From Maps to Models: A Survey on the Reliability of Small Studies of Task-Based fMRI.

Task-based functional magnetic resonance imaging is a powerful tool for studying brain function, but neuroimaging research produces ongoing concerns regarding small-sample studies and how to interpret them. Although it is well understood that larger samples are preferable, many situations require researchers to make judgments from small studies, including reviewing the existing literature, analyzing pilot data, or assessing subsamples. Quantitative guidance on how to make these judgments remains scarce. To address this, we leverage the Human Connectome Project's Young Adult dataset to survey various analyses--from regional activation maps to predictive models. We find that, for some classic analyses such as detecting regional activation or cluster peak location, studies with as few as 40 subjects are adequate, although this depends crucially on effect sizes. For predictive modeling, similar sizes can be adequate for detecting whether features are predictable, but at least an order of magnitude more (at least hundreds) may be required for developing consistent predictions. These results offer valuable insights for designing and interpreting fMRI studies, emphasizing the importance of considering effect size, sample size, and analysis approach when assessing the reliability of findings. We hope that this survey serves as a reference for identifying which kinds of research questions can be reliably answered with small-scale studies.

Comparing Automated Subcortical Volume Estimation Methods; Amygdala Volumes Estimated by FSL and FreeSurfer Have Poor Consistency.

Subcortical volumes are a promising source of biomarkers and features in biosignatures, and automated methods facilitate extracting them in large, phenotypically rich datasets. However, while extensive research has verified that the automated methods produce volumes that are similar to those generated by expert annotation, the consistency of methods with each other is understudied. Using data from the UK Biobank, we compare the estimates of subcortical volumes produced by two popular software suites: FSL and FreeSurfer. Although most subcortical volumes exhibit good to excellent consistency across the methods, the tools produce diverging estimates of amygdalar volume. Through simulation, we show that this poor consistency can lead to conflicting results, where one but not the other tool suggests statistical significance, or where both tools suggest a significant relationship but in opposite directions. Considering these issues, we discuss several ways in which care should be taken when reporting on relationships involving amygdalar volume.

Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain.

Drug treatments for pain often do not outperform placebo, and a better understanding of placebo mechanisms is needed to improve treatment development and clinical practice. In a large-scale fMRI study (N = 392) with pre-registered analyses, we tested whether placebo analgesic treatment modulates nociceptive processes, and whether its effects generalize from conditioned to unconditioned pain modalities. Placebo treatment caused robust analgesia in conditioned thermal pain that generalized to unconditioned mechanical pain. However, placebo did not decrease pain-related fMRI activity in brain measures linked to nociceptive pain, including the Neurologic Pain Signature (NPS) and spinothalamic pathway regions, with strong support for null effects in Bayes Factor analyses. In addition, surprisingly, placebo increased activity in some spinothalamic regions for unconditioned mechanical pain. In contrast, placebo reduced activity in a neuromarker associated with higher-level contributions to pain, the Stimulus Intensity Independent Pain Signature (SIIPS), and affected activity in brain regions related to motivation and value, in both pain modalities. Individual differences in behavioral analgesia were correlated with neural changes in both modalities. Our results indicate that cognitive and affective processes primarily drive placebo analgesia, and show the potential of neuromarkers for separating treatment influences on nociception from influences on evaluative processes.

A multimodal fMRI dataset unifying naturalistic processes with a rich array of experimental tasks.

Cognitive neuroscience has advanced significantly due to the availability of openly shared datasets. Large sample sizes, large amounts of data per person, and diversity in tasks and data types are all desirable, but are difficult to achieve in a single dataset. Here, we present an open dataset with N = 101 participants and 6 hours of scanning per participant, with 6 multifaceted cognitive tasks including 2 hours of naturalistic movie viewing. This datasets' combination of ample sample size, extensive data per participant, more than 600 hours worth of data, and a wide range of experimental conditions - including cognitive, affective, social, and somatic/interoceptive tasks - positions it uniquely for probing important questions in cognitive neuroscience.

EEG functional connectivity as a Riemannian mediator: An application to malnutrition and cognition.

