As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether pr... more As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16×16×4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) (∼35% of total monkey brain) volume of interest was also calculated for each ani...
Major depressive disorder (MDD) in pediatric populations represents a significant public health c... more Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.
Major depressive disorder (MDD) in pediatric populations represents a significant public health c... more Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.
Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidi... more Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidity and mortality. Newly available noninvasive neuroimaging techniques provide unique opportunities to illuminate the underlying neurobiological factors of MDD. This article reviews structural and functional neuroimaging data in pediatric MDD. In general, neuroimaging studies in pediatric MOD tend to confirm findings in adult depression implicating the prefrontal cortex, amygdala, and hippocampus. These brain regions are linked and believed to be critical in modulating emotional responses. However, neuroimaging research in pediatric MDD is still in its infancy, and inconsistencies are rife. These inconsistencies are largely due to the small samples and lack of agreement regarding methodology in ascertainment as well as in imaging. Greater focus on careful delineation of clinically and neurobiologically defined subgroups will likely lead to improved understanding of the pathophysiology of MDD.
We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the ... more 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.
p<0.02) at all days of culture. We also observed a trend for correlation between white matter MTR... more p<0.02) at all days of culture. We also observed a trend for correlation between white matter MTR values and number of O4 positive cells at all time points (p¼0.07) in 5 cases and 6 control subjects. (One subject had no available MTR value). Conclusions: There is a significant correlation between generation of oligodendrocytes from patient-derived fibroblasts and myelin content measured using MRI in the same patients. The findings suggest that the mechanisms underlying reduced myelination in SZ in vivo may be studied in cell culture in vitro.
The mechanism producing psychosis appears to include hippocampal inflammation, which could be ass... more 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.
Background: Quantitative measurement is a routine, defining feature of every clinical science exc... more Background: Quantitative measurement is a routine, defining feature of every clinical science except for psychiatry. Multiple research groups have shown that cross-sectional and longitudinal measures of speech and facial features predict common clinical measures and could supplement the classic mental status exam. Here, we report the feasibility of feature generation from longitudinal data collected in an active inpatient psychiatric unit. Methods: Eight inpatients were voluntarily recorded with consumer-grade camera and microphone equipment in sterile interview rooms over 41 conversations averaging 4 minutes each. Facial features were generated using OpenFace; acoustic voice features with Praat and OpenSmile; transcribed speech content with LIWC, and GloVe. Results: Automated facial feature generation was 99.1% successful, with an overall mean confidence for successful frames of 95.25%. In a patient recovering from mania features for gaze density tightened on the clinician, pause duration increased as speech pressure decreased, and LIWC category weight reflecting perseveration declined. Conclusions: We found relevant, quantitative features could be generated from audio and video collected with inexpensive technology in an inpatient unit using minimal computational resources. These features quantified phenomena in a preliminary cohort that would otherwise be reflected only in high level instrument scores or not captured at all.
Objectives-To compare testicular metabolite concentrations between fertile control subjects and i... more Objectives-To compare testicular metabolite concentrations between fertile control subjects and infertile men. Materials and Methods-Single voxel 1 H-MRS was performed in the testes with and without water suppression at 3T in 9 fertile control subjects and 9 infertile patients (8 with azoospermia and 1 with oligospermia). In controls only, the T1 and T2 values of water and metabolites were also measured. Absolute metabolite concentrations were calculated using the unsuppressed water signal as a reference and correcting for the relative T1 and T2 weighting of the water and metabolite signals. Results-Testicular T1 values of water, total choline and total creatine were 2028 ± 125 ms, 1164 ± 105 ms and 1421 ± 314 ms respectively (mean ± standard deviation). T2 values were 154 ± 11 ms, 342 ± 53 ms and 285 ± 167 ms respectively. Total choline concentration was lower in patients (mean 1.5mM, range 0.9-2.1mM) than controls (mean 4.4mM, range 3.2-5.7mM), p = 4 x 10 −5. Total creatine concentration was likewise reduced in patients (mean 1.1mM, range: undetectable-2.7mM) compared to controls (mean 3.6mM, range 2.5-4.7mM), p = 1.6 x 10 −4. The myo-inositol signal normalized to the water reference was also lower in patients than controls (p = 4 x 10 −5). Conclusions-Testicular metabolite concentrations, measured by proton spectroscopy at 3T, may be valuable as noninvasive biomarkers of spermatogenesis.
