Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals.

Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm3) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics.ConclusionsTwelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained

Longitudinal Effects of Combination Antiretroviral Therapy on Cognition and Neuroimaging Biomarkers in Treatment-Naive People With HIV

BACKGROUND AND OBJECTIVES: While combination antiretroviral therapy (cART) has dramatically increased the life expectancy of people with HIV (PWH), nearly 50% develop HIV-associated neurocognitive disorders. This may be due to previously uncontrolled HIV viral replication, immune activation maintained by residual viral replication or activation from other sources, or cART-associated neurotoxicity. The aim of this study was to determine the effect of cART on cognition and neuroimaging biomarkers in PWH before and after initiation of cART compared with that in HIV-negative controls (HCs) and HIV elite controllers (ECs) who remain untreated. METHODS: We recruited 3 groups of participants from the University of Rochester, McGovern Medical School, and SUNY Upstate Medical University: (1) ART treatment-naive PWH; (2) age-matched HCs; and (3) ECs. Participants underwent brain MRI and clinical and neuropsychological assessments at baseline, 1 year, and 2 years. PWH were also assessed 12 weeks after initiating cART. Volumetric analysis and fractal dimensionality (FD) were calculated for cortical and subcortical regions. Mixed effect regressions examined the effect of group and imaging variables on cognition. RESULTS: We enrolled 47 PWH, 58 HCs, and 10 ECs. At baseline, PWH had worse cognition and lower cortical volumes than HCs. Cognition improved after initiation of cART and remained stable over time. Greater cortical thickness was associated with better cognition at baseline; greater FD of parietal, temporal, and occipital lobes was associated with better cognition at baseline and longitudinally. At baseline, ECs had worse cognition, lower cortical thickness, and lower FD in all 4 lobes and caudate than PWH and HCs. Greater cortical thickness, hippocampal volumes, and FD of frontal, temporal, and occipital lobes were associated with better cognition longitudinally. DISCUSSION: Initiation of cART in PWH is associated with improvement in brain structure and cognition. However, significant differences persist over time when compared with HCs. Similar trends in ECs suggest that results are due to HIV infection rather than treatment. Stronger associations between cognition and FD suggest this imaging metric may be a more sensitive marker of neuronal injury than cortical thickness and volumetric measures

Independent Component Analysis of the Effect of L-dopa on fMRI of Language Processing

L-dopa, which is a precursor for dopamine, acts to amplify strong signals, and dampen weak signals as suggested by previous studies. The effect of L-dopa has been demonstrated in language studies, suggesting restriction of the semantic network. In this study, we aimed to examine the effect of L-dopa on language processing with fMRI using Independent Component Analysis (ICA). Two types of language tasks (phonological and semantic categorization tasks) were tested under two drug conditions (placebo and L-dopa) in 16 healthy subjects. Probabilistic ICA (PICA), part of FSL, was implemented to generate Independent Components (IC) for each subject for the four conditions and the ICs were classified into task-relevant source groups by a correlation threshold criterion. Our key findings include: (i) The highly task-relevant brain regions including the Left Inferior Frontal Gyrus (LIFG), Left Fusiform Gyrus (LFUS), Left Parietal lobe (LPAR) and Superior Temporal Gyrus (STG) were activated with both L-dopa and placebo for both tasks, and (ii) as compared to placebo, L-dopa was associated with increased activity in posterior regions, including the superior temporal area (BA 22), and decreased activity in the thalamus (pulvinar) and inferior frontal gyrus (BA 11/47) for both tasks. These results raise the possibility that L-dopa may exert an indirect effect on posterior regions mediated by the thalamus (pulvinar)

Disrupted functional connectivity affects resting state based language lateralization

Pre-operative assessment of language localization and lateralization is critical to preserving brain function after lesion or epileptogenic tissue resection. Task fMRI (t-fMRI) has been extensively and reliably used to this end, but resting state fMRI (rs-fMRI) is emerging as an alternative pre-operative brain mapping method that is independent of a patient's ability to comply with a task. We sought to evaluate if language lateralization obtained from rs-fMRI can replace standard assessment using t-fMRI. In a group of 43 patients scheduled for pre-operative fMRI brain mapping and 17 healthy controls, we found that existing methods of determining rs-fMRI lateralization by considering interhemispheric and intrahemispheric functional connectivity are inadequate compared to t-fMRI when applied to the language network. We determined that this was attributable to widespread but nuanced disturbances in the functional connectivity of the language network in patients. We found changes in interhemispheric and intrahemispheric functional connectivity that were dependent on lesion location, and particularly impacted patients with lesions in the left temporal lobe. We then tested whether a simpler measure of functional connectivity to the language network has a better relation to t-fMRI based language lateralization. Remarkably, we found that functional connectivity between the language network and the frontal pole, and superior frontal gyrus, as well as the supramarginal gyrus, significantly correlated to task based language lateralization indices in both patients and healthy controls. These findings are consistent with prior work with epilepsy patients, and provide a framework for evaluating language lateralization at rest

