Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated with Psychopathology Across Independent Cohorts.

Background: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions. Methods: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders. Results: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use. Conclusions: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

Connectome reorganization associated with temporal lobe pathology and its surgical resection.

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data-derived from diffusion MRI tractography from each subject-into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, individuals with TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical-imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency, and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and inter-individual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.

Controlling the human connectome with spatially diffuse input signals.

The human brain is never at "rest"; its activity is constantly fluctuating over time, transitioning from one brain state-a whole-brain pattern of activity-to another. Network control theory offers a framework for understanding the effort - energy - associated with these transitions. One branch of control theory that is especially useful in this context is "optimal control", in which input signals are used to selectively drive the brain into a target state. Typically, these inputs are introduced independently to the nodes of the network (each input signal is associated with exactly one node). Though convenient, this input strategy ignores the continuity of cerebral cortex - geometrically, each region is connected to its spatial neighbors, allowing control signals, both exogenous and endogenous, to spread from their foci to nearby regions. Additionally, the spatial specificity of brain stimulation techniques is limited, such that the effects of a perturbation are measurable in tissue surrounding the stimulation site. Here, we adapt the network control model so that input signals have a spatial extent that decays exponentially from the input site. We show that this more realistic strategy takes advantage of spatial dependencies in structural connectivity and activity to reduce the energy (effort) associated with brain state transitions. We further leverage these dependencies to explore near-optimal control strategies such that, on a per-transition basis, the number of input signals required for a given control task is reduced, in some cases by two orders of magnitude. This approximation yields network-wide maps of input site density, which we compare to an existing database of functional, metabolic, genetic, and neurochemical maps, finding a close correspondence. Ultimately, not only do we propose a more efficient framework that is also more adherent to well-established brain organizational principles, but we also posit neurobiologically grounded bases for optimal control.

Pervasive alterations of intra-axonal volume and network organization in young children with a 16p11.2 deletion.

Reciprocal Copy Number Variants (CNVs) at the 16p11.2 locus confer high risk for autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs). Morphometric MRI studies have revealed large and pervasive volumetric alterations in carriers of a 16p11.2 deletion. However, the specific neuroanatomical mechanisms underlying such alterations, as well as their developmental trajectory, are still poorly understood. Here we explored differences in microstructural brain connectivity between 24 children carrying a 16p11.2 deletion and 66 typically developing (TD) children between 2 and 8 years of age. We found a large pervasive increase of intra-axonal volume widespread over a high number of white matter tracts. Such microstructural alterations in 16p11.2 deletion children were already present at an early age, and led to significant changes in the global efficiency and integration of brain networks mainly associated to language, motricity and socio-emotional behavior, although the widespread pattern made it unlikely to represent direct functional correlates. Our results shed light on the neuroanatomical basis of the previously reported increase of white matter volume, and align well with analogous evidence of altered axonal diameter and synaptic function in 16p11.2 mice models. We provide evidence of a prevalent mechanistic deviation from typical maturation of brain structural connectivity associated with a specific biological risk to develop ASD. Future work is warranted to determine how this deviation contributes to the emergence of symptoms observed in young children diagnosed with ASD and other NDDs.

99mTc-HMPAO SPECT Perfusion Signatures Associated With Clinical Progression in Patients With Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD. METHODS: Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline 99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease. RESULTS: Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features. DISCUSSION: This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Connectome-based reservoir computing with the conn2res toolbox.

The connection patterns of neural circuits form a complex network. How signaling in these circuits manifests as complex cognition and adaptive behaviour remains the central question in neuroscience. Concomitant advances in connectomics and artificial intelligence open fundamentally new opportunities to understand how connection patterns shape computational capacity in biological brain networks. Reservoir computing is a versatile paradigm that uses high-dimensional, nonlinear dynamical systems to perform computations and approximate cognitive functions. Here we present conn2res: an open-source Python toolbox for implementing biological neural networks as artificial neural networks. conn2res is modular, allowing arbitrary network architecture and dynamics to be imposed. The toolbox allows researchers to input connectomes reconstructed using multiple techniques, from tract tracing to noninvasive diffusion imaging, and to impose multiple dynamical systems, from spiking neurons to memristive dynamics. The versatility of the conn2res toolbox allows us to ask new questions at the confluence of neuroscience and artificial intelligence. By reconceptualizing function as computation, conn2res sets the stage for a more mechanistic understanding of structure-function relationships in brain networks.