Mediation analysis assesses whether an exposure directly produces changes in cognitive behavior or is influenced by intermediate "mediators". Electroencephalographic (EEG) spectral measurements have been previously used as effective mediators representing diverse aspects of brain function. However, it has been necessary to collapse EEG measures onto a single scalar using standard mediation methods. In this article, we overcome this limitation and examine EEG frequency-resolved functional connectivity measures as a mediator using the full EEG cross-spectral tensor (CST). Since CST samples do not exist in Euclidean space but in the Riemannian manifold of positive-definite tensors, we transform the problem, allowing for the use of classic multivariate statistics. Toward this end, we map the data from the original manifold space to the Euclidean tangent space, eliminating redundant information to conform to a "compressed CST." The resulting object is a matrix with rows corresponding to frequencies and columns to cross spectra between channels. We have developed a novel matrix mediation approach that leverages a nuclear norm regularization to determine the matrix-valued regression parameters. Furthermore, we introduced a global test for the overall CST mediation and a test to determine specific channels and frequencies driving the mediation. We validated the method through simulations and applied it to our well-studied 50+-year Barbados Nutrition Study dataset by comparing EEGs collected in school-age children (5-11 years) who were malnourished in the first year of life with those of healthy classmate controls. We hypothesized that the CST mediates the effect of malnutrition on cognitive performance. We can now explicitly pinpoint the frequencies (delta, theta, alpha, and beta bands) and regions (frontal, central, and occipital) in which functional connectivity was altered in previously malnourished children, an improvement to prior studies. Understanding the specific networks impacted by a history of postnatal malnutrition could pave the way for developing more targeted and personalized therapeutic interventions. Our methods offer a versatile framework applicable to mediation studies encompassing matrix and Hermitian 3D tensor mediators alongside scalar exposures and outcomes, facilitating comprehensive analyses across diverse research domains.

Statistical modeling of acute and chronic pain patient-reported outcomes obtained from ecological momentary assessment.

ABSTRACT: Ecological momentary assessment (EMA) allows for the collection of participant-reported outcomes (PROs), including pain, in the normal environment at high resolution and with reduced recall bias. Ecological momentary assessment is an important component in studies of pain, providing detailed information about the frequency, intensity, and degree of interference of individuals' pain. However, there is no universally agreed on standard for summarizing pain measures from repeated PRO assessment using EMA into a single, clinically meaningful measure of pain. Here, we quantify the accuracy of summaries (eg, mean and median) of pain outcomes obtained from EMA and the effect of thresholding these summaries to obtain binary clinical end points of chronic pain status (yes/no). Data applications and simulations indicate that binarizing empirical estimators (eg, sample mean, random intercept linear mixed model) can perform well. However, linear mixed-effect modeling estimators that account for the nonlinear relationship between average and variability of pain scores perform better for quantifying the true average pain and reduce estimation error by up to 50%, with larger improvements for individuals with more variable pain scores. We also show that binarizing pain scores (eg, <3 and ≥3) can lead to a substantial loss of statistical power (40%-50%). Thus, when examining pain outcomes using EMA, the use of linear mixed models using the entire scale (0-10) is superior to splitting the outcomes into 2 groups (<3 and ≥3) providing greater statistical power and sensitivity.

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Sliding windows analysis can undo the effects of preprocessing when applied to fMRI data.

Resting-state fMRI (rs-fMRI) data is used to study the intrinsic functional connectivity (FC) in the human brain. In the past decade, interest has focused on studying the temporal dynamics of FC on short timescales, ranging from seconds to minutes. These studies of time-varying FC (TVFC) have enabled the classification of whole-brain dynamic FC profiles into distinct "brain states", defined as recurring whole-brain connectivity profiles reliably observed across subjects and sessions. The analysis of rs-fMRI data is complicated by the fact that the measured BOLD signal consists of changes induced by neuronal activation, as well as non-neuronal nuisance fluctuations that should be removed prior to further analysis. Thus, the data undergoes significant preprocesing prior to analysis. In previous work, we illustrated the potential pitfalls involved with using modular preprocessing pipelines, showing how later preprocessing steps can reintroduce correlation with signal previously removed from the data. Here we show that the problem runs deeper, and that certain statistical analysis techniques can potentially interact with preprocessing and reintroduce correlations with previously removed signal. One such technique is the popular sliding window analysis, used to compute TVFC. In this paper, we discuss the problem both theoretically and empirically in application to test-retest rs-fMRI data. Importantly, we show that we are able to obtain essentially the same brain states and state transitions when analyzing motion induced signal as we do when analyzing the preprocessed but windowed data. Our results cast doubt on whether the estimated brain states obtained using sliding window analysis are neuronal in nature, or simply reflect non-neuronal nuisance signal variation (e.g., motion).

