Parkinson's disease dementia: a neural networks perspective.

In the long-term, with progression of the illness, Parkinson's disease dementia affects up to 90% of patients with Parkinson's disease. With increasing life expectancy in western countries, Parkinson's disease dementia is set to become even more prevalent in the future. However, current treatments only give modest symptomatic benefit at best. New treatments are slow in development because unlike the pathological processes underlying the motor deficits of Parkinson's disease, the neural mechanisms underlying the dementing process and its associated cognitive deficits are still poorly understood. Recent insights from neuroscience research have begun to unravel the heterogeneous involvement of several distinct neural networks underlying the cognitive deficits in Parkinson's disease dementia, and their modulation by both dopaminergic and non-dopaminergic transmitter systems in the brain. In this review we collate emerging evidence regarding these distinct brain networks to give a novel perspective on the pathological mechanisms underlying Parkinson's disease dementia, and discuss how this may offer new therapeutic opportunities

Resting state functional connectivity in addiction: drug abuse and reward dysregulation

INTRODUCTION: With the advent of advanced neuroimaging, strides have been made towards better understanding the cognitive elements necessary for task processing. Resting state functional connectivity assessments using functional magnetic resonance imaging has allowed patient assessments of underlying neural networks in patient populations with variable constraints. Drug addiction, a chronically relapsing disorder, presents many variable constraints. Cellular and molecular changes in neural reward pathway of drug addicted patient populations have advanced, but circuit-level alterations with reward deficits are yet to be completely understood. Resting state functional connectivity investigations in patient populations that use illicit drugs are seen to have repercussions on neural networks. OBJECTIVE: Assess and compare reward-network resting state functional connectivity investigations in patient populations with illicit drug use. METHODS: A meta-analysis of several resting state functional connectivity studies. Patient populations for each study contained an experimental group of drug users with a group of non-drug using controls to assess changes in resting state functional connectivity of the reward network. Studies utilized Diagnostic and Statistical Manuel of Mental disorders, 4th edition, as the basis of diagnosing drug dependence and abuse. A 3 Tesla MRI scanner was utilized to assess the reward pathway of the drug abuse in all experiments with the exception of one group using a 4 Tesla scanner. Band-pass temporal filtering from roughly 0.01 Hz to 0.1 Hz on residual signals was used to obtain low-frequency fluctuations needed for resting state connectivity analyses. Correlation maps were created by computing the correlation coefficients between the blood oxygen level dependent time course from the seed regions and from all other brain voxels. Regions of interest were chosen based on data from databases or previous studies. RESULTS: Four papers found widespread reductions in the connectivity of multiple reward pathway components. Results of these studies are consistent with perspectives suggesting that transition from drug use to addiction is driven by reduced functioning of reward systems and concurrently increased activation of anti-reward systems. Two studies suggested an increase in reward pathway of drug use, suggesting enhanced connectivity within reward and motivation circuits may be interpreted in the perspective of altered incentive salience for drugs and drug-associated stimuli. CONCLUSION: At early stage of experimental data in this field, data interpretation necessitates caution. Small sample sizes, heterogeneous subject groups and variable experimental paradigms may have lead to opposing findings. With certainty, chronic drug use was found to alter reward pathway in patient populations

Brain networks of the imaginative mind: Dynamic functional connectivity of default and cognitive control networks relates to openness to experience

Imagination and creative cognition are often associated with the brain's default network (DN). Recent evidence has also linked cognitive control systems to performance on tasks involving imagination and creativity, with a growing number of studies reporting functional interactions between cognitive control and DN regions. We sought to extend the emerging literature on brain dynamics supporting imagination by examining individual differences in large-scale network connectivity in relation to Openness to Experience, a personality trait typified by imagination and creativity. To this end, we obtained personality and resting-state fMRI data from two large samples of participants recruited from the United States and China, and we examined contributions of Openness to temporal shifts in default and cognitive control network interactions using multivariate structural equation modeling and dynamic functional network connectivity analysis. In Study 1, we found that Openness was related to the proportion of scan time (i.e., “dwell time”) that participants spent in a brain state characterized by positive correlations among the default, executive, salience, and dorsal attention networks. Study 2 replicated and extended the effect of Openness on dwell time in a correlated brain state comparable to the state found in Study 1, and further demonstrated the robustness of this effect in latent variable models including fluid intelligence and other major personality factors. The findings suggest that Openness to Experience is associated with increased functional connectivity between default and cognitive control systems, a connectivity profile that may account for the enhanced imaginative and creative abilities of people high in Openness to Experience

The association between lifelong personality and clinical phenotype in the FTD-ALS spectrum

