Introduction:Total and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses cases could be a roadblock if these differ in cellular pathology. Method:We examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations ( 1 H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis (Psy), including 20 schizophrenia and 13 affective psychoses (aff-P) cases. Results:NP-aff and HC had similar total cognition (46.64±12.01 vs 41.10±17.88), both superior to Psy (28.34±12.34; p's<0.01). Mean metabolite concentrations were similar across all groups but showed significant within-group associations to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, p's<.05), although no biomarker predicted total cognition in the clinical groups. For NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). Opposite NP-aff, reduced myelin/membrane concentrations predicted cognitive deficits in Psy (-.514, p<.05). Separating schizophrenia from aff-P on social cognition showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) but higher myelin/membrane turnover and neuronal integrity concentrations in aff-P (.575, .581, p's<.05). Conclusions:Schizophrenia and affective psychosis significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.

INTRODUCTION:The NIMH Research Domain Criteria (RDoC) posits similar cellular pathologies for particular symptom domains across diagnostic categories. Conversely, knowledge that these differ could advance treatment discovery, especially for affective and non-affective psychoses, as studies usually intermix them. METHODS:We tested this by comparing metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic spectroscopic imaging (1H MRSI) with symptoms from the original and five factor PANSS, and the Hamilton Depression and Young Mania Scales. Participants were 26 healthy controls; 22 non-psychotic affective cases (NP-aff); and 33 with psychosis (including 20 schizophrenia (Scz) and 13 affective psychosis (aff-P) cases). RESULTS:PANSS activation factor was related to reductions in all cellular component biomarkers in Scz, including glia, membrane turnover, neural integrity, glutaminergic neurotransmission, and energy metabolism (p's<.05), but only to energy metabolism in NP-aff (p=.03). Biomarkers for mood symptoms also varied across categories, suggesting gliosis for mania and depression in HC (p's≤.025), but increased membrane turnover for mania in aff-P (p=.015), and decreased neural integrity and energy metabolism for depression in Scz (p's<.05). In contrast, negative symptoms and autistic preoccupation were related to reduced glia in both NP-aff and aff-P (p's<.05). Autistic preoccupation in Scz was related to both reduced glia and membrane turnover (p's<.05). Only Scz showed a significant finding for positive symptoms, specifically reduced membrane turnover (p=.018). DISCUSSION:These results suggest both distinct and similar cellular pathologies for symptoms across diagnoses, including affective and non-affective psychoses. The differences support categorizing disorders and stratifying different psychoses in research rather than transdiagnostic approaches.

Research supports an association between diet and health, and emerging evidence suggests that diet is associated with neuropsychiatric symptoms. However, no human study has examined an anti-inflammatory diet across rigorously defined psychiatric diagnoses and its associations with symptom severity and cognition. As inflammation is implicated in mental illness, we investigated adherence to the Mediterranean diet (MD), an anti-inflammatory diet, and the standard American diet (SAD), and examined cross-sectional relationships with psychiatric symptoms and cognition. Method: Participants included 54 individuals with psychotic disorders, 30 with non-psychosis affective disorders and 40 healthy controls. Participants underwent diagnostic interviews, PANSS symptom ratings, and MATRICS cognitive assessments. The self-report GBAQ was used to assess adherence to the MD versus SAD. Results: The psychosis group was significantly more likely to consume the SAD than healthy controls (p = 0.007), with MD adherence predicting better working memory (r = 0.461, p < 0.001). In the non-psychosis affective disorders group, MD adherence predicted slower processing speed (r = -0.376, p = 0.049). In the non-psychosis affective disorders group, MD predicted reduced PANSS General Psychopathology scale (r = -0.449, p = 0.013), as well as the Activation (r = -0.362, p = 0.049), and Dysphoric Mood factors (r = -0.403, p = 0.027).Discussion: This first-of-its kind study identified poor dietary choices in persons with psychosis, showing significantly lower symptoms and better cognition in association with the MD in transdiagnostic analyses. It supports the study of dietary interventions for prevention and treatment of psychiatric conditions.

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.

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.

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.

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.

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.

