Akinesia
Akinesia is primarily a disorder of movement, not motivation. However, the two syndromes are not necessarily unassociated. A mildly akinetic patient can be severely apathetic, and a severely akinetic patient can be highly motivated. Akinetic patients show diminution or loss of the initiation of speech and actions. Basal ganglia disease and use of neuroleptic medications, the most prominant causes of akinesia, also cause apathy.
Aprosodia
Aprosodia is a disorder of emotion in which patients show impaired ability to perceive, interpret, or express emotion. Aprosodias are generally attributed to disease of the right hemisphere. Flat affect and inappropriate cheerfulness can occur in both apathy and aprosodia. Therefore, apathy and aprosodia may be difficult to distinguish from each other on the basis of emotional responsivity.
Neural substrates of apathy
The neural mechanisms of apathy in neuropsychiatric disorders have been described in a review by Mega and Cummingslo. Clinical research suggests that dopaminergic activity mediates diminished motivation in a number of conditions, such as subcortical diseases, frontal lobe syndromes, negative symptoms of schizophrenia, and post psychotic depression. Thus, increasing dopaminergic activity is the primary strategy or the pharmacologic treatment of patients with apathyB. Apathy, however, should not be viewed simply as a problem ofdopaminergic hypoactivity 11.
Dopamine systems
Apathy has been associated with hypofunctionality of the frontal cortexlO. The mesocortical dopaminergic system arises in the ventral tegmental area of the mesencephalon and innervates the cerebral cortex, particularly the frontal cortex. Increased mesocortical dopaminergic function associated with dopamine against or stimulant therapy is presumed to be an important source of clinical improvement in patients whose apathy is primarily associated with frontal rather than subcorticl dysfunctonB.
The mesolimbic dopaminergic system, which also emerges from the ventral tegmental area, innervates the nucleus accumbens, amygdala, hippocampus, ventral pallidum and other forebrain structures. These and other interconnected structures (eg, the medial dorsal nucleus of the thalamus, the prefrontal cortex, and the pedunculopontine region of the brainstem) comprise a highly integrated series of circuits that represent the motivational state of the organism. This network translates motivition into action 12. Output of this motivation circuitry depends substantially on the pedunculopontine region and its connection to the basal ganglia and reticulospinal system. The benefit of dopamine aganist therapy in cases of subcortical disorders are believed to result from an increase in mesolimbic dopaminergic activity 8.
Frontal-Subcortical circuits
Three syndromes produced by frontal lobe damage are associated with apathy. Each frontal region is part of a specific cortical-subcortical circuit involving the thalamus, basal ganglia and forebrain 10,13,14. Damage affecting the anterior cingulate/mesiofrontal region produces a clinical syndrome of apathy. Dorsolateral prefrontal dysfunction is associates with impairment in the executive cognition necessary for planining and monitoring goal-directed behavior. Patients with damage to the lateral orbitoforntal cortex present with charges in personality marked by irritability, angry outbursts, or disinhibited sexuaj behavior. In these patients, however, there is often an underlying background of abulia and apathy that pervades the clinical picture.15 These frontal regions are connected to specific regions of caudate nucles, nucles accumbens, globus pallidus, and medical dorsal nucleus of the thalamus. Injury to any component of these three circuits produces the behavioral, emotional, and/or cognitive symptoms of that circuit.
Clinical causes of apathy
Clinically significant apathy can be due to primary neurologic processes and medical conditions that alter the neural systems subserving motivation. Table-2 lists clinical conditions associated with apathy.
Alzheimer disease
Apathy is a pervasive neurobehavioral disturbance in Alzheimer disease16. The prevalence and severity of the syndrome of apathy increases with the progression of Alzheimer disease, with prevalence reports varying from 29% to 88%.17-19 Functional imaging studies suggest that the syndrom of apathy in this patient group is related to the severity of prefrontal and anterior temporal dysfunction 20.
Frontal lobe dysfunction
Neurologic diseases of any etiology affecting the frontal lobes produce changes in cognition and behavior in which motivational loss is often sufficiently prominent to be characterized as a syndrome of apathy. Multiple sclerosis, Pick's disease, other non-Alzheimer frontal dementias, frontal tumors, stroke, and hydrocephalus are examples of patholigic processes that may produce frontal lobe syndromes 21
Basal ganglia disease
The syndrom of apathy has been associated with damage to the ventral striatum and globus pallidus 10,14. Systematic investigations of basal ganglia disease have focused primarily on Parkinson's disease 7,20,22, Huntington's disease l7,18 Progressive supranuclear palsy 23. and human immunodeficiency virus HIV) infection.24 In these and other subcortical diseases, loss of motivation often occurs in association with symptoms of mood disturbance and cognitive loss. HIV infection can leadto significant neuronal cell loss in the basal ganglia. Clinical studies indicate that apathy may reach syndromal proportions in the latter stages of disease progression 24. A recent study examined the relationship between apathy, depression and neurocognitive functioning during the asymptomatic stage of HIV infection 25. The study results showed that psychomotor slowing was associated with an increase in apathy but not depression in this cohort. These findings support the notion that apathy.symptoms may be one of the earliest clinical manifestations of central of nervous system involvement in HIV-infected patients.
Diencephalic and amygdala damage
Dysfunction of the diencephalon and amygdala may also produce the syndrome of apathy. The best known of the conditions affecting these areas of the brain is Korsakoff's syndrome. Tumor, stroke, and trauma injuring the diencephalon may also produce a syndrome of apathy. The
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