Stress-induced alterations in resting-state functional connectivity among adolescents with non-suicidal self-injury.

BACKGROUND: Non-suicidal self-injury (NSSI) is a major mental health problem among youth worldwide. Dysfunction in emotion regulation contributes to NSSI, but research on the underlying neurobiological mechanisms of NSSI is limited. Adolescents with emotion regulation difficulties are vulnerable to stress, making them susceptible to maladaptive coping mechanisms such as NSSI. METHODS: This study examined the functional neurocircuitry relevant to emotion regulation and stress coping in individuals with NSSI compared with healthy controls. This case-control study included 34 adolescents with NSSI (15.91 years) and 28 (16.0 years) unaffected controls. Participants underwent a functional magnetic resonance imaging scan before and after completing a laboratory stress-induction paradigm (the Montreal Imaging Stress Test). The effects of stress induction were quantified by both physiological measures and self-reports. RESULTS: Participants with NSSI showed distinctive alterations in functional resting-state following stress induction, which differentiated them from unaffected controls. Results show a reduction in functional connectivity between frontoparietal regions and the angular gyrus within the patient group compared to controls, as well as an increase in functional connectivity between visual regions, the insular cortex, the planum polare, and the central opercular cortex. After conditions of acute stress, adolescents with NSSI show changes in functional connectivity of regions associated with sensorimotor alertness, attention, and effortful emotion regulation. LIMITATIONS: The patient group showed both NSSI and suicidal behavior, therefore results might be partly due to suicidality. CONCLUSION: The findings emphasize the importance of targeting emotion regulation within therapeutic approaches to enhance stress coping capacity, which in turn may contribute to counteracting self-injurious behavior.

The relationship between adolescents' externalizing and internalizing symptoms and brain development over a period of three years.

BACKGROUND: Adolescence is a crucial period for both brain maturation and the emergence of mental health disorders. Associations between brain morphology and internalizing/externalizing symptomatology have been identified in clinical or at-risk samples, but age-related developmental differences were rarely considered. The current study investigated the longitudinal relationship between internalizing/externalizing symptoms and brain development in the absence of psychiatric disorders during early and late adolescence. METHODS: 98 healthy adolescents within two cohorts (younger: 9 years, older: 12 years) participated in annual assessments for three years; a clinical assessment measuring their externalizing and internalizing symptoms (SDQ) and an MRI assessment measuring their brain volume and white matter microstructure, including fractional anisotropy (FA), mean diffusivity (MD) and average path length. RESULTS: Linear mixed effect models and cross-lagged panel models showed that larger subcortical gray matter volume predicted more externalizing symptoms in older adolescents whereas decreases of subcortical gray matter volume predicted more externalizing symptoms for younger adolescents. Additionally, longer average white matter path length predicted more externalizing symptoms for older adolescents, while decreases in cerebral white matter volume were predictive of more externalizing symptoms for younger adolescents. There were no predictive effects for internalizing symptoms, FA or MD. CONCLUSIONS: Delays in subcortical brain maturation, in both early and late adolescence, are associated with increases in externalizing behavior which indicates a higher risk for psychopathology and warrants further investigations.

Calendar age and puberty-related development of regional gray matter volume and white matter tracts during adolescence.

BACKGROUND: Adolescence is a critical time for brain development. Findings from previous studies have been inconsistent, failing to distinguish the influence of pubertal status and aging on brain maturation. The current study sought to address these inconsistencies, addressing the trajectories of pubertal development and aging by longitudinally tracking structural brain development during adolescence. METHODS: Two cohorts of healthy children were recruited (cohort 1: 9-10 years old; cohort 2: 12-13 years old at baseline). MRI data were acquired for gray matter volume and white matter tract measures. To determine whether age, pubertal status, both or their interaction best modelled longitudinal data, we compared four multi-level linear regression models to the null model (general brain growth indexed by total segmented volume) using Bayesian model selection. RESULTS: Data were collected at baseline (n = 116), 12 months (n = 97) and 24 months (n = 84) after baseline. Findings demonstrated that the development of most regional gray matter volume, and white matter tract measures, were best modelled by age. Interestingly, precentral and paracentral regions of the cortex, as well as the accumbens demonstrated significant preference for the pubertal status model. None of the white matter tract measures were better modelled by pubertal status. LIMITATIONS: The major limitation of this study is the two-cohort recruitment. Although this allowed a faster coverage of the age span, a complete per person trajectory over 6 years of development (9-15 years) could not be investigated. CONCLUSIONS: Comparing the impact of age and pubertal status on regional gray matter volume and white matter tract measures, we found age to best predict longitudinal changes. Further longitudinal studies investigating the differential influence of puberty status and age on brain development in more diverse samples are needed to replicate the present results and address mechanisms underlying norm-variants in brain development.

