Research at the WIN
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Email: win@uwo.ca
Tel: 519-661-2111 x82205
Western Institute for Neuroscience
Western Interdisciplinary Research Building,
Western University,
1151 Richmond Street,
London, Ontario N6A 3K7
Recent Publications by WIN members
The neural basis of movement preparation has been extensively studied during self-initiated actions, in which motor cortical activity during preparation shows a lawful relationship to the parameters of the subsequent action1,2. However, movements are regularly triggered or corrected on the basis of sensory inputs caused by disturbances to the body. Since such disturbances are often predictable, and since preparing for disturbances would make movements more prescise, we hypothesized that expectations about sensory inputs also influence preparatory activity in motor circuits. Here we show that when humans or monkeys are probabilistically cued about the direction of future mechanical perturbations, they incorporate sensory expectations into their movement preparation and improve their corrective responses. Using high-density neural recordings, we establish that sensory expectations are widespread across the brain, including the motor cortical areas involved in preparing self-initiated actions. The geometry of these preparatory signals in the neural population state is simple, and scales directly with the probability of each perturbation direction. After perturbation onset, a condition-independent signal shifts the neural state leading to rapid responses that initially reflect sensory expectations. Using neural networks coupled to a biomechanical model of the arm3, we show that this neural geometry emerges only when sensory inputs signal that a perturbation has occurred, before resolving the direction of the perturbation. Thus, just as preparatory activity sets the stage for self-initiated movement, it also configures motor circuits to respond efficiently to sensory inputs.
Background: Formation of Diagnostic and Statistical Manual of Mental Disorders (DSM) subcommittees combined with recently approved coding designations for bulimia nervosa (BN) in partial remission highlights the need to examine the validity of the threshold that distinguishes BN from other specified feeding or eating disorders (OSFED) BN of low frequency and/or limited duration (OSFED-BN).
Methods: Women (N = 344) who met DSM-5 criteria for BN (n = 153) or OSFED-BN (n = 118) or had no lifetime eating disorder symptoms (n = 78) completed assessments of height, weight, weight history, percent body fat, structured clinical interviews for DSM-5 disorders, suicidality, trauma, and treatment histories, and self-report questionnaires covering a range of validators related to eating disorders, psychological traits, and general psychopathology. Comparisons across groups tested the validity of OSFED-BN and whether prior history of DSM-5 BN impacted evidence of its clinical significance and distinctiveness.
Results: Lower frequency of binge eating was the primary reason for diagnosis of OSFED-BN vs. BN; more than 80% of those with OSFED-BN met or exceeded frequency and duration criteria for inappropriate compensatory behaviors. The current DSM-5 threshold distinguishing BN from its OSFED variant or from BN in partial remission produced few differences relative to several large differences observed for comparisons of these diagnostic groups and non-eating disorder controls.
Discussion: Despite being associated with distinct DSM-5 diagnostic codes, BN, BN in partial remission, and OSFED-BN appear to represent a single condition that may, at most, capture some dimensional differences in severity. Findings support lowering the current minimum frequency thresholds for diagnosing BN.
Background: Accumulating evidence suggests that the incidence of cancer and dementia are inversely associated. Bias does not appear to fully account for the relationship, but causal explanations have not been adequately investigated. We thus considered a possible inverse shared genetic basis.
Methods: We constructed polygenic risk scores for cancer (PRScancer) and Alzheimer disease (PRSAD) in European ancestry UK Biobank (UKB) and Health and Retirement Study (HRS) participants aged 60 years or older. Linear mixed-effects models evaluated associations of PRScancer with cognition, and logistic regression evaluated associations of PRSAD with cancer.
Results: In UKB, PRScancer was nominally associated with improved fluid intelligence (β: 0.12, 95% CI: 0.01-0.22). Twelve variants in PRScancer, including 7 in the human leukocyte antigen (HLA) complex, were positively associated with fluid intelligence, and 7 were inversely associated (P<5.8×10-5). PRScancer and its contributing variants were not associated with cognitive outcomes in HRS. PRSAD was not associated with cancer risk in either study cohort.
Discussion: Though not conclusive, the direction of the association between PRScancer and fluid intelligence was consistent with our a priori hypothesis that cancer risk variants would decrease cognitive decline. The association pattern with HLA-related variants suggests potential relevance of immune surveillance for the inverse association between dementia and cancer.
Objective: Brain cancer treatment using low intensity electrotherapy techniques is gaining interest. Localized electric field delivery via an implanted array of electrodes, termed Intratumoral Modulation Therapy (IMT), was found efficacious against brain cancers preclinically. With prior IMT studies supporting the transition towards patient application, we consider optimizing the design of electrodes, such that power consumption is minimized while retaining tumor field coverage and field shaping capability.
Methods: Cylindrical multi-contact electrodes were modelled with variable radius, spacing between contacts and contact length, and applied to spherical tumors ranging from 20-40 mm in diameter. Stimulation programming was optimized and the overall power analyzed for each design such that target coverage was maintained. To investigate the field shaping potential, designs were further optimized on 11 glioma patient MR images with irregular shaped tumors.
Results: The IMT electrode parameters found to minimize power consumption were maximal electrode radius (0.8 mm) and minimal contact spacing (1 mm). Analysis of treatment plans on patient images found 4 mm contact length to minimize complexity (total number of contacts) while maintaining field shaping capability.
Conclusion: In this study, electrodes were designed specifically for IMT that minimized power consumption while maintaining field coverage and shaping. This design was robust in its applicability to patient samples.
Significance: Due to the complexity of dynamic IMT electric field delivery, the established planning system and the custom IMT hardware designed in this study are necessary precursors to human applications. With this work we are one step closer to treating patients with brain cancer.
