HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection.

MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.

Mental health outcomes in HIV and childhood maltreatment: a systematic review.

BACKGROUND: High rates of childhood maltreatment have been documented in HIV-positive men and women. In addition, mental disorders are highly prevalent in both HIV-infected individuals and victims of childhood maltreatment. However, there is a paucity of research investigating the mental health outcomes associated with childhood maltreatment in the context of HIV infection. The present systematic review assessed mental health outcomes in HIV-positive individuals who were victims of childhood maltreatment. METHODS: A systematic search of all retrospective, prospective, or clinical trial studies assessing mental health outcomes associated with HIV and childhood maltreatment. The following online databases were searched on 25-31 August 2010: PubMed, Social Science Citation Index, and the Cochrane Library (the Cochrane Central Register of Controlled Trials and the Cochrane Developmental, Psychosocial and Learning Problems, HIV/AIDS, and Depression, Anxiety and Neurosis registers). RESULTS: We identified 34 studies suitable for inclusion. A total of 14,935 participants were included in these studies. A variety of mixed mental health outcomes were reported. The most commonly reported psychiatric disorders among HIV-positive individuals with a history of childhood maltreatment included: substance abuse, major depressive disorder, and posttraumatic stress disorder. An association between childhood maltreatment and poor adherence to antiretroviral regimens was also reported in some studies. CONCLUSION: A broad range of adult psychopathology has been reported in studies of HIV-infected individuals with a history of childhood maltreatment. However, a direct causal link cannot be well established. Longer term assessment will better delineate the nature, severity, and temporal relationship of childhood maltreatment to mental health outcomes.

Functional interactions of HIV-infection and methamphetamine dependence during motor programming.

Methamphetamine (METH) dependence is frequently comorbid with HIV infection and both have been linked to alterations of brain structure and function. In a previous study, we showed that the brain volume loss characteristic of HIV infection contrasts with METH-related volume increases in striatum and parietal cortex, suggesting distinct neurobiological responses to HIV and METH (Jernigan et al., 2005). Functional magnetic resonance imaging (fMRI) has the potential to reveal functional interactions between the effects of HIV and METH. In the present study, 50 participants were studied in four groups: an HIV+ group, a recently METH-dependent group, a dually affected group, and a group of unaffected community comparison subjects. An fMRI paradigm consisting of motor sequencing tasks of varying levels of complexity was administered to examine blood oxygenation level dependent (BOLD) changes. Within all groups, activity increased significantly with increasing task complexity in large clusters within sensorimotor and parietal cortex, basal ganglia, cerebellum, and cingulate. The task complexity effect was regressed on HIV status, METH status, and the HIV×METH interaction term in a simultaneous multiple regression. HIV was associated with less complexity-related activation in striatum, whereas METH was associated with less complexity-related activation in parietal regions. Significant interaction effects were observed in both cortical and subcortical regions; and, contrary to expectations, the complexity-related activation was less aberrant in dually affected than in single risk participants, in spite of comparable levels of neurocognitive impairment among the clinical groups. Thus, HIV and METH dependence, perhaps through their effects on dopaminergic systems, may have opposing functional effects on neural circuits involved in motor programming.

Caudate volume predicts neurocognitive performance in youth with heavy prenatal alcohol exposure.

BACKGROUND: Fetal alcohol spectrum disorders result from heavy prenatal alcohol exposure and are characterized, in some cases, by central nervous system anomalies and cognitive impairment. Regional patterns of neuroanatomical abnormalities suggest that alcohol exerts selective damage on the developing fetal brain. This study assessed brain-behavior relationships in a sample of youth with histories of heavy prenatal alcohol exposure. The aim was to characterize how structural brain alterations observed in our previous studies relate to cognitive deficits commonly reported in individuals with histories of heavy prenatal alcohol exposure. METHODS: Twenty-one youth (mean age 13 years) with histories of heavy prenatal alcohol exposure and 7 nonexposed healthy comparison subjects underwent structural magnetic resonance imaging and neurobehavioral testing. Regional brain volumes within the alcohol-exposed group were correlated with neuropsychological measures of cognitive control and verbal learning/recall, as these aspects of cognition have previously been shown to be vulnerable to alcohol teratogenesis. RESULTS: Between-group effect sizes revealed moderate to large cognitive performance and brain volume decrements in alcohol-exposed subjects, compared with typically developing peers. Within the alcohol-exposed group, volume of the caudate nuclei was the most consistent predictor of neuropsychological performance, after controlling for potentially confounding variables including total brain volume, IQ, and age. CONCLUSIONS: These data are consistent with previous research associating gestational alcohol exposure with structural and functional changes of the caudate nucleus. Our findings extend this previous work by demonstrating that volume reductions of the caudate have behavioral relevance for this population, in relation to cognitive control and verbal learning and recall abilities.

