MR Imaging in Ataxias: Consensus Recommendations by the Ataxia Global Initiative Working Group on MRI Biomarkers.

With many viable strategies in the therapeutic pipeline, upcoming clinical trials in hereditary and sporadic degenerative ataxias will benefit from non-invasive MRI biomarkers for patient stratification and the evaluation of therapies. The MRI Biomarkers Working Group of the Ataxia Global Initiative therefore devised guidelines to facilitate harmonized MRI data acquisition in clinical research and trials in ataxias. Recommendations are provided for a basic structural MRI protocol that can be used for clinical care and for an advanced multi-modal MRI protocol relevant for research and trial settings. The advanced protocol consists of modalities with demonstrated utility for tracking brain changes in degenerative ataxias and includes structural MRI, magnetic resonance spectroscopy, diffusion MRI, quantitative susceptibility mapping, and resting-state functional MRI. Acceptable ranges of acquisition parameters are provided to accommodate diverse scanner hardware in research and clinical contexts while maintaining a minimum standard of data quality. Important technical considerations in setting up an advanced multi-modal protocol are outlined, including the order of pulse sequences, and example software packages commonly used for data analysis are provided. Outcome measures most relevant for ataxias are highlighted with use cases from recent ataxia literature. Finally, to facilitate access to the recommendations by the ataxia clinical and research community, examples of datasets collected with the recommended parameters are provided and platform-specific protocols are shared via the Open Science Framework.

History of conditioned reward association disrupts inhibitory control: an examination of neural correlates.

The neural processes that support inhibitory control in the face of stimuli with a history of reward association are not yet well understood. Yet, the ability to flexibly adapt behavior to changing reward-contingency contexts is important for daily functioning and warrants further investigation. This study aimed to characterize neural and behavioral impacts of stimuli with a history of conditioned reward association on motor inhibitory control in healthy young adults by investigating group-level effects as well as individual variation in the ability to inhibit responses to stimuli with a reward history. Participants (N = 41) first completed a reward conditioning phase, during which responses to rewarded stimuli were associated with money and responses to unrewarded stimuli were not. Rewarded and unrewarded stimuli from training were carried forward as No-Go targets in a subsequent go/no-go task to test the effect of reward history on inhibitory control. Participants underwent functional brain imaging during the go/no-go portion of the task. On average, a history of reward conditioning disrupted inhibitory control. Compared to inhibition of responses to stimuli with no reward history, trials that required inhibition of responses to previously rewarded stimuli were associated with greater activity in frontal and striatal regions, including the inferior frontal gyrus, insula, striatum, and thalamus. Activity in the insula and thalamus during false alarms and in the ventromedial prefrontal cortex during correctly withheld trials predicted behavioral performance on the task. Overall, these results suggest that reward history serves to disrupt inhibitory control and provide evidence for diverging roles of the insula and ventromedial prefrontal cortex while inhibiting responses to stimuli with a reward history.

Examining cognitive control and reward interactions in adolescent externalizing symptoms.

During adolescence, rapid development and reorganization of the dopaminergic system supports increasingly sophisticated reward learning and the ability to exert behavioral control. Disruptions in the ability to exert control over previously rewarded behavior may underlie some forms of adolescent psychopathology. Specifically, symptoms of externalizing psychopathology may be associated with difficulties in flexibly adapting behavior in the context of reward. However, the direct interaction of cognitive control and reward learning in adolescent psychopathology symptoms has not yet been investigated. The present study used a Research Domain Criteria framework to investigate whether behavioral and neuronal indices of inhibition to previously rewarded stimuli underlie individual differences in externalizing symptoms in N = 61 typically developing adolescents. Using a task that integrates the Monetary Incentive Delay and Go-No-Go paradigms, we observed a positive association between externalizing symptoms and activation of the left middle frontal gyrus during response inhibition to cues with a history of reward. These associations were robust to controls for internalizing symptoms and neural recruitment during inhibition of cues with no reward history. Our findings suggest that inhibitory control over stimuli with a history of reward may be a useful marker for future inquiry into the development of externalizing psychopathology in adolescence.

Age and environment-related differences in gait in healthy adults using wearables.