Connectome-wide structure-function coupling models implicate polysynaptic alterations in autism.

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diagnoses. Although incompletely understood, structural and functional network alterations are increasingly recognized to be at the core of the condition. We utilized multimodal imaging and connectivity modeling to study structure-function coupling in ASD and probed mono- and polysynaptic mechanisms on structurally-governed network function. We examined multimodal magnetic resonance imaging data in 80 ASD and 61 neurotypical controls from the Autism Brain Imaging Data Exchange (ABIDE) II initiative. We predicted intrinsic functional connectivity from structural connectivity data in each participant using a Riemannian optimization procedure that varies the times that simulated signals can unfold along tractography-derived personalized connectomes. In both ASD and neurotypical controls, we observed improved structure-function prediction at longer diffusion time scales, indicating better modeling of brain function when polysynaptic mechanisms are accounted for. Prediction accuracy differences (∆prediction accuracy) were marked in transmodal association systems, such as the default mode network, in both neurotypical controls and ASD. Differences were, however, lower in ASD in a polysynaptic regime at higher simulated diffusion times. We compared regional differences in ∆prediction accuracy between both groups to assess the impact of polysynaptic communication on structure-function coupling. This analysis revealed that between-group differences in ∆prediction accuracy followed a sensory-to-transmodal cortical hierarchy, with an increased gap between controls and ASD in transmodal compared to sensory/motor systems. Multivariate associative techniques revealed that structure-function differences reflected inter-individual differences in autistic symptoms and verbal as well as non-verbal intelligence. Our network modeling approach sheds light on atypical structure-function coupling in autism, and suggests that polysynaptic network mechanisms are implicated in the condition and that these can help explain its wide range of associated symptoms.

Integrating brainstem and cortical functional architectures.

The brainstem is a fundamental component of the central nervous system yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.

The human brain connectome weighted by the myelin content and total intra-axonal cross-sectional area of white matter tracts.

A central goal in neuroscience is the development of a comprehensive mapping between structural and functional brain features, which facilitates mechanistic interpretation of brain function. However, the interpretability of structure-function brain models remains limited by a lack of biological detail. Here, we characterize human structural brain networks weighted by multiple white matter microstructural features including total intra-axonal cross-sectional area and myelin content. We report edge-weight-dependent spatial distributions, variance, small-worldness, rich club, hubs, as well as relationships with function, edge length, and myelin. Contrasting networks weighted by the total intra-axonal cross-sectional area and myelin content of white matter tracts, we find opposite relationships with functional connectivity, an edge-length-independent inverse relationship with each other, and the lack of a canonical rich club in myelin-weighted networks. When controlling for edge length, networks weighted by either fractional anisotropy, radial diffusivity, or neurite density show no relationship with whole-brain functional connectivity. We conclude that the co-utilization of structural networks weighted by total intra-axonal cross-sectional area and myelin content could improve our understanding of the mechanisms mediating the structure-function brain relationship.

Integrating brainstem and cortical functional architectures.

The brainstem is a fundamental component of the central nervous system yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.

The biological role of local and global fMRI BOLD signal variability in human brain organization.

Variability drives the organization and behavior of complex systems, including the human brain. Understanding the variability of brain signals is thus necessary to broaden our window into brain function and behavior. Few empirical investigations of macroscale brain signal variability have yet been undertaken, given the difficulty in separating biological sources of variance from artefactual noise. Here, we characterize the temporal variability of the most predominant macroscale brain signal, the fMRI BOLD signal, and systematically investigate its statistical, topographical and neurobiological properties. We contrast fMRI acquisition protocols, and integrate across histology, microstructure, transcriptomics, neurotransmitter receptor and metabolic data, fMRI static connectivity, and empirical and simulated magnetoencephalography data. We show that BOLD signal variability represents a spatially heterogeneous, central property of multi-scale multi-modal brain organization, distinct from noise. Our work establishes the biological relevance of BOLD signal variability and provides a lens on brain stochasticity across spatial and temporal scales.

