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Since METH subjects with larger striatal structures had relatively normal cognitive performance and lesser cumulative METH usage, the enlarged putamen and globus pallidus might represent a compensatory response to maintain function. Possible mechanisms for the striatal enlargement include glial activation and inflammatory changes associated with METH-induced injury.

Attention and memory deficits have been reported in heavy marijuana users, but these effects may be reversible after prolonged abstinence. It remains unclear whether the reversibility of these cognitive deficits indicates that chronic marijuana use does not alter cortical networks, or that such changes occur but the brain adapts to the drug-induced changes. Blood oxygenation-level dependent (BOLD) functional MRI (fMRI) was performed in 24 chronic marijuana users (12 abstinent and 12 active) and 19 age-, sex- and education-matched control subjects during a set of visual-attention tasks with graded levels of difficulty. Neuropsychological tests were also administered on each subject. The two marijuana user groups showed no significant difference in usage pattern (frequency or duration of use, age of first use, cumulative joints used, averaged >2000 joints) or estimated cumulative lifetime exposure of Delta-9-tetrahydrocannabinol (THC) (mean 168 +/- 45 versus 244 +/- 135 g). Despite similar task and cognitive test performance compared with control subjects, active and abstinent marijuana users showed decreased activation in the right prefrontal, medial and dorsal parietal, and medial cerebellar regions, but greater activation in various frontal, parietal and occipital brain regions during the visual-attention tasks (all with P < or = 0.001, corrected, cluster level). However, the BOLD signals in the right frontal and medial cerebellar regions normalized with duration of abstinence in the abstinent users. Active marijuana users, with positive urine tests for THC, showed greater activation in the frontal and medial cerebellar regions than abstinent marijuana users and greater usage of the reserve network (regions with load effect), suggesting a neuroadaptive state. Both earlier age of first use and greater estimated cumulative dose of THC exposure were related to lower BOLD signals in the right prefrontal region and medial cerebellum. The altered BOLD activation pattern in the attention network and hypoactivation of the cerebellum suggest neuroadaptive processes or alteration of brain development in chronic marijuana users. These changes also may be related to marijuana-induced alteration in resting cerebral blood volume/flow or downregulation of cannabinoid (CB1) receptors. The greater activation in the active compared with abstinent marijuana users demonstrates a neuroadaptive state in the setting of active marijuana use, while the long-term chronic effect of marijuana on the altered brain network may be reversible with prolonged abstinence.

Chronic infection with HIV is associated with neuroinflammation. Prior diffusion tensor imaging (DTI) studies demonstrated increased mean diffusion (MD) and decreased fractional anisotropy (FA) in the white matter (WM) and subcortical brain regions of HIV patients. The current study aims to detect whether there are greater than age-related brain changes in HIV patients after a 1-year followup period using DTI. Thirty-nine antiretroviral-stable HIV subjects and 32 HIV-seronegative (SN) controls were evaluated, with neuropsychological tests and DTI, at baseline and after 1 year. MD and FA in the genu and splenium of the corpus callosum and in six other subcortical and white matter regions were evaluated bilaterally. Compared to SN controls, HIV subjects had significantly higher MD in the frontal WM (p=0.0104) and lower FA in the parietal WM (p=0.006). After 1 year, HIV subjects showed increase in MD in frontal and parietal WM, putamen, and genu; HIV subjects also showed greater increased genu diffusion than SN controls (p=0.005). Changes in global cognitive deficit score correlated with changes in MD in the genu and FA in the parietal and frontal WM and putamen (multiple regression, p=0.0008). Lastly, normal age-dependent changes in frontal WM diffusion and FA in genu and putamen were not observed in HIV subjects. Since increased MD may reflect increased neuroinflammation, our findings suggest greater than normal age-related inflammatory changes in the genu of these HIV patients, which may contribute to the cognitive deficits. Measurements of MD in the genu may be useful for monitoring disease progression in HIV brain infection. KeywordsHIV; diffusion tensor; neuroinflammation; aging; brain Human immunodeficiency virus (HIV) infection of the brain is often associated with significant inflammation. This inflammation may be mediated by HIV viral proteins (e.g., tat, gp120, gp41) that upregulate macrophage secretion of proinflammatory cytokines (e.g., tumor necrosis factor, interleukin-1-beta, interlekin-6; Connolly et al. 2005) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript macrophage chemotactic protein or MCP-1, RANTES, MIP-1alpha, and MIP-1beta), which in turn would activate microglia and increase astroglial-derived chemokines in the brain (ElHage et al. 2006;Hauser et al. 2007). These proteins also could lead to elevation of inducible nitric oxide synthetase (Adamson et al. 1996) and other proteins (e.g., matrix metalloproteinases; Conant et al. 2004) that might increase blood-brain barrier permeability and would lead to further ingress of HIV-infected monocytes into the brain and a feed-forward loop of the inflammatory cascade (Banks et al. 2006). In addition to the direct neurotoxic effect of the HIV viral proteins (Nath 2002), the myriad of inflammatory proteins may lead to oxidative stress and ultimately neuronal injury or death, although some of these proteins are activated as a protective response (Steiner et al. 2006).Several magnetic resonance (MR) techniques have be...