Neuropsychological development in adolescents: Longitudinal associations with white matter microstructure.

Important neuropsychological changes during adolescence coincide with the maturation of white matter microstructure. Few studies have investigated the association between neuropsychological development and white matter maturation longitudinally. We aimed to characterize developmental trajectories of inhibition, planning, emotion recognition and risk-taking and examine whether white matter microstructural characteristics were associated with neuropsychological development above and beyond age. In an accelerated longitudinal cohort design, n = 112 healthy adolescents between ages 9 and 16 underwent cognitive assessment and diffusion MRI over three years. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted for major white matter pathways using an automatic probabilistic reconstruction technique and mixed models were used for statistical analyses. Inhibition, planning and emotion recognition performance improved linearly across adolescence. Risk-taking developed in a quadratic fashion, with stable performance between 9 and 12 and an increase between ages 12 and 16. Including cingulum and superior longitudinal fasciculus FA slightly improved model fit for emotion recognition across age. We found no evidence that FA or MD were related to inhibition, planning or risk-taking across age. Our results challenge the additional value of white matter microstructure to explain neuropsychological development in healthy adolescents, but more longitudinal research with large datasets is needed to identify the potential role of white matter microstructure in cognitive development.

Effective Self-Management for Early Career Researchers in the Natural and Life Sciences.

Early career researchers (ECRs) are faced with a range of competing pressures in academia, making self-management key to building a successful career. The Organization for Human Brain Mapping undertook a group effort to gather helpful advice for ECRs in self-management.

Altered neural activity in brain cough suppression networks in cigarette smokers.

Cough is important for airway defence, and studies in healthy animals and humans have revealed multiple brain networks intimately involved in the perception of airway irritation, cough induction and cough suppression. Changes in cough sensitivity and/or the ability to suppress cough accompany pulmonary pathologies, suggesting a level of plasticity is possible in these central neural circuits. However, little is known about how persistent inputs from the lung might modify the brain processes regulating cough.In the present study, we used human functional brain imaging to investigate the central neural responses that accompany an altered cough sensitivity in cigarette smokers.In nonsmokers, inhalation of the airway irritant capsaicin induced a transient urge-to-cough associated with the activation of a distributed brain network that included sensory, prefrontal and motor cortical regions. Cigarette smokers demonstrated significantly higher thresholds for capsaicin-induced urge-to-cough, consistent with a reduced sensitivity to airway irritation. Intriguingly, this was accompanied by increased activation in brain regions known to be involved in both cough sensory processing (primary sensorimotor cortex) and cough suppression (dorsolateral prefrontal cortex and the midbrain nucleus cuneiformis). Activations in the prefrontal cortex were highest among participants with the least severe smoking behaviour, whereas those in the midbrain correlated with more severe smoking behaviour.These outcomes suggest that smoking-induced sensitisation of central cough neural circuits is offset by concurrently enhanced central suppression. Furthermore, central suppression mechanisms may evolve with the severity of smoke exposure, changing from initial prefrontal inhibition to more primitive midbrain processes as exposure increases.

Frontal slow wave resting EEG power is higher in individuals at Ultra High Risk for psychosis than in healthy controls but is not associated with negative symptoms or functioning.

