Brain communications最新文献

Multiple sclerosis and neuromyelitis optica spectrum disorder are two debilitating inflammatory demyelinating diseases of the CNS. Although grey matter alterations have been linked to both multiple sclerosis and neuromyelitis optica spectrum disorder in observational studies, it is unclear whether these associations indicate causal relationships between these diseases and grey matter changes. Therefore, we conducted a bidirectional two-sample Mendelian randomization analysis to investigate the causal relationships between 202 grey matter imaging-derived phenotypes (33 224 individuals) and multiple sclerosis (47 429 cases and 68 374 controls) as well as neuromyelitis optica spectrum disorder (215 cases and 1244 controls). Our results suggested that genetically predicted multiple sclerosis was positively associated with the surface area of the left parahippocampal gyrus (β = 0.018, P = 2.383 × 10^-4) and negatively associated with the volumes of the bilateral caudate (left: β = -0.020, P = 7.203 × 10^-5; right: β = -0.021, P = 3.274 × 10^-5) and putamen nuclei (left: β = -0.030, P = 2.175 × 10^-8; right: β = -0.024, P = 1.047 × 10^-5). In addition, increased neuromyelitis optica spectrum disorder risk was associated with an increased surface area of the left paracentral gyrus (β = 0.023, P = 1.025 × 10^-4). Conversely, no evidence was found for the causal impact of grey matter imaging-derived phenotypes on disease risk in the opposite direction. We provide suggestive evidence that genetically predicted multiple sclerosis and neuromyelitis optica spectrum disorder are associated with increased cortical surface area and decreased subcortical volume in specific regions. Our findings shed light on the associations of grey matter alterations with the risk of multiple sclerosis and neuromyelitis optica spectrum disorder.

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.

Dementia is a burgeoning global problem. Novel magnetic resonance imaging (MRI) metrics beyond volumetry may bring new insight and aid clinical trial evaluation of interventions early in the Alzheimer's disease course to complement existing imaging and clinical metrics. To determine whether: (i) normalized regional sodium-MRI values (Na-SI) are better predictors of neurocognitive status than volumetry (ii) cerebral amyloid PET status improves modelling. Nondemented older adult (>60 years) volunteers of known Alzheimer's Disease Assessment Scale (ADAS-Cog11), Mini-Mental State Examination (MMSE) and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurocognitive test scores, ApolipoproteinE (APOE) e4 +/- cerebral amyloid PET status were prospectively recruited for 3T sodium-MRI brain scans. Left and right hippocampal, entorhinal and precuneus volumes and Na-SI (using the proportional intensity scaling normalization method with field inhomogeneity and partial volume corrections) were obtained after segmentation and co-registration of 3D-T1-weighted proton images. Descriptive statistics, correlation and best-subset regression analyses were performed. In our 76 nondemented participants (mean(standard deviation) age 75(5) years; woman 47(62%); cognitively unimpaired 54/76(71%), mildly cognitively impaired 22/76(29%)), left hippocampal Na-SI, not volume, was preferentially in the best models for predicting MMSE (Odds Ratio (OR) = 0.19(Confidence Interval (CI) = 0.07,0.53), P-value = 0.001) and ADAS-Cog11 (Beta(B) = 1.2(CI = 0.28,2.1), P-value = 0.01) scores. In the entorhinal analysis, right entorhinal Na-SI, not volume, was preferentially selected in the best model for predicting ADAS-Cog11 (B = 0.94(CI = 0.11,1.8), P-value = 0.03). While right entorhinal Na-SI and volume were both selected for MMSE modelling (Na-SI OR = 0.23(CI = 0.09,0.6), P-value = 0.003; volume OR = 2.6(CI = 1.0,6.6), P-value = 0.04), independently, Na-SI explained more of the variance (Na-SI R ² = 10.3; volume R ² = 7.5). No imaging variable was selected in the best CERAD models. Adding cerebral amyloid status improved model fit (Akaike Information Criterion increased 2.0 for all models, P-value < 0.001-0.045). Regional Na-SI were more predictive of MMSE and ADAS-Cog11 scores in our nondemented older adult cohort than volume, hippocampal more robust than entorhinal region of interest. Positive amyloid status slightly further improved model fit.

