Altered Insula Connectivity under MDMA

Recent work with noninvasive human brain imaging has started to investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations-both of which are known to be associated with insular functioning

Visual hallucinations are characterized by impaired sensory evidence accumulation : insights from Hierarchical drift diffusion modeling in Parkinson’s disease

Background: Models of hallucinations emphasise an imbalance between sensory input and top-down influences over perception, as false perceptual inference can arise when top-down predictions are afforded too much precision (certainty) relative to sensory evidence. Visual hallucinations in Parkinson’s disease (PD) are associated with lower-level visual and attentional impairments, accompanied by over activity in higher-order association brain networks. PD therefore provides an attractive framework to explore the contributions of bottom-up versus top-down disturbances in hallucinations. Methods: We characterised sensory processing during perceptual decision-making in PD patients with (n=20) and without (n=25) visual hallucinations, and controls (n=12), by fitting a hierarchical drift diffusion model (hDDM) to an attentional task. The hDDM uses Bayesian estimates to decompose task performance into parameters reflecting drift rates of evidence accumulation, decision thresholds and non-decision time. Results: We observed slower drift rates in patients with hallucinations, which were less sensitive to changes in task demand. In contrast, wider decision boundaries and shorter non decision times relative to controls were found in PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerge as unique features of PD hallucinators. Conclusions: We integrate these results with evidence accumulation and predictive coding models of hallucinations, suggesting that in PD sensory evidence is less informative, and may therefore be down-weighted resulting in over reliance on top-down influences. Considering impaired drift rates as an approximation of reduced sensory precision, our findings provide a novel computational framework to specify the impairments in sensory processing that contribute to the development of visual hallucinations

Mind-wandering in Parkinson's disease hallucinations reflects primary visual and default network coupling

Visual hallucinations are an underappreciated symptom affecting the majority of patients during the natural history of Parkinson's disease. Little is known about other forms of abstract and internally generated cognition – such as mind-wandering – in this population, but emerging evidence suggests that an interplay between the brain's primary visual and default networks might play a crucial role in both internally generated imagery and hallucinations. Here, we explored the association between mind-wandering and visual hallucinations in Parkinson's disease, and their relationship with brain network coupling. We administered a validated thought-sampling task to 38 Parkinson's disease patients (18 with hallucinations; 20 without) and 40 controls, to test the hypothesis that individuals with hallucinations experience an increased frequency of mind-wandering. Group differences in the association between mind-wandering frequency and brain network coupling were also examined using resting state functional magnetic resonance imaging. Our results showed that patients with hallucinations exhibited significantly higher mind-wandering frequencies compared to non-hallucinators, who in turn had reduced levels of mind-wandering relative to controls. At the level of brain networks, inter-network connectivity and seed-to-voxel analyses identified that increased mind-wandering in the hallucinating versus non-hallucinating group was associated with greater coupling between the primary visual cortex and dorsal default network. Taken together, our results suggest a relative preservation of mind-wandering in Parkinson's disease patients who experience visual hallucinations, which is associated with increased visual cortex-default network coupling. We propose that the preservation of florid abstract and internally generated cognition in the context of the Parkinson's disease can contribute to visual hallucinations, whereas healthy individuals experience only the vivid images of the mind's eye. These findings refine current models of visual hallucinations by identifying a specific cognitive phenomenon and neural substrate consistent with the top-down influences over perception that have been implicated in hallucinations across neuropsychiatric disorders

Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

ObjectiveTo identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.MethodsWe stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.ResultsWe found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.ConclusionsOur results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment

Altered Insula Connectivity under MDMA

Recent work with noninvasive human brain imaging has started to investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations–both of which are known to be associated with insular functioning