Impact of childhood trauma on functionality and quality of life in HIV-infected women.

BACKGROUND: While there are many published studies on HIV and functional limitations, there are few in the context of early abuse and its impact on functionality and Quality of Life (QoL) in HIV. METHODS: The present study focused on HIV in the context of childhood trauma and its impact on functionality and Quality of Life (QoL) by evaluating 85 HIV-positive (48 with childhood trauma and 37 without) and 52 HIV-negative (21 with childhood trauma and 31 without) South African women infected with Clade C HIV. QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), the Patient's Assessment of Own Functioning Inventory (PAOFI), the Activities of Daily Living (ADL) scale and the Sheehan Disability Scale (SDS). Furthermore, participants were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Childhood Trauma Questionnaire (CTQ). RESULTS: Subjects had a mean age of 30.1 years. After controlling for age, level of education and CES-D scores, analysis of covariance (ANCOVA) demonstrated significant individual effects of HIV status and childhood trauma on self-reported QoL. No significant interactional effects were evident. Functional limitation was, however, negatively correlated with CD4 lymphocyte count. CONCLUSIONS: In assessing QoL in HIV-infected women, we were able to demonstrate the impact of childhood trauma on functional limitations in HIV.

Clinical factors related to brain structure in HIV: the CHARTER study.

Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.

Brain structure in prenatal stroke: quantitative magnetic resonance imaging (MRI) analysis.

Neonatal stroke outcome studies demonstrate variable findings of either relatively spared intellectual function or persistent impairments. Volumetric measurement of the brain can provide more precise data on lesion-cognition outcomes. We studied 7 children with unilateral focal lesions from prenatal stroke. Whole-brain magnetic resonance imaging scans were analyzed to produce volumes of cortical gray matter, total white matter, cerebrospinal fluid, lesion, and lesion constricted fluid, and we ascertained the relationship of morphometric variables to intellectual and clinical outcome. Children with cystic encephalomalacia plus atrophy had poorer outcomes than children with atrophy or gliosis alone. These children also demonstrated the largest lesion size, smallest gray matter volume, and greatest proportion of hyperintense white matter in the affected hemisphere. Findings suggest that the type and size of the lesion, in addition to the integrity of white matter and residual cortex, may be better predictors of intellectual functioning than either of these indices alone.

Does amygdalar perfusion correlate with antidepressant response to partial sleep deprivation in major depression?

This study used functional MRI (fMRI) to clarify the sites of brain activity associated with the antidepressant effects of sleep deprivation (SD). We hypothesized: (1) baseline perfusion in right and left amygdalae will be greater in responders than in nonresponders; (2) following partial sleep deprivation (PSD), perfusion in responders' right and left amygdalae would decrease. Seventeen unmedicated outpatients with current major depression and eight controls received perfusion-weighted fMRI and structural MRI at baseline and following 1 night of late-night PSD. Baseline bilateral amygdalar perfusion was greater in responders than nonresponders. Clusters involving both amygdalae decreased from baseline to PSD specifically in responders. Right amygdalar perfusion diverged with PSD, increasing in nonresponders and decreasing in responders. These novel amygdalar findings are consistent with the overarousal hypothesis of SD as well as other functional imaging studies showing increased baseline amygdalar activity in depression and decreased amygdalar activity with remission or antidepressant medications.

Effects of methamphetamine dependence and HIV infection on cerebral morphology.

