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Kotikalapudi, R.

Publications and source records attributed to Kotikalapudi, R..

11 recordsLinked to original sources

Reinforcement Learning via Brain Feedback for real-time fMRI-based adaptive stimulus generation

Traditional fMRI studies rely on predefined task paradigms, where fixed stimulus designs limit the flexibility with which brain-stimulus relationships can be explored. Here, we introduce Reinforcement Learning via Brain Feedback (RLBF), a framework and open-source software package for adaptive stimulus optimization using real-time fMRI. RLBF reverses the conventional direction of inference by using neural responses to guide the exploration of stimulus spaces through reinforcement learning, enabling optimization of predefined brain targets such as regional activity or multivariate neural signatures. The accompanying Python-based software provides a modular framework integrating real-time fMRI data processing, reinforcement learning agents, adaptive stimulus generation, simulation-based testing, and experiment monitoring. Its flexible architecture allows researchers to customize preprocessing pipelines, reward functions, stimulus spaces, and RL strategies for diverse closed-loop neuroimaging applications. We validate the framework in a proof-of-concept study (N=10), demonstrating real-time optimization of a simple visual stimulus space by adapting checkerboard contrast and frequency to maximize primary visual cortex (V1) responses within a single 10-minute fMRI session. RLBF provides an extensible foundation for brain-guided stimulus optimization and enables new approaches for investigating neural specificity, individualized brain-stimulus relationships, and adaptive experimental design.

bioinformatics↗

Associations between epilepsy-related polygenic risk and brain morphology in childhood

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions.

neuroscience↗

On the replicability of diffusion weighted MRI-based brain-behavior models

Establishing replicable inter-individual brain-wide associations is key to advancing our understanding of the crucial links between brain structure, function, and behavior, as well as applying this knowledge in clinical contexts. While the replicability and sample size requirements for anatomical and functional MRI-based brain-behavior associations have been extensively discussed recently, systematic replicability assessments are still lacking for diffusion-weighted imaging (DWI), despite it being the dominant non-invasive method to investigate white matter microstructure and structural connectivity. We report results of a comprehensive evaluation of the replicability of various DWI-based multivariate brain-behavior models. This evaluation is based on large-scale data from the Human Connectome Project, including five different DWI-based brain features (from fractional anisotropy to structural connectivity) and 58 different behavioral phenotypes. Our findings show an overall moderate replicability, with 24-31% of phenotypes replicable with sample sizes of fewer than 500. As DWI yields trait-like brain features, we restricted the analysis to trait-like phenotypes, such as cognitive and motor skills, and found much more promising replicability estimates, with 67-75% of these phenotypes replicable with n<500. Contrasting our empirical results to analytical replicability estimates substantiated that the replicability of DWI-based models is primarily a function of the true, unbiased effect size. Our work highlights the potential of DWI to produce replicable brain-behavior associations. However, it shows that achieving replicability with small-to-moderate samples requires stable, reliable and neurobiologically relevant target phenotypes. Our work highlights the potential of DWI to produce replicable brain-behavior associations, but only for stable, reliable and neurobiologically relevant target phenotypes. HIGHLIGHTSO_LIModerate replicability in DWI-based models: Overall replicability of DWI-based brain-behavior associations ranges from 24-31% with sample sizes under 500. C_LIO_LIImproved replicability for trait-like phenotypes: Trait-like phenotypes e.g., cognitive and motor skills exhibit higher replicability estimates of 67-75%, compared to state-like phenotypes such as emotion. C_LIO_LIEffect size as a key factor: Replicability is primarily influenced by the true, unbiased effect size, highlighting the importance of targeting stable and reliable phenotypes. C_LIO_LIPromise of -based multivariate associations: DWI-based brain-behaviour models should focus on phenotypes that display a sufficient temporal stability and test-retest reliability. C_LI

neuroscience↗

A worldwide ENIGMA study on epilepsy-related gray and white matter compromise across the adult lifespan

ObjectivesTemporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. MethodsWe studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. ResultsIn TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. ConclusionsThis study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

neuroscience↗

External validation of machine learning models - registered models and adaptive sample splitting