Decreased brain activity in the frontal region, as indicated by increased slow wave EEG power measured by electrodes place on the skull over this area, in association with negative symptoms has previously been shown to distinguish ultra-high risk (UHR) individuals who later transitioned to psychosis (UHR-P) from those who did not transition (UHR-NP). The aims of the current study were to: 1) replicate these results and 2) investigate whether similar association between increased frontal slow wave activity and functioning shows any value in the prediction of transition to psychosis in UHR individuals. The brain activity, recorded using EEG, of 44 UHR individuals and 38 healthy controls was included in the analyses. Symptom severity was assessed in UHR participants and functioning was measured in both groups. The power in the theta frequency band in the frontal region of UHR individuals was higher than in controls. However, there was no difference between the UHR-P and the UHR-NP groups, and no change in slow frequency power following transition to psychosis. The correlation between delta frequency power and negative symptoms previously observed was not present in our UHR cohort, and there was no association between frontal delta or theta and functioning in either group. Increased delta power was rather correlated with depressive symptoms in the UHR group. Future research will be needed to better understand when, in the course of the illness, does the slow wave activity in the frontal area becomes impaired.

Establishing online mentorship for early career researchers: Lessons from the Organization for Human Brain Mapping International Mentoring Programme.

Mentorship facilitates personal growth through pairing trainees with mentors who can share their expertise. In times of global integration, geographical proximity between mentors and mentees is relevant to a lesser degree. This has led to popularization of online mentoring programs. In this editorial, we introduce the history and architecture of the International Online Mentoring Programme organized by the Student and Postdoc Special Interest Group of the Organization for Human Brain Mapping.

Regional grey matter volume reduction in adolescents engaging in non-suicidal self-injury.

There is a high prevalence of non-suicidal self-injury (NSSI) amongst adolescents worldwide and therefore an urgency to investigate the underlying mechanisms that may facilitate such behaviours. This study aimed to investigate neurobiological alterations, specifically in regional brain volumes of the frontolimbic system, in adolescents engaging in NSSI in comparison to healthy controls. Regional grey matter volumes were compared between 29 adolescent female patients who presented with incidents of NSSI on ≥5 days within the last 12 months (DSM-5 criteria for NSSI) and 21 healthy age, gender and education matched controls who had never received any psychiatric diagnosis/treatment, or engaged in NSSI. Significant group effects in regional brain volumes were observed in insula, and a suggested change in the anterior cingulate cortex (ACC), while controlling for total segmented volume. Additionally, ACC volume showed a significant association with past suicide attempts, where estimated marginal means showed even smaller ACC volume in adolescents engaging in NSSI with a history of suicide attempt in comparison to those with no history of suicide attempt, including healthy controls. This study provides the first evidence of volumetric changes in adolescents engaging in NSSI and a potential neurobiological link between NSSI and suicide attempt.

Cortical thickness, resting state heart rate, and heart rate variability in female adolescents.

Resting state heart rate variability (HRV) is a psychophysiological marker that has gained increasing research interest, in particular in developmental neuroscience. HRV has been shown to be associated with mental and physical health, beyond simple measures of heart rate (HR) and shows inter- and intraindividual variance across aging. Recently, three studies reported on a positive correlation between resting state HRV and cortical thickness in selected regions of interest (ROIs) in adult samples. Structural thickness, HRV, and HR change during the sensitive period of adolescence. Previously, no study has addressed the structural concomitants of resting HR and HRV in adolescents. Cortical thickness (3-T MRI), HR, and HRV were recorded in 20 healthy, female adolescents (mean age: 15.92 years; SD = 1.06; range: 14-17). In line with existing research in adults, cortical thickness in a number of ROIs was associated with resting state HRV but not HR. The comparison of regression analyses using the Bayes factor revealed evidence for a correlation between HRV and cortical thickness of the bilateral rostral anterior cingulate cortex. However, unlike in adults, greater cortical thickness was associated with reduced HRV in female adolescents. Analyses on HR showed no superior model fit. Results suggest that greater HRV might be beneficial for cortical development during adolescence (cortical thinning). On the other hand, cortical development might determine changes in autonomic nervous system function in adolescents. Future studies are needed to replicate these findings in larger samples including boys and to test these hypotheses in longitudinal designs.

Impaired mismatch negativity to frequency deviants in individuals at ultra-high risk for psychosis, and preliminary evidence for further impairment with transition to psychosis.

