White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis

White-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge’s g = 0.38, 95% confidence interval (CI) 0.07–0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females (z = −2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

Real-time whole-brain imaging of hemodynamics and oxygenation at micro-vessel resolution with ultrafast wide-field photoacoustic microscopy

High-speed high-resolution imaging of the whole-brain hemodynamics is urgently needed to facilitate the next level of neurovascular research. Image acquisition speed and image quality are crucial to visualizing real-time hemodynamics in complex brain vascular networks, and displaying fast pathophysiological dynamics on a micro and macro-level, enabling advances in current queries in neurovascular and brain metabolism research, including stroke, dementia and acute brain injury. Further, real-time oxygen saturation of hemoglobin (sO2) imaging to differentiate arteries from veins and capture fast-paced oxygen delivery dynamics is needed to solve pertinent questions in these fields and beyond. Here, we present a novel ultrafast functional photoacoustic microscopy (UFF-PAM) to image the whole-brain hemodynamics and oxygen delivery. UFF-PAM takes advantage of several key engineering innovations, including Raman-shifter-based dual-wavelength laser excitation, water-immersible 12-facet-polygon scanner, high-sensitivity ultrasound transducer, and deep-learning-based image upsampling. A volumetric imaging rate of 2 Hz has been achieved over a field of view (FOV) of 11× 7.5 × 1.5 mm3 with a high spatial resolution of ~10 µm. Using the UFF-PAM system, we have demonstrated proof-of-concept functional studies on the mouse brains in response to systemic hypoxia, sodium nitroprusside, and stroke. We observed the mouse brain’s fast morphological and functional changes over the entire cortex, including vasoconstriction, vasodilation, and deoxygenation. More interestingly, for the first time, under the whole-brain FOV and micro-vessel resolution, we captured the vasoconstriction and oxygenation change simultaneously in the spreading depolarization (SD) wave. Our work provides a great potential for fundamental brain research under various pathological and physiological conditions.

A host-gut microbial co-metabolite of aromatic amino acids, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo

Purpose: The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Methods: Male C57Bl/6J mice were used to assess blood-brain barrier (BBB) permeability and whole brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Results: Mice exposed to pCG showed reduced BBB permeability and significant changes in whole brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilising effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. Conclusion: The amino acid phase II metabolic product pCG is biologically active at the BBB, highlighting the complexity of gut microbe to host communication and the gut-brain axis.

Spatiotemporal Patterns of Adaptation-Induced Slow Oscillations in a Whole-Brain Model of Slow-Wave Sleep

During slow-wave sleep, the brain is in a self-organized regime in which slow oscillations (SOs) between up- and down-states travel across the cortex. While an isolated piece of cortex can produce SOs, the brain-wide propagation of these oscillations are thought to be mediated by the long-range axonal connections. We address the mechanism of how SOs emerge and recruit large parts of the brain using a whole-brain model constructed from empirical connectivity data in which SOs are induced independently in each brain area by a local adaptation mechanism. Using an evolutionary optimization approach, good fits to human resting-state fMRI data and sleep EEG data are found at values of the adaptation strength close to a bifurcation where the model produces a balance between local and global SOs with realistic spatiotemporal statistics. Local oscillations are more frequent, last shorter, and have a lower amplitude. Global oscillations spread as waves of silence across the undirected brain graph, traveling from anterior to posterior regions. These traveling waves are caused by heterogeneities in the brain network in which the connection strengths between brain areas determine which areas transition to a down-state first, and thus initiate traveling waves across the cortex. Our results demonstrate the utility of whole-brain models for explaining the origin of large-scale cortical oscillations and how they are shaped by the connectome.

