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To date, most functional Magnetic Resonance Imaging (fMRI) studies have assumed that the functional connectivity (FC) between time series from distinct brain regions is constant across time. However, recently, there has been an increased interest in quantifying possible dynamic changes in FC during fMRI experiments, as it is thought that this may provide insight into the fundamental workings of brain networks. In this work we focus on the specific problem of estimating the dynamic behavior of pair-wise correlations between time courses extracted from two different regions of the brain. We critique the commonly used sliding-window technique, and discuss some alternative methods used to model volatility in the finance literature that could also prove to be useful in the neuroimaging setting. In particular, we focus on the Dynamic Conditional Correlation (DCC) model, which provides a model-based approach towards estimating dynamic correlations. We investigate the properties of several techniques in a series of simulation studies and find that DCC achieves the best overall balance between sensitivity and specificity in detecting dynamic changes in correlations. We also investigate its scalability beyond the bivariate case to demonstrate its utility for studying dynamic correlations between more than two brain regions. Finally, we illustrate its performance in an application to test–retest resting state fMRI data. •We investigate a variety of methods for estimating dynamic pair-wise correlations.•We show that the sliding-window technique can give rise to spurious results.•We propose the Dynamic Conditional Correlation (DCC) model as an alternative.•This provides a model-based approach towards estimating dynamic correlations.•DCC outperforms other methods in simulation studies.

•Compared single-band 3.3 mm, 2 mm and multiband factors 2, 3, 4, 6, 8, 9, 12 at 2 mm.•Multiband noise amplification creates spatial biases in rs-fMRI correlations.•Temporal filtering reduces spatial biases but decreases effect sizes.•Single-band 3.3 mm recommended for seed-based analyses involving subcortical regions.•Multiband 4 is a good choice for whole-brain analyses with 2 mm isotropic voxels. [Display omitted] Multiband acquisition, also called simultaneous multislice, has become a popular technique in resting-state functional connectivity studies. Multiband (MB) acceleration leads to a higher temporal resolution but also leads to spatially heterogeneous noise amplification, suggesting the costs may be greater in areas such as the subcortex. We evaluate MB factors of 2, 3, 4, 6, 8, 9, and 12 with 2 mm isotropic voxels, and additionally 2 mm and 3.3 mm single-band acquisitions, on a 32-channel head coil. Noise amplification was greater in deeper brain regions, including subcortical regions. Correlations were attenuated by noise amplification, which resulted in spatially varying biases that were more severe at higher MB factors. Temporal filtering decreased spatial biases in correlations due to noise amplification, but also tended to decrease effect sizes. In seed-based correlation maps, left-right putamen connectivity and thalamo-motor connectivity were highest in the single-band 3.3 mm protocol. In correlation matrices, MB 4, 6, and 8 had a greater number of significant correlations than the other acquisitions (both with and without temporal filtering). We recommend single-band 3.3 mm for seed-based subcortical analyses, and MB 4 provides a reasonable balance for studies analyzing both seed-based correlation maps and connectivity matrices. In multiband studies including secondary analyses of large-scale datasets, we recommend reporting effect sizes or test statistics instead of correlations. If correlations are reported, temporal filtering (or another method for thermal noise removal) should be used. The Emory Multiband Dataset is available on OpenNeuro.

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI–inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted. Cerebellar right Crus I (RCrusI) has been implicated in autism spectrum disorder (ASD). RCrusI modulation altered RCrusI–inferior parietal lobule connectivity, and this connectivity was atypical in children with ASD and in a TscI mouse model of ASD. Inhibition of RCrusI in mice led to autism-related behaviors, and RCrusI activation rescued social impairments in TscI mice.

Due to the dynamic, condition-dependent nature of brain activity, interest in estimating rapid functional connectivity (FC) changes that occur during resting-state functional magnetic resonance imaging (rs-fMRI) has recently soared. However, studying dynamic FC is methodologically challenging, due to the low signal-to-noise ratio of the blood oxygen level dependent (BOLD) signal in fMRI and the massive number of data points generated during the analysis. Thus, it is important to establish methods and summary measures that maximize reliability and the utility of dynamic FC to provide insight into brain function. In this study, we investigated the reliability of dynamic FC summary measures derived using three commonly used estimation methods - sliding window (SW), tapered sliding window (TSW), and dynamic conditional correlations (DCC) methods. We applied each of these techniques to two publicly available rs-fMRI test-retest data sets - the Multi-Modal MRI Reproducibility Resource (Kirby Data) and the Human Connectome Project (HCP Data). The reliability of two categories of dynamic FC summary measures were assessed, specifically basic summary statistics of the dynamic correlations and summary measures derived from recurring whole-brain patterns of FC (“brain states”). The results provide evidence that dynamic correlations are reliably detected in both test-retest data sets, and the DCC method outperforms SW methods in terms of the reliability of summary statistics. However, across all estimation methods, reliability of the brain state-derived measures was low. Notably, the results also show that the DCC-derived dynamic correlation variances are significantly more reliable than those derived using the non-parametric estimation methods. This is important, as the fluctuations of dynamic FC (i.e., its variance) has a strong potential to provide summary measures that can be used to find meaningful individual differences in dynamic FC. We therefore conclude that utilizing the variance of the dynamic connectivity is an important component in any dynamic FC-derived summary measure. •Investigated the reliability of dynamic functional connectivity measures.•Performed study on two resting-state fMRI test-retest data sets.•The DCC method demonstrated the highest overall reliability.•Reliability of brain state-derived measures were low across the board.

