Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease—A Computational Study

Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson’s disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD)Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS.Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model’s STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions.Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P<0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P<0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P<0.001). Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients

Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning

IntroductionThe cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood.MethodsIn this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across different age ranges. Tractography and fixel-based analysis were performed on the 3 T diffusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in different domains of Addenbrooke’s Cognitive Examination.ResultsTractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain.ConclusionWe validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with different cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study offers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum

Towards a systems-level view of cerebellar function::the interplay between cerebellum, basal ganglia and cortex

Contains fulltext : 170319.pdf (Publisher’s version ) (Open Access)Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field

Challenges and opportunities in mixed method data collection on mental health issues of health care workers during COVID-19 pandemic in India

Background: The present paper describes the key challenges and opportunities of mixed method telephonic data collection for mental health research using field notes and the experiences of the investigators in a multicenter study in ten sites of India. The study was conducted in public and private hospitals to understand the mental health status, social stigma and coping strategies of different healthcare personnel during the COVID-19 pandemic in India.Methods: Qualitative and quantitative interviews were conducted telephonically. The experiences of data collection were noted as a field notes/diary by the data collectors and principal investigators.Results: The interviewers reported challenges such as network issues, lack of transfer of visual cues and sensitive content of data. Although the telephonic interviews present various challenges in mixed method data collection, it can be used as an alternative to face-to-face data collection using available technology.Conclusions: It is important that the investigators are well trained keeping these challenges in mind so that their capacity is built to deal with these challenges and good quality data is obtained

Factors associated with stigma and manifestations experienced by Indian health care workers involved in COVID-19 management in India: A qualitative study

Healthcare personnel who deal with COVID-19 experience stigma. There is a lack of national-level representative qualitative data to study COVID-19-related stigma among healthcare workers in India. The present study explores factors associated with stigma and manifestations experienced by Indian healthcare workers involved in COVID-19 management. We conducted in-depth interviews across 10 centres in India, which were analysed using NVivo software version 12. Thematic and sentiment analysis was performed to gain deep insights into the complex phenomenon by categorising the qualitative data into meaningful and related categories. Healthcare workers (HCW) usually addressed the stigma they encountered when doing their COVID duties under the superordinate theme of stigma. Among them, 77.42% said they had been stigmatised in some way. Analyses revealed seven interrelated themes surrounding stigma among healthcare workers. It can be seen that the majority of the stigma and coping sentiments fall into the mixed category, followed by the negative sentiment category. This study contributes to our understanding of stigma and discrimination in low- and middle-income settings. Our data show that the emergence of fear of the virus has quickly turned into a stigma against healthcare workers

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Cerebellar influence on motor cortex plasticity: behavioral implications for Parkinson's disease

International audienceNormal motor behavior involves the creation of appropriate activity patterns across motor networks, enabling firing synchrony, synaptic integration, and normal functioning of these networks. Strong topography-specific connections among the basal ganglia, cerebellum, and their projections to overlapping areas in the motor cortices suggest that these networks could influence each other's plastic responses and functions. The defective striatal signaling in Parkinson's disease (PD) could therefore lead to abnormal oscillatory activity and aberrant plasticity at multiple levels within the interlinked motor networks. Normal striatal dopaminergic signaling and cerebellar sensory processing functions influence the scaling and topographic specificity of M1 plasticity. Both these functions are abnormal in PD and appear to contribute to the abnormal M1 plasticity. Defective motor map plasticity and topographic specificity within M1 could lead to incorrect muscle synergies, which could manifest as abnormal or undesired movements, and as abnormal motor learning in PD. We propose that the loss of M1 plasticity in PD reflects a loss of coordination among the basal ganglia, cerebellar, and cortical inputs which translates to an abnormal plasticity of motor maps within M1 and eventually to some of the motor signs of PD.The initial benefits of dopamine replacement therapy on M1 plasticity and motor signs are lost during the progressive course of disease. Levodopa-induced dyskinesias in patients with advanced PD is linked to a loss of M1 sensorimotor plasticity and the attenuation of dyskinesias by cerebellar inhibitory stimulation is associated with restoration of M1 plasticity. Complimen-tary interventions should target reestablishing physiological communication between the striatal and cerebellar circuits, and within striato-cerebellar loop. This may facilitate correct motor synergies and reduce abnormal movements in PD

LRRK2 G2019S mutation does not contribute to Parkinson's disease in South India

Background : The frequency of leucine-rich repeat kinase 2 (LRRK2) G2019S mutation, the most common genetic cause of Parkinson′s disease (PD), shows significant variation based on ethnicity. Earlier reports suggest a very low frequency or absence of this mutation in Asians. Objective : To analyze the frequency of LRRK2 G2019S mutation in sporadic and familial cases of PD and normal controls of common ethnicity from South India. Patients and Methods : We used direct sequencing technique of all DNA samples in a clinic-based study of sporadic (n = 100) and familial PD patients (n = 86 index cases) and normal controls (n = 100) of common ethnicity from South India. Results : None among the patients or controls had the G2019S mutation. Conclusion : The founding events that influenced a number of other populations/ethnicities had no impact on the genetic makeup of PD patients from South India. Our findings support the current view that G2019S-associated PD may be population-specific. This has implications in genetic testing for PD and selection of subjects for potential future gene-based therapeutic trials for G2019S carriers in such populations