Heatwaves have serious impacts on human health and constitute a key health concern from anthropogenic climate change. People have different individual tolerance for heatwaves or unaccustomed temperatures. Those with epilepsy may be particularly affected by temperature as the electroclinical hallmarks of brain excitability in epilepsy (inter-ictal epileptiform discharges and seizures) are influenced by a range of physiological and non-physiological conditions. Heatwaves are becoming more common and may affect brain excitability. Leveraging spontaneous heatwaves during periods of intracranial EEG recording in participants with epilepsy in a non-air-conditioned telemetry unit at the National Hospital for Neurology and Neurosurgery in London from May to August 2015-22, we examined the impact of heatwaves on brain excitability. In London, a heatwave is defined as three or more consecutive days with daily maximum temperatures ≥28°C. For each participant, we counted inter-ictal epileptiform discharges using four 10-min segments within, and outside of, heatwaves during periods of intracranial EEG recording. Additionally, we counted all clinical and subclinical seizures within, and outside of, heatwaves. We searched for causal rare genetic variants and calculated the epilepsy PRS. Nine participants were included in the study (six men, three women), median age 30 years (range 24-39). During heatwaves, there was a significant increase in the number of inter-ictal epileptiform discharges in three participants. Five participants had more seizures during the heatwave period, and as a group, there were significantly more seizures during the heatwaves. Genetic data, available for eight participants, showed none had known rare, genetically-determined epilepsies, whilst all had high polygenic risk scores for epilepsy. For some people with epilepsy, and not just those with known, rare, temperature-sensitive epilepsies, there is an association between heatwaves and increased brain excitability. These preliminary data require further validation and exploration, as they raise concerns about the impact of heatwaves directly on brain health.

Cognitive symptoms in Parkinson's disease are common and can significantly affect patients' quality of life. Therefore, there is an urgent clinical need to identify a signature derived from behavioural and/or neuroimaging indicators that could predict which patients are at increased risk for early and rapid cognitive decline. Recently, converging evidence identified that aperiodic activity of the EEG reflects meaningful physiological information associated with age, development, cognitive and perceptual states or pathologies. In this study, we aimed to investigate aperiodic activity in Parkinson's disease during cognitive control and characterize its possible association with behaviour. Here, we recorded high-density EEG in 30 healthy controls and 30 Parkinson's disease patients during a Simon task. We analysed task-related behavioural data in the context of the activation-suppression model and extracted aperiodic parameters (offset, exponent) at both scalp and source levels. Our results showed lower behavioural performances in cognitive control as well as higher offsets in patients in the parieto-occipital areas, suggesting increased excitability in Parkinson's disease. A small congruence effect on aperiodic parameters in pre- and post-central brain areas was also found, possibly associated with task execution. Significant differences in aperiodic parameters between the resting-state, pre- and post-stimulus phases were seen across the whole brain, which confirmed that the observed changes in aperiodic activity are linked to task execution. No correlation was found between aperiodic activity and behaviour or clinical features. Our findings provide evidence that EEG aperiodic activity in Parkinson's disease is characterized by greater offsets, and that aperiodic parameters differ depending on arousal state. However, our results do not support the hypothesis that the behaviour-related differences observed in Parkinson's disease are related to aperiodic changes. Overall, this study highlights the importance of considering aperiodic activity contributions in brain disorders and further investigating the relationship between aperiodic activity and behaviour.

In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.

