Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study.

Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.

Baroreflex sensitivity is associated with markers of hippocampal gliosis and dysmyelination in patients with psychosis.

PURPOSE: Hippocampal dysfunction plays a key role in the pathology of psychosis. Given hippocampal sensitivity to changes in cerebral perfusion, decreased baroreflex function could contribute to psychosis pathogenesis. This study had two aims: (1) To compare baroreflex sensitivity in participants with psychosis to two control groups: participants with a nonpsychotic affective disorder and participants with no history of psychiatric disease; (2) to examine the relationship between hippocampal neurometabolites and baroreflex sensitivities in these three groups. We hypothesized that baroreflex sensitivity would be reduced and correlated with hippocampal neurometabolite levels in participants with psychosis, but not in the control groups. METHODS: We assessed baroreflex sensitivity during the Valsalva maneuver separated into vagal and adrenergic components. Metabolite concentrations for cellular processes were quantitated in the entire multivoxel hippocampus using H1-MR spectroscopic (MRS) imaging and were compared with baroreflex sensitivities in the three groups. RESULTS: Vagal baroreflex sensitivity (BRS-V) was reduced in a significantly larger proportion of participants with psychosis compared with patients with nonpsychotic affective disorders, whereas participants with psychosis had increased adrenergic baroreflex sensitivity (BRS-A) compared with participants with no history of psychiatric disease. Only in psychotic cases were baroreflex sensitivities associated with hippocampal metabolite concentrations. Specifically, BRS-V was inversely correlated with myo-inositol, a marker of gliosis, and BRS-A was positively correlated with energy dependent dysmyelination (choline, creatine) and excitatory activity (GLX). CONCLUSIONS: Abnormal baroreflex sensitivity is common in participants with psychosis and is associated with MRS markers of hippocampal pathology. Future longitudinal studies are needed to examine causality.

Microstructural and Microvascular Alterations in Psychotic Spectrum Disorders: A Three-Compartment Intravoxel Incoherent Imaging and Free Water Model.

BACKGROUND AND HYPOTHESIS: Microvascular and inflammatory mechanisms have been hypothesized to be involved in the pathophysiology of psychotic spectrum disorders (PSDs). However, data evaluating these hypotheses remain limited. STUDY DESIGN: We applied a three-compartment intravoxel incoherent motion free water imaging (IVIM-FWI) technique that estimates the perfusion fraction (PF), free water fraction (FW), and anisotropic diffusion of tissue (FAt) to examine microvascular and microstructural changes in gray and white matter in 55 young adults with a PSD compared to 37 healthy controls (HCs). STUDY RESULTS: We found significantly increased PF, FW, and FAt in gray matter regions, and significantly increased PF, FW, and decreased FAt in white matter regions in the PSD group versus HC. Furthermore, in patients, but not in the HC group, increased PF, FW, and FAt in gray matter and increased PF in white matter were significantly associated with poor performance on several cognitive tests assessing memory and processing speed. We additionally report significant associations between IVIM-FWI metrics and myo-inositol, choline, and N-acetylaspartic acid magnetic resonance spectroscopy imaging metabolites in the posterior cingulate cortex, which further supports the validity of PF, FW, and FAt as microvascular and microstructural biomarkers of PSD. Finally, we found significant relationships between IVIM-FWI metrics and the duration of psychosis in gray and white matter regions. CONCLUSIONS: The three-compartment IVIM-FWI model provides metrics that are associated with cognitive deficits and may reflect disease progression.

Patient-reported exposures and outcomes link the gut-brain axis and inflammatory pathways to specific symptoms of severe mental illness.

We developed a "gut-brain-axis questionnaire" (GBAQ) to obtain standardized person-specific "review of systems" data for microbiome-gut-brain-axis studies. Individual items were compared to PANSS symptom measures using dimensional, transdiagnostic and traditional categorical approaches. METHOD: Forty psychotic participants, independent of diagnoses, and 42 without psychosis (18 nonpsychotic affective disorders, 24 healthy controls) completed the GBAQ and underwent research diagnostic and symptom assessments. The PANSS scales and its dysphoric mood, autistic preoccupation and activation factors were computed. RESULTS: Transdiagnostic analyses robustly linked psychosis severity to constipation (p<.001), and Negative (p=.045) and General Psychopathology scores (p=.016) with bowel hypomotility. Activation factor scores predicted numbers of psychiatric (p=.009) and medical conditions (p=.003), BMI (p=.003), skin (p<.001) and other conditions. Categorical analyses comparing psychotic, nonpsychotic and control groups revealed behavioral differences: cigarette smoking (p=.013), alcohol use (p=.007), diet (p's <.05), exercise (p<.001). All subjects accurately self-reported their diagnosis. CONCLUSIONS: The GBAQ is a promising tool. Transdiagnostic analyses associated psychotic symptoms to gut hypomotility, indicative of low gut vagal tone, consistent with reduced cardiovagal activity in psychosis. Activation, similar to delirium symptoms, predicted medical comorbidity and systemic inflammatory conditions. Group level comparisons only showed behavioral differences. Underpinnings of psychiatric disorders may include reduced gut vagal function, producing psychosis, and systemic inflammation, impacting risks for psychotic and nonpsychotic conditions.