General anaesthesia reduces the uniqueness of brain connectivity across individuals and across species.

The human brain is characterised by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain: both with respect to the brains of other individuals, and the brains of another species. We report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organised: it co-localises with the archetypal sensory-association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol, and reversed upon recovery. Providing convergent evidence, we show that under anaesthesia the functional connectivity of the human brain becomes more similar to the macaque brain. Finally, anaesthesia diminishes the match between spontaneous brain activity and meta-analytic brain patterns aggregated from the NeuroSynth engine. Collectively, the present results reveal that anaesthetised human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia.

Network connectivity and local transcriptomic vulnerability underpin cortical atrophy progression in Parkinson's disease.

Parkinson's disease pathology is hypothesized to spread through the brain via axonal connections between regions and is further modulated by local vulnerabilities within those regions. The resulting changes to brain morphology have previously been demonstrated in both prodromal and de novo Parkinson's disease patients. However, it remains unclear whether the pattern of atrophy progression in Parkinson's disease over time is similarly explained by network-based spreading and local vulnerability. We address this gap by mapping the trajectory of cortical atrophy rates in a large, multi-centre cohort of Parkinson's disease patients and relate this atrophy progression pattern to network architecture and gene expression profiles. Across 4-year follow-up visits, increased atrophy rates were observed in posterior, temporal, and superior frontal cortices. We demonstrated that this progression pattern was shaped by network connectivity. Regional atrophy rates were strongly related to atrophy rates across structurally and functionally connected regions. We also found that atrophy progression was associated with specific gene expression profiles. The genes whose spatial distribution in the brain was most related to atrophy rate were those enriched for mitochondrial and metabolic function. Taken together, our findings demonstrate that both global and local brain features influence vulnerability to neurodegeneration in Parkinson's disease.

Towards a biologically annotated brain connectome.

The brain is a network of interleaved neural circuits. In modern connectomics, brain connectivity is typically encoded as a network of nodes and edges, abstracting away the rich biological detail of local neuronal populations. Yet biological annotations for network nodes - such as gene expression, cytoarchitecture, neurotransmitter receptors or intrinsic dynamics - can be readily measured and overlaid on network models. Here we review how connectomes can be represented and analysed as annotated networks. Annotated connectomes allow us to reconceptualize architectural features of networks and to relate the connection patterns of brain regions to their underlying biology. Emerging work demonstrates that annotated connectomes help to make more veridical models of brain network formation, neural dynamics and disease propagation. Finally, annotations can be used to infer entirely new inter-regional relationships and to construct new types of network that complement existing connectome representations. In summary, biologically annotated connectomes offer a compelling way to study neural wiring in concert with local biological features.

Resolving inter-regional communication capacity in the human connectome.

Applications of graph theory to the connectome have inspired several models of how neural signaling unfolds atop its structure. Analytic measures derived from these communication models have mainly been used to extract global characteristics of brain networks, obscuring potentially informative inter-regional relationships. Here we develop a simple standardization method to investigate polysynaptic communication pathways between pairs of cortical regions. This procedure allows us to determine which pairs of nodes are topologically closer and which are further than expected on the basis of their degree. We find that communication pathways delineate canonical functional systems. Relating nodal communication capacity to meta-analytic probabilistic patterns of functional specialization, we also show that areas that are most closely integrated within the network are associated with higher order cognitive functions. We find that these regions' proclivity towards functional integration could naturally arise from the brain's anatomical configuration through evenly distributed connections among multiple specialized communities. Throughout, we consider two increasingly constrained null models to disentangle the effects of the network's topology from those passively endowed by spatial embedding. Altogether, the present findings uncover relationships between polysynaptic communication pathways and the brain's functional organization across multiple topological levels of analysis and demonstrate that network integration facilitates cognitive integration.

Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model.