Lack of noradrenergic modulation of indirect semantic priming

Abstract. Norepinephrine and dopamine are both believed to affect signal-to-noise in the cerebral cortex. Dopaminergic agents appear to modulate semantic networks during indirect semantic priming, but do not appear to affect problem solving dependent on access to semantic networks. Noradrenergic agents, though, do affect semantic network dependent problem solving. We wished to examine whether noradrenergic agents affect indirect semantic priming. Subjects attended three sessions: one each after propranolol (40 mg) (noradrenergic antagonist), ephedrine (25 mg) (noradrenergic agonist), and placebo. During each session, closely related, distantly related, and unrelated pairs were presented. Reaction times for a lexical decision task on the target words (second word in the pair) were recorded. No decrease in indirect semantic priming occurred with ephedrine. Furthermore, across all three drugs, a main effect of semantic relatedness was found, but no main effect of drug, and no drug/semantic relatedness interaction effect. These findings suggest that noradrenergic agents, with these drugs and at these doses, do not affect indirect semantic priming with the potency of dopaminergic drugs at the doses previously studied. In the context of this previous work, this suggests that more automatic processes such as priming and more controlled searches of the lexical and semantic networks such as problem solving may be mediated, at least in part, by distinct mechanisms with differing effects of pharmacological modulation

Lack of Noradrenergic Modulation of Indirect Semantic Priming

Norepinephrine and dopamine are both believed to affect signal-to-noise in the cerebral cortex. Dopaminergic agents appear to modulate semantic networks during indirect semantic priming, but do not appear to affect problem solving dependent on access to semantic networks. Noradrenergic agents, though, do affect semantic network dependent problem solving. We wished to examine whether noradrenergic agents affect indirect semantic priming. Subjects attended three sessions: one each after propranolol (40 mg) (noradrenergic antagonist), ephedrine (25 mg) (noradrenergic agonist), and placebo. During each session, closely related, distantly related, and unrelated pairs were presented. Reaction times for a lexical decision task on the target words (second word in the pair) were recorded. No decrease in indirect semantic priming occurred with ephedrine. Furthermore, across all three drugs, a main effect of semantic relatedness was found, but no main effect of drug, and no drug/semantic relatedness interaction effect. These findings suggest that noradrenergic agents, with these drugs and at these doses, do not affect indirect semantic priming with the potency of dopaminergic drugs at the doses previously studied. In the context of this previous work, this suggests that more automatic processes such as priming and more controlled searches of the lexical and semantic networks such as problem solving may be mediated, at least in part, by distinct mechanisms with differing effects of pharmacological modulation

Assessing combinatorial effects of HIV infection and former cocaine dependence on cognitive control processes:A functional neuroimaging study of response inhibition

Individuals with a diagnosis of co-morbid HIV infection and cocaine use disorder are at higher risk of poor health outcomes. Active cocaine users, both with and without HIV infection, show clear deficits in response inhibition and other measures of executive function that are instrumental in maintaining drug abstinence, factors that may complicate treatment. Neuroimaging and behavioral evidence indicate normalization of executive control processes in former cocaine users as a function of the duration of drug abstinence, but it is unknown to what extent co-morbid diagnosis of HIV affects this process. To this end, we investigate the combinatorial effects of HIV and cocaine dependence on the neural substrates of cognitive control in cocaine-abstinent individuals with a history of cocaine dependence. Blood-oxygen level dependent signal changes were measured as 86 participants performed a Go/NoGo response inhibition task while undergoing functional magnetic resonance imaging (fMRI). Four groups of participants were selected based on HIV and cocaine-dependence status. Participants affected by both conditions demonstrated the lowest response accuracy of all participant groups. In a region of interest analysis, hyperactivation in the left putamen and midline-cingulate hyperactivation was observed in individuals with both HIV and cocaine dependence relative to individuals with only one condition. Results of a whole-brain analysis indicate response inhibition-related hyperactivation in the bilateral supplementary motor area, bilateral hippocampi, bilateral primary somatosensory areas, right dorsal anterior cingulate, and left insula in the CD+/HIV+ group relative to all other groups. These results indicate complex and interactive alterations in neural activation during response inhibition and highlight the importance of examining the neurocognitive effects of co-morbid conditions

The neural correlates of statistical learning in a word segmentation task: An fMRI study

Functional magnetic resonance imaging (fMRI) was used to assess neural activation as participants learned to segment continuous streams of speech containing syllable sequences varying in their transi- tional probabilities. Speech streams were presented in four runs, each followed by a behavioral test to measure the extent of learning over time. Behavioral performance indicated that participants could dis- criminate statistically coherent sequences (words) from less coherent sequences (partwords). Individual rates of learning, defined as the difference in ratings for words and partwords, were used as predictors of neural activation to ask which brain areas showed activity associated with these measures. Results showed significant activity in the pars opercularis and pars triangularis regions of the left inferior frontal gyrus (LIFG). The relationship between these findings and prior work on the neural basis of statistical learning is discussed, and parallels to the frontal/subcortical network involved in other forms of implicit sequence learning are considered

Dopaminergic Modulation of Semantic Priming in Parkinson Disease

Looking out over Frenchman Bay and the Porcupine Islands northeast of town from Acadia National Park; Bar Harbor is a town on the northeast shore of Mount Desert Island in Hancock County, Maine. As of the 2010 census, its population is 5,235. Bar Harbor is a famous summer colony in the Down East region of Maine. In 1604 French explorer Samuel de Champlain ran aground on the island, which he named Isles des Monts Deserts, meaning "island of barren mountains". It was first settled by the British in 1763, and originally named Eden (after Sir Richard Eden). By 1880, there were 30 hotels, with tourists arriving by train and ferry to the Gilded Age resort that would rival Newport. On March 3, 1918, Eden was renamed Bar Harbor. In 1947, a month long wildfire destroyed the east side of the island, including 67 of the palatial homes. The business district was spared. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 7/22/2012