Technological advances in multimodal wearable and connected devices have enabled the measurement of human movement and physiology in naturalistic settings. The ability to collect continuous activity monitoring data with digital devices in real-world environments has opened unprecedented opportunity to establish clinical digital phenotypes across diseases. Many traditional assessments of physical function utilized in clinical trials are limited because they are episodic, therefore, cannot capture the day-to-day temporal fluctuations and longitudinal changes in activity that individuals experience. In order to understand the sensitivity of gait speed as a potential endpoint for clinical trials, we investigated the use of digital devices during traditional clinical assessments and in real-world environments in a group of healthy younger (n = 33, 18-40 years) and older (n = 32, 65-85 years) adults. We observed good agreement between gait speed estimated using a lumbar-mounted accelerometer and gold standard system during the performance of traditional gait assessment task in-lab, and saw discrepancies between in-lab and at-home gait speed. We found that gait speed estimated in-lab, with or without digital devices, failed to differentiate between the age groups, whereas gait speed derived during at-home monitoring was able to distinguish the age groups. Furthermore, we found that only three days of at-home monitoring was sufficient to reliably estimate gait speed in our population, and still capture age-related group differences. Our results suggest that gait speed derived from activities during daily life using data from wearable devices may have the potential to transform clinical trials by non-invasively and unobtrusively providing a more objective and naturalistic measure of functional ability.

Basal forebrain volume reliably predicts the cortical spread of Alzheimer's degeneration.

Alzheimer's disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer's degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-ß and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-ß moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer's disease pathogenesis.

Registration-free analysis of diffusion MRI tractography data across subjects through the human lifespan.

Diffusion MRI tractography produces massive sets of streamlines that need to be clustered into anatomically meaningful white-matter bundles. Conventional clustering techniques group streamlines based on their proximity in Euclidean space. We have developed AnatomiCuts, an unsupervised method for clustering tractography streamlines based on their neighboring anatomical structures, rather than their coordinates in Euclidean space. In this work, we show that the anatomical similarity metric used in AnatomiCuts can be extended to find corresponding clusters across subjects and across hemispheres, without inter-subject or inter-hemispheric registration. Our proposed approach enables group-wise tract cluster analysis, as well as studies of hemispheric asymmetry. We evaluate our approach on data from the pilot MGH-Harvard-USC Lifespan Human Connectome project, showing improved correspondence in tract clusters across 184 subjects aged 8-90. Our method shows up to 38% improvement in the overlap of corresponding clusters when comparing subjects with large age differences. The techniques presented here do not require registration to a template and can thus be applied to populations with large inter-subject variability, e.g., due to brain development, aging, or neurological disorders.

Free Water in White Matter Differentiates MCI and AD From Control Subjects.

Recent evidence shows that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple but powerful whole-brain FW measure designed for easy translation to clinical settings and potential use as a priori outcome measure in clinical trials. These simple FW measures use a "safe" white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WM safe) near ventricles and sulci. We investigated if FW inside the WM safe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

Parallel distributed networks resolved at high resolution reveal close juxtaposition of distinct regions.

Examination of large-scale distributed networks within the individual reveals details of cortical network organization that are absent in group-averaged studies. One recent discovery is that a distributed transmodal network, often referred to as the "default network," comprises two closely interdigitated networks, only one of which is coupled to posterior parahippocampal cortex. Not all studies of individuals have identified the same networks, and questions remain about the degree to which the two networks are separate, particularly within regions hypothesized to be interconnected hubs. In this study we replicate the observation of network separation across analytical (seed-based connectivity and parcellation) and data projection (volume and surface) methods in two individuals each scanned 31 times. Additionally, three individuals were examined with high-resolution (7T; 1.35 mm) functional magnetic resonance imaging to gain further insight into the anatomical details. The two networks were identified with separate regions localized to adjacent portions of the cortical ribbon, sometimes inside the same sulcus. Midline regions previously implicated as hubs revealed near complete spatial separation of the two networks, displaying a complex spatial topography in the posterior cingulate and precuneus. The network coupled to parahippocampal cortex also revealed a separate region directly within the hippocampus, at or near the subiculum. These collective results support that the default network is composed of at least two spatially juxtaposed networks. Fine spatial details and juxtapositions of the two networks can be identified within individuals at high resolution, providing insight into the network organization of association cortex and placing further constraints on interpretation of group-averaged neuroimaging data. NEW & NOTEWORTHY Recent evidence has emerged that canonical large-scale networks such as the "default network" fractionate into parallel distributed networks when defined within individuals. This research uses high-resolution imaging to show that the networks possess juxtapositions sometimes evident inside the same sulcus and within regions that have been previously hypothesized to be network hubs. Distinct circumscribed regions of one network were also resolved in the hippocampal formation, at or near the parahippocampal cortex and subiculum.

Development of Prefrontal Cortical Connectivity and the Enduring Effect of Learned Value on Cognitive Control.