BACKGROUND AND PURPOSE: Accurate differentiation of paragangliomas and schwannomas in the jugular foramen has important clinical implications because treatment strategies may vary but differentiation is not always straightforward with conventional imaging. Our aim was to evaluate the accuracy of both qualitative and quantitative metrics derived from dynamic contrast-enhanced MR imaging using golden-angle radial sparse parallel MR imaging to differentiate paragangliomas and schwannomas in the jugular foramen. MATERIALS AND METHODS: A retrospective study of imaging data was performed on patients (n?=?30) undergoing MR imaging for jugular foramen masses with the golden-angle radial sparse parallel MR imaging technique. Imaging data were postprocessed to obtain time-intensity curves and quantitative parameters. Data were normalized to the dural venous sinus for relevant parameters and analyzed for statistical significance using a Student t test. A univariate logistic model was created with a binary output, paraganglioma or schwannoma, using a wash-in rate as a variable. Additionally, lesions were clustered on the basis of the wash-in rate and washout rate using a 3-nearest neighbors method. RESULTS: There were 22 paragangliomas and 8 schwannomas. All paragangliomas demonstrated a type 3 time-intensity curve, and all schwannomas demonstrated a type 1 time-intensity curve. There was a statistically significant difference between paragangliomas and schwannomas when comparing their values for area under the curve, peak enhancement, wash-in rate, and washout rate. A univariate logistic model with a binary output (paraganglioma or schwannoma) using wash-in rate as a variable was able to correctly predict all observed lesions (P?<?.001). All 30 lesions were classified correctly by using a 3-nearest neighbors method. CONCLUSIONS: Paragangliomas at the jugular foramen can be reliably differentiated from schwannomas using golden-angle radial sparse parallel MR imaging?dynamic contrast-enhanced imaging when imaging characteristics cannot suffice.

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.

1H‐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.

Cognitive dysfunction is a central feature of schizophrenia spectrum disorders (SZ) with alterations in autonomic and higher-order functions that might be mediated by the putamen. While examining putamen’s neuro-metabolic profile might inform the underlying disease mechanisms and cell types involved, such data remains sparse in SZ. Here we contrast key neuro-metabolites in putamen in SZ patients relative to age-matched healthy controls (HC) and relate these neuro-metabolite patterns to cognitive impairment in SZ.

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. (c) 2020 Elsevier Inc. All rights reserved.

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.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.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.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.

BackgroundRare variants in the TRIO gene are associated with schizophrenia and autism spectrum disorders (ASD), which are commonly comorbid. ASD may define a specific schizophrenia subtype. This study examined person-specific hippocampal metabolite concentrations for 4 schizophrenia cases harboring rare variants in TRIO or its interaction partner ARMS/KIDINS220 and 5 cases with other rare variants.MethodsNine of 19 cases from a prior imaging study underwent targeted exome sequencing. Multi-voxel 1H-MRS imaging of the entire 3-dimensional hippocampus found only increased Creatine [Cr] (cellular energy use) concentration, distinguished cases at the group level. However, concentrations of N-acetyl-aspartate [NAA] (neuronal integrity) and choline [Cho] (membrane turnover/myelination) concentrations had a greater variance in cases than controls.ResultsFour cases with rare, missense-coding mutations or non-frameshift deletions in TRIO or ARMS/KIDINS220 had significantly lower [Cho] than the other 5 (1.78 ± 0.18 mM versus 2.67 ± 0.8 mM: t = 3.55, p = 0.005) but similar [NAA]. Two cases harboring rare variants in the SLC39A1 zinc transporter had the lowest [NAA]. (8.41 ± 0 80 mM versus 10.35 ± 2.03 mM, t = 4.52, p = 0.001). The highest [Cho] accompanied rare variants in SORCS2 and SORT, associated with schizophrenia and Alzheimer’s Disease.LimitationsThis preliminary study of a small sample of exceptionally well characterized cases requires replication in larger samples for clinical utility.ConclusionsThe hippocampus is vulnerable to more than one pathology causing schizophrenia. TRIO rare variants predicted significantly lower Cho, indicating reduced myelin. [Cho] and [NAA] may have importance for choosing and monitoring schizophrenia treatment.

