Zack Shan

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder with suspected neuroinflammatory pathophysiology. However, previous diffusion tensor imaging (DTI) studies have reported inconsistent white matter abnormalities in ME/CFS, and specific white matter inflammatory changes remain poorly characterised. This study employed an advanced diffusion‐based neuroinflammation imaging (NII) model to investigate white matter neuroinflammation in ME/CFS. Diffusion MRI data from 67 ME/CFS patients (median age, 38; and 54 women) and 67 rigorously matched healthy controls (HCs) (median age 38; and 52 women) were analysed. Seven NII‐derived metrics were computed: hindered water ratio (NII‐HR), restricted fraction (NII‐RF), fibre fraction (NII‐FF), axial diffusivity (NII‐AD), radial diffusivity (NII‐RD), mean diffusivity (NII‐MD) and fractional anisotropy (NII‐FA). Conventional DTI metrics were also calculated. Tract‐based spatial statistics were used to perform voxel‐wise group comparisons, and multiple regression analysis was conducted to examine the relationship between NII/DTI metrics and clinical measures of mental health, physical health, sleep quality, disability, disease severity and disease duration. Compared to HCs, ME/CFS patients exhibited widespread white matter abnormalities, including significantly lower NII‐HR and NII‐RF, and significantly higher NII‐FF, NII‐AD, NII‐MD and NII‐FA across association, commissural and projection fibres. Additionally, some regions showed decreased NII‐AD and NII‐MD in ME/CFS. Lower NII‐RF, NII‐AD and NII‐MD in ME/CFS were significantly associated with worse mental health, while lower NII‐RF was also associated with a higher level of disability. Among ME/CFS patients, higher NII‐FF was associated with lower disease severity. Conventional DTI showed minimal group differences and no significant clinical associations. This study provides in vivo evidence of white matter neuroinflammation in ME/CFS, characterised by cerebral edema (reduced NII‐HR), cellular infiltration (reduced NII‐RF) and axonal reorganisation (increased NII‐FF). This suggests NII‐derived indices may serve as sensitive biomarkers for neuroinflammation in ME/CFS. Diffusion‐based neuroinflammation imaging (NII) reveals widespread white matter abnormalities in ME/CFS patients, undetected by conventional DTI. NII metrics associate with mental health, disability and disease severity, providing novel evidence of neuroinflammation and highlighting NII's potential as a biomarker in ME/CFS.

Objectives
Xerostomia toxicity continues to contribute towards a decrease in quality of life in head and neck cancer patients. Diffusion weighted MRI and the associated apparent diffusion coefficient (ADC) may identify the radiosensitive region within the parotid gland (PG). This study retrospectively assesses the feasibility of using percentile threshold values from the ADC map to generate a biological at-risk volume (BRV). The location and distribution of BRV are evaluated across the PG.

Methods
Image registration between the planning CT and MRI-simulation images was performed and reviewed to ensure accurate translation of ADC data when contouring the PG. Histogram analysis was undertaken using the 20th, 30th, and 50th percentile ADC values of each contoured PG to form the BRV. The whole PG was split into 8 anatomical sectors at a common intersection point to evaluate the distribution of BRV throughout.

Results
The BRV distribution for each percentile was mapped across the whole contoured PG and each anatomical sector contour. The largest distribution was predominantly found in the superolateral sectors.

Conclusions
The 20th and 30th percentile ADC values can be used to form a BRV of the PG. The location of the BRV distribution indicates a potential relationship between ADC thresholds and the functional region of the PG.

Advances in knowledge
The BRV is located in a favourable position within the PG and could be used to further spare this salivary gland during dose optimization. The feasibility of this approach will be explored in a future retrospective dosimetry study.

While post-infectious (PI-ME/CFS) and gradual onset (GO-ME/CFS) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) manifest similar symptoms, it has long been suspected that different disease processes underlie them. However, the lack of biological evidence has left this question unanswered. In this study, how white matter microstructural changes in PI-ME/CFS and GO-ME/CFS patients were investigated. PI-ME/CFS and GO-ME/CFS patients were recruited based on consensus diagnoses made by two experienced clinicians and compared their diffusion MRI features with those of rigorously matched healthy controls (HCs) with sedentary lifestyles. PI-ME/CFS participants showed significantly higher axial diffusivity (AD) in several association and projection fibres compared to HCs. Higher AD in PI-ME/CFS was significantly related to worse physical health. In contrast, GO-ME/CFS participants exhibited significantly decreased AD in the corpus callosum. Lower AD in GO-ME/CFS was significantly associated with worse mental health in commissural and projection fibres. No significant group differences were found for fractional anisotropy, mean diffusivity, or radial diffusivity. Distinct patterns of AD alterations in PI-ME/CFS and GO-ME/CFS provide neurophysiological evidence of different disease processes and highlight the heterogeneities of ME/CFS.