Inhibitory control, the capacity to suppress an inappropriate response, is a process employed for guiding action selection in the service of goal-directed behavior. Under neutral circumstances, inhibitory control success improves from childhood to adulthood and has been associated with developmental shifts in functional activation and connectivity of the PFC. However, the ability to exercise inhibitory control is challenged in certain contexts by including appetitive cues, a phenomenon that may be particularly pronounced in youths. Here, we examine the magnitude and temporal persistence of learned value's influence on inhibitory control in a cross-sectional sample of 8- to 25-year-olds. Participants first underwent conditioning of a motor approach response to two initially neutral cues, with one cue reinforced with monetary reward and the other with no monetary outcome. Subsequently, during fMRI, participants reencountered these cues as no-go targets in a nonreinforced go/no-go paradigm. Although the influence of learned value increasingly disrupted inhibitory control with increasing age, in young adults this pattern remitted over the course of the task, whereas during adolescence the impairing effect of reward history persisted. Successful no-go performance to the previously rewarded target was related to greater recruitment of the right inferior frontal gyrus and age-related increase in functional connectivity between the inferior frontal gyrus and the ventromedial PFC for the previously rewarded no-go target over the control target. Together, results indicate the complex influence of value on goals over development relies upon the increased coordination of distinct higher-order regions in the PFC.

Connectome-derived diffusion characteristics of the fornix in Alzheimer's disease.

The fornix bundle is a major white matter pathway of the hippocampus. While volume of the hippocampus has been a primary imaging biomarker of Alzheimer's disease progression, recent research has suggested that the volume and microstructural characteristics of the fornix bundle connecting the hippocampus could add relevant information for diagnosing and staging Alzheimer's disease. Using a robust fornix bundle isolation technique in native diffusion space, this study investigated whether diffusion measurements of the fornix differed between normal older adults and Alzheimer's disease patients when controlling for volume measurements. Data were collected using high gradient multi-shell diffusion-weighted MRI from a Siemens CONNECTOM scanner in 23 Alzheimer's disease and 23 age- and sex-matched control older adults (age range = 53-92). These data were used to reconstruct a continuous fornix bundle in every participant's native diffusion space, from which tract-derived volumetric and diffusion metrics were extracted and compared between groups. Diffusion metrics included those from a tensor model and from a generalized q-sampling imaging model. Results showed no significant differences in tract-derived fornix volumes but did show altered diffusion metrics within tissue classified as the fornix in the Alzheimer's disease group. Comparisons to a manual tracing method indicated the same pattern of results and high correlations between the methods. These results suggest that in Alzheimer's disease, diffusion characteristics may provide more sensitive measures of fornix degeneration than do volume measures and may be a potential early marker for loss of medial temporal lobe connectivity.

Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects.

BACKGROUND: Patients with bipolar depression are characterized by dysregulation across the full spectrum of mood, differentiating them from patients with unipolar depression. The ability to switch neural resources among the default mode network, salience network, and executive control network (ECN) has been proposed as a key mechanism for adaptive mood regulation. The anterior insula is implicated in the modulation of functional network switching. Differential connectivity between anterior insula and functional networks may provide insights into pathophysiological differences between bipolar and unipolar mood disorders, with implications for diagnosis and treatment. METHODS: Resting-state functional magnetic resonance imaging data were collected from 98 subjects (35 unipolar, 24 bipolar, and 39 healthy control subjects). Pearson correlations were computed between bilateral insula seed regions and a priori defined target regions from the default mode network, salience network, and ECN. After r-to-z transformation, a one-way multivariate analysis of covariance was conducted to identify significant differences in connectivity between groups. Post hoc pairwise comparisons were conducted and Bonferroni corrections were applied. Receiver-operating characteristics were computed to assess diagnostic sensitivity. RESULTS: Patients with bipolar depression evidenced significantly altered right anterior insula functional connectivity with the inferior parietal lobule of the ECN relative to patients with unipolar depression and control subjects. Right anterior insula-inferior parietal lobule connectivity significantly discriminated patients with bipolar depression. CONCLUSIONS: Impaired functional connectivity between the anterior insula and the inferior parietal lobule of the ECN distinguishes patients with bipolar depression from those with unipolar depression and healthy control subjects. This finding highlights a pathophysiological mechanism with potential as a therapeutic target and a clinical biomarker for bipolar disorder, exhibiting reasonable sensitivity and specificity.

Less head motion during MRI under task than resting-state conditions.

