Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks.

Inflammation is associated with depressive symptoms and innate immune mechanisms are likely causal in some cases of major depression. Systemic inflammation also perturbs brain function and microstructure, though how these are related remains unclear. We recruited N = 46 healthy controls, and N = 83 depressed cases stratified by CRP (> 3 mg/L: N = 33; < 3 mg/L: N = 50). All completed clinical assessment, venous blood sampling for C-reactive protein (CRP) assay, and brain magnetic resonance imaging (MRI). Micro-structural MRI parameters including proton density (PD), a measure of tissue water content, were measured at 360 cortical and 16 subcortical regions. Resting-state fMRI time series were correlated to estimate functional connectivity between individual regions, as well as the sum of connectivity (weighted degree) of each region. Multiple tests for regional analysis were controlled by the false discovery rate (FDR = 5%). We found that CRP was significantly associated with PD in precuneus, posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC); and with functional connectivity between pC/pCC, mPFC and hippocampus. Depression was associated with reduced weighted degree of pC/pCC, mPFC, and other nodes of the default mode network (DMN). Thus CRP-related increases in proton density-a plausible marker of extracellular oedema-and changes in functional connectivity were anatomically co-localised with DMN nodes that also demonstrated significantly reduced hubness in depression. We suggest that effects of peripheral inflammation on DMN node micro-structure and connectivity may mediate inflammatory effects on depression.

Variant connective tissue (joint hypermobility) and dysautonomia are associated with multimorbidity at the intersection between physical and psychological health.

The symptoms of joint hypermobility extend beyond articular pain. Hypermobile people commonly experience autonomic symptoms (dysautonomia), and anxiety or related psychological issues. We tested whether dysautonomia might mediate the association between hypermobility and anxiety in adults diagnosed with mental health disorders and/or neurodevelopmental conditions (hereon referred to as patients), by quantifying joint hypermobility and symptoms of autonomic dysfunction. Prevalence of generalized joint laxity (hypermobility) in 377 individuals with diagnoses of mental health disorders and/or neurodevelopmental conditions was compared to prevalence recorded in the general population. Autonomic symptom burden was compared between hypermobile and non-hypermobile patients. Mediation analysis explored relationships between hypermobility, autonomic dysfunction, and anxiety. Patient participants had elevated prevalence of generalized joint laxity (38%) compared to the general population rate of 19% (odds ratio: 2.54 [95% confidence interval: 2.05, 3.16]). Hypermobile participants reported significantly more autonomic symptoms. Symptoms of orthostatic intolerance mediated the relationship between hypermobility and diagnosis of an anxiety disorder. Patients with mental health disorders and/or neurodevelopmental conditions have high rates of joint hypermobility. Accompanying autonomic dysfunction mediates the association between joint hypermobility and clinical anxiety status. Increased recognition of this association can enhance mechanistic understanding and improve the management of multimorbidity expressed in physical symptoms and mental health difficulties.

Comparing multiband and singleband EPI in NODDI at 3 T: what are the implications for reproducibility and study sample sizes?

OBJECTIVE: The reproducibility of Neurite orientation dispersion and density imaging (NODDI) metrics from time-saving multiband (MB) EPI compared with singleband (SB) has not been considered. This study aims to evaluate the reproducibility of NODDI parameters from SB and MB acquisitions, determine the agreement between acquisitions and estimate the sample sizes required to detect between-group change. METHODS: Brain diffusion MRI data were acquired using SB and MB (acceleration factors 2 (MB2) and 3 (MB3)) on 8 healthy subjects on 2 separate visits. NODDI maps of isotropic volume fraction (FISO), neurite density (NDI) and orientation dispersion index (ODI) were estimated. Region-of-interest analysis was performed; variability across subjects and visits was measured using coefficients of variation (CoV). Intraclass correlation coefficient and Bland-Altman analysis were performed to assess reproducibility and detect any systematic bias between SB, MB2 and MB3. Power calculations were used to determine sample sizes required to detect group differences. RESULTS: Both NDI and ODI were reproducible between visits; however, FISO was variable. All parameters were not reproducible across methods; a systematic bias was observed with the derived values decreasing as the MB factor increases. The number of subjects needed to detect a between-group change is not significantly different between methods; however, ODI needs considerably higher sample sizes than NDI. CONCLUSIONS: Both SB and MB yield highly reproducible NDI and ODI measures, but direct comparison of these parameters between methods is complicated by systematic differences that exist between the two approaches.

