Biology subjects

Trappenberg, T.

Publications and source records attributed to Trappenberg, T..

5 recordsLinked to original sources

bioRxiv2024

The Effects of Bipolar Disorder Granule Cell Hyperexcitability and Lithium Therapy on Pattern Separation in a Computational Model of the Dentate Gyrus

Induced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. These abnormalities are normalised after the application of lithium in neurons derived from lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus (DG). We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into DG networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using linear mixed effects modelling. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results agree with a hypothesised relationship between behavioural mnemonic discrimination and DG PS, as previous research has suggested that mnemonic discrimination improves after lithium therapy in lithium responders only. Our work can be expanded on in the future by simulating the effects of lithium-induced neurogenesis on PS.

neuroscience↗

bioRxiv2023

The Impact of Electrophysiological Diversity on Pattern Completion in Lithium Nonresponsive Bipolar Disorder: A Computational Modelling Approach

Patients with bipolar disorder (BD) demonstrate episodic memory deficits, which may be hippocampal-dependent and may be attenuated in lithium responders. Induced pluripotent stem-cell derived CA3 pyramidal cell-like neurons show significant hyperexcitability in lithium responsive BD patients, while lithium nonresponders show marked variance in hyperexcitability. We hypothesize that this variable excitability will impair episodic memory recall, as assessed by cued retrieval (pattern completion) within a computational model of the hippocampal CA3. We simulated pattern completion tasks using a computational model of the CA3 with different degrees of pyramidal cell excitability variance. Since pyramidal cell excitability variance naturally leads to a mix of hyperexcitability and hypoexcitability, we also examined what fraction (hyper-vs. hypoexcitable) was predominantly responsible for pattern completion errors in our model. Pyramidal cell excitability variance impaired pattern completion (linear model {beta}=-1.94, SE=0.01, p<0.001). The effect was invariant to the number of patterns stored in the network, as well as general inhibitory tone and pyramidal cell sparsity in the network. Excitability variance, and more specifically hyperexcitability, increased the number of spuriously active neurons, increasing false alarm rates and producing pattern completion deficits. Excessive inhibition also induces pattern completion deficits by limiting the number of correctly active neurons during pattern retrieval. Excitability variance in CA3 pyramidal cell-like neurons observed in lithium nonresponders may predict pattern completion deficits in these patients. These cognitive deficits may not be fully corrected by medications that minimize excitability. Future studies should test our predictions by examining behavioural correlates of pattern completion in lithium responsive and nonresponsive BD patients. Author summaryPatients with bipolar disorder experience debilitating cognitive impairments whose mechanisms are unknown, and these deficits may be greater in patients who do not respond to the mood stabilizer lithium. Studies using induced pluripotent stem cell (iPSC) derived neurons have suggested that CA3 pyramidal cells in lithium nonresponders may have wide diversity of excitability. Our study examines how this diversity of neuronal excitability would impact the computation of pattern completion in the CA3. In a computational model of the CA3, we found that variance in pyramidal cell excitability reliably impaired pattern completion abilities. Furthermore, we found that both the hyperexcitable and hypoexcitable fractions of cells were each responsible for distinct pattern completion errors, depending on the overall level of network inhibition. These results suggest that lithium nonresponsive patients with bipolar disorder will have worse performance on behavioural tasks that are sensitive to pattern completion, potentially including cued recall paradigms. Our results also suggest that mood stabilizers that simply reduce cellular hyperexcitability may not be sufficient to correct micro-circuit level computations in lithium nonresponsive bipolar disorder. Rather, these patients may require development of mood stabilizers that normalize the distribution of neuronal hyperexcitability among CA3 pyramidal cells.

neuroscience↗

bioRxiv2019

Classification and Analysis of Minimally-Processed Data from a Large Magnetoencephalography Dataset using Convolutional Neural Networks

Convolutional neural networks were used to classify and analyse a large magnetoencephalography (MEG) dataset. Networks were trained to classify between active and baseline intervals of minimally-processed data recorded during cued button pressing. There were two primary objectives for this study: (1) develop networks that can effectively classify MEG data, and (2) identify the important data features that inform classification. Networks with a simple architecture were trained using sensor and source-localised data. Networks trained with sensor data were also trained using varying amounts of data. The important features within the data were identified via saliency and occlusion mapping. An ensemble of networks trained using sensor data performed best (average test accuracy 0.974 {+/-} 0.001). A dataset containing on the order of hundreds of participants was required for optimal performance of this network with these data. Visualisation maps highlighted features known to occur during neuromagnetic recordings of cued button pressing.

neuroscience↗

bioRxiv2019

Asymmetrical reliability of the Alda Score favours a dichotomous representation of lithium responsiveness

The Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into "responder" and "non-responder" categories, respectively. This practice is often criticized as inappropriate, since continuous variables are thought to invariably be "more informative" than their dichotomizations. We therefore investigated the degree of informativeness across raw and dichotomized versions of the Alda score, using data from a published study of the scales inter-rater reliability (n=59 raters of 12 standardized vignettes each). After learning a generative model for the relationship between observed and ground truth scores (the latter defined by a consensus rating of the 12 vignettes), we show that the dichotomized scale is more robust to inter-rater disagreement than the raw 0-10 scale. Further theoretical analysis shows that when a measures reliability is stronger at one extreme of the continuum--a scenario which has received little-to-no statistical attention, but which likely occurs for the Alda score [≥] 7--dichotomization of a continuous variable may be more informative concerning its ground truth value, particularly in the presence of noise. Our study suggests that research employing the Alda score of lithium responsiveness should continue using the dichotomous definition, particularly when data are sampled across multiple raters.

pharmacology and toxicology↗

bioRxiv2018

Characteristic impairments of goal-directed and habitual control in bulimia nervosa

The relationship between clinical eating disorder symptom severity and balance of model-based (MB) and model-free (MF) control is unclear, and these traits predictive capacity is untested in this population. In 25 healthy controls (HCs), 25 subjects with binge eating disorder (BED), and 25 subjects with bulimia nervosa (BN), we show an inverse relationship between symptom severity and MB (though not MF) control. However, trial-by-trial behavioural data discriminated BN from other groups (area under receiver operating characteristic curve of 0.78; 95% CI=0.64-0.92) based primarily on impaired MF control. Our data--including analyses of reaction time and theory-driven computational modeling--support the hypothesis that among pathological binge eating groups, BN may be characterized by impaired value function learning. Our results suggest that trial-by-trial analysis of behavioural data may provide unique insights into the BN phenotype, which may thus be computationally distinct from the related disorder of BED and the HC state.

neuroscience↗