Head motion reduces data quality of neuroimaging data. In three functional magnetic resonance imaging (MRI) experiments we demonstrate that people make less head movements under task than resting-state conditions. In Experiment 1, we observed less head motion during a memory encoding task than during the resting-state condition. In Experiment 2, using publicly shared data from the UCLA Consortium for Neuropsychiatric Phenomics LA5c Study, we again found less head motion during several active task conditions than during a resting-state condition, although some task conditions also showed comparable motion. In the healthy controls, we found more head motion in men than in women and more motion with increasing age. When comparing clinical groups, we found that patients with a clinical diagnosis of bipolar disorder, or schizophrenia, move more compared to healthy controls or patients with ADHD. Both these experiments had a fixed acquisition order across participants, and we could not rule out that a first or last scan during a session might be particularly prone to more head motion. Therefore, we conducted Experiment 3, in which we collected several task and resting-state fMRI runs with an acquisition order counter-balanced. The results of Experiment 3 show again less head motion during several task conditions than during rest. Together these experiments demonstrate that small head motions occur during MRI even with careful instruction to remain still and fixation with foam pillows, but that head motion is lower when participants are engaged in a cognitive task. These finding may inform the choice of functional runs when studying difficult-to-scan populations, such as children or certain patient populations. Our findings also indicate that differences in head motion complicate direct comparisons of measures of functional neuronal networks between task and resting-state fMRI because of potential differences in data quality. In practice, a task to reduce head motion might be especially useful when acquiring structural MRI data such as T1/T2-weighted and diffusion MRI in research and clinical settings.

Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer's disease.

Prior studies have identified white matter abnormalities in Alzheimer's disease (AD). Yet, cross-sectional studies in normal older individuals show little evidence for an association between markers of AD risk (APOE4 genotype and amyloid deposition), and white matter integrity. Here, 108 normal older adults (age, 66-87) with assessments of apolipoprotein e4 (APOE4) genotype and assessment of amyloid burden by positron emission tomography underwent diffusion tensor imaging scans for measuring white matter integrity at 2 time points, on average 2.6 years apart. Linear mixed-effects models showed that amyloid burden at baseline was associated with steeper decline in fractional anisotropy in the parahippocampal cingulum (p < 0.05). This association was not significant between baseline measures suggesting that longitudinal analyses can provide novel insights that are not detectable in cross-sectional designs. Amyloid-related changes in hippocampus volume did not explain the association between amyloid burden and change in fractional anisotropy. The results suggest that accumulation of cortical amyloid and white matter changes in parahippocampal cingulum are not independent processes in individuals at increased risk for AD.

Signal Fluctuation Sensitivity: An Improved Metric for Optimizing Detection of Resting-State fMRI Networks.

Task-free connectivity analyses have emerged as a powerful tool in functional neuroimaging. Because the cross-correlations that underlie connectivity measures are sensitive to distortion of time-series, here we used a novel dynamic phantom to provide a ground truth for dynamic fidelity between blood oxygen level dependent (BOLD)-like inputs and fMRI outputs. We found that the de facto quality-metric for task-free fMRI, temporal signal to noise ratio (tSNR), correlated inversely with dynamic fidelity; thus, studies optimized for tSNR actually produced time-series that showed the greatest distortion of signal dynamics. Instead, the phantom showed that dynamic fidelity is reasonably approximated by a measure that, unlike tSNR, dissociates signal dynamics from scanner artifact. We then tested this measure, signal fluctuation sensitivity (SFS), against human resting-state data. As predicted by the phantom, SFS-and not tSNR-is associated with enhanced sensitivity to both local and long-range connectivity within the brain's default mode network.

Cortico-Cortical Connections of Primary Sensory Areas and Associated Symptoms in Migraine.

Migraine is a recurring, episodic neurological disorder characterized by headache, nausea, vomiting, and sensory disturbances. These events are thought to arise from the activation and sensitization of neurons along the trigemino-vascular pathway. From animal studies, it is known that thalamocortical projections play an important role in the transmission of nociceptive signals from the meninges to the cortex. However, little is currently known about the potential involvement of cortico-cortical feedback projections from higher-order multisensory areas and/or feedforward projections from principle primary sensory areas or subcortical structures. In a large cohort of human migraine patients (N = 40) and matched healthy control subjects (N = 40), we used resting-state intrinsic functional connectivity to examine the cortical networks associated with the three main sensory perceptual modalities of vision, audition, and somatosensation. Specifically, we sought to explore the complexity of the sensory networks as they converge and become functionally coupled in multimodal systems. We also compared self-reported retrospective migraine symptoms in the same patients, examining the prevalence of sensory symptoms across the different phases of the migraine cycle. Our results show widespread and persistent disturbances in the perceptions of multiple sensory modalities. Consistent with this observation, we discovered that primary sensory areas maintain local functional connectivity but express impaired long-range connections to higher-order association areas (including regions of the default mode and salience network). We speculate that cortico-cortical interactions are necessary for the integration of information within and across the sensory modalities and, thus, could play an important role in the initiation of migraine and/or the development of its associated symptoms.

