Biology subjects

Demirtas, M.

Publications and source records attributed to Demirtas, M..

9 recordsLinked to original sources

bioRxiv2025

Disruption of Striatal Intrinsic Ignition in Huntington's Disease: an In-Silico Perturbational Approach to Emulate Disease Progression and Recovery

Huntingtons disease (HD) is a neurodegenerative disorder caused by a single gene that severely affects motor, cognitive, and behavioral functions and is ultimately fatal. While disruptions in the structural integrity of the striatum are well documented, less is known about how the underlying functional impairments relate to the disease. We developed a large-scale modeling framework based on intrinsic ignition to uncover functional anomalies during HD progression. We first measured how much a spontaneous event in one brain region influences the rest of the brain, then systematically perturbed the activity of the striatum to predict the empirical changes in functional connectivity (FC) by re-optimizing the model parameters and conducting in-silico experiments. Results showed that disruption of the activity dynamics in the caudate, and to some extent the putamen, are the key factors that explain a substantial amount of the variance in FC alterations during HD progression. We then assessed the ability to recover whole-brain functional activity by driving the caudate and putamen activity towards a healthy-like regime and found that, by tuning the local bifurcation parameter of caudate and putamen, it is possible to recover whole-brain healthy functional activity, albeit moderately. Surprisingly, although the functional disruptions in the caudate better explained the alterations in FC, the recovery of the dynamics was more effective in the putamen. Overall, our results suggest that the disruptions of the dynamics in the striatum can explain the gross functional connectivity changes in HD. Our study demonstrates that computational modeling is an important tool to reveal the underlying patterns behind the observed data and provides an opportunity to test interventional mechanisms in silico.

neuroscience↗

bioRxiv2025

Large Scale Functional and Effective Connectivity Alterations cross the Huntington's Disease Integrated Staging System

Huntingtons disease (HD) is a progressive neurodegenerative disease with severe motor, cognitive and behavioral symptoms. There is a recent impetus to develop treatments that slow progression before clinical signs emerge. Such early interventions require biomarkers sensitive to the very earliest HD progression. Here we applied cutting-edge fMRI analysis on data collected in the Track-On HD study to evaluate whether functional and effective connectivity obtained from model-free and model-based approaches can produce useful biomarkers of HD progression. We analyzed data from 231 participants with up to three annual visits each and created five groups comprising normative controls and four HD groups according to the Huntingtons Disease Integrated Staging System (HD-ISS). We found significant differences across the HD-ISS stages but not in their longitudinal change. Specifically, we found attenuated functional and effective connectivity in the caudate nucleus in HD-ISS-2, and this effect extended to other corticostriatal connections in HD-ISS-3. Overall, most of the alterations were only evident in advanced HD stages, and we did not observe widespread alterations in cortical connectivity and graph topography. Although HD-ISS groups did not differ in the amount of in-scanner motion, we did find measures of functional and effective connectivity to be sensitive to motion. We conclude that fMRI can indeed capture attenuation of cortico-striatal functional and effective connectivity across HD progression. This is the first study to investigate fMRI alterations across the recently created HD-ISS stages within a novel framework of signal flow across the whole brain.

neuroscience↗

bioRxiv2024

Personalized circuit modeling captures variation in cortical functional connectivity

Functional magnetic resonance imaging (fMRI) of the human cortex reveals patterns of correlated neural dynamics that are individual-specific and associated with phenotypic variation. However, circuit mechanisms underlying individual variation in functional connectivity (FC) are not well understood. Here, we fit individual-level FC patterns with a biophysically-based circuit model of large-scale cortical dynamics. This model is fit with a small number of neurophysiologically interpretable parameters, and incorporates a hierarchical gradient in local synaptic strengths across cortex parameterized via the structural MRI-derived T1w/T2w map. We applied our modeling framework to resting-state fMRI FC from a large cohort of subjects (N=842) from the Human Connectome Project. We found that the model captures a substantial portion of individual variation in FC, especially with personalized degrees of local synaptic specialization along the hierarchical gradient. Furthermore, the model can capture to the within-subject variation in FC across scans. Empirically, we found that principal modes of individual variation in FC follow interpretable topographic patterns. We developed a framework to assess model expressivity via how these empirical modes of FC variation align with variations in simulated FC induced by parameter perturbations. This framework reveals a straightforward mapping between key parameters and the leading modes of variation across subjects and provides a principled approach to extending computational models. Collectively, our modeling results establish a foundation for personalized computational modeling of functional dynamics in large-scale brain circuits.

neuroscience↗

bioRxiv2023

Design of effective personalised perturbation strategies for enhancing cognitive intervention in Alzheimer's disease

One of the potential and promising adjuvant therapies for Alzheimers disease is that of non-invasive transcranial neurostimulation to potentiate cognitive training interventions. Conceptually, this is achieved by driving brain dynamics towards an optimal state for an effective facilitation of cognitive training interventions. However, current neurostimulation protocols rely on experimental trial-and-error approaches that result in variability of symptom improvements and suboptimal progress. Here, we leveraged whole-brain computational modelling by assessing the regional susceptibility towards optimal brain dynamics from Alzheimers disease. In practice, we followed the three-part concept of Dynamic Sensitivity Analysis by first understanding empirical differences between healthy controls and patients with mild cognitive impairment and mild dementia due to Alzheimers Disease; secondly, by building computational models for all individuals in the mild cognitive impairment and mild dementia cohorts; and thirdly, by perturbing brain regions and assessing the impact on the recovery of brain dynamics to the healthy state (here defined in functional terms, summarised by a measure of metastability for the healthy group). By doing so, we show the importance of key regions, along the anterior-posterior medial line, in driving in-silico improvement of mild dementia and mild cognitive impairment groups. Moreover, this subset consists mainly of regions with high structural nodal degree. Overall, this in-silico perturbational approach could inform the design of stimulation strategies for re-establishing healthy brain dynamics, putatively facilitating effective cognitive interventions targeting the cognitive decline in Alzheimers disease.

