Kevin G. F. Thomas

Characterization of HIV-Associated Neurocognitive Disorders among individuals starting antiretroviral therapy in South Africa.

HIV-Associated Neurocognitive Disorders (HAND) exert an impact on everyday functions, including adherence. The prevalence of and risk factors for HAND in patients commencing anti-retroviral therapy in Southern Africa are unknown. Participants from primary care clinics in Cape Town, South Africa underwent detailed neuropsychological, neuropsychiatric, and neuromedical evaluation. Using the updated American Academy of Neurology (AAN) criteria, participants were classified into categories of HAND, and demographic and clinical risk factors for HIV-dementia (HIV-D) were assessed. The prevalence of mild neurocognitive disorder (MND) and HIV-D were 42.4 and 25.4%, respectively. There were significant associations between lower levels of education and older age with HIV-D, and a trend to association with HIV-D and lower CD4 count. In a regression model, a lower level of education and male gender were predictive of HIV-D. These findings suggest that HAND are highly prevalent in primary care settings in South Africa where clade C HIV is predominant.

Psychobiology of mindfulness.

There is controversy about whether mindfulness-based approaches to psychotherapy represent a new wave of cognitive-behavioral therapy or a core process in all psychotherapies. One way of conceptualizing mindfulness is in terms of emotion regulation; mindfulness is a strategy aimed at opposing suppression and avoidance. Dispositional mindfulness has been associated with greater activation in prefrontal cortex and greater deactivation of amygdala during affect labeling. A number of rigorous studies of mindfulness-based cognitive therapy for depression have been positive. However, much remains to be discovered about the underlying mechanisms of and clinical indications for mindfulness-based approaches.

Validity of the International HIV Dementia Scale in South Africa

HIV-associated neurocognitive disorders (HAND) remain prevalent, especially in regions like South Africa where HIV prevalence is high but access to antiretroviral treatment (ART) is limited. The incidence of HIV dementia (HAD) has been halved with the use of ART, but the prevalence remains high. Appropriate brief screening tools to screen for HAD are needed in order to facilitate treatment initiation. The validity of the International HIV Dementia Scale has not been established in a region where infection with HIV clade C is predominant. The International HIV Dementia Scale (IHDS) was administered together with a detailed neuropsychological test battery to 96 HIV-positive individuals who had not received ART and who were attending primary care HIV clinics. The validity of the IHDS was established using a receiver operating characteristic (ROC) analysis. HIV-positive individuals displayed greater impairment when compared to HIV-negative controls on the IHDS and a range of neuropsychological tests. Neuropsychological tests discriminated well across HAND categories for HIV-positive individuals. In ROC analysis, the IHDS showed an area under the curve of 0.64, with a sensitivity of 45% and specificity of 79% at a cutoff score of 10. Individuals with HAD, who screened negative on the IHDS, performed poorly on some tests of executive function. These data suggest that the IHDS may have limitations as a tool to screen for HAD in South Africans infected with HIV. Variable performance in neuropsychological testing may account for false negative screens. The inclusion of brief tests of executive function in a screening battery should be considered.

Place learning in virtual space. III: Investigation of spatial navigation training procedures and their application to fMRI and clinical neuropsychology.

This paper describes the utilization of a desktop virtual environment task, the Computer-Generated (C-G) Arena, in the study of human spatial navigation. First, four experiments examined the efficacy of various training procedures in the C-G Arena. In Experiment 1, participants efficiently located a hidden target after only observing the virtual environment from a fixed position (placement learning). In Experiment 2, participants efficiently located a hidden target after only observing an experimenter search the virtual environment (observational learning). In Experiment 3, participants failed to display alatent learning effect in the virtual environment. In Experiment 4, all training procedures effectively taught participants the layout of the virtual environment, but the observational learning procedure most effectivelytaught participants the location of a hidden target within the environment. Finally, two experiments demonstrated the application of C-G Arena procedures to neuroimaging (Experiment 5) and neuropsychological (Experiment 6) investigations of human spatial navigation.

Neuropsychological outcomes in adults commencing highly active anti-retroviral treatment in South Africa: a prospective study.

BackgroundInfection with HIV may result in significant neuropsychological impairment, especially in late stage disease. To date, there have been no cohort studies of the impact of highly active anti-retroviral treatment (HAART) in South Africa where clade C HIV is predominant.MethodsParticipants in the current study were recruited from a larger study of HIV-associated neurocognitive disorders (HAND) and included a group of individuals commencing HAART (n = 82). Baseline and one-year neuropsychological function was assessed using a detailed battery, and summary global deficit scores (GDS) obtained. Associations with change in GDS were calculated.ResultsParticipants had a median CD4 cell count of 166 at baseline and 350 at follow-up. There were significant difference across groups of GDS severity at baseline with respect to level of education and GDS change at one year (p = 0.00 and 0.00 respectively). Participants with severe impairment at baseline improved significantly more than those with lesser degrees of impairment. Significant improvements were observed in the domains of attention, verbal fluency, motor function, and executive functions. There were unadjusted associations between GDS change and male gender, lower levels of education, baseline CD4 count and baseline GDS severity. In an adjusted model, only baseline GDS severity (p = 0.00) remained significant, with a lower level of education nearing significance (p = 0.05). The overall model was highly significant (p = 00; r-squared = 0.58).DiscussionIn individuals in late stage HIV commencing HAART in South Africa, those with severe baseline neuropsychological impairment improved significantly more than those less impaired. While improvement across a number of neuropsychological domains was observed, high rates of impairment persisted.ConclusionsThe effects of HAART and participant variables, such as test experience, require clarification. Studies with larger comparison groups, and where HIV disease characteristics are needed to establish whether the trends we identified are clinically meaningful.