Neurite orientation and dispersion density imaging (NODDI) detects cortical and corticospinal tract degeneration in ALS.

BACKGROUND: Corticospinal tract (CST) degeneration and cortical atrophy are consistent features of amyotrophic lateral sclerosis (ALS). We hypothesised that neurite orientation dispersion and density imaging (NODDI), a multicompartment model of diffusion MRI, would reveal microstructural changes associated with ALS within the CST and precentral gyrus (PCG) 'in vivo'. METHODS: 23 participants with sporadic ALS and 23 healthy controls underwent diffusion MRI. Neurite density index (NDI), orientation dispersion index (ODI) and free water fraction (isotropic compartment (ISO)) were derived. Whole brain voxel-wise analysis was performed to assess for group differences. Standard diffusion tensor imaging (DTI) parameters were computed for comparison. Subgroup analysis was performed to investigate for NODDI parameter differences relating to bulbar involvement. Correlation of NODDI parameters with clinical variables were also explored. The results were accepted as significant where p<0.05 after family-wise error correction at the cluster level, clusters formed with p<0.001. RESULTS: In the ALS group NDI was reduced in the extensive regions of the CST, the corpus callosum and the right PCG. ODI was reduced in the right anterior internal capsule and the right PCG. Significant differences in NDI were detected between subgroups stratified according to the presence or absence of bulbar involvement. ODI and ISO correlated with disease duration. CONCLUSIONS: NODDI demonstrates that axonal loss within the CST is a core feature of degeneration in ALS. This is the main factor contributing to the altered diffusivity profile detected using DTI. NODDI also identified dendritic alterations within the PCG, suggesting microstructural cortical dendritic changes occur together with CST axonal damage.

Binge drinking differentially affects cortical and subcortical microstructure.

Young adult binge drinkers represent a model for endophenotypic risk factors for alcohol misuse and early exposure to repeated binge cycles. Chronic or harmful alcohol use leads to neurochemical, structural and morphological neuroplastic changes, particularly in regions associated with reward processing and motivation. We investigated neural microstructure in 28 binge drinkers compared with 38 matched healthy controls. We used a recently developed diffusion magnetic resonance imaging acquisition and analysis, which uses three-compartment modelling (of intracellular, extracellular and cerebrospinal fluid) to determine brain tissue microstructure features including neurite density and orientation dispersion index (ODI). Binge drinkers had reduced ODI, a proxy of neurite complexity, in frontal cortical grey matter and increased ODI in parietal grey matter. Neurite density was higher in cortical white matter in adjacent regions of lower ODI in binge drinkers. Furthermore, binge drinkers had higher ventral striatal grey matter ODI that was positively correlated with binge score. Healthy volunteers showed no such relationships. We demonstrate disturbed dendritic complexity of higher-order prefrontal and parietal regions, along with higher dendritic complexity of a subcortical region known to mediate reward-related motivation. The findings illustrate novel microstructural abnormalities that may reflect an infnce of alcohol bingeing on critical neurodevelopmental processes in an at-risk young adult group.

Altered white matter integrity in whole brain and segments of corpus callosum, in young social drinkers with binge drinking pattern.

