Resting-state anticorrelations between medial and lateral prefrontal cortex: Association with working memory, aging, and individual differences

We examined how variation in working memory (WM) capacity due to aging or individual differences among young adults is associated with intrinsic or resting-state anticorrelations, particularly between (1) the medial prefrontal cortex (MPFC), a component of the default-mode network (DMN) that typically decreases in activation during external, attention-demanding tasks, and (2) the dorsolateral prefrontal cortex (DLPFC), a component of the fronto-parietal control network that supports executive functions and WM and typically increases in activation during attention-demanding tasks. We compared the magnitudes of MPFC-DLPFC anticorrelations between healthy younger and older participants (Experiment 1) and related the magnitudes of these anticorrelations to individual differences on two behavioral measures of WM capacity in two independent groups of young adults (Experiments 1 and 2). Relative to younger adults, older adults exhibited reductions in WM capacity and in MPFC-DLPFC anticorrelations. Within younger adults, greater MPFC-DLPFC anticorrelation at rest correlated with greater WM capacity. These findings show that variation in MPFC-DLPFC anticorrelations, whether related to aging or to individual differences, may reflect an intrinsic functional brain architecture supportive of WM capacity.National Institutes of Health (U.S.) (National Institute on Aging Grant R21 AG030770)National Institutes of Health (U.S.) (Grant T32 GM007484)Barbara J. Weedon Fund Fellowshi

Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior

Sedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change in time spent sedentary over the course of that intervention. In 143 healthy, low-active older adults participating in a 6-month aerobic exercise intervention (with three conditions: walking, dance, stretching), we aimed to use baseline neuroimaging (resting state functional connectivity of two a priori defined seed regions), and baseline accelerometer measures of time spent sedentary to predict future pre-post changes in objectively measured time spent sedentary in daily life over the 6-month intervention. Our results demonstrated that functional connectivity between (1) the anterior cingulate cortex and the supplementary motor area and (2) the right anterior insula and the left temporoparietal/temporooccipital junction, predicted changes in time spent sedentary in the walking group. Functional connectivity of these brain regions did not predict changes in time spent sedentary in the dance nor stretch and tone conditions, but baseline time spent sedentary was predictive in these conditions. Our results add important knowledge toward understanding mechanistic associations underlying complex out-of-session sedentary behaviors within a walking intervention setting in older adults

Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R2 = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety

Neurodevelopmental and Psychiatric Symptoms in Patients with a Cyst Compressing the Cerebellum: an Ongoing Enigma

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap—namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?NIH (Grant R01 EB020740

Exploring Functional Connectivity Networks with Multichannel Brain Array Coils

The use of multichannel array head coils in functional and structural magnetic resonance imaging (MRI) provides increased signal-to-noise ratio (SNR), higher sensitivity, and parallel imaging capabilities. However, their benefits remain to be systematically explored in the context of resting-state functional connectivity MRI (fcMRI). In this study, we compare signal detectability within and between commercially available multichannel brain coils, a 32-Channel (32Ch), and a 12-Channel (12Ch) at 3T, in a high-resolution regime to accurately map resting-state networks. We investigate whether the 32Ch coil can extract and map fcMRI more efficiently and robustly than the 12Ch coil using seed-based and graph-theory-based analyses. Our findings demonstrate that although the 12Ch coil can be used to reveal resting-state connectivity maps, the 32Ch coil provides increased detailed functional connectivity maps (using seed-based analysis) as well as increased global and local efficiency, and cost (using graph-theory-based analysis), in a number of widely reported resting-state networks. The exploration of subcortical networks, which are scarcely reported due to limitations in spatial-resolution and coil sensitivity, also proved beneficial with the 32Ch coil. Further, comparisons regarding the data acquisition time required to successfully map these networks indicated that scan time can be significantly reduced by 50% when a coil with increased number of channels (i.e., 32Ch) is used. Switching to multichannel arrays in resting-state fcMRI could, therefore, provide both detailed functional connectivity maps and acquisition time reductions, which could further benefit imaging special subject populations, such as patients or pediatrics who have less tolerance in lengthy imaging sessions.Martinos Imaging Center at MI

Hyper-Connectivity of Subcortical Resting-State Networks in Social Anxiety Disorder