Multivariate predictive models play a crucial role in enhancing our understanding of complex biological systems and in developing innovative, replicable tools for translational medical research. However, the complexity of machine learning methods and extensive data pre-processing and feature engineering pipelines can lead to overfitting and poor generalizability. An unbiased evaluation of predictive models necessitates external validation, which involves testing the finalized model on independent data. Despite its importance, external validation is often neglected in practice due to the associated costs. Here we propose that, for maximal credibility, model discovery and external validation should be separated by the public disclosure (e.g. pre-registration) of feature processing steps and model weights. Furthermore, we introduce a novel approach to optimize the trade-off between efforts spent on training and external validation in such studies. We show on data involving more than 3000 participants from four different datasets that, for any "sample size budget", the proposed adaptive splitting approach can successfully identify the optimal time to stop model discovery so that predictive performance is maximized without risking a low powered, and thus inconclusive, external validation. The proposed design and splitting approach (implemented in the Python package "AdaptiveSplit") may contribute to addressing issues of replicability, effect size inflation and generalizability in predictive modeling studies.

bioinformatics↗

Connectome-Based Attractor Dynamics Guide Brain Activity in Rest, Task, and Disease

Functional brain connectivity has been instrumental in uncovering the large-scale organization of the brain and its relation to various behavioral and clinical phenotypes. Understanding how this functional architecture relates to the brains dynamic activity repertoire is an essential next step towards interpretable generative models of brain function. We propose functional connectivity-based Attractor Neural Networks (fcANNs), a theoretically inspired model of macro-scale brain dynamics, simulating recurrent activity flow among brain regions based on first principles of self-organization. In the fcANN framework, brain dynamics are understood in relation to attractor states; neurobiologically meaningful activity configurations that minimize the free energy of the system. We provide the first evidence that large-scale brain attractors - as reconstructed by fcANNs - exhibit an approximately orthogonal organization, which is a signature of the self-orthogonalization mechanism of the underlying theoretical framework of free-energy-minimizing attractor networks. Analyses of 7 distinct datasets demonstrate that fcANNs can accurately reconstruct and predict brain dynamics under a wide range of conditions, including resting and task states, and brain disorders. By establishing a formal link between connectivity and activity, fcANNs offer a simple and interpretable computational alternative to conventional descriptive analyses. Key PointsO_LIWe present a simple yet powerful generative computational model for large-scale brain dynamics C_LIO_LIBased on the theory of artificial attractor neural networks emerging from first principles of self-organization C_LIO_LIModel dynamics accurately reconstruct several characteristics of resting-state brain dynamics and confirm theoretical predictions of emergent attractor self-orthogonalization C_LIO_LIOur model captures both task-induced and pathological changes in brain activity C_LIO_LIfcANNs offer a simple and interpretable computational alternative to conventional descriptive analyses of brain function C_LI Project website (with interactive manuscript)https://pni-lab.github.io/connattractor

neuroscience↗

Gray matter cortical thickness predicts individual pain sensitivity: a multi-center machine learning approach

Pain sensitivity is known to considerably vary across individuals. While the variability in pain has been linked to structural neural correlates, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity utilising structural MRI-based cortical thickness data from a multi-center dataset (3 centers, 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearsons r = 0.36, p < 0.0005). The predictions were found to be specific to pain sensitivity and not biased towards potential confounding effects (e.g., anxiety, stress, depression, center-effects). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain. HighlightsO_LIWe present a robust, brain structure-based multi-center predictive model for pain sensitivity. C_LIO_LIOur model based on gray matter cortical thickness explains 13% of the variance in pain sensitivity and generalizes to out-of-center data. C_LIO_LIThe predictions are specific to pain sensitivity and not driven by potential confounders such as stress, depression, anxiety, and center-effects. C_LIO_LIThe most important predictors were rostral anterior cingulate cortex, parahippocampal gyrus and temporal pole, all negatively correlated with pain sensitivity. C_LI

neuroscience↗

Structural network alterations in focal and generalized epilepsy follow axes of epilepsy risk gene expression: An ENIGMA study

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.

neuroscience↗

Topographic divergence of atypical cortical asymmetry and regional atrophy patterns in temporal lobe epilepsy: a worldwide enigma study

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

neuroscience↗

Network-based atrophy modelling in the common epilepsies: a worldwide ENIGMA study

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of common epilepsies.

neuroscience↗

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across "all epilepsies" lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

neuroscience↗