Biology subjects

Hu, M. T.

Publications and source records attributed to Hu, M. T..

4 recordsLinked to original sources

bioRxiv2021

Reduced cortico-muscular beta coupling in Parkinsons disease predicts motor impairment

Long-range communication through the motor system is thought to be facilitated by phase coupling between neural activity in the 15-30 Hz beta range. During periods of sustained muscle contraction (grip), such coupling is manifest between motor cortex and the contralateral forearm muscles - measured as the cortico-muscular coherence (CMC). We examined alterations in CMC in individuals with Parkinsons disease (PD), while equating grip strength between individuals with PD (off their medication) and healthy control participants. We show a marked reduction in beta CMC in the PD group, even though the grip strength was comparable between the two groups. Moreover, the reduced CMC was related to motor symptoms, so that individuals with lower CMC also displayed worse motor symptoms. These findings highlight the CMC as a simple, effective, and clinically relevant neural marker of PD pathology, with the potential to aid monitoring of disease progression and the efficacy of novel treatments for PD.

neuroscience↗

bioRxiv2020

Dopamine promotes instrumental motivation, but reduces reward-related vigour

We can be motivated when reward depends on performance, or merely by the prospect of a guaranteed reward. Performance-dependent (contingent) reward is instrumental, relying on an internal action-outcome model, whereas motivation by guaranteed reward may serve to minimise opportunity cost in reward-rich environments. Competing theories propose that each type of motivation should be dependent on dopaminergic activity. We contrasted these two types of motivation with a rewarded saccade task, in patients with Parkinsons disease (PD). When PD patients were ON dopamine, they had greater response vigour (peak saccadic velocity) for contingent rewards, whereas when PD patients were OFF medication, they had greater vigour for guaranteed rewards. These results support the view that reward expectation and contingency drive distinct motivational processes, and can be dissociated by manipulating dopaminergic activity. We posit that dopamine is necessary for goal-directed motivation, but dampens reward-driven vigour, challenging the theory that tonic dopamine encodes reward expectation.

neuroscience↗

bioRxiv2019

Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies

ObjectiveREM-sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.\n\nMethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinsons disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.\n\nResultsA 5-region SNCA variant (rs10005233) was associated with iRBD (OR=1.43, p=1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5 risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3 of SNCA (OR=1.32, p=4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR=5.74, p=2E-06). The known top PD-associated variant (3 variant rs356182) had an opposite direction of effect in iRBD compared to PD.\n\nInterpretationThere is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3 of SNCA. Several 5 SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies, and may suggest a cognitive component to this region.

genetics↗

bioRxiv2019

Universal continuous severity traits underlying hundreds of Parkinson’s disease clinical features

The generation of deeply phenotyped patient cohorts offers an enormous potential to identify disease subtypes but are currently limited by the cohort size and the heterogeneity of the clinical assessments collected across different cohorts. Identifying the universal axes of clinal severity and progression is key to accelerating our understanding of how disease manifests and progresses. These universal axes would accelerate our understanding of how Parkinsons disease (PD) manifests and progresses through which patients may be appropriately compared appropriately stratified, and personalised therapeutic strategies and treatments can be developed and targeted. We developed a Bayesian multiple phenotype mixed model incorporating the genetic relationships between individuals which is able to reduce a wide-array of different clinical measurements into a smaller number of continuous underlying factors named phenotypic axis. We identify three principal axes of PD patient phenotypic variation which are reproducibly found across three independent, deeply and diversely phenotyped cohorts. Together they explain over 75% of the observed clinical variation and remain robustly captured with a fraction of the clinically-recorded features. The most influential axis was associated with the genetic risk of Alzheimers disease (AD) and involves genetic pathways associated with neuroinflammation. Our results suggest PD patients with a high genetic risk for AD are more likely to develop a more aggressive form of PD including, but not limited to, dementia.

neuroscience↗