Social anxiety disorder–related alterations in basal ganglia regions, such as striatum and globus pallidus, though evident from metabolic imaging, remain to be explored using seed-based resting-state functional connectivity magnetic resonance imaging. Capitalizing on the enhanced sensitivity of a multichannel array coil, we collected high-resolution (2-mm isotropic) data from medication-naive patients and healthy control participants. Subcortical resting-state networks from structures including the striatum (caudate and putamen), globus pallidus, thalamus, amygdala, and periaqueductal gray were compared between the two groups. When compared with controls, the caudate seed revealed significantly higher functional connectivity (hyper-connectivity) in the patient group in medial frontal, prefrontal (anterior and dorsolateral), orbito-frontal, and anterior cingulate cortices, which are regions that are typically associated with emotional processing. In addition, with the putamen seed, the patient data exhibited increased connectivity in the fronto-parietal regions (executive control network) and subgenual cingulate (affective network). The globus pallidus seed showed significant increases in connectivity in the patient group, primarily in the precuneus, which is part of the default mode network. Significant hyper-connectivity in the precuneus, interior temporal, and parahippocampal cortices was also observed with the thalamus seed in the patient population, when compared with controls. With amygdala as seed region, between-group differences were primarily in supplementary motor area, inferior temporal gyrus, secondary visual cortex, angular gyrus, and cingulate gyrus. Seed from periaqueductal gray resulted in hyper-connectivity in the patient group, when compared with controls, in dorsolateral prefrontal cortex, precuneus, middle temporal gyrus, and inferior parietal lobule. In all the subcortical regions examined in this study, the control group did not have any significant enhancements in functional connectivity when compared with the patient group.Martinos Imaging Center at MI

Resting-State Functional Connectivity of the Subthalamic Nucleus to Limbic, Associative, and Motor Networks

The subthalamic nucleus (STN) is a small structure situated deep in the midbrain that exhibits wide-ranging functionality. In addition to its role in motor control, the STN is considered a hub for synchronizing aspects of emotion and cognition including attention, inhibitory control, motivation, and working memory. Evidence from neuroanatomical tracer studies suggests that the medial, ventromedial, and dorsolateral parts of the STN correspond to limbic, associative, and motor subdivisions, respectively. Although the extent of STN functional anatomical overlap remains unclear, blood oxygenation level dependent imaging of the STN may provide complementary information about the diverse functions of this structure. Methodological limitations in spatial and temporal resolutions, however, have prevented a comprehensive exploration of temporal correlations from the STN to the whole brain. In this study, we optimize spatial (2 mm isotropic) and temporal (TR = 1 s) resolutions to take full advantage of the time series signal-to-noise ratio capabilities of multichannel array coils and simultaneous multislice imaging. We interrogated STN seed-to-voxel resting-state functional MRI connectivity in a group of 30 healthy participants that included the whole brain at high-temporal and spatial resolutions. This analysis revealed STN functional connectivity to limbic, associative, and motor networks. Our findings contribute to the understanding of STN functional neuroanatomy in humans and are clinically relevant for ongoing research in deep brain stimulation

Hyperactivation of Posterior Default Mode Network During Self-Referential Processing in Children at Familial High-Risk for Psychosis

Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7–12 years) at familial high risk (FHR) for psychosis (N = 17), compared to an age and sex-matched group of healthy control (HC) children (N = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving N = 15 FHR and N = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC (p = 0.004) and anterior cerebellum / temporo-occipital cortex (p = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing (r = 0.60, p = 0.032) and total (r = 0.69, p = 0.009) problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children

Integration and Segregation of Default Mode Network Resting-State Functional Connectivity in Transition-Age Males with High-Functioning Autism Spectrum Disorder: A Proof-of-Concept Study

The aim of this study is to assess the resting-state functional connectivity (RsFc) profile of the default mode network (DMN) in transition-age males with autism spectrum disorder (ASD). Resting-state blood oxygen level-dependent functional magnetic resonance imaging data were acquired from adolescent and young adult males with high-functioning ASD (n = 15) and from age-, sex-, and intelligence quotient-matched healthy controls (HCs; n = 16). The DMN was examined by assessing the positive and negative RsFc correlations of an average of the literature-based conceptualized major DMN nodes (medial prefrontal cortex [mPFC], posterior cingulate cortex, bilateral angular, and inferior temporal gyrus regions). RsFc data analysis was performed using a seed-driven approach. ASD was characterized by an altered pattern of RsFc in the DMN. The ASD group exhibited a weaker pattern of intra- and extra-DMN-positive and -negative RsFc correlations, respectively. In ASD, the strength of intra-DMN coupling was significantly reduced with the mPFC and the bilateral angular gyrus regions. In addition, the polarity of the extra-DMN correlation with the right hemispheric task-positive regions of fusiform gyrus and supramarginal gyrus was reversed from typically negative to positive in the ASD group. A wide variability was observed in the presentation of the RsFc profile of the DMN in both HC and ASD groups that revealed a distinct pattern of subgrouping using pattern recognition analyses. These findings imply that the functional architecture profile of the DMN is altered in ASD with weaker than expected integration and segregation of DMN RsFc. Future studies with larger sample sizes are warranted. Keywords: autism spectrum disorder; default mode network; resting-state fMRINational Institute of Mental Health (U.S.) (Grant K23MH100450