neuroscience↗

bioRxiv2021

Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD

Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically-induced effects. This paradigm has revealed that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to its agonist activity at the serotonin-2A receptor. Here, we integrate brainwide transcriptomics with biophysically-based large-scale circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical dynamics. Our model captures the topographic effects of LSD-induced changes in cortical BOLD functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal cell gain is the circuit mechanism through which LSD alters cortical functional topography. Individual-subject fitting reveals that the model captures patterns of individual neural differences in drug response that predict altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to salient changes in brain function, with implications for precision medicine.

neuroscience↗

bioRxiv2018

Hierarchical heterogeneity across human cortex shapes large-scale neural dynamics

The large-scale organization of dynamical neural activity across cortex emerges through long-range interactions among local circuits. We hypothesized that large-scale dynamics are also shaped by heterogeneity of intrinsic local properties across cortical areas. One key axis along which microcircuit properties are specialized relates to hierarchical levels of cortical organization. We developed a large-scale dynamical circuit model of human cortex that incorporates heterogeneity of local synaptic strengths, following a hierarchical axis inferred from MRI-derived T1w/T2w mapping, and fit the model using multimodal neuroimaging data. We found that incorporating hierarchical heterogeneity substantially improves the model fit to fMRI-measured resting-state functional connectivity and captures sensory-association organization of multiple fMRI features. The model predicts hierarchically organized high-frequency spectral power, which we tested with resting-state magnetoencephalography. These findings suggest circuit-level mechanisms linking spatiotemporal levels of analysis and highlight the importance of local properties and their hierarchical specialization on the large-scale organization of human cortical dynamics.

neuroscience↗

bioRxiv2018

Distinct Functional Connectivity Mode during Viewing Natural Scenes Revealed by Principal Component Analysis

A fundamental question in systems neuroscience is how spontaneous activity at rest is reorganized during task performance. Recent studies suggest a strong relationship between resting and task FC. Furthermore, the relationship between resting and task FC has been shown to reflect individual differences. Particularly, various studies have demonstrated that the FC has higher reliability and provides enhanced detection of individual differences while viewing natural scenes. Although the large-scale organization of FC during rest and movie-viewing conditions have been well studied in relation to individual variations, the re-organization of FC during viewing natural scenes have not been studied in depth. In this study, we used principal component analysis on FC during rest and movie-viewing condition to characterize the dimensionality of FC patterns across conditions and subjects. We found that the variations in FC patterns related to viewing natural scenes can be explained by a single component, which enables identification of the task over subjects with 100% accuracy. We showed that the FC mode associated to viewing natural scenes better reflects individual variations. Furthermore, we investigated the signatures of movie-viewing-specific functional modes in dynamic FC based on phase-locking values between brain regions. We found that the movie-specific functional mode is persistent across time; suggesting the emergence of a stable processing mode. To explain the reorganization of whole-brain FC through the changes in local dynamics, we appeal to a large-scale computational model. This modelling suggested that the reorganization of whole-brain FC is associated to the interaction between frontal-parietal and frontal-temporal activation patterns.

neuroscience↗

bioRxiv2017

Hierarchy of transcriptomic specialization across human cortex captured by myelin map topography

Hierarchy provides a unifying principle for the macroscale organization of anatomical and functional properties across primate cortex, yet the microscale bases of specialization across human cortex are poorly understood. Cortical hierarchy is conventionally informed by invasive measurements of long-range projections, creating the need for a principled proxy measure of hierarchy in humans. Moreover, cortex exhibits marked interareal variation in patterns of gene expression, yet organizing principles of its transcriptional architecture remain unclear. We hypothesized that functional specialization of human cortical microcircuitry involves hierarchical gradients of gene expression. We found that a noninvasive neuroimaging measure, the MRI-derived myelin map, reliably indexes hierarchy and closely resembles the dominant pattern of transcriptomic variation across human cortex. We found strong hierarchical gradients in expression profiles of genes related to microcircuit function and neuropsychiatric disorders. Our findings suggest that hierarchy defines an axis shared by the transcriptomic and anatomical architectures of human cortex, and that hierarchical gradients of microscale properties contribute to macroscale specialization of cortical function.

neuroscience↗

bioRxiv2016

Exploring Anti-correlated Resting State BOLD Signals Through Dynamic Functional Connectivity and Whole-brain Computational Modeling

Resting-state functional magnetic resonance imaging and diffusion weight imaging became a conventional tool to study brain connectivity in healthy and diseased individuals. However, both techniques provide indirect measures of brain connectivity leading to controversies on their interpretation. Among these controversies, interpretation of anti-correlated functional connections and global average signal is a major challenge for the field. In this paper, we used dynamic functional connectivity to calculate the probability of anti-correlations between brain regions. The brain regions forming task-positive and task-negative networks showed high anti-correlation probabilities. The fluctuations in anti-correlation probabilities were significantly correlated with those in global average signal and functional connectivity. We investigated the mechanisms behind these fluctuations using whole-brain computational modeling approach. We found that the underlying effective connectivity and intrinsic noise reflect the static spatiotemporal patterns, whereas the hemodynamic response function is the key factor defining the fluctuations in functional connectivity and anti-correlations. Furthermore, we illustrated the clinical implications of these findings on a group of bipolar disorder patients suffering a depressive relapse (BPD).

neuroscience↗