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

McKenna, Faye; Gupta, Pradeep Kumar; Sui, Yu Veronica; Bertisch, Hilary; Gonen, Oded; Goff, Donald C; Lazar, Mariana
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.
PMID: 36921060
ISSN: 1745-1701
CID: 5590612

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

Lee, Jakleen J; Piras, Enrica; Tamburini, Sabrina; Bu, Kevin; Wallach, David S; Remsen, Brooke; Cantor, Adam; Kong, Jennifer; Goetz, Deborah; Hoffman, Kevin W; Bonner, Mharisi; Joe, Peter; Mueller, Bridget R; Robinson-Papp, Jessica; Lotan, Eyal; Gonen, Oded; Malaspina, Dolores; Clemente, Jose C
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.
PMID: 37331068
ISSN: 1872-7123
CID: 5542462

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

Mueller, Bridget; Robinson-Papp, Jessica; Suprun, Maria; Suarez-Farinas, Mayte; Lotan, Eyal; Gonen, Oded; Malaspina, Dolores
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:-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.
PMID: 36877302
ISSN: 1619-1560
CID: 5542032

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

Joe, Peter; Clemente, Jose C; Piras, Enrica; Wallach, David S; Robinson-Papp, Jessica; Boka, Emeka; Remsen, Brooke; Bonner, Mharisi; Kimhy, David; Goetz, Deborah; Hoffman, Kevin; Lee, Jakleen; Ruby, Eugene; Fendrich, Sarah; Gonen, Oded; Malaspina, Dolores
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.
PMID: 34625336
ISSN: 1573-2509
CID: 5067852

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

Fendrich, Sarah J; Koralnik, Lauren R; Bonner, Mharisi; Goetz, Deborah; Joe, Peter; Lee, Jakleen; Mueller, Bridget; Robinson-Papp, Jessica; Gonen, Oded; Clemente, Jose C; Malaspina, Dolores
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.
PMID: 35462090
ISSN: 1872-7123
CID: 5217222

Differentiation of Jugular Foramen Paragangliomas versus Schwannomas Using Golden-Angle Radial Sparse Parallel Dynamic Contrast-Enhanced MRI

Pires, A; Nayak, G; Zan, E; Hagiwara, M; Gonen, O; Fatterpekar, G
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: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:< .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.
PMID: 34503944
ISSN: 1936-959x
CID: 5033132

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

Tal, Assaf; Zhao, Tiejun; Schirda, Claudiu; Hetherington, Hoby P; Pan, Jullie W; Gonen, Oded
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 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.
PMID: 33754420
ISSN: 1099-1492
CID: 4822542

MR spectroscopic imaging at 3 T and outcomes in surgical epilepsy

Pan, Jullie W; Antony, Arun; Tal, Assaf; Yushmanov, Victor; Fong, Joanna; Richardson, Mark; Schirda, Claud; Bagic, Anto; Gonen, Oded; Hetherington, Hoby P
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.
PMID: 33751687
ISSN: 1099-1492
CID: 4822412

Preliminary Findings Associate Hippocampal 1H-MR Spectroscopic Metabolite Concentrations with Psychotic and Manic Symptoms in Patients with Schizophrenia

Malaspina, D; Lotan, E; Rusinek, H; Perez, S A; Walsh-Messinger, J; Kranz, T M; Gonen, O
BACKGROUND AND PURPOSE/OBJECTIVE: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/METHODS:, 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: ≥  .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.
PMID: 33184071
ISSN: 1936-959x
CID: 4673542

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

Kirov, Ivan I; Sollberger, Marc; Davitz, Matthew S; Glodzik, Lidia; Soher, Brian J; Babb, James S; Monsch, Andreas U; Gass, Achim; Gonen, Oded
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.
PMID: 33232854
ISSN: 1558-1497
CID: 4680542