For the spectroscopic assessment of brain disorders that require large-volume coverage, the requi... more 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 frontoparietal regions, and a contiguous parallel two-slice Hadamard-encoded acquisition to cover the temporal-occipital region, both with T R /T E = 2000/40 ms and matched acquisition times. With restricted (static, first/second-order) B 0 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 temporaloccipital regions. We applied these acquisitions at a nominal 400 mm 3 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 postsurgical outcome. This finding suggests that a larger burden of metabolic dysfunction is seen in patients with poorer post-surgical seizure control.
Introduction The purpose of this study is to investigate brain metabolic changes in patients with... more Introduction The purpose of this study is to investigate brain metabolic changes in patients with amnestic mild cognitive impairment (aMCI) using multivoxel proton MR spectroscopy (1 H-MVS). Methods Fourteen aMCI patients and fifteen healthy control subjects participated in this experiment. All MR measurements were acquired using a 1.5-T GE scanner. 1 H-MVS point resolved spectroscopy (2D PROBE-CSI PRESS) pulse sequence (TE= 35 ms; TR = 1,500 ms; phase×frequency, 18×18) was used for acquiring MRS data. All data were post-processed using Spectroscopy Analysis by General Electric software and linear combination of model (LCModel). The absolute concentrations of N-acetylaspartate (NAA), choline (Cho), myoinositol (MI), creatine (Cr), and the metabolite ratios of NAA/Cr, Cho/Cr, MI/Cr, and NAA/MI were measured bilaterally in the posterior cingulate gyrus (PCG), inferior precuneus (Pr), paratrigonal white matter (PWM), dorsal thalamus (DT), and lentiform nucleus (LN). Results Patients with aMCI displayed significantly lower NAA levels in the bilateral PCG (p<0.01), PWM (p<0.05), and left inferior Pr (p<0.05). The metabolite ratio of NAA/ MI was decreased in the bilateral PCG (p<0.01) and PWM (p<0.05) and in the left DT (p<0.01). NAA/Cr was decreased in the left PCG (p<0.01), DT (p<0.05), right PWM (p<0.05), and LN (p<0.05). However, MI/Cr was elevated in the right PCG (p<0.01) and left PWM (p<0.05). Significantly increased Cho level was also evident in the left PWM (p<0.05). Conclusions Our observations of decreased NAA, NAA/Cr, and NAA/MI, in parallel with increased Cho and MI/Cr might be characteristic of aMCI patients.
BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural ... more BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used 1 H-MR spectroscopy to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS: Nineteen patients with schizophrenia (11 men; mean age, 40.6 Ϯ 10.1 years; mean disease duration, 19.5 Ϯ 10.5 years) and 11 matched healthy controls (5 men; mean age, 33.7 Ϯ 10.1 years) underwent MR imaging and multivoxel point-resolved spectroscopy (TE/TR, 35/1400 ms) 1 H-MRS at 3T to obtain their hippocampal GM absolute NAA, Cr, Cho, and mIns concentrations. Unequal variance t tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared by using unequal variance t tests. RESULTS: Patients' average hippocampal GM Cr concentrations were 19% higher than that of controls, 8.7 Ϯ 2.2 versus 7.4 Ϯ 1.2 mmol/L (P Ͻ .05); showing no differences, concentrations in NAA were 8.8 Ϯ 1.6 versus 8.7 Ϯ 1.2 mmol/L; in Cho, 2.3 Ϯ 0.7 versus 2.1 Ϯ 0.3 mmol/L; and in mIns, 6.1 Ϯ 1.5 versus 5.2 Ϯ 0.9 (all P Ͼ .1). There was a positive correlation between mIns and Cr in patients (r ϭ 0.57, P ϭ .05) but not in controls. The mean bilateral hippocampal volume was ϳ10% lower in patients: 7.5 Ϯ 0.9 versus 8.4 Ϯ 0.7 cm 3 (P Ͻ .05). CONCLUSIONS: These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1 H-MR spectroscopy reports. Elevated Cr is consistent with hippocampal hypermetabolism, and its correlation with mIns may also suggest an inflammatory process affecting some cases; these findings may suggest treatment targets and markers to monitor them. ABBREVIATIONS: CSI ϭ chemical shift imaging; 1 H-MRSI ϭ 3D multivoxel 1 H-MRS imaging; SZ ϭ schizophrenia
Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but ... more Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but lacking. Objective: To test whether the MS Severity Scale (MSSS) and global neuronal viability, assessed through the quantification of the whole-brain N-acetylaspartate concentration (WBNAA), concur or complement the assessment of individual patients’ disease course. Methods: The MSSS and average WBNAA loss rate (ΔWBNAA, extrapolated based on one current measurement and the assumption that at disease onset neural sparing was similar to healthy controls, obtained with proton magnetic resonance (MR) spectroscopy and magnetic resonance imaging (MRI)) from 61 patients with MS (18 male and 43 female) with long disease duration (15 years or more) were retrospectively examined. Some 27 patients exhibited a ‘benign’ disease course, characterized by an Expanded Disability Status Scale score (EDSS) of 3.0 or less, and 34 were ‘non-benign’: EDSS score higher than 3.0. Results: The two cohorts were ...
To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhib... more To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-l-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials.
Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total chol... more Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS ((1) H-MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%-65% of the brain. Here we wish to demonstrate that non-localized, whole-head (WH) (1) H-MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T1 -weighted MRI for tissue segmentation, non-localizing, approximately 3 min WH (1) H-MRS (TE /TR /TI = 5/10/940 ms) and 30 min (1) H-MR spectroscopic imaging (MRSI) (TE /TR = 35/2100 ms) in a 360 cm(3) volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The m...
Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total chol... more Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS ((1) H-MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%-65% of the brain. Here we wish to demonstrate that non-localized, whole-head (WH) (1) H-MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T1 -weighted MRI for tissue segmentation, non-localizing, approximately 3 min WH (1) H-MRS (TE /TR /TI = 5/10/940 ms) and 30 min (1) H-MR spectroscopic imaging (MRSI) (TE /TR = 35/2100 ms) in a 360 cm(3) volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The m...
To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophr... more To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophrenia are metabolically different from those in healthy control subjects. Materials and Methods: This institutional review board-approved study was HIPAA compliant, and all participants provided written informed consent. Twenty-two patients with schizophrenia (13 male, nine female; 39.4 years 6 10.6 [standard deviation]) and 11 age-and sex-matched control subjects (seven male, four female; 35.5 years 6 10.7) underwent magnetic resonance (MR) imaging and three-dimensional 3-T voxel proton MR spectroscopy to measure absolute rostral and caudal ACC N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) concentrations. Exact Mann-Whitney test was used to compare patient data with control data, paired-sample Wilcoxon signed rank test was used to compare subregions within groups, and receiver operating characteristic curve analysis was used to assess sensitivity and specifi city in diagnosis of schizophrenia. Results: There were no signifi cant metabolic differences between patients and control subjects or between ACC subregions in control subjects. In patients, rostral ACC NAA and Cr concentrations were signifi cantly lower than those in caudal ACC (6.2 mM 6 1.3 vs 7.1 mM 6 1.3, P , .01; 5.7 mmol/L 6 1.4 vs 6.3 mmol/L 6 1.6, P , .01; respectively); however, this did not hold true for Cho concentrations (1.7 mmol/L 6 0.5 vs 1.8 mmol/L 6 0.5). For individual differences between caudal and rostral measurements, only NAA in patients was different from that in control subjects (0.9 mmol/L 6 1.3 vs 2 0.1 mmol/L 6 0.5, P , .01), enabling prediction of schizophrenia with 68% sensitivity and 91% specifi city, for a difference of more than 0.4. Conclusion: Signifi cant differences between caudal and rostral NAA concentration are found in ACC of patients with schizophrenia but not in ACC of healthy control subjects, indicating that neuronal density or integrity differences between ACC subregions may be characteristic of the disease.