BACKGROUND: There is evidence to suggest that people with established psychotic disorders show impairments in the mismatch negativity induced by a frequency-deviant sound (fMMN), and that these impairments worsen with the deterioration of psychotic symptoms. This study aimed to test whether individuals at ultra-high risk (UHR) for psychosis show pre-morbid impairments in fMMN, and if so, whether fMMN continues to deteriorate with transition to psychosis. METHOD: fMMN was recorded in a cohort of UHR individuals (n=42) and compared to healthy controls (n=29). Of the 27 UHR participants who returned for a second EEG session, six participants had transitioned to psychosis by 12-month follow-up (UHR-T) and were compared to the 21 participants who did not transition (UHR-NT). RESULTS: fMMN amplitude was significantly reduced, relative to healthy controls, in the UHR cohort. Furthermore, UHR-T individuals showed a significant decrease in fMMN amplitude over the period from baseline to post-transition; this reduction was not observed in UHR-NT. CONCLUSIONS: These results suggest that fMMN is abnormal in UHR individuals, as has repeatedly been found previously in people with established psychotic disorders. The finding that fMMN impairment worsens with transition to psychosis is consistent with the staging model of psychosis; however, caution must be taken in interpreting these findings, given the extremely small sample size of the UHR-T group.

Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control.

INTRODUCTION: Chronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in patients with cough is an enhanced sensitivity of the respiratory system to stimuli that subsequently evoke excessive coughing. The aetiology of this 'cough hypersensitivity syndrome' is unclear but believed to involve hypersensitivity of the sensory neural pathways that innervate the airways and lungs. METHODS: In the present study, we used functional brain imaging to compare central neural responses to airway stimulation using inhaled capsaicin in healthy people and patients with cough hypersensitivity. RESULTS: Hypersensitivity in response to inhaled capsaicin coincided with elevated neural activity in the midbrain in a region encompassing the nucleus cuneiformis (left: p<0.001; right: p<0.001) and periaqueductal gray (p=0.008) in comparison to normal sensitivity in controls. The enhanced activity noted in the midbrain is similar to that occurring in patients with chronic pain, thus providing empirical evidence to support the notion that cough and pain share neurobiological similarities. Furthermore, patients with cough hypersensitivity displayed difficulty controlling their cough, which manifested as a failure to suppress cough during capsaicin challenge (ie, reduced cough frequency) in controls compared with patients with cough hypersensitivity (p=0.046). Cough suppression was associated with reduced activity in a forebrain network that included the dorsomedial prefrontal and anterior mid-cingulate cortices. Additionally, cough frequency was correlated with activity in the right inferior frontal gyrus (R(2)=0.6, p<0.001) and right anterior insula (R(2)=0.6, p<0.001), regions previously implicated in voluntary cough suppression. CONCLUSIONS: These findings provide insight into the central neurobiology of cough hypersensitivity and suggest that both central amplification of cough sensory inputs and reduced capacity to suppress cough motor behaviours define patients with problematic cough.

Cough-related neural processing in the brain: a roadmap for cough dysfunction?

Cough is a complex respiratory behavior essential for airway protection, consisting of sensory, motor, affective and cognitive attributes. Accordingly, the cough neural circuitry extends beyond a simple pontomedullary reflex arc to incorporate a network of neurons that are also widely distributed throughout the subcortical and cortical brain. Studies have described discrete regional responses in the brain that likely give rise to sensory discriminative processes, voluntary and urge-related cough control mechanisms and aspects of the emotive responses following airways irritation and coughing. Data from these studies highlight the central nervous system as a plausible target for therapeutic intervention and, consistent with this, a careful appraisal of the many and varied clinical disorders of coughing control would argue that more diversified therapies are needed to treat patients with cough dysfunction. In this paper we explore these concepts in detail to highlight unanswered questions and stimulate discussion for potential research of cough in the future.

Functionally connected brain regions in the network activated during capsaicin inhalation.

Coughing and the urge-to-cough are important mechanisms that protect the patency of the airways, and are coordinated by the brain. Inhaling a noxious substance leads to a widely distributed network of responses in the brain that are likely to reflect multiple functional processes requisite for perceiving, appraising, and behaviorally responding to airway challenge. The broader brain network responding to airway challenge likely contains subnetworks that are involved in the component functions required for coordinated protective behaviors. Functional connectivity analyses were used to determine whether brain responses to airway challenge could be differentiated regionally during inhalation of the tussive substance capsaicin. Seed regions were defined according to outcomes of previous activation studies that identified regional brain responses consistent with cough suppression, stimulus intensity coding, and perception of urge-to-cough. The subnetworks during continuous inhalation of capsaicin recapitulated the distributed regions previously implicated in discrete functional components of airway challenge. The outcomes of this study highlight the central representation of airways defence as a distributed network.