Delirium is a common and acute neurocognitive disorder in older adults associated with increased risk of dementia and death. Understanding the interaction between brain vulnerability and acute stressors is key to delirium pathophysiology, but the neurophysiology of delirium vulnerability is not well defined. This study aimed to identify pre-operative resting-state EEG and event-related potential markers of incident delirium and its subtypes in older adults undergoing elective cardiac procedures. This prospective observational study included 58 older participants (mean age = 75.6 years, SD = 7.1; 46 male/12 female); COVID-19 restrictions limited recruitment. Baseline assessments were conducted in the weeks before elective cardiac procedures and included a 4-min resting-state EEG recording (2-min eyes open and 2-min eyes closed), a 5-min frequency auditory oddball paradigm recording, and cognitive and depression examinations. Periodic peak power, peak frequency and bandwidth measures, and aperiodic offsets and exponents were derived from resting-state EEG data. Event-related potentials were measured as mean component amplitudes (first positive component, first negative component, early third positive component, and mismatch negativity) following standard and deviant auditory stimuli. Incident delirium occurred in 21 participants: 10 hypoactive, 6 mixed, and 5 hyperactive. Incident hyperactive delirium was associated with higher pre-operative eyes open (P = 0.045, d = 1.0) and closed (P = 0.036, d = 1.0) aperiodic offsets. Incident mixed delirium was associated with significantly larger pre-operative first positive component amplitudes to deviants (P = 0.037, d = 1.0) and larger third positive component amplitudes to standards (P = 0.025, d = 1.0) and deviants (P = 0.041, d = 0.9). Other statistically non-significant but moderate-to-large effects were observed in relation to all subtypes. We report evidence of neurophysiological markers of delirium risk weeks prior to elective cardiac procedures in older adults. Despite being underpowered due to COVID-19-related recruitment impacts, these findings indicate pre-operative dysfunction in neural excitation/inhibition balance associated with different delirium subtypes and warrant further investigation on a larger scale.

Depression is a common consequence of traumatic brain injury. Separately, spontaneous depression-arising without brain injury-has been linked to abnormal responses in motivational neural circuitry to the anticipation or receipt of rewards. It is unknown if post-injury and spontaneously occurring depression share similar phenotypic profiles. This issue is compounded by the fact that nearly all examinations of these psychiatric sequelae are post hoc: there are rarely any prospective assessments of mood and neural functioning before and after a brain injury. In this Stage 2 Registered Report, we used the Adolescent Brain Cognitive Development Consortium dataset to examine if a disruption in functional neural responses to rewards is present in patients with depression after a mild traumatic brain injury. Notably, this study provides an unparalleled opportunity to examine the trajectory of neuropsychiatric symptoms longitudinally within-subjects. This allowed us to isolate mild traumatic brain injury-specific variance independent from pre-existing functioning. Here, we focus on a case-control comparison between 43 youth who experienced a mild traumatic brain injury between MRI visits, and 43 well-matched controls. Contrary to pre-registered predictions (https://osf.io/h5uba/), there was no statistically credible increase in depression in mild traumatic brain injury cases relative to controls. Mild traumatic brain injury was associated with subtle changes in motivational neural circuit recruitment during the anticipation of incentives on the Monetary Incentive Delay paradigm. Specifically, changes in neural recruitment appeared to reflect a failure to deactivate 'task-negative' brain regions (ventromedial prefrontal cortex), alongside blunted recruitment of 'task-positive' regions (anterior cingulate, anterior insula and caudate), during the anticipation of reward and loss in adolescents following mild brain injuries. Critically, these changes in brain activity were not correlated with depressive symptoms at either visit or depression change scores before and after the brain injury. Increased time since injury was associated with a recovery of cognitive functioning-driven primarily by processing speed differences-but depression did not scale with time since injury. These cognitive changes were also uncorrelated with neural changes after mild traumatic brain injury. This report provides evidence that acquired depression may not be observed as commonly after a mild traumatic brain injury in late childhood and early adolescence, relative to findings in adult cases. Several reasons for these differing findings are considered, including sampling enrichment in retrospective cohort studies, under-reporting of depressive symptoms in parent-report data, and neuroprotective factors in childhood and adolescence.

This scientific commentary refers to 'Understanding the mechanisms of fatigue in multiple sclerosis: linking interoception, metacognition and white matter dysconnectivity', by Danciut et al. (https://doi.org/10.1093/braincomms/fcae292).