Functional MRI of the Brainstem for Assessing Its Autonomic Functions: From Imaging Parameters and Analysis to Functional Atlas.

BACKGROUND: The brainstem is a crucial component of the central autonomic nervous (CAN) system. Functional MRI (fMRI) of the brainstem remains challenging due to a range of factors, including diverse imaging protocols, analysis, and interpretation. PURPOSE: To develop an fMRI protocol for establishing a functional atlas in the brainstem. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Ten healthy subjects (four males, six females). FIELD STRENGTH/SEQUENCE: Using a 3.0 Tesla MR scanner, we acquired T1-weighted images and three different fMRI scans using fMRI protocols of the optimized functional Imaging of Brainstem (FIBS), the Human Connectome Project (HCP), and the Adolescent Brain Cognitive Development (ABCD) project. ASSESSMENT: The temporal signal-to-noise-ratio (TSNR) of fMRI data was compared between the FIBS, HCP, and ABCD protocols. Additionally, the main normalization algorithms (i.e., FSL-FNIRT, SPM-DARTEL, and ANTS-SyN) were compared to identify the best approach to normalize brainstem data using root-mean-square (RMS) error computed based on manually defined reference points. Finally, a functional autonomic brainstem atlas that maps brainstem regions involved in the CAN system was defined using meta-analysis and data-driven approaches. STATISTICAL TESTS: ANOVA was used to compare the performance of different imaging and preprocessing pipelines with multiple comparison corrections (P ≤ 0.05). Dice coefficient estimated ROI overlap, with 50% overlap between ROIs identified in each approach considered significant. RESULTS: The optimized FIBS protocol showed significantly higher brainstem TSNR than the HCP and ABCD protocols (P ≤ 0.05). Furthermore, FSL-FNIRT RMS error (2.1 ± 1.22 mm; P ≤ 0.001) exceeded SPM (1.5 ± 0.75 mm; P ≤ 0.01) and ANTs (1.1 ± 0.54 mm). Finally, a set of 12 final brainstem ROIs with dice coefficient ≥0.50, as a step toward the development of a functional brainstem atlas. DATA CONCLUSION: The FIBS protocol yielded more robust brainstem CAN results and outperformed both the HCP and ABCD protocols. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Oral ketamine effects on dynamics of functional network connectivity in patients treated for chronic suicidality.

The underlying brain mechanisms of ketamine in treating chronic suicidality and the characteristics of patients who will benefit from ketamine treatment remain unclear. To address these gaps, we investigated temporal variations of brain functional synchronisation in patients with suicidality treated with ketamine in a 6-week open-label oral ketamine trial. The trial's primary endpoint was the Beck Scale for Suicide Ideation (BSS). Patients who experienced greater than 50% improvement in BSS scores or had a BSS score less than 6 at the post-treatment and follow-up (10 weeks) visits were considered responders and persistent responders, respectively. The reoccurring and transient connectivity pattern (termed brain state) from 29 patients (45.6 years ± 14.5, 15 females) were investigated by dynamic functional connectivity analysis of resting-state functional MRI at the baseline, post-treatment, and follow-up. Post-treatment patients showed significantly more (FDR-Q = 0.03) transitions among whole brain states than at baseline. We also observed increased dwelling time (FDR-Q = 0.04) and frequency (FDR-Q = 0.04) of highly synchronised brain state at follow-up, which were significantly correlated with BSS scores (both FDR-Q = 0.008). At baseline, persistent responders had higher fractions (FDR-Q = 0.03, Cohen's d = 1.39) of a cognitive control network state with high connectivities than non-responders. These findings suggested that ketamine enhanced brain changes among different synchronisation patterns and enabled high synchronisation patterns in the long term, providing a possible biological pathway for its suicide-prevention effects. Moreover, differences in cognitive control states at baseline may be used for precise ketamine treatment planning.

A longitudinal study of functional connectome uniqueness and its association with psychological distress in adolescence.