BACKGROUND AND PURPOSE: Previous hippocampal proton MR spectroscopic imaging distinguished patients with schizophrenia from controls by elevated Cr levels and significantly more variable NAA and Cho concentrations. This goal of this study was to ascertain whether this metabolic variability is associated with clinical features of the syndrome, possibly reflecting heterogeneous hippocampal pathologies and perhaps variability in its “positive” (psychotic) and “negative” (social and emotional deficits) symptoms. MATERIALS AND METHODS: In a sample of 15 patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, we examined the association of NAA and Cho levels with research diagnostic interviews and clinical symptom ratings of the patients. Metabolite concentrations were previously obtained with 3D proton MR spectroscopic imaging at 3T, a technique that facilitates complete coverage of this small, irregularly shaped, bilateral, temporal lobe structure. RESULTS: The patient cohort comprised 8 men and 7 women (mean age, 39.1 [SD, 10.8] years, with a mean disease duration of 17.2 [SD, 10.8] years. Despite the relatively modest cohort size, we found the following: 1) Elevated Cho levels predict the positive (psychotic, r = 0.590, P = .021) and manic (r = 0.686, P = .005) symptom severity; and 2) lower NAA levels trend toward negative symptoms (r = 0.484, P = .08). No clinical symptoms were associated with Cr level or hippocampal volume (all, P ≥  .055). CONCLUSIONS: These preliminary findings suggest that NAA and Cho variations reflect different pathophysiologic processes, consistent with microgliosis/astrogliosis and/or lower vitality (reduced NAA) and demyelination (elevated Cho). In particular, the active state–related symptoms, including psychosis and mania, were associated with demyelination. Consequently, their deviations from the means of healthy controls may be a marker that may benefit precision medicine in selection and monitoring of schizophrenia treatment.

Background 3D brain proton MR spectroscopic imaging (H-1 MRSI) facilitates simultaneous metabolic profiling of multiple loci, at higher, sub-1 cm(3), spatial resolution than single-voxel H-1 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 H-1 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 H-1 MRSI over a 360-cm(3) volume of interest (VOI) centered over the corpus callosum, partitioned into 480 voxels, each 0.75 cm(3). 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 H-1 MRSI detection threshold in small regions. Therefore, larger, ie, more sensitive, single-voxel H-1 MRS, placed anywhere in WM regions, may be well suited for mTBI H-1 MRS studies, given that these results are confirmed in other cohorts. Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1424-1432.

Epilepsy, a chronic neurological condition characterized by recurrent seizures, affects ~50 million worldwide, nearly 1% of the population (Walsh et al., 2016). Its most common adult form is localization-related epilepsy, in which EEG and MRI can localize an epileptogenic focus, often within the temporal lobe. Despite its inferred localized nature, however, it is well documented that abnormalities can extend beyond the epileptogenic zone (Doucet et al., 2016; Hetherington et al., 2007; Ji et al., 2013). Indeed, the contemporary view of epilepsy is of a network disorder, with EEG, neuroanatomical and functional changes consistent with widely distributed dysfunction. Its pathophysiologic nature has multiple hypotheses, including overlapping contributions from inflammation (Butler et al., 2016), aberrant neurocircuitry (Ji et al., 2013), redistribution of excitatory and inhibitory function (Chowdhury et al., 2015), and metabolic dysfunction (Hetherington et al., 2007; van Veenendaal et al., 2015). For the latter, there is strong clinical and experimental evidence; e.g., FDG-PET use is predicated on identification of hypometabolic regions as possible seizure onset sites (Butler et al., 2016; Hodolic et al., 2016). Experimentally, mitochondrial dysfunction was found to relate to cellular excitability via calcium mishandling (Kann and Kovacs, 2007). Furthermore, reactive oxygen species that contribute to mitochondrial dysfunction, are increased in epilepsy models (Rowley et al., 2015).

Receptor protein tyrosine phosphatases, gamma (PTPRZ) and zeta (PTPRG), are cell surface ligands for contactin molecules, they bind with Contactins and are crucial for cell adhesion, signaling and neurodevelopment. Their main expression is in microglia and neurons, respectively; PTPRZ is essential for recovery from neuroinflammation. Both regulate neurotransmitter receptor function and are genetically associated with schizophrenia, affective disorders, Alzheimer's and autism.