Search bioRxiv⌕ Search

Biology subjects

Mackenzie, G.

Publications and source records attributed to Mackenzie, G..

4 recordsLinked to original sources

Focused ultrasound neuromodulation of mediodorsal thalamus disrupts decision flexibility during reward learning

When learning to find the most beneficial course of action, the prefrontal cortex guides decisions by comparing estimates of the relative value of the options available. Basic neuroscience studies in animals support the view that the thalamus can regulate this activity within and across the prefrontal cortex. We studied a group of patients (n=37) undergoing unilateral MR guided focused ultrasound for essential tremor, performing the restless bandit, a reward reinforcement learning task, immediately before and after thalamotomy. Thalamotomy significantly impaired the proportion of switch choices during the task without affecting overall performance. This effect was observed when the task was delivered to co-incide with maximal vasogenic thalamic oedema but not in a control group tested on the same day of their treatment. A reinforcement learning model fitted to the patients choices replicated the effect of thalamotomy when the model increased exploitation of the bandits learnt value estimate. This shift in the explore-exploit trade-off, manifesting as reduced choice flexibility, co-varied with the pattern of post-operative oedema extension into mediodorsal nucleus. These findings confirm a causal role of the thalamus and specifically the mediodorsal nucleus, in regulating the extent to which value estimates are used to guide decisions and learning from reward.

neuroscience↗

Impaired value-based decision-making in Parkinson's Disease Apathy

Apathy is a common and disabling complication of Parkinsons disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within pre-frontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision making. Specifically, non-dopaminergic neuromodulators, influence decisions to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesised that Apathy in Parkinsons disease should be associated with a failure to adequately monitor and make adaptive choices when the rewarding outcome of decisions are uncertain. Using a 4-armed restless bandit reinforcement learning task, we studied decision making in 75 volunteers; 53 patients with Parkinsons disease, with and without clinical apathy, and 22 age matched healthy controls. Patients with Apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patients apathy severity measured using the Lille Apathy Rating scale (R = -0.46, p<0.001). Computational modelling of the patients choices confirmed the apathy group made decisions that that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration which also correlated with apathy scores (R = -0.5, p<0.001). We went on to acquire fMRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age matched controls performing the restless bandit task. Analysis of the fMRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinsons disease, which was more marked in Apathy, but not predictive of their individual Apathy severity. Using a model-based categorisation of choice type, decisions to explore lower value bandits in the apathy group activated pre-frontal cortex to a similar degree to the age-matched controls. In contrast, Parkinsons patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched controls, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinsons disease.

neuroscience↗

Invasive atypical non-typhoidal Salmonella in The Gambia

BackgroundInvasive non-typhoidal Salmonella (iNTS) disease continues to be a significant public health problem in sub-Saharan Africa. Common clinical misdiagnosis, antimicrobial resistance, high case fatality and lack of a vaccine make iNTS a priority for global health research. Using whole genome sequence analysis of 164 invasive Salmonella isolates obtained through population-based surveillance between 2008 and 2016, we conducted genomic analysis of the serovars causing invasive Salmonella diseases in rural Gambia. ResultsThe incidence of iNTS varied over time. The proportion of atypical serovars causing disease increased over time from 40% to 65% compared to the typical serovars Enteritidis and Typhimurium decreasing from 30% to 12%. Overall iNTS case fatality was 10% with 10% fatality in cases of atypical iNTS. Genetic virulence factors were identified in 14/70 (20%) typical serovars and 45/68 (66%) of the atypical serovars and were associated with: invasion, proliferation and/or translocation (Clade A); and host colonization and immune modulation (Clade G). Among Enteritidis isolates, 33/40 were resistant to [&ge;]4 the antimicrobials tested, except for ciprofloxacin, to which all isolates were susceptible. Resistance was low in Typhimurium isolates, however, all16 isolates were resistant to gentamicin. ConclusionThe increase in incidence and proportion of iNTS disease caused by atypical serovars is concerning. The increased proportion of atypical serovars and the high associated case fatality may be related to acquisition of specific genetic virulence factors. These factors may provide a selective advantage to the atypical serovars. Investigations should be conducted elsewhere in Africa to identify potential changes in the distribution iNTS serovars and the extent of these virulence elements.

genomics↗

Varia: Prediction, analysis and visualisation of variable genes

Assessing the diversity or expression of variable gene families in pathogens can inform about immune escape mechanisms or host interaction phenotypes of clinical relevance. However, obtaining the sequences and quantifying their expression is a challenge. Here, we present a tool, which based on unique sequence tag similarity between members of a gene family, predicts the domains encoded by the queried gene. As an example, we are using the var gene family, encoding the major virulence proteins (PfEMP1) of the human malaria parasite, Plasmodium falciparum. We developed Varia, which predicts the likely var gene sequence and encoded protein domain composition of a gene from short sequence tags. We provide a new extended annotated var genome database, in which Varia identifies genes with identical tag sequences and compares these to return the most probable domain composition of the query gene. Varias ability to predict correct PfEMP1 domain compositions from short var sequence tags was tested in two complementary pipelines to (a) return the putative gene sequences and domain compositions of the query gene from any partial sequence provided, thereby enabling detailed assessment of specific genes putative function and experimental validation of these (b) to accommodate rapid profiling of var gene expression in complex patient samples, by compiling the overall domain prevalence among var transcripts predicted identified and quantified by next generation sequencing of so-called var DBL-sequence tags. Availability and implementationVaria is available on GitHub (https://github.com/GCJMacken-zie/Varia) under the MIT license. Contactthomasl@sund.ku.dk, thomasdan.otto@glasgow.ac.uk

bioinformatics↗