Each human brain has a unique functional synchronisation pattern (functional connectome) analogous to a fingerprint that underpins brain functions and related behaviours. Here we examine functional connectome (whole-brain and 13 networks) maturation by measuring its uniqueness in adolescents who underwent brain scans longitudinally from 12 years of age every four months. The uniqueness of a functional connectome is defined as its ratio of self-similarity (from the same subject at a different time point) to the maximal similarity-to-others (from a given subject and any others at a different time point). We found that the unique whole brain connectome exists in 12 years old adolescents, with 92% individuals having a whole brain uniqueness value greater than one. The cingulo-opercular network (CON; a long-acting 'brain control network' configuring information processing) demonstrated marginal uniqueness in early adolescence with 56% of individuals showing uniqueness greater than one (i.e., more similar to her/his own CON four months later than those from any other subjects) and this increased longitudinally. Notably, the low uniqueness of the CON correlates (ß = -18.6, FDR-Q < < 0.001) with K10 levels at the subsequent time point. This association suggests that the individualisation of CON network is related to psychological distress levels. Our findings highlight the potential of longitudinal neuroimaging to capture mental health problems in young people who are undergoing profound neuroplasticity and environment sensitivity period.

Can measures of sleep quality or white matter structural integrity predict level of worry or rumination in adolescents facing stressful situations? Lessons from the COVID-19 pandemic.

INTRODUCTION: COVID-19 has resulted in major life changes to the majority of the world population, particularly adolescents, with social-distancing measures such as home-based schooling likely to impact sleep quality. Increased worry is also likely considering the substantial financial, educational and health concerns accompanying COVID-19. White matter (WM) integrity has been shown to be associated with anxiety and depression symptoms, including worry, as well being closely associated with sleep quality. This study aimed to investigate the associations between pre-COVID sleep quality, WM structural integrity and levels of worry and rumination about COVID. METHODS: N = 30 adolescent participants from Queensland, Australia, completed diffusion tensor imaging (DTI) scanning pre-COVID, the Pittsburgh Sleep Quality Index (PSQI) pre and during COVID, and 9 items designed to measure 3 constructs, perceived impact of COVID, general worry, and COVID-specific worry and rumination. RESULTS: Sleep quality (PSQI total) was significantly poorer during COVID compared with pre-COVID. Sleep onset latency measured pre-COVID was significantly associated with COVID-specific worry and rumination. While the structural integrity of a number of WM tracts (measured pre-COVID) were found to be significantly associated with COVID-specific worry and rumination. Follow-up regression analysis using a model including pre-COVID sleep onset latency, structural integrity of the posterior limb of the internal capsule (PLIC), gender and change in PSQI explained a significant 47% of the variance in COVID-specific worry and rumination. CONCLUSIONS: These findings suggest that adolescents with poor sleep quality and perturbed WM integrity may be at risk of heightened reactivity to future stressful events and interventions should focus on improving sleep onset latency.

Neurobiological underpinnings of cyberbullying: A pilot functional magnetic resonance imaging study.

There is a dearth of research that has investigated the neural correlates of cyberbullying, using task-based functional magnetic resonance imaging (fMRI) and, specifically, in a real-time context such as observing cyberbullying scenarios. This article presents pilot data from a novel protocol designed to undertake such research with the overall aim being to elucidate the neurobiological underpinnings of cyberbullying via task-based fMRI (tb-fMRI)) in passive cyberbystanders. Young adults (N = 32, 18 to 25 years old) viewed six negative (cyberbullying) and six neutral stimuli from the Cyberbullying Picture Series (CyPicS) while undergoing tb-fMRI. Our results revealed 12 clusters of significantly greater blood-oxygenation-level-dependent (BOLD) responses (family wise error corrected p FWE < .05) in participants when viewing cyberbullying stimuli compared to neutral stimuli, across a distributed network of regions including left and right middle temporal gyrus, default mode network hubs, left and right posterior cerebellum/vermis, and putamen. Further analysis also revealed greater BOLD response in females compared to males, as well as in those with no prior experience of cyberbullying compared to those with prior experience (despite gender), when viewing the cyberbullying stimuli compared to the neutral stimuli. These results bring us closer to understanding the neurobiological underpinnings that may be associated with cybervictim/bully status and outcomes.