Regional Distribution of Brain Injury After Cardiac Arrest: Clinical and Electrographic Correlates

Background and Objectives:Disorders of consciousness, EEG background suppression and epileptic seizures are associated with poor outcome after cardiac arrest. Our objective was to identify the distribution of diffusion MRI-measured anoxic brain injury after cardiac arrest and to define the regional correlates of disorders of consciousness, EEG background suppression, and seizures.Methods:We analyzed patients from a single-center database of unresponsive patients who underwent diffusion MRI following cardiac arrest (n=204). We classified each patient based on recovery of consciousness (command-following) before discharge, the most continuous EEG background (burst suppression versus continuous), and the presence or absence of seizures. Anoxic brain injury was measured using the apparent diffusion coefficient (ADC) signal. We identified ADC abnormalities relative to control subjects without cardiac arrest (n=48) and used voxel lesion symptom mapping to identify regional associations with disorders of consciousness, EEG background suppression, and seizures. We then used a bootstrapped lasso regression procedure to identify robust, multivariate regional associations with each outcome variable. Finally, using area under receiver operating characteristic curves, we then compared the classification ability of the strongest regional associations to that of brain-wide summary measures.Results:Compared to controls, cardiac arrest patients demonstrated ADC signal reduction most significant in the occipital lobes. Disorders of consciousness were associated with reduced ADC most prominently in the occipital lobes, but also in deep structures. Regional injury more accurately classified patients with disorders of consciousness than whole-brain injury. Background suppression mapped to a similar set of brain regions, but regional injury could no better classify patients than whole-brain measures. Seizures were less common in patients with more severe anoxic injury, particularly in those with injury to the lateral temporal white matter.Discussion:Anoxic brain injury was most prevalent in posterior cerebral regions, and this regional pattern of injury was a better predictor of disorders of consciousness than whole-brain injury measures. EEG background suppression lacked a specific regional association, but patients with injury to the temporal lobe were less likely to have seizures. Regional patterns of anoxic brain injury are relevant to the clinical and electrographic sequelae of cardiac arrest and may hold importance for prognosis.Classification of Evidence:This study provides Class IV evidence that disorders of consciousness after cardiac arrest are associated with widely lower ADC values on diffusion MRI and are most strongly associated with reductions in occipital ADC.

Graph theory analysis of whole brain functional connectivity to assess disturbances associated with suicide attempts in bipolar disorder

Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph‐theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD.

Mapping whole-brain seizure network recruitment with optogenetic kindling

Epilepsy is often labelled a network disorder, though a common view of seizures holds that they initiate in a singular onset zone before expanding contiguously outward. A recent report by Choy et al. (2021) leverages new tools to study whole-brain dynamics during epileptic seizures originating in the hippocampus. Cell-type-specific kindling and functional imaging revealed how various brain regions were recruited to seizures and uncovered a novel form of migrating seizure core.

Contribution of Inflammation and Hypoperfusion to White Matter Hyperintensities-Related Cognitive Impairment

White matter hyperintensities (WMHs) of presumed vascular origin are one of the most important neuroimaging markers of cerebral small vessel disease (CSVD), which are closely associated with cognitive impairment. The aim of this study was to elucidate the pathogenesis of WMHs from the perspective of inflammation and hypoperfusion mechanisms. A total of 65 patients with WMHs and 65 healthy controls were enrolled in this study. Inflammatory markers measurements [hypersensitive C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2)], cognitive evaluation, and pseudocontinuous arterial spin labeling (PCASL) MRI scanning were performed in all the subjects. The multivariate logistic regression analysis showed that Lp-PLA2 was an independent risk factor for WMHs. Cerebral blood flow (CBF) in the whole brain, gray matter (GM), white matter (WM), left orbital medial frontal gyrus [MFG.L (orbital part)], left middle temporal gyrus (MTG.L), and right thalamus (Tha.R) in the patients was lower than those in the controls and CBF in the left triangular inferior frontal gyrus [IFG.L (triangular part)] was higher in the patients than in the controls. There was a significant correlation between Lp-PLA2 levels and CBF in the whole brain (R = −0.417, p &lt; 0.001) and GM (R = −0.278, p = 0.025), but not in the WM in the patients. Moreover, CBF in the MFG.L (orbital part) and the Tha.R was, respectively, negatively associated with the trail making test (TMT) and the Stroop color word test (SCWT), suggesting the higher CBF, the better executive function. The CBF in the IFG.L (triangular part) was negatively correlated with attention scores in the Cambridge Cognitive Examination-Chinese Version (CAMCOG-C) subitems (R = −0.288, p = 0.020). Our results revealed the vascular inflammation roles in WMHs, which may through the regulation of CBF in the whole brain and GM. Additionally, CBF changes in different brain regions may imply a potential role in the modulation of cognitive function in different domains.