Binge drinking is associated with impaired cognitive functioning, but the relationship of cognitive impairments and white matter integrity is less known. We used diffusion tensor imaging (DTI) to investigate the relationships of binge drinking, whole brain white matter integrity and cognitive performance during young adulthood (18 to 25 years), a period of continued brain development in two sessions 1 year apart. Binge drinkers (n = 20) and non-binge drinkers (n = 20) underwent DTI and completed measures of spatial working memory and motor impulsivity. Fractional anisotropy (FA), a measure derived from DTI, was estimated from whole brain and from five segments of the corpus callosum (CC): prefrontal, premotor/supplementary motor, motor, (SMA) sensory and parietal/temporal/occipital (PTO). FA was lower for binge than for non-binge men but not women at Session 1 and 2 for all measurements except for FA in the motor segment, which was significantly increased from Session 1 to Session 2. Lower FA in the prefrontal and PTO CC segments was associated with higher binge score, whereas lower FA in all five segments was associated with greater drug use in men and worse spatial working memory both in men and women. These findings extend the literature by showing that in early adulthood, binge drinking and drug use are linked with degradations in neural white matter and that compromised white matter at this period of brain development is linked with impaired cognitive functioning.

Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-e4 carriers compared with non-APOE-e4 carriers.

The presence of the e4 allele of the apolipoprotein E (APOE) gene is the best-known genetic risk factor for Alzheimer's disease. In this study, we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences in those who carry the e4 allele (e4+) and those who only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age, 21 years) and a mid-age group (average age, 50 years). High-resolution T1 -weighted MRI scans were analysed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. These data were correlated with behavioural findings in the same cohort. Resting-state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there was a positive correlation between the thickness of the parahippocampal cortex in young e4+ individuals and performance on an episodic memory task. Young e4+ individuals also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid-age, e4+ individuals had structural differences relative to e3/e3 individuals in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than in e3/e3 individuals. We discuss the possibility that an over-engagement with these regions by e4+ individuals in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE-driven differences in the brain, with greater functional connectivity among young e3/e3 individuals and greater white matter volume in young e4+ individuals.

Long-Term High-Effort Endurance Exercise in Older Adults: Diminishing Returns for Cognitive and Brain Aging.

While there is evidence that age-related changes in cognitive performance and brain structure can be offset by increased exercise, little is known about the impact long-term high-effort endurance exercise has on these functions. In a cross-sectional design with 12-month follow-up, we recruited older adults engaging in high-effort endurance exercise over at least 20 years, and compared their cognitive performance and brain structure with a nonsedentary control group similar in age, sex, education, IQ, and lifestyle factors. Our findings showed no differences on measures of speed of processing, executive function, incidental memory, episodic memory, working memory, or visual search for older adults participating in long-term high-effort endurance exercise, when compared without confounds to nonsedentary peers. On tasks that engaged significant attentional control, subtle differences emerged. On indices of brain structure, long-term exercisers displayed higher white matter axial diffusivity than their age-matched peers, but this did not correlate with indices of cognitive performance.

In vivo quantitative magnetization transfer imaging correlates with histology during de- and remyelination in cuprizone-treated mice.

The pool size ratio measured by quantitative magnetization transfer MRI is hypothesized to closely reflect myelin density, but their relationship has so far been confirmed mostly in ex vivo conditions. We investigate the correspondence between this parameter measured in vivo at 7.0 T, with Black Gold II staining for myelin fibres, and with myelin basic protein and beta-tubulin immunofluorescence in a hybrid longitudinal study of C57BL/6 and SJL/J mice treated with cuprizone, a neurotoxicant causing relatively selective myelin loss followed by spontaneous remyelination upon treatment suspension. Our results confirm that pool size ratio measurements correlate with myelin content, with the correlation coefficient depending on strain and staining method, and demonstrate the in vivo applicability of this MRI technique to experimental mouse models of multiple sclerosis.

Understanding the mechanisms of fatigue in multiple sclerosis: linking interoception, metacognition and white matter dysconnectivity.

