The basal ganglia are involved in two major brain systems associated with the regulation of emotions, mood, and behavior: (a) the "limbic" structures with widely distributed brainstem, striatal, and paralimbic sites, with rich reciprocal connections to the basal ganglia, in particular between the amygdalae and caudate (17); and (b) five frontosubcortical circuits, linking frontal lobe regions to subcortical structures, including the basal ganglia, and back to frontal lobe areas (18). These circuits receive input from brainstem nuclei, including dopaminergic input from substantia nigra and pars compacta. In addition to motor and eye movement control, the frontosubcortical circuits subserve key behaviors including executive functioning, motivated behavior, and integration of emotional information into contextually appropriate behavior. Thus, the basal ganglia are interpositioned as an interface between internal personal drives (mood and motivation) and behavioral responses to external stimuli.
On the other hand, imaging studies have revealed that the basal ganglia are involved in "functional" psychiatric disorders. Magnetic resonance imaging (MRI) studies report reductions in caudate and putamen volume in unipolar and bipolar depression in addition to the prefrontal cortex, and positron emission tomography (PET) studies reveal hypermetabolism of globus pallidus in patients with unipolar and bipolar depression (19). Similarly, in obsessive compulsive disorder (20); changes in caudate activity have been reported. Thus, it is not surprising that diseases of the basal ganglia are associated with a wide range of neuropsychiatry disturbances. Furthermore, since the three frontosubcortical circuits mediating cognitive and emotional control transverse different regions of the basal ganglia, it is likely that the differential involvement of the basal ganglia in different diseases results in different patterns of neuropsychiatric symptoms.
Since parkinsonian disorders usually involve several subcortical structures, particularly at more advanced disease stages, focal lesions may provide a better opportunity to unravel the relationship between different basal ganglia regions and neuropsychiatry symptoms. In a literature review, Bhatia and Marsden reported the motor and behavioral changes in 240 patients with lesions affecting the basal ganglia (2). Although publication bias and wide variations in the assessment of neuropsychiatry symptoms employed limit the generalizability of the findings, some interesting results emerged. First, "behavioral disturbances" were reported in 46% of the cases. Second, such disturbances occurred nearly exclusively in patients with lesions involving the caudate nucleus, whereas lesions confined to the putamen or globus pallidus, or the combination of these, rarely were associated with neuropsychi-atric changes. Finally, in lesions involving the caudate nucleus, apathy (28%), disinhibition (11%), and depression (29%) were the most common neuropsychiatric symptoms. Notably, neuropsychiatric symptoms were more common than motor disturbances after such lesions (2). Thus, lesions involving the caudate nucleus or other aspects of the three frontosubcortical circuits mediating behavior are associated with neuropsychiatric symptoms. Apathy, disinhibition, depression, and obsessive-compulsive symptoms are common behavioral correlates of such disturbances. Further empirical support for the involvement of basal ganglia in cognition and emotion was reported in a study of 143 patients with bilateral basal ganglia mineralization, which was associated with an increased risk for affective and paranoid disorders (21).
Cummings proposed an integrating hypothesis linking observations from molecular biologic, neu-ropathologic, and neurochemical studies in neurodegenerative disorders to neuropsychiatric manifestations of these disorders. According to this model, proteinopathies, such as tauopathies and alpha-synucleinopathies, are associated with a distinct anatomic pattern of degeneration. Cell death in specific brain nuclei responsible for transmitter synthesis leads to deficits in a variety of transmitter systems. Specifically, a-synuclein disturbances, such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), mainly involve substantia nigra, brainstem, and limbic system neurons, whereas frontal and basal ganglionic neurons are predominantly affected in tau metabolism disturbances, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), resulting in frontal and subcortical abnormalities (22). These differential regional and transmitter involvements may result in differential patterns of motor, cognitive, and neuropsychiatric changes.
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