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review.

BACKGROUND: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. METHOD: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. RESULTS: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. CONCLUSION: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome.

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE  < 0.05) and between PSQI and T1w intensities (PFWE  < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study.

PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.

Hippocampal subfield volumes predict treatment response to oral ketamine in people with suicidality.

Ongoing stress results in hippocampal neuro-structural alterations which produce pathological consequences, including depression and suicidality. Ketamine may ameliorate stress related illnesses, including suicidality, via neuroplasticity processes. This novel study sought to determine whether oral ketamine treatment specifically affects hippocampal (whole and subfield) volumes in patients with chronic suicidality and MDD. It was hypothesised that oral ketamine treatment would differentially alter hippocampal volumes in trial participants categorised as ketamine responders, versus those who were non-responders. Twenty-eight participants received 6 single, weekly doses of oral ketamine (0.5-3 mg/kg) and underwent MRI scans at pre-ketamine (week 0), post-ketamine (week 6), and follow up (week 10). Hippocampal subfield volumes were extracted using the longitudinal pipeline in FreeSurfer. Participants were grouped according to ketamine response status and then compared in terms of grey matter volume (GMV) changes, among 10 hippocampal regions, over 6 and 10 weeks. Mixed ANOVAs were used to analyse interactions between time and group. Post treatment analysis revealed a significant main effect of group for three left hippocampal GMVs as well in the left and right whole hippocampus. Ketamine acute responders (Week 6) showed increased GMVs in both left and right whole hippocampus and in three subfields compared to acute non-responders, across all three timepoints, suggesting that pre-treatment increased hippocampal GMVs (particularly left hemisphere) may be predictive biomarkers of acute treatment response. Future studies should further investigate the potential of hippocampal volumes as a biomarker of ketamine treatment response.

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI.

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.

Precision Medicine for Brain Disorders: New and Emerging Approaches.

The brain is the most complex organ in the human body, making it susceptible to many abnormalities [...].

Self-reported Fatigue was Associated with Increased White-matter Alterations in Long-term Traumatic Brain Injury and Posttraumatic Stress Disorder Patients.

Fatigue is a long-lasting problem in traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), with limited research that investigated the fatigue-related white-matter changes within TBI and/or PTSD cohorts. This exploratory cross-sectional study used diffusion tensor imaging (DTI) and neuropsychological data collected from 153 male Vietnam War veterans, as part of the Alzheimer's Disease Neuroimaging Initiative - Department of Defense, and were divided clinically into control veterans, PTSD, TBI, and with both TBI and PTSD (TBI + PTSD). The existence of fatigue was defined by the question "Do you often feel tired, fatigued, or sleepy during the daytime?". DTI data were compared between fatigue and non-fatigue subgroups in each clinical group using tract-based spatial statistics voxel-based differences. Fatigue was reported in controls (29.55%), slightly higher in TBI (52.17%, PBenf = 0.06), and significantly higher in both TBI + PTSD (66.67%, PBenf = 0.001) and PTSD groups (79.25%, PBenf < 0.001). Compared to non-fatigued subgroups, no white-matter differences were observed in the fatigued subgroups of control or TBI, while the fatigued PTSD subgroup only showed increased diffusivity measures (i.e., radial and axial), and the fatigued TBI + PTSD subgroup showed decreased fractional anisotropy and increased diffusivity measures (PFWE ≤ 0.05). The results act as preliminary findings suggesting fatigue to be significantly reported in TBI + PTSD and PTSD decades post-trauma with a possible link to white-matter microstructural differences in both PTSD and TBI + PTSD. Future studies with larger cohorts and detailed fatigue assessments would be required to identify the white-matter changes associated with fatigue in these cohorts.

Treatment response with ketamine in chronic suicidality: An open label functional connectivity study.