One of the most prominent symptoms in multiple sclerosis is pathological fatigue, often described by sufferers as one of the most debilitating symptoms, affecting quality of life and employment. However, the mechanisms of both, physical and cognitive fatigue in multiple sclerosis remain elusive. Here, we use behavioural tasks and quantitative MRI to investigate the neural correlates of interoception (the ability to sense internal bodily signals) and metacognition (the ability of the brain to assess its own performance), in modulating cognitive fatigue. Assuming that structural damage caused by multiple sclerosis pathology might impair the neural pathways subtending interoception and/or metacognition, we considered three alternative hypotheses to explain fatigue as a consequence of, respectively: (i) reduced interoceptive accuracy, (ii) reduced interoceptive insight or (iii) reduced global metacognition. We then explored associations between these behavioural measures and white matter microstructure, assessed by diffusion and magnetisation transfer MRI. Seventy-one relapsing-remitting multiple sclerosis patients participated in this cross-sectional study (mean age 43, 62% female). Patient outcomes relevant for fatigue were measured, including disability, disease duration, depression, anxiety, sleepiness, cognitive function, disease modifying treatment and quality of life. Interoceptive and metacognitive parameters were measured using heartbeat tracking and discrimination tasks, and metacognitive visual and memory tasks. MRI was performed in 69 participants, including diffusion tensor MRI, neurite orientation dispersion and density imaging and quantitative magnetisation transfer. Associations between interoception and metacognition and the odds of high cognitive fatigue were tested by unconditional binomial logistic regression. The odds of cognitive fatigue were higher in the people with low interoceptive insight (P = 0.03), while no significant relationships were found between fatigue and other interoceptive or metacognitive parameters, suggesting a specific impairment in interoceptive metacognition, rather than interoception generally, or metacognition generally. Diffusion MRI-derived fractional anisotropy and neurite density index showed significant (P < 0.05) negative associations with cognitive fatigue in a widespread bilateral white matter network. Moreover, there was a significant (P < 0.05) interaction between cognitive fatigue and interoceptive insight, suggesting that the poorer the white matter structure, the lower the interoceptive insight, and the worse the fatigue. The results point towards metacognitive impairment confined to the interoceptive domain, in relapsing-remitting patients with cognitive fatigue. The neural basis of this impairment is supported by a widespread white matter network in which loss of neurite density plays a role.

MRI of carriers of the apolipoprotein E e4 allele-evidence for structural differences in normal-appearing brain tissue in e4+ relative to e4- young adults.

Apolipoprotein E is a protein involved in cholesterol and lipid transport. The gene coding for this protein has three different alleles: e2, e3 and e4. The e4 allele is recognised as a significant risk factor for the development of Alzheimer's disease in later life. Paradoxically, behavioural and functional evidence has demonstrated that the e4 allele may confer a cognitive advantage to the carrier in youth. In this article, a range of sophisticated and novel structural imaging techniques were used to identify subtle differences in the brain tissue of groups of young e4 and homozygous e3 carriers that might support this paradox. Using voxel-based morphometry of high-resolution structural MR images, we identified a higher white matter volume ratio in e4 relative to homozygous e3 carriers. Furthermore, diffusion tensor imaging and tract-based spatial statistics studies identified increases in axial diffusivity and mode of anisotropy in carriers of the e4 allele. In addition, quantitative magnetisation transfer data were analysed using tract-based spatial statistics. Evidence of a trend towards an increased transverse relaxation time of the bound proton pool was detected in e4 carriers, indicative of altered white matter composition. These changes were found to correlate with indices of cognitive performance across the two groups, supporting the notion that such subtle differences in white matter integrity may confer neural advantages that contribute to cognitive outcomes and, potentially, to performance differences, such as observed here in a test of verbal fluency and reported previously by other researchers. Copyright © 2013 John Wiley & Sons, Ltd.

Evidence of emerging BBB changes in mid-age apolipoprotein E epsilon-4 carriers.