OBJECTIVE: The authors examined the separate and combined effects of methamphetamine dependence and HIV infection on brain morphology. METHOD: Morphometric measures obtained from magnetic resonance imaging of methamphetamine-dependent and/or HIV-positive participants and their appropriate age- and education-matched comparison groups were analyzed. Main effects of age, HIV infection, methamphetamine dependence, and the interactions of these factors were examined in analyses of cerebral gray matter structure volumes. RESULTS: Independent of the effect of age, HIV infection was associated with reduced volumes of cortical, limbic, and striatal structures. There was also some evidence of an interaction between age and HIV infection such that older HIV-positive participants suffered disproportionate loss. Methamphetamine dependence was surprisingly associated with basal ganglia and parietal cortex volume increases, and in one of these structures-the nucleus accumbens-there appeared to be a larger effect in younger methamphetamine abusers. Neurocognitive impairment was associated with decreased cortical volumes in HIV-positive participants but with increased cortical volumes in methamphetamine-dependent participants. CONCLUSIONS: These results suggest significant brain structure alterations associated with both HIV infection and methamphetamine dependence. The regional patterns of the changes associated with these factors were distinct but overlapping, and the effects on brain volumes were opposing. Although the results of the present study provide little information about the specific mechanisms leading to the unexpected methamphetamine effects, they may be related to glial activation or neuritic growth, both of which have been associated with methamphetamine exposure in animal studies. These results have implications for the interpretation of brain morphological findings in methamphetamine-dependent, HIV-positive individuals, a group whose numbers are unfortunately increasing.

Correlation of in vivo neuroimaging abnormalities with postmortem human immunodeficiency virus encephalitis and dendritic loss.

BACKGROUND: In the absence of significant opportunistic infection, the most common alterations on neuroimaging in the brains of patients with AIDS include enlarged cerebrospinal fluid spaces, white-matter loss, volume loss in striatal structures, and white-matter signal abnormalities. Although previous studies have linked brain viral levels to these alterations, other neuropathological mechanisms might also contribute to them. OBJECTIVE: To examine the relationship between findings on premortem magnetic resonance images and postmortem neuropathologic evidence of human immunodeficiency virus (HIV) encephalitis and neurodegeneration. DESIGN: Morphometric analysis of magnetic resonance imaging in seropositive cases with matched seronegative controls, and the correlation of these volumes to neuropathological measures in autopsied seropositive cases. SETTING: University of California, San Diego, HIV Neurobehavioral Research Center. SUBJECTS: Twenty-one seropositive subjects studied at autopsy and 19 seronegative cases. MAIN OUTCOME MEASURES: In vivo structural magnetic resonance imaging data analyzed by quantitative methods, with comparison of volumes from magnetic resonance imaging and neuropathological data from autopsies. RESULTS: The HIV-seropositive subjects demonstrated cerebrospinal fluid increases relative to seronegative controls. These increases were associated with a significant decrease in the volumes of cerebral and cerebellar white matter, caudate nucleus, hippocampus, and, to a lesser extent, cerebral cortex. The volume of cerebral white-matter tissue with elevated signal was also increased. This signal elevation in white matter predicted the autopsy diagnosis of HIV encephalitis, as well as the extent of dendritic loss as assessed by analysis of microtubule-associated protein 2 immunoreactivity. CONCLUSIONS: White-matter and cortical damage resulting from HIV disease are closely related. In vivo magnetic resonance imaging may be a valuable adjunct in the assessment of patients at risk for developing HIV encephalitis.

Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder.

BACKGROUND: To examine neuroanatomical morphometry in adult female victims of intimate partner violence with and without posttraumatic stress disorder. METHODS: Seventeen nonvictimized comparison subjects and 22 victims of intimate partner violence, 11 with and 11 without posttraumatic stress disorder, were studied. Using quantitative magnetic resonance imaging, three mesial temporal lobe areas were measured: hippocampus, amygdala, and parahippocampal gyrus. Additionally, whole brain morphometry provided fluid, gray, and white matter volumes of the cortex and cerebellum for exploratory analyses. Relationships of morphometric measures to symptoms, abuse history, and neuropsychological function were examined. RESULTS: Intimate partner violence subjects with posttraumatic stress disorder did not demonstrate significantly smaller hippocampal or other mesial temporal lobe volumes. Overall, intimate partner violence subjects had smaller supratentorial cranial vaults and smaller frontal and occipital gray matter volumes relative to nonvictimized comparison subjects. Supratentorial cranial vault volume was negatively correlated with severity of childhood physical abuse, but not with intimate partner violence or posttraumatic stress disorder severity. Trails B performance was negatively correlated with frontal gray matter volume. CONCLUSIONS: These findings are inconsistent with prior reports of smaller hippocampal volumes in patients with posttraumatic stress disorder. Rather, the findings point to cerebral abnormalities that may reflect the influence of early trauma on neurodevelopmental processes or denote brain morphometric characteristics of persons at increased risk for serious psychosocial adversity.