Omar M. Alhassoon

Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors.

Nucleoside reverse transcriptase inhibitors (NRTIs) suppress human immunodeficiency virus (HIV) replication, but are often associated with mitochondrial toxicity. Although well studied outside of the central nervous system, no investigation has examined the effects of these drugs on brain mitochondria of individuals living with HIV. The authors used proton magnetic resonance spectroscopy to evaluate NRTI-related changes in brain mitochondria. N-acetylaspartate (NAA; sensitive to alterations in mitochondrial integrity) was measured in frontal lobe white and gray matter of 18 HIV+ individuals taking didanosine and/or stavudine (two NRTIs likely to cause mitochondrial toxicity), 14 HIV+ individuals taking zidovudine and lamivudine, 16 HIV+ individuals not currently taking antiretrovirals, and 17 HIV− controls. The HIV+ groups were comparable on demographic measures, estimates of illness severity, and estimated length of HIV infection. Those taking didanosine and/or stavudine had a significant 11.4% decrease in concentrations of frontal white matter NAA compared to HIV− controls, whereas NAA levels of the other HIV+ groups were intermediate. Group differences in metabolites were not found in frontal gray matter. Lower levels of frontal white matter NAA were associated with longer periods of didanosine and/or stavudine treatment (r = −.41, P = .06). Levels of NAA were not related to length of zidovudine/lamivudine treatment (r = −.04, P= .44). Furthermore, taking more than one of stavudine, didanosine, and abacavir increased the likelihood of having reduced NAA. The results are consistent with previous studies finding HIV-related changes in neuronal integrity. However, because NRTIs can injure mitochondria, we propose that the observed reductions in NAA in individuals taking didanosine and/or stavudine may be the result of depleted brain mitochondria and/or alterations in cellular respiration. Measurement of brain metabolites sensitive to impairments in energy metabolism, including NAA, may aid in early detection of subclinical NRTI-mediated mitochondrial toxicity.

White matter tract injury and cognitive impairment in human immunodeficiency virus–infected individuals

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4=529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.

Effects of human immunodeficiency virus and methamphetamine on cerebral metabolites measured with magnetic resonance spectroscopy

Human immunodeficiency virus (HIV) and methamphetamine (METH) use disorders are associated with cerebral dysfunction. To determine whether these effects were evident on in vivo neuroimaging, quantitative, single voxel magnetic resonance (MR) spectroscopy was used to assess frontal white matter, frontal gray matter, and basal ganglia in 40 HIV+/METH+, 66 HIV+/METH-, 48 HIV-/METH+, and 51 HIV-/METH-participants. HIV was associated with lower N-acetylaspartate (NAA) in frontal white and frontal gray matter but METH was not associated with cerebral metabolite differences in any region. Among HIV+ individuals, lower CD4 counts and higher plasma HIV viral loads were associated with lower NAA in frontal gray matter and basal ganglia. The relationship between detectable plasma HIV viral load and NAA in frontal white matter was significantly stronger in the HIV+/METH+ group, compared to HIV+/METH-. Higher detectable plasma HIV viral load was significantly associated with higher myo-inositol (MI) in frontal white and gray matter for HIV+/METH+, but not HIV+/METH-. For the HIV-/METH+ group, lifetime duration of METH use was associated with higher choline levels in frontal gray matter and higher MI levels in basal ganglia. Our findings are consistent with significant disruption of neuronal integrity in the frontal lobes of HIV-infected individuals. Although METH was not associated with cerebral metabolite levels, other findings suggested that METH use did affect the brain. For example, the relationship between detectable plasma HIV viral load and NAA levels was limited to HIV+/METH+ individuals. This evidence indicates when HIV is poorly suppressed, METH may modify the effects of the virus on neuronal integrity.

