Investigating White Matter Lesion Load, Intrinsic Functional Connectivity, and Cognitive Abilities in Older Adults

Changes to the while matter of the brain disrupt neural communication between spatially distributed brain regions and are associated with cognitive changes in later life. While approximately 95% of older adults experience these brain changes, not everyone who has significant white matter damage displays cognitive impairment. Few studies have investigated the association between white matter changes and cognition in the context of functional brain network integrity. This study used a data-driven, multivariate analytical model to investigate intrinsic functional connectivity patterns associated with individual variability in white matter lesion load as related to fluid and crystallized intelligence in a sample of healthy older adults (n = 84). Several primary findings were noted. First, a reliable pattern emerged associating whole-brain resting-state functional connectivity with individual variability in measures of white matter lesion load, as indexed by total white matter lesion volume and number of lesions. Secondly, white matter lesion load was associated with increased network disintegration and dedifferentiation. Specifically, lower white matter lesion load was associated with greater within- versus between-network connectivity. Higher white matter lesion load was associated with greater between-network connectivity compared to within. These associations between intrinsic functional connectivity and white matter lesion load were not reliably associated with crystallized and fluid intelligence performance. These results suggest that changes to the white matter of the brain in typically aging older adults are characterized by increased functional brain network dedifferentiation. The findings highlight the role of white matter lesion load in altering the functional network architecture of the brain

Dynamic Configuration of Large-Scale Cortical Networks: A Useful Framework for Clarifying the Heterogeneity Found in Attention-Deficit/Hyperactivity Disorder

The heterogeneity of attention-deficit/hyperactivity disorder(ADHD) traits (inattention vs. hyperactivity/impulsivity) complicates diagnosis and intervention. Identifying how the configuration of large-scale functional brain networks during cognitive processing correlate with this heterogeneity could help us understand the neural mechanisms altered across ADHD presentations. Here, we recorded high-density EEG while 62 non-clinical participants (ages 18-24; 32 male) underwent an inhibitory control task (Go/No-Go). Functional EEG networks were created using sensors as nodes and across-trial phase-lag index values as edges. Using cross-validated LASSO regression, we examined whether graph-theory metrics applied to both static networks (averaged across time-windows: -500–0ms, 0–500ms) and dynamic networks (temporally layered with 2ms intervals), were associated with hyperactive/impulsive and inattentive traits. Network configuration during response execution/inhibition was associated with hyperactive/impulsive (mean R2across test sets = .20, SE = .02), but not inattentive traits. Post-stimulus results at higher frequencies (Beta, 14-29Hz; Gamma, 30-90Hz) showed the strongest association with hyperactive/impulsive traits, and predominantly reflected less burst-like integration between modules in oscillatory beta networks during execution, and increased integration/small-worldness in oscillatory gamma networks during inhibition. We interpret the beta network results as reflecting weaker integration between specialized pre-frontal and motor systems during motor response preparation, and the gamma results as reflecting a compensatory mechanism used to integrate processing between less functionally specialized networks. This research demonstrates that the neural network mechanisms underlying response execution/inhibition might be associated with hyperactive/impulsive traits, and that dynamic, task-related changes in EEG functional networks may be useful in disentangling ADHD heterogeneity

Generative whole-brain dynamics models from healthy subjects predict functional alterations in stroke at the level of individual patients

Computational whole-brain models describe the resting activity of each brain region based on a local model, inter-regional functional interactions, and a structural connectome that specifies the strength of inter-regional connections. Strokes damage the healthy structural connectome that forms the backbone of these models and produce large alterations in inter-regional functional interactions. These interactions are typically measured by correlating the time series of the activity between two brain regions in a process, called resting functional connectivity. We show that adding information about the structural disconnections produced by a patient’s lesion to a whole-brain model previously trained on structural and functional data from a large cohort of healthy subjects enables the prediction of the resting functional connectivity of the patient and fits the model directly to the patient’s data (Pearson correlation = 0.37; mean square error = 0.005). Furthermore, the model dynamics reproduce functional connectivity-based measures that are typically abnormal in stroke patients and measures that specifically isolate these abnormalities. Therefore, although whole-brain models typically involve a large number of free parameters, the results show that, even after fixing those parameters, the model reproduces results from a population very different than that on which the model was trained. In addition to validating the model, these results show that the model mechanistically captures the relationships between the anatomical structure and the functional activity of the human brain

Disentangling causal webs in the brain using functional Magnetic Resonance Imaging: A review of current approaches