Parkinson's disease is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in Parkinson's disease: In its misfolded pathologic state, it favors the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation, and toxicity of alpha-synuclein molecules in the brain. In this study, we test this model with longitudinal MRI collected over 4 years from the Parkinson's Progression Markers Initiative (1,068 T1 MRI scans, 790 Parkinson's disease scans, and 278 matched control scans). We find that brain deformation progresses in subcortical and cortical regions. The SIR model recapitulates the spatiotemporal distribution of brain atrophy observed in Parkinson's disease. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in Parkinson's disease is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.

Functional connectome fingerprinting across the lifespan.

Systematic changes have been observed in the functional architecture of the human brain with advancing age. However, functional connectivity (FC) is also a powerful feature to detect unique "connectome fingerprints," allowing identification of individuals among their peers. Although fingerprinting has been robustly observed in samples of young adults, the reliability of this approach has not been demonstrated across the lifespan. We applied the fingerprinting framework to the Cambridge Centre for Ageing and Neuroscience cohort (n = 483 aged 18 to 89 years). We found that individuals are "fingerprintable" (i.e., identifiable) across independent functional MRI scans throughout the lifespan. We observed a U-shape distribution in the strength of "self-identifiability" (within-individual correlation across modalities), and "others-identifiability" (between-individual correlation across modalities), with a decrease from early adulthood into middle age, before improving in older age. FC edges contributing to self-identifiability were not restricted to specific brain networks and were different between individuals across the lifespan sample. Self-identifiability was additionally associated with regional brain volume. These findings indicate that individual participant-level identification is preserved across the lifespan despite the fact that its components are changing nonlinearly.

Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization.

Background: Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development in otherwise typically developing children and adolescents may be revealed using polygenic risk scores for schizophrenia (PRS-SCZ). Methods: We assessed PRS-SCZ and cortical morphometry in typically developing children and adolescents (3-21 years, 46.8% female) using whole-genome genotyping and T1-weighted magnetic resonance imaging (n = 390) from the PING (Pediatric Imaging, Neurocognition, and Genetics) cohort. We contextualized the findings using 1) age-matched transcriptomics, 2) histologically defined cytoarchitectural types and functionally defined networks, and 3) case-control differences of schizophrenia and other major psychiatric disorders derived from meta-analytic data of 6 ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) working groups, including a total of 12,876 patients and 15,670 control participants. Results: Higher PRS-SCZ was associated with greater cortical thickness, which was most prominent in areas with heightened gene expression of dendrites and synapses. PRS-SCZ-related increases in vertexwise cortical thickness were mainly distributed in association cortical areas, particularly the ventral attention network, while relatively sparing koniocortical type cortex (i.e., primary sensory areas). The large-scale pattern of cortical thickness increases related to PRS-SCZ mirrored the pattern of cortical thinning in schizophrenia and mood-related psychiatric disorders derived from the ENIGMA consortium. Age group models illustrate a possible trajectory from PRS-SCZ-associated cortical thickness increases in early childhood toward thinning in late adolescence, with the latter resembling the adult brain phenotype of schizophrenia. Conclusions: Collectively, combining imaging genetics with multiscale mapping, our work provides novel insight into how genetic risk for schizophrenia affects the cortex early in life.

Neurophysiological signatures of cortical micro-architecture.

Systematic spatial variation in micro-architecture is observed across the cortex. These micro-architectural gradients are reflected in neural activity, which can be captured by neurophysiological time-series. How spontaneous neurophysiological dynamics are organized across the cortex and how they arise from heterogeneous cortical micro-architecture remains unknown. Here we extensively profile regional neurophysiological dynamics across the human brain by estimating over 6800 time-series features from the resting state magnetoencephalography (MEG) signal. We then map regional time-series profiles to a comprehensive multi-modal, multi-scale atlas of cortical micro-architecture, including microstructure, metabolism, neurotransmitter receptors, cell types and laminar differentiation. We find that the dominant axis of neurophysiological dynamics reflects characteristics of power spectrum density and linear correlation structure of the signal, emphasizing the importance of conventional features of electromagnetic dynamics while identifying additional informative features that have traditionally received less attention. Moreover, spatial variation in neurophysiological dynamics is co-localized with multiple micro-architectural features, including gene expression gradients, intracortical myelin, neurotransmitter receptors and transporters, and oxygen and glucose metabolism. Collectively, this work opens new avenues for studying the anatomical basis of neural activity.