Body image-related cyberbullying (BRC), which targets an individual’s body shape, weight, and/or size, is associated with body dissatisfaction and maladaptive eating behaviours among adolescent females. However, its neurobiological mechanisms remain unclear. Using functional magnetic resonance imaging, we examined neural responses to BRC stimuli in 26 females (14–18 years; Mage = 15.54) from the Longitudinal Adolescent Brain Study. BRC stimuli elicited greater BOLD responses in regions implicated in emotional regulation (insula, anterior cingulate cortex), visual processing (lateral occipital cortex, fusiform gyrus), and social cognition (temporal pole, angular gyrus). Adolescents with recent cyberbullying experiences exhibited greater BOLD responses in the parahippocampal gyrus and lateral occipital cortex, whereas those without body dissatisfaction showed greater responses in the caudate and amygdala. Longitudinally, increased cyberbullying perpetration was associated with greater BOLD responses in the angular and middle temporal gyri. These findings provide insights into neurobiological pathways through which BRC may influence adolescent brain function and mental health.

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.

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.

Objectives
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating chronic illness for which there are no well-accepted treatments, aside from some preliminary trials and symptom management strategies, such as low-dose naltrexone and NICE guidelines. A clinician administered a synergistic off-label treatment (SOT) involving spironolactone, colchicine, low-dose naltrexone, and multivitamins to ME/CFS patients, resulting in reported symptom improvement. This study sought to investigate neuroimaging characteristics linked with the treatment.

Methods
A group of treatment-naive patients (N = 8, control) was selected to age – and sex-match eight patients who had received the treatment (SOT). Diffusion-weighted imaging data and clinical measures from the two groups were compared.

Results
Compared to the control group, the SOT group showed reduced depression (Bonferroni corrected P value (PBonf) = .04) and mental deficit symptoms (PBonf = .02). Furthermore, the SOT group at post-treatment showed significantly reduced clinical scores (PBonf < .001) than at the pre-treatment baseline. We also observed higher fractional anisotropy and lower diffusivity measures in various white-matter tracts of the SOT group compared to the control group (Family-wise-error-corrected P value (PFWE) ≤ .05).

Conclusion
These findings provide a first line of evidence for the potential effectiveness of SOT treatment in ME/CFS patients, as indicated by microstructural changes in the brain associated with improved clinical symptoms. Formal randomized controlled trials are required to determine the efficacy of SOT components in treating ME/CFS.

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

Background: The Stroop task was used to investigate differences in cognitive function between Long COVID (LC), Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and healthy control subjects. Methods: Subjects viewed four color words or neutral (XXXX) stimuli with the same (congruent) or different color ink (incongruent). Cognitive conflict was inferred from response times for pairings of prestimuli and subsequent stimuli. Overall effects were assessed by univariate analysis with time courses determined for binned response times. Results: LC and ME/CFS had significantly longer response times than controls indicating cognitive dysfunction. Initial response times were ranked LC > ME > HC, and decreased according to power functions. At the end of the task (900s), times were ranked LC = ME > HC. Response times were significantly slower for stimuli following an incongruent prestimulus. Time series for Stroop effect, facilitation, interference, surprise index and practice power law parameters were generally similar in LC, ME/CFS and HC suggesting comparable patterns for recruitment of cognitive resources. The prestimulus data were analyzed and generated positive Stroop and interference effects that were distinct from stimulus effects. Conclusion: LC and ME/CFS have global slowing of response times that cannot be overcome by practice suggesting impaired communications between network nodes during problem solving. Analysis of matched prestimulus – stimulus effects adds a new dimension for understanding cognitive conflict. Brief Summary: Cognitive dysfunction in Long COVID and ME/CFS was demonstrated using the Stroop task which found global slowing of response times and limitations of practice effects.