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Regression models for partially localized fMRI connectivity analyses.

Background: Brain functional connectivity analysis of resting-state functional magnetic resonance imaging (fMRI) data is typically performed in a standardized template space assuming consistency of connections across subjects. Analysis methods can come in the form of one-edge-at-a-time analyses or dimension reduction/decomposition methods. Common to these approaches is an assumption that brain regions are functionally aligned across subjects; however, it is known that this functional alignment assumption is often violated. Methods: In this paper, we use subject-level regression models to explain intra-subject variability in connectivity. Covariates can include factors such as geographic distance between two pairs of brain regions, whether the two regions are symmetrically opposite (homotopic), and whether the two regions are members of the same functional network. Additionally, a covariate for each brain region can be included, to account for the possibility that some regions have consistently higher or lower connectivity. This style of analysis allows us to characterize the fraction of variation explained by each type of covariate. Additionally, comparisons across subjects can then be made using the fitted connectivity regression models, offering a more parsimonious alternative to edge-at-a-time approaches. Results: We apply our approach to Human Connectome Project data on 268 regions of interest (ROIs), grouped into eight functional networks. We find that a high proportion of variation is explained by region covariates and network membership covariates, while geographic distance and homotopy have high relative importance after adjusting for the number of predictors. We also find that the degree of data repeatability using our connectivity regression model-which uses only partial location information about pairs of ROI's-is comparably as high as the repeatability obtained using full location information. Discussion: While our analysis uses data that have been transformed into a common template-space, we also envision the method being useful in multi-atlas registration settings, where subject data remains in its own geometry and templates are warped instead. These results suggest the tantalizing possibility that fMRI connectivity analysis can be performed in subject-space, using less aggressive registration, such as simple affine transformations, multi-atlas subject-space registration, or perhaps even no registration whatsoever.

Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain.

Placebo analgesia is a replicable and well-studied phenomenon, yet it remains unclear to what degree it includes modulation of nociceptive processes. Some studies find effects consistent with nociceptive effects, but meta-analyses show that these effects are often small. We analyzed placebo analgesia in a large fMRI study (N = 392), including placebo effects on brain responses to noxious stimuli. Placebo treatment caused robust analgesia in both conditioned thermal and unconditioned mechanical pain. Placebo did not decrease fMRI activity in nociceptive pain regions, including the Neurologic Pain Signature (NPS) and pre-registered spinothalamic pathway regions, with strong support from Bayes Factor analyses. However, placebo treatment affected activity in pre-registered analyses of a second neuromarker, the Stimulus Intensity Independent Pain Signature (SIIPS), and several associated a priori brain regions related to motivation and value, in both thermal and mechanical pain. Individual differences in behavioral analgesia were correlated with neural changes in both thermal and mechanical pain. Our results indicate that processes related to affective and cognitive aspects of pain primarily drive placebo analgesia.

Improved fMRI-based pain prediction using Bayesian group-wise functional registration.

In recent years, the field of neuroimaging has undergone a paradigm shift, moving away from the traditional brain mapping approach towards the development of integrated, multivariate brain models that can predict categories of mental events. However, large interindividual differences in both brain anatomy and functional localization after standard anatomical alignment remain a major limitation in performing this type of analysis, as it leads to feature misalignment across subjects in subsequent predictive models. This article addresses this problem by developing and validating a new computational technique for reducing misalignment across individuals in functional brain systems by spatially transforming each subject's functional data to a common latent template map. Our proposed Bayesian functional group-wise registration approach allows us to assess differences in brain function across subjects and individual differences in activation topology. We achieve the probabilistic registration with inverse-consistency by utilizing the generalized Bayes framework with a loss function for the symmetric group-wise registration. It models the latent template with a Gaussian process, which helps capture spatial features in the template, producing a more precise estimation. We evaluate the method in simulation studies and apply it to data from an fMRI study of thermal pain, with the goal of using functional brain activity to predict physical pain. We find that the proposed approach allows for improved prediction of reported pain scores over conventional approaches. Received on 2 January 2017. Editorial decision on 8 June 2021.

Evaluating the prediction performance of objective physical activity measures for incident Parkinson's disease in the UK Biobank.

