The results of our study provide preliminary evidence that apathy is related to neural changes induced by HIV. Apathy was elevated among the sample of HIV patients compared to healthy comparison subjects, and the severity of apathy strongly correlated with the volume of the nucleus accumbens. The finding is highly consistent with current neuroanatomical models of brain circuitry and function.
Alexander and colleagues described the presence of five parallel circuits connecting the frontal lobes to subcortical brain structures.19–21
These circuits connect subcortical nuclei with cortical regions. Three of these circuits (dorsolateral prefrontal, lateral orbital frontal, and anterior cingulate) are involved in the regulation of cognitive and neuropsychiatric behavior. In each circuit, neural processing projects from the cortex through the striatum, then to the globus pallidus and, eventually to specific thalamic nuclei. Reciprocal connections project back to the cortex, resulting in “closed” functional loops. The caudate nucleus is the critical subcortical nucleus in the dorsolateral and orbital frontal circuits, while the nucleus accumbens is the primary subcortical structure in the anterior cingulate circuit. While this characterization of the subcortical circuitry is likely oversimplified, the linear relationships described within and between each system provides a useful model to test the effects of disease on neurobehavioral and neuropsychiatric function.
An apathetic behavioral syndrome has previously been associated with disruption to the frontal cortex;22–23
however, there is also evidence that similar behavioral alterations occur with disruption to the frontal-subcortical anterior cingulate circuitry. Specifically, behavioral changes such as apathy, withdrawal, and loss of initiative arise from damage not only to the frontal lobes but also to the ventral striatum or other areas of the loop. This striatal syndrome characterized by apathy has been associated with pathologically confirmed bilateral damage to the nucleus accumbens and adjacent structures (e.g., rostroventral globus pallidus, septal gray matter;24–25
Thus, the classic apathetic behavioral syndrome seen in frontal lobe anterior cingulate lesions also occurs with damage to the nucleus accumbens. This model supports the contention that apathy in HIV is associated with disruption of subcortical function secondary to the effects of the virus.
to determine whether apathy results from subcortical dysfunction in HIV examined the relationship apathy and severity of cognitive impairment, since the latter was also believed to result from disruption of frontal subcortical circuits (the dorsolateral circuit in particular). Two of these studies reported modest relationships between apathy and cognitive dysfunction, a finding not surprising given the neuroanatomical proximity of the caudate and the nucleus accumbens. More robust relationships between the two symptoms were likely not observed because apathy and cognitive dysfunction may emanate from different subcortical circuits. This difference could account for the lack of significant relationship between apathy and caudate volume in the present study, and it explains the significant relationship between volume of the caudate nucleus and severity of dementia in HIV patients reported in previous studies.26–27
The cross-sectional nature of our data do not definitely conclude that HIV directly impacts the function and structure of the nucleus accumbens, and in turn produces increased apathy. A longitudinal study that includes a more robust acquisition sequence for the MRI analyses and imaging of healthy comparison subjects is needed to determine whether the nucleus accumbens is atrophic in patients with HIV and whether these relationships exist among patients without a significant history of substance abuse. Until these studies are completed, the specific underlying process associated with the development of apathy in HIV will remain conjecture. Nevertheless, the fact that apathy scores were not elevated among the healthy comparison group in the present study provides some assurance that the relationship between apathy and morphometry of the nucleus accumbens is not a general relationship that exists independent of HIV.
Additional work is needed to more comprehensively examine the clinical and functional relevance of brain volume and neuropsychiatric symptoms in HIV. In particular, is important to examine morphometric changes to the nucleus accumbens relative to demographically similar healthy comparison group, and whether measures of central viral load correlate with the volume measurements. It is also important to determine the course of change that occurs in volumetrics as a function of illness duration, age, treatment exposure and treatment adherence. These factors are almost certainly critical in determining the overall impact of HIV on brain function. A more comprehensive investigation of these factors will lead to a better understanding of the impact of HIV on the expression of neuropsychiatric symptoms.