cancer, describe mood symptoms in subsets of patients. As with the more diffuse neurodegenerative diseases, such as Alzheimer's disease (Cummings and Victoroff, 1990), a classic lesion-deficit approach is generally difficult because consistent focal abnormalities are uncommon. Studies of plaque loci in patients with multiple sclerosis suggest an association of depression with lesions in the temporal lobes, although it is not yet clear whether this effect is lateralized (Honer et al., 1987).

Despite these apparent patterns, certain paradoxes remain. First, despite comparable underlying pathologies, not all patients with a given disorder develop depressive symptoms. For instance, in Parkinson's disease and Huntington's disease, the reported rate is about 50 percent. As postulated for primary affective disorders, mechanisms for this discordance focus on genetic and temperament markers. In Huntington's disease, a genetic disorder by definition, is associated with consistent affective symptoms in some but not all families, suggesting a more complex interaction at the molecular level (Folstein et al., 1983). Furthermore, in this population, depression and mania are both recognized. Unlike stroke, no localizing or regional differences can be offered to explain this phenomenon. In general, there is also no consensus as to whether the left or the right hemisphere is dominant in the expression of depressive symptoms in any neurological disorder. Reports of patients with traumatic frontal lobe injury indicate a high correlation between affective disturbances and right-hemisphere pathology (Grafman et al., 1986). Secondary mania, although rare, is most consistently seen with right-sided basal frontal-temporal or subcortical damage (Starkstein et al., 1990c). On the other hand, students of stroke patients suggest that left-sided lesions of both the frontal cortex and the basal ganglia are more likely to result in depressive symptoms than are right-sided lesions, where displays of euphoria or indifference predominate (Robinson et al., 1984). There is, however, considerable debate on this issue (Carson et al., 2000). Similar contradictions are seen in studies of patients with temporal lobe epilepsy where an association between affective symptoms (both mania and depression) and left, right, and nonlateralized foci have been described (Altshuler et al., 1990). Anatomic studies have yet to define the critical sites within the temporal lobe most closely associated with mood changes.

Lastly, and in some ways counterintuitive, is the absence of reported depressive symptoms with primary injury to limbic structures such as the amygdala, hippocampus, and hypothalamus, despite their fundamental involvement in critical aspects of motivational and emotional processes. This apparent contradiction would suggest that these key regions have a much more complex organizational structure than that revealed by classic lesion-deficit correlation methods.

Primary Unipolar Depression. Macroscopic anatomical findings in patients with primary affective disorders have been less consistent than those of depressed patients with neurological disorders (reviewed in Harrison, 2002; Soars and Mann, 1997). Brain anatomy is grossly normal, and focal neocortical abnormalities have not been identified using standard structural neuroimaging methods. Focal volume loss has been described using MRI in subgenual medial frontal cortex (Drevets et al., 1997). Also described are small hippocampi in patients with recurrent major depression (Sheline et al., 1999), with a postulated mechanism of glucocorticoid neurotoxicity, consistent with both animal models and studies of patients with posttraumatic stress disorder (Bremner and Narayan, 1998). Nonspecific changes in ventricular size, and T2-weighted MRI changes in subcortical gray and periventricular white matter have also been reported in some patient subgroups, most notably, elderly depressed patients (Coffey et al., 1993). The parallels, if any, of these observations with the regional abnormalities described in lesion and neurological patients with depression are unclear. Further studies of new-onset patients, or preclinical at-risk subjects, are needed to clarify whether these changes reflect disease pathophysiology or are the consequence of chronic illness or treatment.

Neuropathology Studies. In vivo structural abnormalities identified using MRI, have provided a foundation for the systematic examination of histological and cellular correlates in postmortem brain (reviewed in Harrison, 2002; Rajkowska, 2000). To this end, morphometric and immunocytochemical changes in neurons and glia as well as synaptic and dendritic markers have been reported, with studies targeting some but not all subdivisions of the frontal cortex, anterior cingulate, hippocampus, and brainstem. A loss of glia is the best replicated and most robust finding, affecting orbital frontal (ventral prefrontal) and prefrontal cortex (BA9), as well as the cingulate (subgenual, pregenual). Glial abnormalities are seen in both bipolar and unipolar disorder, and are most consistent in patients with a positive family history of mood disorder. Neuronal abnormalities are less consistently identified and generally involve a decrease in size, not number. Synaptic terminal and dendritic abnormalities, in support of aberrant cellular plasticity or impaired neurodevelopment, are also reported but appear to be a more selective marker of bipolar disorder. Despite repeated demonstration of hippocampal atrophy on MRI, there are no consistent cellular correlates to support the hypothesis of stress-induced hippocampal vulnerability. Neither are there clear correlates of the stress-induced apoptosis and decreased hippocampal neurogenesis demonstrated in animal stress models.

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