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.
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 overreliance on top-down influences. Considering impaired drift rates as an approximation of reduced sensory precision, our findings provide a novel computational framework to specify impairments in sensory processing that contribute to development of visual hallucinations.
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, doubleblind, 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.
Mind-wandering has become a captivating topic for cognitive neuroscientists. By now, it is reasonably well described in terms of its phenomenology and the large-scale neural networks that support it. However, we know very little about what neurobiological mechanisms trigger a mind-wandering episode and sustain the mind-wandering brain state. Here, we focus on the role of ascending neuromodulatory systems (i.e. acetylcholine, noradrenaline, serotonin and dopamine) in shaping mind-wandering. We advance the hypothesis that the hippocampal sharp wave-ripple (SWR) is a compelling candidate for a brain state that can trigger mind-wandering episodes. This hippocampal rhythm, which occurs spontaneously in quiescent behavioural states, is capable of propagating widespread activity in the default network and is functionally associated with recollective, associative, imagination and simulation processes. The occurrence of the SWR is heavily dependent on hippocampal neuromodulatory tone. We describe how the interplay of neuromodulators may promote the hippocampal SWR and trigger mind-wandering episodes. We then identify the global neuromodulatory signatures that shape the evolution of the mind-wandering brain state. Under our proposed framework, mind-wandering emerges due to the interplay between neuromodulatory systems that influence the transitions between brain states, which either facilitate, or impede, a wandering mind. This article is part of the theme issue ‘Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation'.
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