INTRODUCTION: Studies have recognized that the loss of the blood-brain barrier (BBB) integrity is a major structural biomarker where neurodegenerative disease potentially begins. Using a combination of high-quality neuroimaging techniques, we investigated potential subtle differences in BBB permeability in mid-age healthy people, comparing carriers of the apolipoprotein E epsilon-4 (APOEε4) genotype, the biggest risk factor for late onset, non-familial AD (LOAD) with APOEε3 carriers, the population norm. METHODS: Forty-one cognitively healthy mid-age participants (42-59) were genotyped and pseudo-randomly selected to participate in the study by a third party. Blind to genotype, all participants had a structural brain scan acquisition including gadolinium-based dynamic contrast-enhanced magnetic resonance imaging acquired using a T1-weighted 3D vibe sequence. A B1 map and T1 map were acquired as part of the multi-parametric mapping acquisition. RESULTS: Non-significant, but subtle differences in blood-brain barrier permeability were identified between healthy mid-age APOEε4 and APOEε3 carriers, matched on age, education, and gender. DISCUSSION: This study demonstrated a tendency toward BBB permeability in APOEε4 participants emerging from mid-age, with quantitative differences observable on a number of the measures. While the differences did not reach a statistical significance, the results from this study hint at early changes in ε4 carrier BBB that may help identify at-risk populations and facilitate the development of early interventions to change the trajectory of decline.

Joint Hypermobility Links Neurodivergence to Dysautonomia and Pain.

OBJECTIVES: Autism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social, and emotional processes. Increased likelihood of chronic physical symptoms, including fatigue and pain, are also recognized. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts susceptibility to psychological symptoms alongside recognized physical symptoms. Here, we tested for increased prevalence of joint hypermobility, autonomic dysfunction, and musculoskeletal symptoms in 109 adults with neurodevelopmental condition diagnoses. METHODS: Rates of generalized joint hypermobility (GJH, henceforth hypermobility) in adults with a formal diagnosis of neurodevelopmental conditions (henceforth neurodivergent group, n = 109) were compared to those in the general population in UK. Levels of orthostatic intolerance and musculoskeletal symptoms were compared to a separate comparison group (n = 57). Age specific cut-offs for GJH were possible to determine in the neurodivergent and comparison group only. RESULTS: The neurodivergent group manifested elevated prevalence of hypermobility (51%) compared to the general population rate of 20% and a comparison population (17.5%). Using a more stringent age specific cut-off, in the neurodivergent group this prevalence was 28.4%, more than double than the comparison group (12.5%). Odds ratio for presence of hypermobility in neurodivergent group, compared to the general population was 4.51 (95% CI 2.17-9.37), with greater odds in females than males. Using age specific cut-off, the odds ratio for GJH in neurodivergent group, compared to the comparison group, was 2.84 (95% CI 1.16-6.94). Neurodivergent participants reported significantly more symptoms of orthostatic intolerance and musculoskeletal skeletal pain than the comparison group. The number of hypermobile joints was found to mediate the relationship between neurodivergence and symptoms of both dysautonomia and pain. CONCLUSIONS: In neurodivergent adults, there is a strong link between the expression of joint hypermobility, dysautonomia, and pain, more so than in the comparison group. Moreover, joint hypermobility mediates the link between neurodivergence and symptoms of dysautonomia and pain. Increased awareness and understanding of this association may enhance the management of core symptoms and allied difficulties in neurodivergent people, including co-occurring physical symptoms, and guide service delivery in the future.

Mid age APOE ε4 carriers show memory-related functional differences and disrupted structure-function relationships in hippocampal regions.

Carriers of the APOE e4 allele are at higher risk of age-related cognitive decline and Alzheimer's disease (AD). The underlying neural mechanisms are uncertain, but genotype differences in medial temporal lobe (MTL) functional activity and structure at mid-age might contribute. We tested 16 non-e4 and 16 e4 carriers (aged 45-55) on a subsequent memory task in conjunction with MRI to assess how hippocampal volume (from T1 structural) and microstructure (neurite orientation-dispersion, from NODDI) differs by genotype and in relation to memory encoding. No previous study has investigated APOE effects on hippocampal microstructure using NODDI. Recall performance did not differ by genotype. A genotype by condition interaction in left parahippocampus indicated that in e4 carriers activity did not differentiate subsequently remembered from forgotten words. Hippocampal volumes and microstructure also did not differ by genotype but hippocampal volumes correlated positively with recognition performance in non-e4 carriers only. Similarly, greater hippocampal neurite orientation-dispersion was linked to better recall but only in non-e4s. Thus, we suggest that mid-age e4 carriers show a breakdown of normal MTL activation and structure-performance relationships. This could reflect an inability to utilise compensatory mechanisms, and contribute to higher risk of cognitive decline and AD in later life.