BACKGROUND: Parkinson's disease (PD) is the fastest-growing neurological condition with over 10 million cases worldwide. While age and sex are known predictors of incident PD, there is a need to identify other predictors. This study compares the prediction performance of accelerometry-derived physical activity (PA) measures and traditional risk factors for incident PD in the UK Biobank. METHODS: The study population consisted of 92,352 UK Biobank participants without PD at baseline (43.8% male, median age 63 years with interquartile range 43-69). 245 participants were diagnosed with PD by April 1, 2021 (586,604 person-years of follow-up). The incident PD prediction performances of 10 traditional predictors and 8 objective PA measures were compared using single- and multi-variable Cox models. Prediction performance was assessed using a novel, stable statistic: the repeated cross-validated concordance (rcvC). Sensitivity analyses were conducted where PD cases diagnosed within the first six months, one year, and two years were deleted. RESULTS: Single-predictor Cox regression models indicated that all PA measures were statistically significant (p-values < 0.0001). The highest-performing individual predictors were total acceleration (TA) (rcvC = 0.813) among PA measures, and age (rcvC = 0.757) among traditional predictors. The two-step forward-selection process produced a model containing age, sex, and TA (rcvC = 0.851). Adding TA to the model increased the rcvC by 9.8% (p-value < 0.0001). Results were largely unchanged in sensitivity analyses. CONCLUSIONS: Objective PA summaries have better single-predictor model performance than known risk factors and increase the prediction performance substantially when added to models with age and sex.

Brain mediators of negative affect-induced physical symptom reporting in patients with functional somatic syndromes.

Functional somatic syndromes (FSS) include fibromyalgia, irritable bowel syndrome (IBS), and others. In FSS patients, merely viewing negative affective pictures can elicit increased physical symptoms. Our aim was to investigate the neural mechanisms underlying such negative affect-induced physical symptoms in FSS patients. Thirty patients with fibromyalgia and/or IBS and 30 healthy controls (all women) watched neutral, positive and negative affective picture blocks during functional MRI scanning and rated negative affect and physical symptoms after every block. We compared brain-wide activation during negative versus neutral picture viewing in FSS patients versus controls using robust general linear model analysis. Further, we compared neurologic pain signature (NPS), stimulus intensity-independent pain signature (SIIPS) and picture-induced negative emotion signature (PINES) responses to the negative versus neutral affect contrast and investigated whether they mediated between-group differences in affective picture-induced physical symptom reporting. More physical symptoms were reported after viewing negative compared to neutral pictures, and this effect was larger in patients than controls (p = 0.025). Accordingly, patients showed stronger activation in somatosensory regions during negative versus neutral picture viewing. NPS, but not SIIPS nor PINES, responses were higher in patients than controls during negative versus neutral pictures (p = 0.026). These differential NPS responses partially mediated between-group differences in physical symptoms. In conclusion, picture-induced negative affect elicits physical symptoms in FSS patients as a result of activation of somatosensory and nociceptive brain patterns, supporting the idea that affect-driven alterations in processing of somatic signals is a critical mechanism underlying FSS.

Quantifying the Association between Objectively Measured Physical Activity and Multiple Sclerosis in the UK Biobank.

INTRODUCTION: Objectively measured physical activity (PA) data were collected in the accelerometry substudy of the UK Biobank. UK Biobank also contains information about multiple sclerosis (MS) diagnosis at the time of and after PA collection. This study aimed to 1) quantify the difference in PA between prevalent MS cases and matched healthy controls, and 2) evaluate the predictive performance of objective PA measures for incident MS cases. METHODS: The first analysis compared eight accelerometer-derived PA summaries between MS patients ( N = 316) and matched controls (30 controls for each MS case). The second analysis focused on predicting time to MS diagnosis among participants who were not diagnosed with MS. A total of 19 predictors including eight measures of objective PA were compared using Cox proportional hazards models (number of events = 47; 585,900 person-years of follow-up). RESULTS: In the prevalent MS study, the difference between MS cases and matched controls was statistically significant for all PA summaries ( P < 0.001). In the incident MS study, the most predictive variable of progression to MS in univariate Cox regression models was lower age ( C = 0.604), and the most predictive PA variable was lower relative amplitude (RA, C = 0.594). A two-stage forward selection using Cox regression resulted in a model with concordance C = 0.693 and four predictors: age ( P = 0.015), stroke ( P = 0.009), Townsend deprivation index ( P = 0.874), and RA ( P = 0.004). A model including age, stroke, and RA had a concordance of C = 0.691. CONCLUSIONS: Objective PA summaries were significantly different and consistent with lower activity among study participants who had MS at the time of the accelerometry study. Among individuals who did not have MS, younger age, stroke history, and lower RA were significantly associated with a higher risk of a future MS diagnosis.

Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures.

ABSTRACT: Chronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps.

A dorsomedial prefrontal cortex-based dynamic functional connectivity model of rumination.

Rumination is a cognitive style characterized by repetitive thoughts about one's negative internal states and is a common symptom of depression. Previous studies have linked trait rumination to alterations in the default mode network, but predictive brain markers of rumination are lacking. Here, we adopt a predictive modeling approach to develop a neuroimaging marker of rumination based on the variance of dynamic resting-state functional connectivity and test it across 5 diverse subclinical and clinical samples (total n = 288). A whole-brain marker based on dynamic connectivity with the dorsomedial prefrontal cortex (dmPFC) emerges as generalizable across the subclinical datasets. A refined marker consisting of the most important features from a virtual lesion analysis further predicts depression scores of adults with major depressive disorder (n = 35). This study highlights the role of the dmPFC in trait rumination and provides a dynamic functional connectivity marker for rumination.

Genetic risk shared across 24 chronic pain conditions: identification and characterization with genomic structural equation modeling.

ABSTRACT: Chronic pain conditions frequently co-occur, suggesting common risks and paths to prevention and treatment. Previous studies have reported genetic correlations among specific groups of pain conditions and reported genetic risk for within-individual multisite pain counts (≤7). Here, we identified genetic risk for multiple distinct pain disorders across individuals using 24 chronic pain conditions and genomic structural equation modeling (Genomic SEM). First, we ran individual genome-wide association studies (GWASs) on all 24 conditions in the UK Biobank ( N ≤ 436,000) and estimated their pairwise genetic correlations. Then we used these correlations to model their genetic factor structure in Genomic SEM, using both hypothesis- and data-driven exploratory approaches. A complementary network analysis enabled us to visualize these genetic relationships in an unstructured manner. Genomic SEM analysis revealed a general factor explaining most of the shared genetic variance across all pain conditions and a second, more specific factor explaining genetic covariance across musculoskeletal pain conditions. Network analysis revealed a large cluster of conditions and identified arthropathic, back, and neck pain as potential hubs for cross-condition chronic pain. Additionally, we ran GWASs on both factors extracted in Genomic SEM and annotated them functionally. Annotation identified pathways associated with organogenesis, metabolism, transcription, and DNA repair, with overrepresentation of strongly associated genes exclusively in brain tissues. Cross-reference with previous GWASs showed genetic overlap with cognition, mood, and brain structure. These results identify common genetic risks and suggest neurobiological and psychosocial mechanisms that should be targeted to prevent and treat cross-condition chronic pain.

Regression models for partially localized fMRI connectivity analyses.

Brain functional connectivity analysis of resting-state functional magnetic resonance imaging (fMRI) data is typically performed in a standardized template space assuming consistency of connections across subjects. This can come in the form of one-edge-at-a-time analyses or dimension reduction/decomposition methods. Common to these approaches is the assumption of complete localization (or spatial alignment) of brain regions across subjects. Alternative approaches completely eschew localization assumptions by treating connections as statistically exchangeable (for example, using the density of connectivity between nodes). Yet other approaches, such as hyperalignment, attempt to align subjects on function as well as structure, thereby achieving a different sort of template-based localization. In this paper, we propose the use of simple regression models to characterize connectivity. To that end, we build regression models on subject-level Fisher transformed regional connection matrices using geographic distance, homotopic distance, network labels, and region indicators as covariates to explain variation in connections. While we perform our analysis in template-space in this paper, we envision the method being useful in multi-atlas registration settings, where subject data remains in its own geometry and templates are warped instead. A byproduct of this style of analysis is the ability to characterize the fraction of variation in subject-level connections explained by each type of covariate. Using Human Connectome Project data, we found that network labels and regional characteristics contribute far more than geographic or homotopic relationships (considered non-parametrically). In addition, visual regions had the highest explanatory power (i.e., largest regression coefficients). We also considered subject repeatability and found that the degree of repeatability seen in fully localized models is largely recovered using our proposed subject-level regression models. Further, even fully exchangeable models retain a sizeable amount of repeatability information, despite discarding all localization information. These results suggest the tantalizing possibility that fMRI connectivity analysis can be performed in subject-space, using less aggressive registration, such as simple affine transformations, multi-atlas subject-space registration, or perhaps even no registration whatsoever.