Aaron Kucyi

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks

Significance The mind easily wanders away from mundane tasks, but pain is presumed to automatically capture attention. We demonstrate that individuals differ in how often their minds spontaneously wander away from pain and that these differences are associated with the disruptive effect of pain on cognitive performance. Brain–behavior relationships underscore these individual differences. When people’s minds wander away from pain, there are increased activations of the default mode network (DMN) and strong interactions between the DMN and periaqueductal gray (PAG), an opiate-rich region mediating pain suppression. Individuals with greater tendencies to mind wander from pain have stronger anatomical links and dynamic functional communication between PAG and DMN. These findings provide clinically important clues about why some individuals cannot disengage from pain. Human minds often wander away from their immediate sensory environment. It remains unknown whether such mind wandering is unsystematic or whether it lawfully relates to an individual’s tendency to attend to salient stimuli such as pain and their associated brain structure/function. Studies of pain–cognition interactions typically examine explicit manipulation of attention rather than spontaneous mind wandering. Here we sought to better represent natural fluctuations in pain in daily life, so we assessed behavioral and neural aspects of spontaneous disengagement of attention from pain. We found that an individual’s tendency to attend to pain related to the disruptive effect of pain on his or her cognitive task performance. Next, we linked behavioral findings to neural networks with strikingly convergent evidence from functional magnetic resonance imaging during pain coupled with thought probes of mind wandering, dynamic resting state activity fluctuations, and diffusion MRI. We found that (i) pain-induced default mode network (DMN) deactivations were attenuated during mind wandering away from pain; (ii) functional connectivity fluctuations between the DMN and periaqueductal gray (PAG) dynamically tracked spontaneous attention away from pain; and (iii) across individuals, stronger PAG–DMN structural connectivity and more dynamic resting state PAG–DMN functional connectivity were associated with the tendency to mind wander away from pain. These data demonstrate that individual tendencies to mind wander away from pain, in the absence of explicit manipulation, are subserved by functional and structural connectivity within and between default mode and antinociceptive descending modulation networks.

Bipolar disorder and metabolic syndrome: an international perspective.

INTRODUCTION The ubiquity and hazards posed by abnormal body composition and metabolic parameters in the bipolar population are a priority research and clinical issue. Herein, we summarize and synthesize international studies describing the rate of US National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III])- and International Diabetes Federation (IDF)-defined metabolic syndrome and its criterion components in individuals with bipolar disorder. METHODS We conducted a PubMed search of all English-language articles published between January 2005 and July 2009 with the following search terms: metabolic syndrome and bipolar disorder, mania and manic-depression. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. RESULTS The rate of metabolic syndrome in individuals with bipolar disorder is increased relative to the general population. Disparate estimates are reported ranging from comparability to approximately twofold greater than the general population. The increased hazard for metabolic syndrome amongst bipolar individuals is now documented in twelve countries from Europe, Australia, Asia, North and South America. The co-occurrence of metabolic syndrome in the bipolar population is associated with a more complex illness presentation, less favourable response to treatment, and adverse course and outcome. The association between metabolic syndrome and bipolar disorder is mediated/moderated by both iatrogenic and non-iatrogenic factors. DISCUSSION The increased hazard for metabolic syndrome in bipolar populations is due to the clustering of traditional (and emerging) risk factors as well as iatrogenic and health systems factors. Extant data support recommendations for prioritizing, surveillance, prevention, diagnosis and management of metabolic syndrome as routine care of the bipolar patient.

Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination.

Rumination is a form of thought characterized by repetitive focus on discomforting emotions or stimuli. In chronic pain disorders, rumination can impede treatment efficacy. The brain mechanisms underlying rumination about chronic pain are not understood. Interestingly, a link between rumination and functional connectivity (FC) of the brains default mode network (DMN) has been identified within the context of mood disorders. We, and others, have also found DMN dysfunction in chronic pain populations. The medial prefrontal cortex (mPFC) is a key node of the DMN that is anatomically connected with the descending pain modulatory system. Therefore, we tested the hypothesis that in patients with chronic pain, the mPFC exhibits abnormal FC related to the patients degree of rumination about their pain. Seventeen patients with idiopathic temporomandibular disorder (TMD) and 17 age- and sex-matched healthy controls underwent resting state functional MRI, and rumination about pain was assessed through the rumination subscale of the Pain Catastrophizing Scale. Compared with healthy controls, we found that TMD patients exhibited enhanced mPFC FC with other DMN regions, including the posterior cingulate cortex (PCC)/precuneus (PCu) and retrosplenial cortex. We also found that individual differences in pain rumination in the chronic pain patients (but not in healthy controls) were positively correlated to mPFC FC with the PCC/PCu, retrosplenial cortex, medial thalamus, and periaqueductal/periventricular gray. These data implicate communication within the DMN and of the DMN with the descending modulatory system as a mechanism underlying the degree to which patients ruminate about their chronic pain.