Frontal White Matter Integrity Predictors of Adult Alcohol Treatment Outcome

BACKGROUND Previous research has associated abnormalities in frontal lobe functioning with alcohol relapse. In this study, we used diffusion tensor imaging to investigate whether frontal white matter integrity measured at the start of treatment differs between persons with alcohol use disorders (AUD) who sustain treatment gains and those who return to heavy use after treatment. METHODS Forty-five treatment-seeking AUD inpatients and 30 healthy control subjects were included in the study. Six months after completing treatment, 16 of the AUD participants had resumed heavy use (RHU) and 29 others remained abstinent or drank minimally (treatment sustainers [TS]). Voxel-wise group comparisons (TS vs. RHU) were performed on fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity maps generated from each subjects diffusion tensor imaging scan at the start of treatment. RESULTS We found significantly lower FA and significantly higher RD in the frontal lobes of the RHU group, relative to the TS group. The RHU group data are consistent with previous reports of abnormal frontal white matter tract abnormalities in persons with AUD. CONCLUSIONS It is possible that the lower FA and higher RD in the RHU group reflect microstructural injury to frontal circuitries, and these may underlie the reduced cognitive control amid heightened reward sensitivity associated with resumption of heavy drinking.

MR spectroscopy in HIV and stimulant dependence HNRC Group. HIV Neurobehavioral Research Center.

HIV infection and abuse of central nervous system (CNS) stimulants are both associated with brain damage and dysfunction. CNS stimulant overdose can lead to microinfarction, hemorrhagic lesions, and vasculitis (Bostwick, 1981; Cahill et al., 1981), and may impact frontostriatal systems. Investigations of HIV-infected (HIV+) individuals have demonstrated deficits in attention, speed of information processing, motor functioning, executive functioning, and learning efficiency. These deficits are consistent with frontostriatal involvement (Heaton et al., 1995; Martin, 1994). Given the rise in AIDS cases attributable to drug use at a time when the number of AIDS cases due to sexual transmission is stable or declining, it is critical to determine if drug use, especially CNS stimulants, potentiates HIV-related neuronal injury.

Gray matter abnormalities in cocaine versus methamphetamine-dependent patients: a neuroimaging meta-analysis

Abstract Background: Voxel-based morphometry has been used to explore gray matter alterations in cocaine and methamphetamine dependence. However, the results of this research are inconsistent. Objectives: The current study meta-analytically examined neuroimaging findings of all studies published before 2014 using the Anisotropic Effect-Size Signed Differential Mapping (ES-SDM). Methods: Independent investigators searched four major databases for relevant neuroimaging studies involving cocaine and methamphetamine dependence. Nine cocaine and four methamphetamine studies met inclusion criteria. Results: Results indicated that cocaine- and methamphetamine-dependent patients share overlapping regional gray matter abnormalities compared to healthy controls. However, subgroup analysis showed some regional differences; with methamphetamine showing more prominent reductions in the left superior temporal gyrus and the right inferior parietal lobe. Reductions in the right insula and the left superior frontal gyrus were more prominent in cocaine dependence. Moderator analyses indicated that with longer use, cocaine is associated with reductions in the right hippocampus, right middle temporal gyrus, and right inferior frontal gyrus, while methamphetamine is associated with reductions in the left precentral gyrus and the right supramarginal gyrus. Conclusion: These findings indicate that cocaine and methamphetamine dependence are significantly and differentially associated with gray matter abnormalities. Results also point to possible gray matter recovery after abstinence from methamphetamine. Although the sample size was adequate, these findings should be considered preliminary and analyses should be revisited with additional primary research focusing on long or short-term duration of use, as well as the length of abstinence.

Statistical support for subtypes in posttraumatic stress disorder: the how and why of subtype analysis.

A number of researchers have argued for the existence of different subtypes of posttraumatic stress disorder (PTSD). In the current paper we present criteria by which to assess these putative subtypes, clarify potential pitfalls of the statistical methods employed to determine them, and propose alternative methods for such determinations. Specifically, three PTSD subtypes are examined: (1) complex PTSD, (2) externalizing/internalizing PTSD, and (3) dissociative/nondissociative PTSD. In addition, three criteria are proposed for subtype evaluation, these are the need for (1) reliability and clarity of definition, (2) distinctions between subtypes either structurally or by mechanism, and (3) clinical meaningfulness. Common statistical evidence for subtyping, such as statistical mean difference and cluster analysis, are presented and evaluated. Finally, more robust statistical methods are suggested for future research on PTSD subtyping.

