On the stability of canonical correlation analysis and partial least squares with application to brain-behavior associations.

Associations between datasets can be discovered through multivariate methods like Canonical Correlation Analysis (CCA) or Partial Least Squares (PLS). A requisite property for interpretability and generalizability of CCA/PLS associations is stability of their feature patterns. However, stability of CCA/PLS in high-dimensional datasets is questionable, as found in empirical characterizations. To study these issues systematically, we developed a generative modeling framework to simulate synthetic datasets. We found that when sample size is relatively small, but comparable to typical studies, CCA/PLS associations are highly unstable and inaccurate; both in their magnitude and importantly in the feature pattern underlying the association. We confirmed these trends across two neuroimaging modalities and in independent datasets with n ≈ 1000 and n = 20,000, and found that only the latter comprised sufficient observations for stable mappings between imaging-derived and behavioral features. We further developed a power calculator to provide sample sizes required for stability and reliability of multivariate analyses. Collectively, we characterize how to limit detrimental effects of overfitting on CCA/PLS stability, and provide recommendations for future studies.

QuNex-An integrative platform for reproducible neuroimaging analytics.

Introduction: Neuroimaging technology has experienced explosive growth and transformed the study of neural mechanisms across health and disease. However, given the diversity of sophisticated tools for handling neuroimaging data, the field faces challenges in method integration, particularly across multiple modalities and species. Specifically, researchers often have to rely on siloed approaches which limit reproducibility, with idiosyncratic data organization and limited software interoperability. Methods: To address these challenges, we have developed Quantitative Neuroimaging Environment & Toolbox (QuNex), a platform for consistent end-to-end processing and analytics. QuNex provides several novel functionalities for neuroimaging analyses, including a "turnkey" command for the reproducible deployment of custom workflows, from onboarding raw data to generating analytic features. Results: The platform enables interoperable integration of multi-modal, community-developed neuroimaging software through an extension framework with a software development kit (SDK) for seamless integration of community tools. Critically, it supports high-throughput, parallel processing in high-performance compute environments, either locally or in the cloud. Notably, QuNex has successfully processed over 10,000 scans across neuroimaging consortia, including multiple clinical datasets. Moreover, QuNex enables integration of human and non-human workflows via a cohesive translational platform. Discussion: Collectively, this effort stands to significantly impact neuroimaging method integration across acquisition approaches, pipelines, datasets, computational environments, and species. Building on this platform will enable more rapid, scalable, and reproducible impact of neuroimaging technology across health and disease.

A common symptom geometry of mood improvement under sertraline and placebo associated with distinct neural patterns.

Importance: Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments. Objective: To perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment. Design: Double blind randomized controlled trial. Setting: Multicenter. Participants: Patients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. Interventions: Either sertraline or placebo during 8 weeks (stage 1), and according to response a second line of treatment for 8 additional weeks (stage 2). Main Outcomes and Measures: To identify a data-driven pattern of symptom variations during these two stages, we performed a Principal Component Analysis (PCA) on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas and manic-like symptoms, resulting in a univariate measure of clinical improvement. We then investigated how initial clinical and neural factors predicted this measure during stage 1. To do so, we extracted resting-state global brain connectivity (GBC) at baseline at the individual level using a whole-brain functional network parcellation. In turn, we computed a linear model for each brain parcel with individual data-driven clinical improvement scores during stage 1 for each group. Results: 192 patients (127 women), age 37.7 years old (standard deviation: 13.5), were included. The first PC (PC1) capturing 20% of clinical variation was similar across treatment groups at stage 1 and stage 2, suggesting a reproducible pattern of symptom improvement. PC1 patients' scores significantly differed according to treatment during stage 1, whereas no difference of response was evidenced between groups with the Clinical Global Impressions (CGI). Baseline GBC correlated to stage 1 PC1 scores in the sertraline, but not in the placebo group. Conclusions and Relevance: Using data-driven reduction of symptoms scales, we identified a common profile of symptom improvement across placebo and sertraline. However, the neural patterns of baseline that mapped onto symptom improvement distinguished between treatment and placebo. Our results underscore that mapping from data-driven symptom improvement onto neural circuits is vital to detect treatment-responsive neural profiles that may aid in optimal patient selection for future trials.