MGH-USC Human Connectome Project datasets with ultra-high b-value diffusion MRI.

The MGH-USC CONNECTOM MRI scanner housed at the Massachusetts General Hospital (MGH) is a major hardware innovation of the Human Connectome Project (HCP). The 3T CONNECTOM scanner is capable of producing a magnetic field gradient of up to 300 mT/m strength for in vivo human brain imaging, which greatly shortens the time spent on diffusion encoding, and decreases the signal loss due to T2 decay. To demonstrate the capability of the novel gradient system, data of healthy adult participants were acquired for this MGH-USC Adult Diffusion Dataset (N=35), minimally preprocessed, and shared through the Laboratory of Neuro Imaging Image Data Archive (LONI IDA) and the WU-Minn Connectome Database (ConnectomeDB). Another purpose of sharing the data is to facilitate methodological studies of diffusion MRI (dMRI) analyses utilizing high diffusion contrast, which perhaps is not easily feasible with standard MR gradient system. In addition, acquisition of the MGH-Harvard-USC Lifespan Dataset is currently underway to include 120 healthy participants ranging from 8 to 90 years old, which will also be shared through LONI IDA and ConnectomeDB. Here we describe the efforts of the MGH-USC HCP consortium in acquiring and sharing the ultra-high b-value diffusion MRI data and provide a report on data preprocessing and access. We conclude with a demonstration of the example data, along with results of standard diffusion analyses, including q-ball Orientation Distribution Function (ODF) reconstruction and tractography.

Amygdala subnuclei resting-state functional connectivity sex and estrogen differences.

The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.

Brain Network Reconfiguration and Perceptual Decoupling During an Absorptive State of Consciousness.

Trance is an absorptive state of consciousness characterized by narrowed awareness of external surroundings and has long been used-for example, by shamans-to gain insight. Shamans across cultures often induce trance by listening to rhythmic drumming. Using functional magnetic resonance imaging (fMRI), we examined the brain-network configuration associated with trance. Experienced shamanic practitioners (n = 15) listened to rhythmic drumming, and either entered a trance state or remained in a nontrance state during 8-min scans. We analyzed changes in network connectivity. Trance was associated with higher eigenvector centrality (i.e., stronger hubs) in 3 regions: posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (dACC), and left insula/operculum. Seed-based analysis revealed increased coactivation of the PCC (a default network hub involved in internally oriented cognitive states) with the dACC and insula (control-network regions involved in maintaining relevant neural streams). This coactivation suggests that an internally oriented neural stream was amplified by the modulatory control network. Additionally, during trance, seeds within the auditory pathway were less connected, possibly indicating perceptual decoupling and suppression of the repetitive auditory stimuli. In sum, trance involved coactive default and control networks, and decoupled sensory processing. This network reconfiguration may promote an extended internal train of thought wherein integration and insight can occur.

Disrupted functional connectivity of cerebellar default network areas in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is increasingly understood as a disorder of spontaneous brain-network interactions. The default mode network (DMN), implicated in ADHD-linked behaviors including mind-wandering and attentional fluctuations, has been shown to exhibit abnormal spontaneous functional connectivity (FC) within-network and with other networks (salience, dorsal attention and frontoparietal) in ADHD. Although the cerebellum has been implicated in the pathophysiology of ADHD, it remains unknown whether cerebellar areas of the DMN (CerDMN) exhibit altered FC with cortical networks in ADHD. Here, 23 adults with ADHD and 23 age-, IQ-, and sex-matched controls underwent resting state fMRI. The mean time series of CerDMN areas was extracted, and FC with the whole brain was calculated. Whole-brain between-group differences in FC were assessed. Additionally, relationships between inattention and individual differences in FC were assessed for between-group interactions. In ADHD, CerDMN areas showed positive FC (in contrast to average FC in the negative direction in controls) with widespread regions of salience, dorsal attention and sensorimotor networks. ADHD individuals also exhibited higher FC (more positive correlation) of CerDMN areas with frontoparietal and visual network regions. Within the control group, but not in ADHD, participants with higher inattention had higher FC between CerDMN and regions in the visual and dorsal attention networks. This work provides novel evidence of impaired CerDMN coupling with cortical networks in ADHD and highlights a role of cerebro-cerebellar interactions in cognitive function. These data provide support for the potential targeting of CerDMN areas for therapeutic interventions in ADHD.