In the past two decades, functional Magnetic Resonance Imaging has been used to relate neuronal network activity to cognitive processing and behaviour. Recently this approach has been augmented by algorithms that allow us to infer causal links between component populations of neuronal networks. Multiple inference procedures have been proposed to approach this research question but so far, each method has limitations when it comes to establishing whole-brain connectivity patterns. In this work, we discuss eight ways to infer causality in fMRI research: Bayesian Nets, Dynamical Causal Modelling, Granger Causality, Likelihood Ratios, LiNGAM, Patel's Tau, Structural Equation Modelling, and Transfer Entropy. We finish with formulating some recommendations for the future directions in this area

Tracking brain dynamics across transitions of consciousness

How do we lose and regain consciousness? The space between healthy wakefulness and unconsciousness encompasses a series of gradual and rapid changes in brain activity. In this thesis, I investigate computational measures applicable to the electroencephalogram to quantify the loss and recovery of consciousness from the perspective of modern theoretical frameworks. I examine three different transitions of consciousness caused by natural, pharmacological and pathological factors: sleep, sedation and coma. First, I investigate the neural dynamics of falling asleep. By combining the established methods of phase-lag brain connectivity and EEG microstates in a group of healthy subjects, a unique microstate is identified, whose increased duration predicts behavioural unresponsiveness to auditory stimuli during drowsiness. This microstate also uniquely captures an increase in frontoparietal theta connectivity, a putative marker of the loss of consciousness prior to sleep onset. I next examine the loss of behavioural responsiveness in healthy subjects undergoing mild and moderate sedation. The Lempel-Ziv compression algorithm is employed to compute signal complexity and symbolic mutual information to assess information integration. An intriguing dissociation between responsiveness and drug level in blood during sedation is revealed: responsiveness is best predicted by the temporal complexity of the signal at single- channel and low-frequency integration, whereas drug level is best predicted by the complexity of spatial patterns and high-frequency integration. Finally, I investigate brain connectivity in the overnight EEG recordings of a group of patients in acute coma. Graph theory is applied on alpha, theta and delta networks to find that increased variability in delta network integration early after injury predicts the eventual coma recovery score. A case study is also described where the re-emergence of frontoparietal connectivity predicted a full recovery long before behavioural improvement. The findings of this thesis inform prospective clinical applications for tracking states of consciousness and advance our understanding of the slow and fast brain dynamics underlying its transitions. Collating these findings under a common theoretical framework, I argue that the diversity of dynamical states, in particular in temporal domain, and information integration across brain networks are fundamental in sustaining consciousness.My PhD was funded by the Cambridge Trust and a MariaMarina award from Lucy Cavendish College

Phenotyping functional brain dynamics:A deep learning prespective on psychiatry

This thesis explores the potential of deep learning (DL) techniques combined with multi-site functional magnetic resonance imaging (fMRI) to enable automated diagnosis and biomarker discovery for psychiatric disorders. This marks a shift from the convention in the field of applying standard machine learning techniques on hand-crafted features from a single cohort.To enable this, we have focused on three main strategies: utilizing minimally pre-processed data to maintain spatio-temporal dynamics, developing sample-efficient DL models, and applying emerging DL training techniques like self-supervised and transfer learning to leverage large population-based datasets.Our empirical results suggest that DL models can sometimes outperform existing machine learning methods in diagnosing Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD) from resting-state fMRI data, despite the smaller datasets and the high data dimensionality. Nonetheless, the generalization performance of these models is currently insufficient for clinical use, raising questions about the feasibility of applying supervised DL for diagnosis or biomarker discovery due to the highly heterogeneous nature of the disorders. Our findings suggest that normative modeling on functional brain dynamics provides a promising alternative to the current paradigm

Modern Views of Machine Learning for Precision Psychiatry

In light of the NIMH's Research Domain Criteria (RDoC), the advent of functional neuroimaging, novel technologies and methods provide new opportunities to develop precise and personalized prognosis and diagnosis of mental disorders. Machine learning (ML) and artificial intelligence (AI) technologies are playing an increasingly critical role in the new era of precision psychiatry. Combining ML/AI with neuromodulation technologies can potentially provide explainable solutions in clinical practice and effective therapeutic treatment. Advanced wearable and mobile technologies also call for the new role of ML/AI for digital phenotyping in mobile mental health. In this review, we provide a comprehensive review of the ML methodologies and applications by combining neuroimaging, neuromodulation, and advanced mobile technologies in psychiatry practice. Additionally, we review the role of ML in molecular phenotyping and cross-species biomarker identification in precision psychiatry. We further discuss explainable AI (XAI) and causality testing in a closed-human-in-the-loop manner, and highlight the ML potential in multimedia information extraction and multimodal data fusion. Finally, we discuss conceptual and practical challenges in precision psychiatry and highlight ML opportunities in future research