Mapping brain-behavior space relationships along the psychosis spectrum.

Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints.

Generative modeling of brain maps with spatial autocorrelation.

Studies of large-scale brain organization have revealed interesting relationships between spatial gradients in brain maps across multiple modalities. Evaluating the significance of these findings requires establishing statistical expectations under a null hypothesis of interest. Through generative modeling of synthetic data that instantiate a specific null hypothesis, quantitative benchmarks can be derived for arbitrarily complex statistical measures. Here, we present a generative null model, provided as an open-access software platform, that generates surrogate maps with spatial autocorrelation (SA) matched to SA of a target brain map. SA is a prominent and ubiquitous property of brain maps that violates assumptions of independence in conventional statistical tests. Our method can simulate surrogate brain maps, constrained by empirical data, that preserve the SA of cortical, subcortical, parcellated, and dense brain maps. We characterize how SA impacts p-values in pairwise brain map comparisons. Furthermore, we demonstrate how SA-preserving surrogate maps can be used in gene set enrichment analyses to test hypotheses of interest related to brain map topography. Our findings demonstrate the utility of SA-preserving surrogate maps for hypothesis testing in complex statistical analyses, and underscore the need to disambiguate meaningful relationships from chance associations in studies of large-scale brain organization.

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 magnetic resonance imaging (MRI)-derived T1- to T2-weighted (T1w/T2w) mapping and fit the model using multimodal neuroimaging data. We found that incorporating hierarchical heterogeneity substantially improves the model fit to functional MRI (fMRI)-measured resting-state functional connectivity and captures sensory-association organization of multiple fMRI features. The model predicts hierarchically organized higher-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.

Gender bias in scholarly peer review.

Peer review is the cornerstone of scholarly publishing and it is essential that peer reviewers are appointed on the basis of their expertise alone. However, it is difficult to check for any bias in the peer-review process because the identity of peer reviewers generally remains confidential. Here, using public information about the identities of 9000 editors and 43000 reviewers from the Frontiers series of journals, we show that women are underrepresented in the peer-review process, that editors of both genders operate with substantial same-gender preference (homophily), and that the mechanisms of this homophily are gender-dependent. We also show that homophily will persist even if numerical parity between genders is reached, highlighting the need for increased efforts to combat subtler forms of gender bias in scholarly publishing.

Model-Free Estimation of Tuning Curves and Their Attentional Modulation, Based on Sparse and Noisy Data.

Tuning curves are the functions that relate the responses of sensory neurons to various values within one continuous stimulus dimension (such as the orientation of a bar in the visual domain or the frequency of a tone in the auditory domain). They are commonly determined by fitting a model e.g. a Gaussian or other bell-shaped curves to the measured responses to a small subset of discrete stimuli in the relevant dimension. However, as neuronal responses are irregular and experimental measurements noisy, it is often difficult to determine reliably the appropriate model from the data. We illustrate this general problem by fitting diverse models to representative recordings from area MT in rhesus monkey visual cortex during multiple attentional tasks involving complex composite stimuli. We find that all models can be well-fitted, that the best model generally varies between neurons and that statistical comparisons between neuronal responses across different experimental conditions are affected quantitatively and qualitatively by specific model choices. As a robust alternative to an often arbitrary model selection, we introduce a model-free approach, in which features of interest are extracted directly from the measured response data without the need of fitting any model. In our attentional datasets, we demonstrate that data-driven methods provide descriptions of tuning curve features such as preferred stimulus direction or attentional gain modulations which are in agreement with fit-based approaches when a good fit exists. Furthermore, these methods naturally extend to the frequent cases of uncertain model selection. We show that model-free approaches can identify attentional modulation patterns, such as general alterations of the irregular shape of tuning curves, which cannot be captured by fitting stereotyped conventional models. Finally, by comparing datasets across different conditions, we demonstrate effects of attention that are cell- and even stimulus-specific. Based on these proofs-of-concept, we conclude that our data-driven methods can reliably extract relevant tuning information from neuronal recordings, including cells whose seemingly haphazard response curves defy conventional fitting approaches.