The effects of sleep deprivation on brain functioning in older adults.

Few studies have examined the effects of total sleep deprivation (TSD) on cognitive performance and brain activation using functional MRI (fMRI) in older adults. The current study examines blood oxygen level-dependent (BOLD) activation in older adults and younger adults during the sustained attention (GO) and response inhibition (NOGO) portions of a GO-NOGO cognitive task following 36 hr of total sleep deprivation. No significant performance differences were observed between the groups on the behavioral outcome measures of total hits and false alarms. Neuroimaging results, however, revealed a significant interaction between age-group and sleep-deprivation status. Specifically, older adults showed greater BOLD activation as compared to younger adults after 36 hours total sleep deprivation in brain regions typically associated with attention and inhibitory processes. These results suggest in order for older adults to perform the GO-NOGO task effectively after sleep deprivation, they rely on compensatory recruitment of brain regions that aide in the maintenance of cognitive performance.

Regional cerebral blood flow in cocaine- versus methamphetamine-dependent patients with a history of alcoholism

Although abuse of cocaine or methamphetamine usually takes place in the context of heavy drinking, there is little information on the effects of such substance use comorbidity on brain perfusion. We explored similarities and differences in the effects of these two drugs in combination with alcohol on brain function using SPECT. Global and regional cerebral blood flow (CBF) were examined in 7 abstinent cocaine-dependent alcoholics (CDA; mean age = 39.2 yr, S.D. = 9.2 yr), 7 abstinent methamphetamine-dependent alcoholics (MDA; mean age = 36.8 yr, S.D. = 5.0 yr), and 7 non-alcoholic/non-stimulant abusing controls (NAC; mean age = 37.3 yr, S.D. = 9.6 yr). MDA had significantly lower global CBF than CDA who, in turn, were significantly lower than NAC. In addition, CDA had abnormal perfusion in the superior posterior frontal region compared to NAC; while MDA did not display specific regional deficits. Therefore, it appears that cocaine alters the relationship between global and regional CBF in alcoholics, while methamphetamine does not.

Meta-analyses of clinical neuropsychological tests of executive dysfunction and impulsivity in alcohol use disorder

ABSTRACT Background: Promising models for cognitive rehabilitation in alcohol treatment rest on a more nuanced understanding of the associated impairments in the multifaceted domains of executive functioning (EF) and impulsivity. Objectives: This meta-analysis examined the effects of alcohol on the individual subcomponents of EF and impulsivity in recently detoxified participants, including 1) Inhibition & Self-Regulation, 2) Flexibility & Set Shifting, 3) Planning & Problem Solving, 4) Reasoning & Abstraction, and 5) Verbal Fluency. Impulsivity was further examined through an analysis of motor, cognitive, and decisional subcategories. Method: Investigators searched, coded, and calculated effect sizes of impairments demonstrated in a broad range of neuropsychological tests for EF. A total of 77 studies were selected covering 48 years of research with a sample size of 5140. Results: Findings ranged from a Hedges’ g effect size of 0.803 for Inhibition to a Hedges’ g of 0.359 for Verbal Fluency. Results also varied for the individual subcategories of Inhibition, including a large effect size for decisional impulsivity (g = 0.817) and cognitive impulsivity (0.860), and a moderate effect size for motor impulsivity (g = 0.529). The Hayling Test, Wisconsin Card Sorting Test, and Iowa Gambling Task were the measures most sensitive for alcohol effects. Conclusion: Planning, problem solving, and inhibitory abilities are significantly affected by alcohol abuse, with decisional and cognitive forms of impulsivity most impacted. Cognitive remediation targeting these deficits might increase the related functions that mediate the ability to moderate or abstain from alcohol, and so lead to improved treatment results.