An integrative study of the microbiome gut-brain-axis and hippocampal inflammation in psychosis: Persistent effects from mode of birth.

The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented. METHOD: Study subjects undergo research diagnostic interviews and symptom assessments to be categorized into one of 3 study groups: psychosis, nonpsychotic affective disorder or healthy control. Hippocampal volume and metabolite concentrations are assessed using 3-dimensional, multi-voxel H1 Magnetic Resonance Imaging (MRSI) encompassing all gray matter in the entire hippocampal volume. Rich self-report information is obtained with the PROMIS interview, which was developed by the NIH Commons for research in chronic conditions. Early trauma is assessed and cognition is quantitated using the MATRICS. The method also includes the most comprehensive autonomic nervous system (ANS) battery used to date in psychiatric research. Stool and oral samples are obtained for microbiome assessments and cytokines and other substances are measured in blood samples. RESULTS: Group level preliminary data shows that C-section birth is associated with higher concentrations of GLX, a glutamate related hippocampal neurotransmitter in psychotic cases, worse symptoms in affective disorder cases and smaller hippocampal volume in controls. CONCLUSION: Mode of birth appears to have persistent influences through adulthood. The methodology described for this study will define pathways through which the MGBA may influence the risk for psychiatric disorders.

MR spectroscopic imaging at 3 T and outcomes in surgical epilepsy.

For the spectroscopic assessment of brain disorders that require large-volume coverage, the requirements of RF performance and field homogeneity are high. For epilepsy, this is also challenging given the inter-patient variation in location, severity and subtlety of anatomical identification and its tendency to involve the temporal region. We apply a targeted method to examine the utility of large-volume MR spectroscopic imaging (MRSI) in surgical epilepsy patients, implementing a two-step acquisition, comprised of a 3D acquisition to cover the fronto-parietal regions, and a contiguous parallel two-slice Hadamard-encoded acquisition to cover the temporal-occipital region, both with TR /TE = 2000/40 ms and matched acquisition times. With restricted (static, first/second-order) B0 shimming in their respective regions, the Cramér-Rao lower bounds for creatine from the temporal lobe two-slice Hadamard and frontal-parietal 3D acquisition are 8.1 ± 2.2% and 6.3 ± 1.9% respectively. The datasets are combined to provide a total 60 mm axial coverage over the frontal, parietal and superior temporal to middle temporal-occipital regions. We applied these acquisitions at a nominal 400 mm3 voxel resolution in n = 27 pre-surgical epilepsy patients and n = 20 controls. In controls, 86.6 ± 3.2% voxels with at least 50% tissue (white + gray matter, excluding CSF) survived spectral quality inclusion criteria. Since all patients were clinically followed for at least 1 year after surgery, seizure frequency outcome was available for all. The MRSI measurements of the total fractional metabolic dysfunction (characterized by the Cr/NAA metric) in FreeSurfer MRI gray matter segmented regions, in the patients compared with the controls, exhibited a significant Spearman correlation with post-surgical outcome. This finding suggests that a larger burden of metabolic dysfunction is seen in patients with poorer post-surgical seizure control.

Fast, regional three-dimensional hybrid (1D-Hadamard 2D-rosette) proton MR spectroscopic imaging in the human temporal lobes.