Introduction: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two phenotypes of the same neurodegenerative disease, the FTD-ALS spectrum. What determines the development of one rather than the other phenotype is still unknown. Based on the clinical observation that patients' personality seems to differ between the two phenotypes, i.e., ALS patients tend to display kind, prosocial behaviors whereas FTD patients tend to present anti-social behaviors, and that these traits are often reported as pre-existing the disease onset by caregivers, we set up to study experimentally patients' personality in their premorbid life.Methods: We first tested for differences between groups, then tested the association between premorbid personality and current functional organization of the brain. Premorbid personality of a cohort of forty patients, 27 FTD and 13 ALS, was explored through the NEO Personality Inventory 3 (NEO-PI-3), which analyses the five main personality factors, completed by the caregiver with reference to patient's personality 20 years before symptoms onset (premorbid). A subgroup of patients underwent a brain MRI including structural and resting-state functional MRI (rsfMRI).Results: A significant difference between FTD and ALS in premorbid personality emerged in the Openness (133.92 FTD vs. 149.84 ALS, p = 0.01) and Extraversion (136.55 FTD vs. 150.53 ALS, p = 0.04) factors. This suggests that ALS patients had been, in their premorbid life, more open to new experiences, more sociable and optimistic than FTD patients. They also showed greater functional connectivity than both FTD and a control group in the Salience resting state network, over and above differences in gray matter atrophy. Finally, there was a positive correlation between premorbid Openness and functional connectivity in the Salience network across all patients, suggesting a possible association between premorbid personality and current functional organization of the brain, irrespective of the degree of atrophy.Discussion: Our proof-of-concept results suggest that premorbid personality may eventually predispose to the development of one, rather than the other, phenotype in the FTD-ALS spectrum

Increased ventral anterior insular connectivity to sports betting availability indexes problem gambling

With the advent of digital technologies, online sports betting is spurring a fast-growing expansion. In this study, we examined how sports betting availability modulates the brain connectivity of frequent sports bettors with [problem bettors (PB)] or without [non-problem bettors (NPB)] problematic sports betting. We conducted functional connectivity analyses centred on the ventral anterior insular cortex (vAI), a brain region playing a key role in the dynamic interplay between reward-based processes. We re-analysed a dataset on sports betting availability undertaken in PB (n = 30) and NPB (n = 35). Across all participants, we observed that sports betting availability elicited positive vAI coupling with extended clusters of brain activation (encompassing the putamen, cerebellum, occipital, temporal, precentral and central operculum regions) and negative vAI coupling with the orbitofrontal cortex. Between-group analyses showed increased positive vAI coupling in the PB group, as compared with the NPB group, in the left lateral occipital cortex, extending to the left inferior frontal gyrus, the anterior cingulate gyrus and the right frontal pole. Taken together, these results are in line with the central assumptions of triadic models of addictions, which posit that the insular cortex plays a pivotal role in promoting the drive and motivation to get a reward by ‘hijacking’ goal-oriented processes toward addiction-related cues. Taken together, these findings showed that vAI functional connectivity is sensitive not only to gambling availability but also to the status of problematic sport betting

Electrophysiological Investigation of Auditory Mismatch Negativity: A Brain-Based Biomarker of N-Methyl-D-Aspartate Signalling

Inconsistent reports on the therapeutic efficacy of increasing synaptic glycine concentration have raised doubt as to the benefit of N-methyl-D-aspartate receptor (NMDAr) mediated treatments for schizophrenia. Categorising individuals based on broad diagnostic criteria does not appear to adequately identify individuals who will benefit from such treatments. Mismatch negativity (MMN) may be a suitable biomarker of NMDAr function, to help clarify the neurobiological relationship between pharmacological intervention and clinical treatment efficacy. MMN is an auditory event-related potential elicited following the presentation of a deviant stimulus, when it violates an established sequence stored in echoic memory. MMN is a robust deficit in schizophrenia and is categorised as a physiological element in the Cognitive Systems domain of the Research Domain Criteria framework. However, few studies have examined direct pharmacological modulation of MMN in schizophrenia patients. The aim of this thesis was to determine the nature of the relationship between MMN and NMDAr function, to inform the relative utility of MMN as a biomarker of NMDAr-mediated improvements in clinical symptoms in schizophrenia. To achieve this aim, three separate empirical studies were performed..

Time-resolved connectome of the five-factor model of personality

Abstract: The human brain is characterized by highly dynamic patterns of functional connectivity. However, it is unknown whether this time-variant ‘connectome’ is related to the individual differences in the behavioural and cognitive traits described in the five-factor model of personality. To answer this question, inter-network time-variant connectivity was computed in n = 818 healthy people via a dynamical conditional correlation model. Next, network dynamicity was quantified throughout an ad-hoc measure (T-index) and the generalizability of the multi-variate associations between personality traits and network dynamicity was assessed using a train/test split approach. Conscientiousness, reflecting enhanced cognitive and emotional control, was the sole trait linked to stationary connectivity across several circuits such as the default mode and prefronto-parietal network. The stationarity in the ‘communication’ across large-scale networks offers a mechanistic description of the capacity of conscientious people to ‘protect’ non-immediate goals against interference over-time. This study informs future research aiming at developing more realistic models of the brain dynamics mediating personality differences