Using event-related fMRI to examine sustained attention processes and effects of APOE ε4 in young adults.

In this study we investigated effects of the APOE ε4 allele (which confers an enhanced risk of poorer cognitive ageing, and Alzheimer's Disease) on sustained attention (vigilance) performance in young adults using the Rapid Visual Information Processing (RVIP) task and event-related fMRI. Previous fMRI work with this task has used block designs: this study is the first to image an extended (6-minute) RVIP task. Participants were 26 carriers of the APOE ε4 allele, and 26 non carriers (aged 18-28). Pupil diameter was measured throughout, as an index of cognitive effort. We compared activity to RVIP task hits to hits on a control task (with similar visual parameters and response requirements but no working memory load): this contrast showed activity in medial frontal, inferior and superior parietal, temporal and visual cortices, consistent with previous work, demonstrating that meaningful neural data can be extracted from the RVIP task over an extended interval and using an event-related design. Behavioural performance was not affected by genotype; however, a genotype by condition (experimental task/control task) interaction on pupil diameter suggested that ε4 carriers deployed more effort to the experimental compared to the control task. fMRI results showed a condition by genotype interaction in the right hippocampal formation: only ε4 carriers showed downregulation of this region to experimental task hits versus control task hits. Experimental task beta values were correlated against hit rate: parietal correlations were seen in ε4 carriers only, frontal correlations in non-carriers only. The data indicate that, in the absence of behavioural differences, young adult ε4 carriers already show a different linkage between functional brain activity and behaviour, as well as aberrant hippocampal recruitment patterns. This may have relevance for genotype differences in cognitive ageing trajectories.

Gadolinium Tagged Osteoprotegerin-Mimicking Peptide: A Novel Magnetic Resonance Imaging Biospecific Contrast Agent for the Inhibition of Osteoclastogenesis and Osteoclast Activity.

The control of osteoblast/osteoclast cross-talk is crucial in the bone remodelling process and provides a target mechanism in the development of drugs for bone metabolic diseases. Osteoprotegerin is a key molecule in this biosignalling pathway as it inhibits osteoclastogenesis and osteoclast activation to prevent run-away bone resorption. This work reports the synthesis of a known osteoprotegerin peptide analogue, YCEIEFCYLIR (OP3-4), and its tagging with a gadolinium chelate, a standard contrast agent for magnetic resonance imaging. The resulting contrast agent allows the simultaneous imaging and treatment of metabolic bone diseases. The gadolinium-tagged peptide was successfully synthesised, showing unaltered magnetic resonance imaging contrast agent properties, a lack of cytotoxicity, and dose-dependent inhibition of osteoclastogenesis in vitro. These findings pave the way toward the development of biospecific and bioactive contrast agents for the early diagnosis, treatment, and follow up of metabolic bone diseases such as osteoporosis and osteosarcoma.

Disrupted neural activity patterns to novelty and effort in young adult APOE-e4 carriers performing a subsequent memory task.