Hemispheric Asymmetry in White Matter Connectivity of the Temporoparietal Junction with the Insula and Prefrontal Cortex

The temporoparietal junction (TPJ) is a key node in the brains ventral attention network (VAN) that is involved in spatial awareness and detection of salient sensory stimuli, including pain. The anatomical basis of this networks right-lateralized organization is poorly understood. Here we used diffusion-weighted MRI and probabilistic tractography to compare the strength of white matter connections emanating from the right versus left TPJ to target regions in both hemispheres. Symmetry of structural connectivity was evaluated for connections between TPJ and target regions that are key cortical nodes in the right VAN (insula and inferior frontal gyrus) as well as target regions that are involved in salience and/or pain (putamen, cingulate cortex, thalamus). We found a rightward asymmetry in connectivity strength between the TPJ and insula in healthy human subjects who were scanned with two different sets of diffusion-weighted MRI acquisition parameters. This rightward asymmetry in TPJ-insula connectivity was stronger in females than in males. There was also a leftward asymmetry in connectivity strength between the TPJ and inferior frontal gyrus, consistent with previously described lateralization of language pathways. The rightward lateralization of the pathway between the TPJ and insula supports previous findings on the roles of these regions in stimulus-driven attention, sensory awareness, interoception and pain. The findings also have implications for our understanding of acute and chronic pains and stroke-induced spatial hemineglect.

Dynamic Brain Network Correlates of Spontaneous Fluctuations in Attention

Abstract Human attention is intrinsically dynamic, with focus continuously shifting between elements of the external world and internal, self‐generated thoughts. Communication within and between large‐scale brain networks also fluctuates spontaneously from moment to moment. However, the behavioral relevance of dynamic functional connectivity and possible link with attentional state shifts is unknown. We used a unique approach to examine whether brain network dynamics reflect spontaneous fluctuations in moment‐to‐moment behavioral variability, a sensitive marker of attentional state. Nineteen healthy adults were instructed to tap their finger every 600 ms while undergoing fMRI. This novel, but simple, approach allowed us to isolate moment‐to‐moment fluctuations in behavioral variability related to attention, independent of common confounds in cognitive tasks (e.g., stimulus changes, response inhibition). Spontaneously increasing tap variance (“out‐of‐the‐zone” attention) was associated with increasing activation in dorsal‐attention and salience network regions, whereas decreasing tap variance (“in‐the‐zone” attention) was marked by increasing activation of default mode network (DMN) regions. Independent of activation, tap variance representing out‐of‐the‐zone attention was also time‐locked to connectivity both within DMN and between DMN and salience network regions. These results provide novel mechanistic data on the understudied neural dynamics of everyday, moment‐to‐moment attentional fluctuations, elucidating the behavioral importance of spontaneous, transient coupling within and between attention‐relevant networks.

Aerobic Physical Exercise as a Possible Treatment for Neurocognitive Dysfunction in Bipolar Disorder

Abstract Background: Neurocognitive dysfunction associated with bipolar disorder (BD) is pervasive, persistent across illness phases, and is demonstrated to predispose and portend psychosocial impairment. Moreover, no approved therapies for various phases of BD have been shown to reliably improve any dimension of neurocognitive performance. In this article, we emphasize that aerobic physical exercise is a viable neurocognitive-enhancing adjunctive treatment for patients with BD. The overarching aim of this review is to emphasize that aerobic physical exercise is a viable neurocognitive-enhancing adjunctive treatment for patients with BD. Methods: We conducted PubMed and Google Scholar searches of all English-language articles published between January 1966 and February 2010 using the search terms bipolar disorder, major depressive disorder, depression, exercise, and physical activity cross-referenced with each other and the following terms: cognition, executive function, learning, memory, attention, emotion, and behavior. Articles selected for review were based on adequacy of sample size, use of standardized experimental procedures, validated assessment measures, and overall quality. Results: Available studies have documented an array of persisting neurocognitive deficits across disparate bipolar populations. Abnormalities in verbal working memory are highly replicated; deficits in executive function, learning, attention, and processing speed are also a consistent abnormality. The effect sizes of neurocognitive deficits in BD are intermediate between those reported in schizophrenia and major depressive disorder. Several original reports and reviews have documented the neurocognitive-enhancing effects of aerobic exercise in the general population as well as across diverse medical populations and ages. Proposed mechanisms involve nonexclusive effects on neurogenesis, neurotrophism, immunoinflammatory systems, insulin sensitivity, and neurotransmitter systems. Each of these effector systems are implicated in both normal and abnormal neurocognitive processes in BD. Conclusion: Available evidence provides a rationale for empirically evaluating the neurocognitive benefits of aerobic exercise in BD.

Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.