Recent studies have illustrated that motion-related artifacts remain in resting-state fMRI (rs-fMRI) data even after common corrective processing procedures have been applied, but the extent to which head motion distorts the data may be modulated by the corrective approach taken. We compare two different methods for estimating nuisance signals from tissues not expected to exhibit BOLD fMRI signals of neuronal origin: 1) the more commonly used mean signal method and 2) the principal components analysis approach (aCompCor: Behzadi et al., 2007). Further, we investigate the added benefit of “scrubbing” (Power et al., 2012) following both methods. We demonstrate that the use of aCompCor removes motion artifacts more effectively than tissue-mean signal regression. In addition, inclusion of more components from anatomically defined regions of no interest better mitigates motion-related artifacts and improves the specificity of functional connectivity estimates. While scrubbing further attenuates motion-related artifacts when mean signals are used, scrubbing provides no additional benefit in terms of motion artifact reduction or connectivity specificity when using aCompCor. •We compared PCA- and mean signal-based artifact reduction methods for rs-fMRI data.•PCA more effectively attenuated motion artifacts than mean signal.•PCA enhanced the specificity of functional connectivity compared to mean signal.•Scan scrubbing following PCA did not further reduce motion artifacts.

•Exclusion of high-motion subjects reduces rs-fMRI artifacts but may bias the study sample.•Autistic children with usable data had less severe symptoms and were older than the original sample.•Among children with usable data, symptom severity and age were related to functional connectivity.•Using doubly robust targeted minimum loss based estimation (DRTMLE) to address these biases, we observe more extensive group differences.•If quality control changes the distribution of a variable related to the outcome, we recommend using DRTMLE. [Display omitted] The exclusion of high-motion participants can reduce the impact of motion in functional Magnetic Resonance Imaging (fMRI) data. However, the exclusion of high-motion participants may change the distribution of clinically relevant variables in the study sample, and the resulting sample may not be representative of the population. Our goals are two-fold: 1) to document the biases introduced by common motion exclusion practices in functional connectivity research and 2) to introduce a framework to address these biases by treating excluded scans as a missing data problem. We use a study of autism spectrum disorder in children without an intellectual disability to illustrate the problem and the potential solution. We aggregated data from 545 children (8–13 years old) who participated in resting-state fMRI studies at Kennedy Krieger Institute (173 autistic and 372 typically developing) between 2007 and 2020. We found that autistic children were more likely to be excluded than typically developing children, with 28.5% and 16.1% of autistic and typically developing children excluded, respectively, using a lenient criterion and 81.0% and 60.1% with a stricter criterion. The resulting sample of autistic children with usable data tended to be older, have milder social deficits, better motor control, and higher intellectual ability than the original sample. These measures were also related to functional connectivity strength among children with usable data. This suggests that the generalizability of previous studies reporting naïve analyses (i.e., based only on participants with usable data) may be limited by the selection of older children with less severe clinical profiles because these children are better able to remain still during an rs-fMRI scan. We adapt doubly robust targeted minimum loss based estimation with an ensemble of machine learning algorithms to address these data losses and the resulting biases. The proposed approach selects more edges that differ in functional connectivity between autistic and typically developing children than the naïve approach, supporting this as a promising solution to improve the study of heterogeneous populations in which motion is common.

•Projection scrubbing is a data-driven, statistically principled scrubbing method for fMRI based on ICA or other projections.•Data-driven scrubbing produces more valid, reliable, and identifiable FC on average, compared with motion scrubbing.•Data-driven scrubbing avoids unnecessary censoring by only flagging volumes that display abnormal patterns.•Data-driven scrubbing dramatically increases sample size by avoiding high rates of subject exclusion. Functional MRI (fMRI) data may be contaminated by artifacts arising from a myriad of sources, including subject head motion, respiration, heartbeat, scanner drift, and thermal noise. These artifacts cause deviations from common distributional assumptions, introduce spatial and temporal outliers, and reduce the signal-to-noise ratio of the data—all of which can have negative consequences for the accuracy and power of downstream statistical analysis. Scrubbing is a technique for excluding fMRI volumes thought to be contaminated by artifacts and generally comes in two flavors. Motion scrubbing based on subject head motion-derived measures is popular but suffers from a number of drawbacks, among them the need to choose a threshold, a lack of generalizability to multiband acquisitions, and high rates of censoring of individual volumes and entire subjects. Alternatively, data-driven scrubbing methods like DVARS are based on observed noise in the processed fMRI timeseries and may avoid some of these issues. Here we propose “projection scrubbing”, a novel data-driven scrubbing method based on a statistical outlier detection framework and strategic dimension reduction, including independent component analysis (ICA), to isolate artifactual variation. We undertake a comprehensive comparison of motion scrubbing with data-driven projection scrubbing and DVARS. We argue that an appropriate metric for the success of scrubbing is maximal data retention subject to reasonable performance on typical benchmarks such as the validity, reliability, and identifiability of functional connectivity. We find that stringent motion scrubbing yields worsened validity, worsened reliability, and produced small improvements to fingerprinting. Meanwhile, data-driven scrubbing methods tend to yield greater improvements to fingerprinting while not generally worsening validity or reliability. Importantly, however, data-driven scrubbing excludes a fraction of the number of volumes or entire sessions compared to motion scrubbing. The ability of data-driven fMRI scrubbing to improve data retention without negatively impacting the quality of downstream analysis has major implications for sample sizes in population neuroscience research.

