Bandit Models of Human Behavior: Reward Processing in Mental Disorders

Drawing an inspiration from behavioral studies of human decision making, we propose here a general parametric framework for multi-armed bandit problem, which extends the standard Thompson Sampling approach to incorporate reward processing biases associated with several neurological and psychiatric conditions, including Parkinson's and Alzheimer's diseases, attention-deficit/hyperactivity disorder (ADHD), addiction, and chronic pain. We demonstrate empirically that the proposed parametric approach can often outperform the baseline Thompson Sampling on a variety of datasets. Moreover, from the behavioral modeling perspective, our parametric framework can be viewed as a first step towards a unifying computational model capturing reward processing abnormalities across multiple mental conditions.Comment: Conference on Artificial General Intelligence, AGI-1

Impaired recognition and regulation of disgust is associated with distinct but partially overlapping patterns of decreased gray matter volume in the ventroanterior insula

Background The ventroanterior insula is implicated in the experience, expression, and recognition of disgust; however, whether this brain region is required for recognizing disgust or regulating disgusting behaviors remains unknown. Methods We examined the brain correlates of the presence of disgusting behavior and impaired recognition of disgust using voxel-based morphometry in a sample of 305 patients with heterogeneous patterns of neurodegeneration. Permutation-based analyses were used to determine regions of decreased gray matter volume at a significance level p <=.05 corrected for family-wise error across the whole brain and within the insula. Results Patients with behavioral variant frontotemporal dementia and semantic variant primary progressive aphasia were most likely to exhibit disgusting behaviors and were, on average, the most impaired at recognizing disgust in others. Imaging analysis revealed that patients who exhibited disgusting behaviors had significantly less gray matter volume bilaterally in the ventral anterior insula. A region of interest analysis restricted to behavioral variant frontotemporal dementia and semantic variant primary progressive aphasia patients alone confirmed this result. Moreover, impaired recognition of disgust was associated with decreased gray matter volume in the bilateral ventroanterior and ventral middle regions of the insula. There was an area of overlap in the bilateral anterior insula where decreased gray matter volume was associated with both the presence of disgusting behavior and impairments in recognizing disgust. Conclusions These findings suggest that regulating disgusting behaviors and recognizing disgust in others involve two partially overlapping neural systems within the insula. Moreover, the ventral anterior insula is required for both processes

Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease

BACKGROUND: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer's disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. METHODS: We retrospectively included 150 participants, including 29 bvAD, 28 "typical" amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. RESULTS: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85-0.91, all p tAD), MRI anterior-DMN-ratios (bvAD<tAD), FDG anterior-DMN-ratios (bvAD<tAD, AUC range 0.71-0.84, all p < 0.05). CONCLUSIONS: Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD

Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.Methods337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.ResultsDRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.ConclusionsWe conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD

Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD

Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease

Objective: To test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically diagnosed Alzheimer disease syndromes (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses. Methods: We measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression, and survival, and cortical thickness. Results: Plasma NfL, but not plasma t-tau, discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology-confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone. Conclusion: Plasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S. Classification of Evidence: This study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance vs plasma t-tau in FTLD and AD

Semantic Dementia: a specific network-opathy

Semantic dementia (SD) is a unique syndrome in the frontotemporal lobar degeneration spectrum. Typically presenting as a progressive, fluent anomic aphasia, SD is the paradigmatic disorder of semantic memory with a characteristic anatomical profile of asymmetric, selective antero-inferior temporal lobe atrophy. Histopathologically, most cases show a specific pattern of abnormal deposition of protein TDP-43. This relatively close clinical, anatomical and pathological correspondence suggests SD as a promising target for future therapeutic trials. Here, we discuss outstanding nosological and neurobiological challenges posed by the syndrome and propose a pathophysiological model of SD based on sequential, regionally determined disintegration of a vulnerable neural network