INTRODUCTION: The APOE e4 allele has been linked to poorer cognitive aging and enhanced dementia risk. Previous imaging studies have used subsequent memory paradigms to probe hippocampal function in e4 carriers across the age range, and evidence suggests a pattern of hippocampal overactivation in young adult e4 carriers. METHODS: In this study, we employed a word-based subsequent memory task under fMRI; pupillometry data were also acquired as an index of cognitive effort. Participants (26 non-e4 carriers and 28 e4 carriers) performed an incidental encoding task (presented as word categorization), followed by a surprise old/new recognition task after a 40 minute delay. RESULTS: In e4 carriers only, subsequently remembered words were linked to increased hippocampal activity. Across all participants, increased pupil diameter differentiated subsequently remembered from forgotten words, and neural activity covaried with pupil diameter in cuneus and precuneus. These effects were weaker in e4 carriers, and e4 carriers did not show greater pupil diameter to remembered words. In the recognition phase, genotype status also modulated hippocampal activity: here, however, e4 carriers failed to show the conventional pattern of greater hippocampal activity to novel words. CONCLUSIONS: Overall, neural activity changes were unstable in e4 carriers, failed to respond to novelty, and did not link strongly to cognitive effort, as indexed by pupil diameter. This provides further evidence of abnormal hippocampal recruitment in young adult e4 carriers, manifesting as both up and downregulation of neural activity, in the absence of behavioral performance differences.

Deficits in Neurite Density Underlie White Matter Structure Abnormalities in First-Episode Psychosis.

BACKGROUND: Structural abnormalities across multiple white matter tracts are recognized in people with early psychosis, consistent with dysconnectivity as a neuropathological account of symptom expression. We applied advanced neuroimaging techniques to characterize microstructural white matter abnormalities for a deeper understanding of the developmental etiology of psychosis. METHODS: Thirty-five first-episode psychosis patients, and 19 healthy controls, participated in a quantitative neuroimaging study using neurite orientation dispersion and density imaging, a multishell diffusion-weighted magnetic resonance imaging technique that distinguishes white matter fiber arrangement and geometry from changes in neurite density. Fractional anisotropy (FA) and mean diffusivity images were also derived. Tract-based spatial statistics compared white matter structure between patients and control subjects and tested associations with age, symptom severity, and medication. RESULTS: Patients with first-episode psychosis had lower regional FA in multiple commissural, corticospinal, and association tracts. These abnormalities predominantly colocalized with regions of reduced neurite density, rather than aberrant fiber bundle arrangement (orientation dispersion index). There was no direct relationship with active symptoms. FA decreased and orientation dispersion index increased with age in patients, but not control subjects, suggesting accelerated effects of white matter geometry change. CONCLUSIONS: Deficits in neurite density appear fundamental to abnormalities in white matter integrity in early psychosis. In the first application of neurite orientation dispersion and density imaging in psychosis, we found that processes compromising axonal fiber number, density, and myelination, rather than processes leading to spatial disruption of fiber organization, are implicated in the etiology of psychosis. This accords with a neurodevelopmental origin of aberrant brain-wide structural connectivity predisposing individuals to psychosis.

Anger in brain and body: the neural and physiological perturbation of decision-making by emotion.

Emotion and cognition are dynamically coupled to bodily arousal: the induction of anger, even unconsciously, can reprioritise neural and physiological resources toward action states that bias cognitive processes. Here we examine behavioural, neural and bodily effects of covert anger processing and its influence on cognition, indexed by lexical decision-making. While recording beat-to-beat blood pressure, the words ANGER or RELAX were presented subliminally just prior to rapid word/non-word reaction-time judgements of letter-strings. Subliminal ANGER primes delayed the time taken to reach rapid lexical decisions, relative to RELAX primes. However, individuals with high trait anger were speeded up by subliminal anger primes. ANGER primes increased systolic blood pressure and the magnitude of this increase predicted reaction time prolongation. Within the brain, ANGER trials evoked an enhancement of activity within dorsal pons and an attenuation of activity within visual occipitotemporal and attentional parietal cortices. Activity within periaqueductal grey matter, occipital and parietal regions increased linearly with evoked blood pressure changes, indicating neural substrates through which covert anger impairs semantic decisions, putatively through its expression as visceral arousal. The behavioural and physiological impact of anger states compromises the efficiency of cognitive processing through action-ready changes in autonomic response that skew regional neural activity.