Reduced fear-recognition sensitivity following acute buprenorphine administration in healthy volunteers

In rodents, the endogenous opioid system has been implicated in emotion regulation, and in the reduction of fear in particular. In humans, while there is evidence that the opioid antagonist naloxone acutely enhances the acquisition of conditioned fear, there are no corresponding data on the effect of opioid agonists in moderating responses to fear. We investigated whether a single 0.2mg administration of the mu-opioid agonist buprenorphine would decrease fear sensitivity with an emotion-recognition paradigm. Healthy human subjects participated in a randomized placebo-controlled within-subject design, in which they performed a dynamic emotion recognition task 120min after administration of buprenorphine and placebo. In the recognition task, basic emotional expressions were morphed between their full expression and neutral in 2% steps, and presented as dynamic video-clips with final frames of different emotional intensity for each trial, which allows for a fine-grained measurement of emotion sensitivity. Additionally, visual analog scales were used to investigate acute effects of buprenorphine on mood. Compared to placebo, buprenorphine resulted in a significant reduction in the sensitivity for recognizing fearful facial expressions exclusively. Our data demonstrate, for the first time in humans, that acute up-regulation of the opioid system reduces fear recognition sensitivity. Moreover, the absence of an effect of buprenorphine on mood provides evidence of a direct influence of opioids upon the core fear system in the human brain.

Autism and the Grand Challenges in Global Mental Health

There is increasing recognition of the global burden related to mental and neurological conditions greatly surpassing many health conditions such as cardiovascular disease and cancer. Recently, partnership among leading funders and academics has given rise to the grand challenges in global mental health initiative, aiming to reduce the global burden associated with mental and neurological conditions [Collins et al., 2011]. Among the actions of this initiative was a priority-setting exercise to articulate the most pressing challenges research in this area needs to address. Representing a diverse group of researchers and practitioners, we collectively considered progress and barriers in these priorities as they apply to autism research. In this editorial, we describe, based on our knowledge of and direct experience with autism in lowand middle-income countries (LMICs), the state of the science corresponding to the grand challenges and offer suggestions for how a truly global approach to autism research can bridge knowledge gaps leading to substantive improvements in quality of life for those affected wherever they may be.

Human Place Learning in a Computer Generated Arena

We describe the development of a computer-generated arena within which one can study human place learning by asking subjects to locate an invisible target. A series of studies demonstrate that such learning is based on acquiring knowledge about the spatial relations among the distal cues presented in this arena. We show that (1) the presence of proximal cues does not prevent learning about the distal cues; (2) the removal of individual cues does not impair performance until all distal cues are removed; and (3) the re-arrangement of distal cues profoundly impairs performance. In further studies we demonstrate that learning can proceed even when the subject is placed on the target rather than having to navigate to it, and even if the subject merely watches someone else navigate to the target. Finally, we demonstrate that learning is impaired by traumatic brain injury, and that aged subjects do not perform as well as young adults. This paradigm should prove useful in investigations of spatial cognition in general, and the role of specific neural systems inparticular.

Exploring the Utility of the Montreal Cognitive Assessment to Detect HIV-Associated Neurocognitive Disorder: The Challenge and Need for Culturally Valid Screening Tests in South Africa

There is a strong need in South Africa for neuropsychological tests that can help detect HIV-associated neurocognitive disorder (HAND) in the country’s 5.6 million people living with HIV. Yet South African neuropsychologists are challenged to do so, as few neuropsychological tests or batteries have been developed or adapted for, and normed on, South Africa’s linguistically, culturally, educationally, and economically diverse population. The purpose of this study was to explore the utility of the Montreal Cognitive Assessment to detect HIV-associated neurocognitive impairment among a sample of HIV+ and HIV– Black, Xhosa-speaking South Africans. HIV+ participants performed significantly worse overall and specifically in the domains of visuospatial, executive, attention, and language (confrontation naming). Regression analysis indicated that HIV status and education were the strongest predictors of total scores. Floor effects were observed on cube drawing, rhinoceros naming, serial 7s, and one abstraction item, suggesting those items might not be useful in this population. While the Montreal Cognitive Assessment holds promise to help detect HAND in South Africa, it will likely need modification before it can be normed and validated for this population. Findings from this study may help neuropsychologists working with similar populations.

White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa.

Objective:To describe the effect of HIV on white matter integrity and neurocognitive function in children vertically infected with HIV, compared to a HIV-negative healthy control group. Design:Cross-sectional. Methods:We compared 75 HIV-infected children aged 6–16 years, including children on antiretroviral therapy (ART) and those who were ART-naive, with 30 controls on diffusion tensor imaging and a neuropsychological battery sensitive to fronto-striatal pathology. In a secondary analysis, we compared ‘slow progressor’ ART-naive children, children on ART without a diagnosis of encephalopathy and children on ART with HIV encephalopathy. Results:Compared to controls (n = 30), HIV-infected children (n = 75) displayed decreased fractional anisotropy and axial diffusion, and increased mean diffusivity and radial diffusion, indicating damaged neuronal microstructure. HIV-infected children performed poorly on the neuropsychological battery (P = <0.001). Within the HIV-infected group, children with HIV encephalopathy (n = 14) had poor white matter integrity when compared to ART-treated children without encephalopathy (n = 41), and there was significant myelin loss in ART-naive children (n = 20), compared with ART-treated children. ART-treated children had significant axonal damage in the corpus callosum (P = 0.009). Conclusion:Children infected with HIV, irrespective of treatment status, displayed significantly poorer white matter integrity and impaired cognition compared to HIV-negative controls. Our findings suggest that despite immune recovery in children on ART, they remain at risk for developing central nervous system disease, and that initiation of ART as early as possible may reduce the risk of developing white matter damage in ART-naive slow progressors.