Classic psychedelics, such as psilocybin and LSD, and other serotonin 2A receptor (5-HT2AR) agonists evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been hypothesized to underlie these effects, which is supported by some functional MRI (fMRI) studies. These studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been previously used to identify reliable group-level functional subdivisions of the thalamus from resting-state fMRI (rsfMRI) data. We build on these efforts with a novel data-maximizing ICA-based approach to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity in individual participants. Baseline rsfMRI data (n=38) from healthy individuals with a long-term meditation practice was utilized to generate a statistical template of thalamic functional subdivisions. This template was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in follow-up scans from a subset of the same individuals (n=18). We examined correlations with subjective reports of drug effect and compared with a previously reported analytic approach (treating the thalamus as a single functional unit). Several intrathalamic components showed significant psilocybin-induced alterations in spatial organization, with effects of psilocybin largely localized to the mediodorsal and pulvinar nuclei. The magnitude of changes in individual participants correlated with reported subjective effects. These components demonstrated predominant decreases in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance. We utilized a novel analytic approach to discover psilocybin-induced changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. These changes were not observed using whole-thalamus analyses, suggesting that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.

Background Attention-deficit/hyperactivity disorder (ADHD) is associated with atypical fronto-subcortical neural circuitry and heightened delay discounting, or a stronger preference for smaller, immediate rewards over larger, delayed rewards. Recent evidence of ADHD-related sex differences in brain structure and function suggests anomalies in fronto-subcortical circuitry may differ among girls and boys with ADHD. The current study examined whether the functional connectivity (FC) within fronto-subcortical neural circuitry differs among girls and boys with ADHD compared to same-sex typically developing (TD) controls and relates to delay discounting. Methods Participants include 8–12-year-old children with ADHD ( n  = 72, 20 girls) and TD controls ( n  = 75, 21 girls). Fronto-subcortical regions of interest were functionally defined by applying independent component analysis to resting-state fMRI data. Intrinsic FC between subcortical components, including the striatum and amygdala, and prefrontal components, including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and anterior dorsolateral prefrontal cortex (dlPFC), was compared across diagnostic groups overall and within sex. Correlations between intrinsic FC of the six fronto-subcortical pairs and delay discounting were also examined. Results Both girls and boys with ADHD show atypical FC between vmPFC and subcortical regions including the striatum (stronger positive FC in ADHD) and amygdala (weaker negative FC in ADHD), with the greatest diagnostic effects among girls. In addition, girls with ADHD show atypical intrinsic FC between the striatum and dlPFC components, including stronger positive FC with ACC and stronger negative FC with dlPFC. Further, girls but not boys, with ADHD, show heightened real-time delay discounting. Brain–behavior correlations suggest (1) stronger negative FC between the striatal and dlPFC components correlated with greater money delay discounting across all participants and (2) stronger FC between the amygdala with both the dlPFC and ACC components was differentially related to heightened real-time discounting among girls and boys with and without ADHD. Conclusions Our findings suggest fronto-subcortical functional networks are affected in children with ADHD, particularly girls, and relate to delay discounting. These results also provide preliminary evidence of greater disruptions in fronto-subcortical FC among girls with ADHD that is not due to elevated inattention symptom severity, intellectual reasoning ability, age, or head motion.

Executive functions (EFs) are used to set goals, plan for the future, inhibit maladaptive responses, and change behavior flexibly. Although some studies point to specific EF profiles in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) — prevalent and often highly comorbid neurodevelopmental disorders — others have not differentiated them. The objective of the current study was to identify distinct profiles of EF across typically developing (TD) children and children with ASD and ADHD. We employed a latent profile analysis using indicators of EF (e.g., working memory, inhibition, and flexibility) in a mixed group of 8–13 year-olds including TD children ( n  = 128), children with ASD without ADHD ( n  = 30), children with ADHD ( n  = 93), and children with comorbid ASD and ADHD ( n  = 66). Three EF classes emerged: “above average,” “average,” and “impaired.” EF classes did not reproduce diagnostic categories, suggesting that differences in EF abilities are present within the ASD and ADHD groups. Further, greater EF dysfunction predicted more severe socioemotional problems, such as anxiety/depression. These results highlight the heterogeneity of current diagnostic groups and identify an “impaired” EF group, consisting of children with both ASD and ADHD, which could specifically be targeted for EF intervention.