1 H-MRSI is commonly performed with gradient phase encoding, due to its simplicity and minimal radio frequency (RF) heating (specific absorption rate). Its two well-known main problems-(i) "voxel bleed" due to the intrinsic point-spread function, and (ii) chemical shift displacement error (CSDE) when slice-selective RF pulses are used, which worsens with increasing volume of interest (VOI) size-have long become accepted as unavoidable. Both problems can be mitigated with Hadamard multislice RF encoding. This is demonstrated and quantified with numerical simulations, in a multislice phantom and in five healthy young adult volunteers at 3 T, targeting a 2-cm thick temporal lobe VOI through the bilateral hippocampus. This frequently targeted region (e.g. in epilepsy and Alzheimer's disease) is subject to strong, 1-2 ppm.cm-1 regional B0, susceptibility gradients that can dramatically reduce the signal-to-noise ratio (SNR) and water suppression effectiveness. The chemical shift imaging (CSI) sequence used a 3-ms Shinnar-Le Roux (SLR) 90° RF pulse, acquiring eight steps in the slice direction. The Hadamard sequence acquired two overlapping slices using the same SLR 90° pulses, under twofold stronger gradients that proportionally halved the CSDE. Both sequences used 2D 20 × 20 rosette spectroscopic imaging (RSI) for in-plane spatial localization and both used RF and gradient performance characteristics that are easily met by all modern MRI instruments. The results show that Hadamard spectroscopic imaging (HSI) suffered dramatically less signal bleed within the VOI compared with CSI (<1% vs. approximately 26% in simulations; and 5%-8% vs. >50%) in a phantom specifically designed to test these effects. The voxels' SNR per unit volume per unit time was also 40% higher for HSI. In a group of five healthy volunteers, we show that HSI with in-plane 2D-RSI facilitates fast, 3D multivoxel encoding at submilliliter spatial resolution, over the bilateral human hippocampus, in under 10 min, with negligible CSDE, spectral and spatial contamination and more than 6% improved SNR per unit time per unit volume.

Global brain volume and N-acetyl-aspartate decline over seven decades of normal aging.

We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the adult lifespan and test the hypothesis that, despite age-related atrophy, neuronal integrity (reflected by WBNAA) is preserved in normal aging. Two-hundred-and-seven participants: 133 cognitively intact older adults (73.6 ± 7.4 mean ± standard deviation, range: 60-90 year old) and 84 young (37.9 ± 11, range: 21-59 year old) were scanned with proton magnetic resonance spectroscopy and T1-weighted MRI. Their WBNAA, fractional brain parenchyma, and gray and white matter volumes (fBPV, fGM, and fWM) were compared and modeled as functions of age and sex. Compared with young, older-adults' WBNAA was lower by ~35%, and fBPV, fGM and fWM were lower by ~10%. Linear regressions found 0.5%/year WBNAA and 0.2%/year fBPV and fGM declines, whereas fWM rose to age ~40 years, and declined thereafter. fBPV and fGM were 1.8% and 4% higher in women, with no sex decline rates difference. We conclude that contrary to our hypothesis, atrophy was accompanied by WBNAA decline. Across the entire age range, women's brains showed less atrophy than men's. Formulas to estimate WBNAA and brain tissue fractions in healthy adults are provided to help differentiate normal from abnormal aging.

Quantitative multivoxel proton MR spectroscopy for the identification of white matter abnormalities in mild traumatic brain injury: Comparison between regional and global analysis.

BACKGROUND: 3D brain proton MR spectroscopic imaging (1 H MRSI) facilitates simultaneous metabolic profiling of multiple loci, at higher, sub-1 cm3 , spatial resolution than single-voxel 1 H MRS with the ability to separate tissue-type partial volume contribution(s). PURPOSE: To determine if: 1) white matter (WM) damage in mild traumatic brain injury (mTBI) is homogeneously diffuse, or if specific regions are more affected; 2) partial-volume-corrected, structure-specific 1 H MRSI voxel averaging is sensitive to regional WM metabolic abnormalities. STUDY TYPE: Retrospective cross-sectional cohort study. POPULATION: Twenty-seven subjects: 15 symptomatic mTBI patients, 12 matched controls. FIELD STRENGTH/SEQUENCE: 3T using 3D 1 H MRSI over a 360-cm3 volume of interest (VOI) centered over the corpus callosum, partitioned into 480 voxels, each 0.75 cm3 . ASSESSMENT: N-acetyl-aspartate (NAA), creatine, choline, and myo-inositol concentrations estimated in predominantly WM regions: body, genu, and splenium of the corpus callosum, corona radiata, frontal, and occipital WM. STATISTICAL TESTS: Analysis of covariance (ANCOVA) to compare patients with controls in terms of regional concentrations. The effect sizes (Cohen's d) of the mean differences were compared across regions and with previously published global data obtained with linear regression of the WM over the entire VOI in the same dataset. RESULTS: Despite patients' global VOI WM NAA being significantly lower than the controls', no regional differences were observed for any metabolite. Regional NAA comparisons, however, were all unidirectional (patients' NAA concentrations < controls') within a narrow range: 0.3 ≤ Cohen's d ≤ 0.6. DATA CONCLUSION: Since the patient group was symptomatic and exhibiting global WM NAA deficits, these findings suggest: 1) diffuse axonal mTBI damage; that is 2) below the 1 H MRSI detection threshold in small regions. Therefore, larger, ie, more sensitive, single-voxel 1 H MRS, placed anywhere in WM regions, may be well suited for mTBI 1 H MRS studies, given that these results are confirmed in other cohorts. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1424-1432.