Adaptive decision making involves selecting the most valuable option, typically by taking an action. Such choices require value comparisons, but there is debate about whether these comparisons occur at the level of stimuli (goods-based) value, action-based value, or both. One view is that value processes occur in series, with stimulus value informing action value. However, lesion work in nonhuman primates suggests that these two kinds of choice are dissociable. Here, we examined action-value and stimulus-value learning in humans with focal frontal lobe damage. Orbitofrontal damage disrupted the ability to sustain the correct choice of stimulus, but not of action, after positive feedback, while damage centered on dorsal anterior cingulate cortex led to the opposite deficit. These findings argue that there are distinct, domain-specific mechanisms by which outcome value is applied to guide subsequent decisions, depending on whether the choice is between stimuli or between actions.
Damage to the orbitofrontal cortex (OFC) has been linked to impaired reinforcement processing and maladaptive behavior in changing environments across species. Flexible stimulus-outcome learning, canonically captured by reversal learning tasks, has been shown to rely critically on OFC in rats, monkeys, and humans. However, the precise role of OFC in this learning remains unclear. Furthermore, whether other frontal regions also contribute has not been definitively established, particularly in humans. In the present study, a reversal learning task with probabilistic feedback was administered to 39 patients with focal lesions affecting various sectors of the frontal lobes and to 51 healthy, demographically matched control subjects. Standard groupwise comparisons were supplemented with voxel-based lesion-symptom mapping to identify regions within the frontal lobes critical for task performance. Learning in this dynamic stimulusreinforcement environment was considered both in terms of overall performance and at the trial-by-trial level. In this challenging, probabilistic context, OFC damage disrupted both initial and reversal learning. Trial-by-trial performance patterns suggest that OFC plays a critical role in interpreting feedback from a particular trial within the broader context of the outcome history across trials rather than in simply suppressing preexisting stimulus-outcome associations. The findings show that OFC, and not other prefrontal regions, plays a necessary role in flexible stimulus-reinforcement learning in humans.
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
Navigating our complex social world requires effective processing of subtle emotional signals, such as those conveyed by facial expressions. Failure to do so may underlie some of the disabling social-emotional deficits common in a range of neuropsychiatric and neurological conditions. Prefrontal cortex (PFC) has long been implicated in these processes, but the particular contributions of subregions within PFC remain unclear. We used a sensitive facial emotion rating task in patients with focal lesions to different regions within PFC to identify distinct contributions of 2 prefrontal regions to recognizing emotions from facial expressions. A combination of region-of-interest and voxel-based lesion-symptom mapping established that damage to ventromedial PFC impaired the detection of subtle facial expressions of emotion. Such patients had difficulty distinguishing emotional from neutral expressions. In contrast, patients with left ventrolateral PFC were able to detect the presence of emotional signals but had difficulty discriminating between specific emotions. These effects were regionally specific: Dorsomedial prefrontal damage had no effect on either aspect of emotion recognition. These findings suggest that separable processes relying critically on distinct regions within PFC responsible, on the one hand, for detecting emotional signals from facial expressions and, on the other, for correctly classifying such signals.
Although prefrontal cortex is clearly important in executive function, the specific processes carried out by particular regions within human prefrontal cortex remain a matter of debate. A rapidly growing corpus of functional imaging work now implicates various areas within prefrontal cortex in a wide range of "executive" tasks. Loss-of-function studies can help constrain the interpretation of such evidence by testing to what extent particular brain areas are necessary for a given cognitive process. Here we apply a component process analysis to understand prefrontal contributions to the n-back task, a widely used test of working memory, in a cohort of patients with focal prefrontal damage. We investigated letter 2-back task performance in 27 patients with focal damage to various regions within prefrontal cortex, compared to 29 demographically matched control subjects. Both "behavior-defined" approaches, using qualitative lesion analyses and voxel-based lesion-symptom mapping methods, and more conventional "lesion-defined" groupwise comparisons were undertaken to determine the relationships between specific sites of damage within prefrontal cortex and particular aspects of n-back task performance. We confirmed a critical role for left lateral prefrontal cortex in letter 2-back performance. We also identified a critical role for medial prefrontal cortex in this task: Damage to dorsal anterior cingulate cortex and adjacent dorsal fronto-medial cortex led to a pattern of impairment marked by high false alarm rates, distinct from the impairment associated with lateral prefrontal damage. These findings provide converging support for regionally specific models of human prefrontal function.
Existing tools for rapid cognitive assessment in HIV-positive individuals with mild cognitive deficits lack sensitivity or do not meet psychometric requirements for tracking changes in cognitive ability over time. MethodsSeventy-five nondemented HIV-positive patients were evaluated with the Montreal Cognitive Assessment (MoCA), a brief battery of standardized neuropsychological tests, and computerized tasks evaluating frontal-executive function and processing speed. Rasch analyses were applied to the MoCA data set and subsequently to the full set of data from all tests. ResultsThe MoCA was found to adequately measure cognitive ability as a single, global construct in this HIV-positive cohort, although it showed poorer precision for measuring patients of higher ability. Combining the additional tests with the MoCA resulted in a battery with better psychometric properties that also better targeted the range of abilities in this cohort. ConclusionThis application of modern test development techniques shows a path towards a quick, quantitative, global approach to cognitive assessment with promise both for initial detection and for longitudinal follow-up of cognitive impairment in patients with HIV infection. IntroductionMild cognitive impairment has been increasingly recognized as a common feature of chronic HIV infection, even in patients with good viral control on highly active antiretroviral therapy (HAART) [1]. It occurs in 30-50% of patients, depending on both the cohort under study and how the impairment is identified [1][2][3][4][5][6][7][8]. The current diagnostic approach is descriptive: HIV-associated neurocognitive disorder (HAND) is termed 'asymptomatic neurocognitive impairment' when found on testing in the absence of symptoms, and 'mild neurocognitive disorder' when both signs and symptoms are present, but are not severe enough to constitute frank dementia [9]. The underlying pathophysiology remains poorly understood [10], posing challenges in the everyday management of these mildly affected patients.How should cognitive impairment be detected in routine practice? Should those found to be affected have their HAART regimen changed, to emphasize antiretrovirals with better central nervous system penetration? Should additional therapies, such as anti-excitotoxic agents or drugs targeting neurodegenerative changes, be added to their treatment? If such changes are made, how should the effects be monitored? The answers to such questions require better tools to assess cognition in HIV-infected individuals. The ideal measure should not only establish the diagnosis, but also quantify the severity of impairment. DOI: 10.1111/j.1468-1293.2010.00910.x HIV Medicine (2011 r 2011 British HIV Association 472It should also be free, brief, easy to administer with minimal training by any health professional, and available to clinics where HIV-infected patients receive their care. The present study describes the initial steps in the development of such a method to measure cognition across the intact to mildly impaired ...
Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing
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