BACKGROUND: Ketamine has recently been proposed as a treatment option for suicidality. Whilst its mechanism of action has been explored at molecular levels, the effect on the brain at the organ level remains unclear. Here we investigate immediate post-treatment and prolonged large-scale resting-state neural network changes to elucidate the neuronal underpinnings associated with ketamine's therapeutic effects. METHODS: Twenty-eight adults (aged 22-72 years) participated in the Oral Ketamine Trial On Suicidality, which is an open-label trial of weekly sub-anaesthetic doses of oral ketamine over 6 weeks. MRI was acquired at baseline, post-treatment, and follow-up. Functional connectivity changes at post-treatment and follow-up were examined using seed based and independent component analysis. RESULTS: The seed-based connectivity analysis revealed significantly reduced connectivity at post-treatment from the right hippocampus to both right and left superior frontal gyrus, from the left anterior parahippocampus to right superior frontal gyrus, left superior frontal gyrus, right middle frontal gyrus, and left frontal operculum cortex. Compared with baseline, the ICA showed reduced anterior default mode network connectivities to bilateral posterior cingulate cortex, middle and anterior cingulate cortex, lingual gyrus, and cuneus and increased connectivity of the frontoparietal network to the right superior parietal lobule at post-treatment. LIMITATIONS: Open label pilot study. CONCLUSIONS: We have shown sub-anaesthetic doses of ketamine alters connectivity in networks which have been shown to be aberrantly hyper-connected in numerous psychiatric conditions. These neurocircuitry changes are supported by significant reductions in suicide ideation. Our results provide support for the use of ketamine as a treatment for suicidality.

Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis.

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases. After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep. Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency. However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency. The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.

The effect of mindfulness training on resting-state networks in pre-adolescent children with sub-clinical anxiety related attention impairments.

Mindfulness training has been associated with improved attention and affect regulation in preadolescent children with anxiety related attention impairments, however little is known about the underlying neurobiology. This study sought to investigate the impact of mindfulness training on functional connectivity of attention and limbic brain networks in pre-adolescents. A total of 47 children with anxiety and/or attention issues (aged 9-11 years) participated in a 10-week mindfulness intervention. Anxiety and attention measures and resting-state fMRI were completed at pre- and post-intervention. Sustained attention was measured using the Conners Continuous Performance Test, while the anxiety levels were measured using the Spence Children's Anxiety Scale. Functional networks were estimated using independent-component analysis, and voxel-based analysis was used to determine the difference between the time-points to identify the effect of the intervention on the functional connectivity. There was a significant decrease in anxiety symptoms and improvement in attention scores following the intervention. From a network perspective, the results showed increased functional connectivity post intervention in the salience and fronto-parietal networks as well as the medial-inferior temporal component of the default mode network. Positive correlations were identified in the fronto-parietal network with Hit Response Time and the Spence Children's Anxiety Scale total and between the default mode network and Hit Response Time. A 10-week mindfulness intervention in children was associated with a reduction in anxiety related attention impairments, which corresponded with concomitant changes in functional connectivity.

Gender differences in brain activity when exposed to cyberbullying: Associations between wellbeing and cyberbullying experience using functional Magnetic Resonance Imaging.

The role of gender and the associated brain activation when witnessing cyberbullying requires investigation. The current study aimed to determine whether brain responses to cyberbullying differ according to gender and level of wellbeing. We hypothesised that females and males would activate different regions of the brain when witnessing cyberbullying, and that this would be influenced by wellbeing levels and prior cyberbullying experiences. Blood-oxygenation-level-dependent (BOLD) responses were examined in participants (N = 32, aged 18-25 years; 66% female) whilst observing cyberbullying versus neutral stimuli during a functional MRI. Results revealed significant correlations between BOLD signal and achievement scores among males, but not females, with previous experiences of cyberbullying, in regions including the cerebellum, the superior and inferior frontal gyrus, and the precuneus. Furthermore, males who previously cyberbullied others, with higher scores in achievement (a wellbeing sub-category), activated brain regions associated with executive function, social cognition, and self-evaluation, when viewing the cyberbullying stimuli. In addition, despite gender, BOLD signal in the cingulate gyrus was negatively correlated with cyberbullying scores, and BOLD signal in the left dorsal caudate and the cerebellum was independently and positively correlated with achievement scores. Taken together, these findings provide insights into brain responses to cyberbullying scenarios and emphasize that there are some significant variations according to gender. The overall finding that males activated brain regions linked to varying aspects of cognition, whereas females more often activated regions linked to emotion processing and empathy is important for future research in this area.

Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study toward its neuropathophysiology and diagnosis.

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis. A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS. NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca2+ influx in adjacent neurons and astrocytes. In turn, increased Ca2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs.This study investigates NVC using multimodal MRIs: (1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modeled from a cognitive task fMRI; (2) respiration response function (RRF) represents autoregulation of regional blood flow due to carbon dioxide and will be modeled from breath-holding fMRI; (3) neural activity associated glutamate changes will be modeled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework. Methods and analysis: This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by consensus diagnosis made by two clinicians using the Canadian Consensus Criteria 2003. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, sex, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator-regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group. Ethics and study registry: This study was reviewed and approved by University of the Sunshine Coast University Ethics committee (A191288) and has been registered with The Australian New Zealand Clinical Trials Registry (ACTRN12622001095752). Dissemination of results: The results will be disseminated through peer reviewed scientific manuscripts and conferences and to patients through social media and active engagement with ME/CFS associations.

Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence.

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them. We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed. We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10-8, 5 × 10-7, 0.002), T2wSE (p =2 × 10-6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets. In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain's primary regulatory nuclei. We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance.

White matter connectivity in neonates at risk of stuttering: Preliminary data.

BACKGROUND: Developmental stuttering is thought to be underpinned by structural impairments in the brain. The only way to support the claim that these are causal is to determine if they are present before onset. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) was conducted on 18 neonates, aged 8-18 weeks, 6 of whom were determined to be genetically at risk of stuttering. RESULTS: With tract-based spatial statistics (TBSS) analysis, no statistically significant differences were found between the at-risk group and the control group. However, fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) in the corpus callosum of the at-risk group were lower (uncorrected) than in the control group. Automated Fiber Quantification (AFQ) yielded lower FA in the at-risk group than in the control group in the medial section of the callosum forceps minor. DISCUSSION: The findings, albeit with a small number of participants, support the proposition that reduced integrity of white matter in the corpus callosum has a causal role in developmental stuttering. Longitudinal research to determine if children with this impairment at birth later start to stutter is needed to confirm this. The left arcuate fasciculus is thought to develop as speech develops, which likely explains why there were no abnormal findings in this area in our at-risk neonates so soon after birth. This is the first study to investigate the brains of children before the onset of stuttering, and the findings warrant further research.

Basal ganglia correlates of wellbeing in early adolescence.

It has been suggested that biological markers that define mental health are different to those that define mental illness. The basal ganglia changes dramatically over adolescence and has been linked to wellbeing and mental health disorders in young people. However, there remains a paucity of research on wellbeing and brain structure in early adolescence. This cross-sectional study examined relationships between grey matter volume (GMV) of basal ganglia regions (caudate, putamen, pallidum and nucleus accumbens) and self-reported wellbeing (COMPAS-W), in a sample of Australian adolescents aged 12 years (N = 49, M = 12.6, 46.9% female). Significant negative associations were found between left hemisphere caudate GMV and scores on 'total wellbeing', 'composure' and 'positivity'. The results of this study indicate that smaller caudate GMV at age 12 is linked to increased subjective wellbeing. While seemingly counter-intuitive, our finding is consistent with previous research of decreased GMV in the pons and increased COMPAS-W scores in adults. Our results suggest that protective neurobiological factors may be identifiable early in adolescence and be linked to specific types of wellbeing (such as positive affect and optimism). This has implications for interventions targeted at building resilience against mental health disorders in young people.