Cortical functioning within the default mode network (DMN) and salience network (SN) is altered in chronic pain patients. The mechanisms underlying these alterations are unknown, but a novel unexamined source is cross-network communication. Aberrant functional connectivity (FC) between the DMN and SN, whose activity is normally anticorrelated, reflects disease severity in many brain disorders. Further, stronger FC between the posterior cingulate cortex (PCC) and anterior insula has been reported in chronic pain, pointing to abnormal DMN–SN interactions. Here, we tested the hypothesis that cross-network FC between the DMN and SN is abnormal in chronic pain, and is related to pain and associated symptoms. We used resting state fMRI to examine FC within and between the DMN and SN in 20 patients with chronic pain due to ankylosing spondylitis and 20 healthy controls. A whole-network analysis revealed that compared to healthy controls, patients exhibited less anticorrelated FC between the SN and DMN, and the degree of cross-network abnormality tracked pain and disease-related symptoms. This suggests that cross-network FC is a metric of functional brain abnormality in chronic pain. In a complementary seed-based analysis, the PCC was strongly connected with the SN and weakly connected with the DMN in chronic pain compared to healthy controls, suggesting that the PCC acts as a hub for altered network interaction. Sensorimotor cortex cross-network FC correlated with measures of physical function, suggesting that physical functioning also impacts brain network interaction in chronic pain. Our study implicates altered communication between brain networks as a key factor underlying chronic pain.

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. Hum Brain Mapp 36:3373–3386, 2015.

Intrinsic functional connectivity of periaqueductal gray subregions in humans

The periaqueductal gray matter (PAG) is a key brain region of the descending pain modulation pathway. It is also involved in cardiovascular functions, anxiety, and fear; however, little is known about PAG subdivisions in humans. The aims of this study were to use resting‐state fMRI‐based functional connectivity (FC) to parcellate the human PAG and to determine FC of its subregions. To do this, we acquired resting‐state fMRI scans from 79 healthy subjects and (1) used a data‐driven method to parcellate the PAG, (2) used predefined seeds in PAG subregions to evaluate PAG FC to the whole brain, and (3) examined sex differences in PAG FC. We found that clustering of the left and right PAG yielded similar patterns of caudal, middle, and rostral subdivisions in the coronal plane, and dorsal and ventral subdivisions in the sagittal plane. FC analysis of predefined subregions revealed that the ventolateral(VL)‐PAG was supfunctionally connected to brain regions associated with descending pain modulation (anterior cingulate cortex (ACC), upper pons/medulla), whereas the lateral (L) and dorsolateral (DL) subregions were connected with brain regions implicated in executive functions (prefrontal cortex, striatum, hippocampus). We also found sex differences in FC including areas implicated in pain, salience, and analgesia including the ACC and the insula in women, and the MCC, parahippocampal gyrus, and the temporal pole in men. The organization of the human PAG thus provides a framework to understand the circuitry underlying the broad range of responses to pain and its modulation in men and women. Hum Brain Mapp 37:1514‐1530, 2016.

Spontaneous default network activity reflects behavioral variability independent of mind-wandering

Significance The brain’s default mode network (DMN) is comprised of regions that are highly active during wakeful rest. In the past 15 y, the DMN has been a target of investigation in thousands of basic and clinical neuroscience studies, yet the fundamental role of this network remains debated and unknown. Some studies suggest that DMN activity increases with self-reported mind-wandering away from the present sensory environment, a state in which task performance tends to be highly unstable. However, we show that DMN activity increases with stable, rather than variable, behavior, independent from increases with mind-wandering. Our work urges reinterpretation of the significance of DMN activity fluctuations in daily life and DMN disruption in disease. The brain’s default mode network (DMN) is highly active during wakeful rest when people are not overtly engaged with a sensory stimulus or externally oriented task. In multiple contexts, increased spontaneous DMN activity has been associated with self-reported episodes of mind-wandering, or thoughts that are unrelated to the present sensory environment. Mind-wandering characterizes much of waking life and is often associated with error-prone, variable behavior. However, increased spontaneous DMN activity has also been reliably associated with stable, rather than variable, behavior. We aimed to address this seeming contradiction and to test the hypothesis that single measures of attentional states, either based on self-report or on behavior, are alone insufficient to account for DMN activity fluctuations. Thus, we simultaneously measured varying levels of self-reported mind-wandering, behavioral variability, and brain activity with fMRI during a unique continuous performance task optimized for detecting attentional fluctuations. We found that even though mind-wandering co-occurred with increased behavioral variability, highest DMN signal levels were best explained by intense mind-wandering combined with stable behavior simultaneously, compared with considering either single factor alone. These brain–behavior–experience relationships were highly consistent within known DMN subsystems and across DMN subregions. In contrast, such relationships were absent or in the opposite direction for other attention-relevant networks (salience, dorsal attention, and frontoparietal control networks). Our results suggest that the cognitive processes that spontaneous DMN activity specifically reflects are only partially related to mind-wandering and include also attentional state fluctuations that are not captured by self-report.