e Lisa Ji

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

Recent theoretical accounts have proposed excitation and inhibition (E/I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. We highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with electroencephalography, magnetoencephalography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging, including effects observed both during task and at rest. Throughout this review, we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human noninvasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.

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.

Mapping the human brain's cortical-subcortical functional network organization

&NA; Understanding complex systems such as the human brain requires characterization of the systems architecture across multiple levels of organization – from neurons, to local circuits, to brain regions, and ultimately large‐scale brain networks. Here we focus on characterizing the human brains large‐scale network organization, as it provides an overall framework for the organization of all other levels. We developed a highly principled approach to identify cortical network communities at the level of functional systems, calibrating our community detection algorithm using extremely well‐established sensory and motor systems as guides. Building on previous network partitions, we replicated and expanded upon well‐known and recently‐identified networks, including several higher‐order cognitive networks such as a left‐lateralized language network. We expanded these cortical networks to subcortex, revealing 358 highly‐organized subcortical parcels that take part in forming whole‐brain functional networks. Notably, the identified subcortical parcels are similar in number to a recent estimate of the number of cortical parcels (360). This whole‐brain network atlas – released as an open resource for the neuroscience community – places all brain structures across both cortex and subcortex into a single large‐scale functional framework, with the potential to facilitate a variety of studies investigating large‐scale functional networks in health and disease. HighlightsLarge‐scale functional network map of the entire human brain.Cortical networks based on multiband fMRI, recently‐identified regions.Subcortical extension of networks covering all subcortical structures.Multiple quality assessments demonstrate robustness of functional networks.Network atlas released as public resource, providing framework for future studies.

Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography

Hierarchy provides a unifying principle for the macroscale organization of anatomical and functional properties across primate cortex, yet microscale bases of specialization across human cortex are poorly understood. Anatomical hierarchy is conventionally informed by invasive tract-tracing measurements, creating a need for a principled proxy measure in humans. Moreover, cortex exhibits marked interareal variation in gene expression, yet organizing principles of cortical transcription remain unclear. We hypothesized that specialization of cortical microcircuitry involves hierarchical gradients of gene expression. We found that a noninvasive neuroimaging measure—MRI-derived T1-weighted/T2-weighted (T1w/T2w) mapping—reliably indexes anatomical hierarchy, and it captures the dominant pattern of transcriptional variation across human cortex. We found hierarchical gradients in expression profiles of genes related to microcircuit function, consistent with monkey microanatomy, and implicated in neuropsychiatric disorders. Our findings identify a hierarchical axis linking cortical transcription and anatomy, along which gradients of microscale properties may contribute to the macroscale specialization of cortical function.Burt et al. analyze patterns of gene expression across human cortex and show expression primarily varies along a sensory-association hierarchy captured by noninvasive neuroimaging, suggesting an organizing principle for microcircuit specialization.

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Background: Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown. Methods: We therefore conducted a double-blind, randomized, counterbalanced, cross-over studyduring which 24 healthy human participants received either (i) placebo+placebo, (ii) placebo+LSD (100 µg po), or (iii) Ketanserin, a selective 5-HT2A receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps. Results: LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans. Conclusions: Together, these results strongly implicate the 5-HT2A receptor in LSD’s neuropharmacology. This study therefore pinpoints the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics. Funding: Funded by the Swiss National Science Foundation, the Swiss Neuromatrix Foundation, the Usona Institute, the NIH, the NIAA, the NARSAD Independent Investigator Grant, the Yale CTSA grant, and the Slovenian Research Agency. Clinical trial number: NCT02451072.

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.

A whole-brain and cross-diagnostic perspective on functional brain network dysfunction

A wide variety of mental disorders have been associated with resting-state functional network alterations, which are thought to contribute to the cognitive changes underlying mental illness. These observations have seemed to support various theories postulating large-scale disruptions of brain systems in mental illness. However, existing approaches isolate differences in network organization without putting those differences in broad, whole-brain perspective. Using a graph distance measure – connectome-wide correlation – we found that whole-brain resting-state functional network organization in humans is highly similar across a variety of mental diseases and healthy controls. This similarity was observed across autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia. Nonetheless, subtle differences in network graph distance were predictive of diagnosis, suggesting that while functional connectomes differ little across health and disease those differences are informative. Such small network alterations may reflect the fact that most psychiatric patients maintain overall cognitive abilities similar to those of healthy individuals (relative to, e.g., the most severe schizophrenia cases), such that whole-brain functional network organization is expected to differ only subtly even for mental diseases with devastating effects on everyday life. These results suggest a need to reevaluate neurocognitive theories of mental illness, with a role for subtle functional brain network changes in the production of an array of mental diseases.