Functional magnetic resonance imaging of working memory in Huntington's disease: cross-sectional data from the IMAGE-HD study.

We used functional magnetic resonance imaging (fMRI) to investigate spatial working memory (WM) in an N-BACK task (0, 1, and 2-BACK) in premanifest Huntington's disease (pre-HD, n = 35), early symptomatic Huntington's disease (symp-HD, n = 23), and control (n = 32) individuals. Overall, both WM conditions (1-BACK and 2-BACK) activated a large network of regions throughout the brain, common to all groups. However, voxel-wise and time-course analyses revealed significant functional group differences, despite no significant behavioral performance differences. During 1-BACK, voxel-wise blood-oxygen-level-dependent (BOLD) signal activity was significantly reduced in a number of regions from the WM network (inferior frontal gyrus, anterior insula, caudate, putamen, and cerebellum) in pre-HD and symp-HD groups, compared with controls; however, time-course analysis of the BOLD response in the dorsolateral prefrontal cortex (DLPFC) showed increased activation in symp-HD, compared with pre-HD and controls. The pattern of reduced voxel-wise BOLD activity in pre-HD and symp-HD, relative to controls, became more pervasive during 2-BACK affecting the same structures as in 1-BACK, but also incorporated further WM regions (anterior cingulate gyrus, parietal lobe and thalamus). The DLPFC BOLD time-course for 2-BACK showed a reversed pattern to that observed in 1-BACK, with a significantly diminished signal in symp-HD, relative to pre-HD and controls. Our findings provide support for functional brain reorganisation in cortical and subcortical regions in both pre-HD and symp-HD, which are modulated by task difficulty. Moreover, the lack of a robust striatal BOLD signal in pre-HD may represent a very early signature of change observed up to 15 years prior to clinical diagnosis.

Sensorimotor circuitry involved in the higher brain control of coughing.

There is an overwhelming body of evidence to support the existence of higher brain circuitries involved in the sensory detection of airways irritation and the motor control of coughing. The concept that cough is purely a reflex response to airways irritation is now superseded by the recognition that perception of an urge-to-cough and altered behavioral modification of coughing are key elements of cough disorders associated with airways disease. Understanding the pathways by which airway sensory nerves ascend into the brain and the patterns of neural activation associated with airways irritation will undoubtedly provide new insights into disordered coughing. This brief review aims to explore our current understanding of higher order cough networks by summarizing data from recent neuroanatomical and functional studies in animals and humans. We provide evidence for the existence of distinct higher order network components involved in the discrimination of signals arising from the airways and the motor control of coughing. The identification of these network components provides a blueprint for future research and the development of targeted managements for cough and the urge-to-cough.

Investigation of the neural control of cough and cough suppression in humans using functional brain imaging.

Excessive coughing is one of the most common reasons for seeking medical advice, yet the available therapies for treating cough disorders are inadequate. Humans can voluntarily cough, choose to suppress their cough, and are acutely aware of an irritation that is present in their airways. This indicates a significant level of behavioral and conscious control over the basic cough reflex pathway. However, very little is known about the neural basis for higher brain regulation of coughing. The aim of the present study was to use functional brain imaging in healthy humans to describe the supramedullary control of cough and cough suppression. Our data show that the brain circuitry activated during coughing in response to capsaicin-evoked airways irritation is not simply a function of voluntarily initiated coughing and the perception of airways irritation. Rather, activations in several brain regions, including the posterior insula and posterior cingulate cortex, define the unique attributes of an evoked cough. Furthermore, the active suppression of irritant-evoked coughing is also associated with a unique pattern of brain activity, including an involvement of the anterior insula, anterior mid-cingulate cortex, and inferior frontal gyrus. These data demonstrate for the first time that evoked cough is not solely a brainstem-mediated reflex response to irritation of the airways, but rather requires active facilitation by cortical regions, and is further regulated by distinct higher order inhibitory processes.