PURPOSE-The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnor... more PURPOSE-The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnormalities in the dentate granule cell layer (DGCL), but its small size (~100 micron thickness) has precluded in vivo human studies. We used ultra high field magnetic resonance imaging (MRI) to compare DGCL morphology of schizophrenic patients to matched controls'. METHOD-Bilateral hippocampi of 16 schizophrenia patients (10 male) 40.7±10.6 years old (mean ±standard deviation) were imaged at 7 Tesla MRI with heavily T 2 *-weighted gradient-echo sequence at 232 micron in-plane resolution (0.08 μL image voxels). Fifteen matched controls (8 male, 35.6±9.4 years old) and one ex vivo post mortem hippocampus (that also underwent histopathology) were scanned with same protocol. Three blinded neuroradiologists rated each DGCL on a qualitative scale of 1 to 6 (from "not discernible" to "easily visible, appearing dark gray or black") and mean left and right DGCL scores were compared using a non-parametric Mann-Whitney test. RESULTS-MRI identification of the DGCL was validated with histopathology. Mean right and left DGCL ratings in patients (3.2±1.0 and 3.5±1.2) were not statistically different from controls' (3.9±1.1 and 3.8±0.8), but patients' had a trend for lower right DGCL score (p=0.07), which was
The neuronal-marker, NAA, a quantitative metric for neurons' health and density, is currently obt... more The neuronal-marker, NAA, a quantitative metric for neurons' health and density, is currently obtained by integration of the manually defined peak in whole-head 1 H-MRS. Our goal was to develop a full spectral modeling approach for estimating automatically the whole-brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency-range peak integration approach previously employed. MRI and WBNAA 1 H-MRS from 18 healthy young were examined. Their non-localized, whole-head 1 H-MRS obtained at 3 T yielded the NAA peak area through both manually-defined frequency-range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T 1-weighted MRI) to yield the WBNAA. A paired sample t test was used to compare the WBNAA paradigms and a likelihood ratio test to compare their coefficients of variation. While the between-subject WBNAA means were nearly identical: 12.8±2.5 mM for integration, 12.8±1.4 mM for spectral modeling, the latter's standard deviation was significantly smaller (∼50%, p=0.026). The within-subject variability was 11.7% (1.3 mM) for integration, versus 7.0% (±0.8 mM) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer-Rao lower bounds ‹0.1% and vanishingly small (experiment-fit) residuals. Modeling the whole-head 1 H-MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality-control feedback. Together, these enhance the usefulness of the technique to monitor neurological disorders' diffuse progression and treatment response.
As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether pr... more As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16×16×4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) (∼35% of total monkey brain) volume of interest was also calculated for each ani...
Major depressive disorder (MDD) in pediatric populations represents a significant public health c... more Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.
Major depressive disorder (MDD) in pediatric populations represents a significant public health c... more Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.
Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidi... more Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidity and mortality. Newly available noninvasive neuroimaging techniques provide unique opportunities to illuminate the underlying neurobiological factors of MDD. This article reviews structural and functional neuroimaging data in pediatric MDD. In general, neuroimaging studies in pediatric MOD tend to confirm findings in adult depression implicating the prefrontal cortex, amygdala, and hippocampus. These brain regions are linked and believed to be critical in modulating emotional responses. However, neuroimaging research in pediatric MDD is still in its infancy, and inconsistencies are rife. These inconsistencies are largely due to the small samples and lack of agreement regarding methodology in ascertainment as well as in imaging. Greater focus on careful delineation of clinically and neurobiologically defined subgroups will likely lead to improved understanding of the pathophysiology of MDD.
We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the ... more 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.
p<0.02) at all days of culture. We also observed a trend for correlation between white matter MTR... more p<0.02) at all days of culture. We also observed a trend for correlation between white matter MTR values and number of O4 positive cells at all time points (p¼0.07) in 5 cases and 6 control subjects. (One subject had no available MTR value). Conclusions: There is a significant correlation between generation of oligodendrocytes from patient-derived fibroblasts and myelin content measured using MRI in the same patients. The findings suggest that the mechanisms underlying reduced myelination in SZ in vivo may be studied in cell culture in vitro.
The mechanism producing psychosis appears to include hippocampal inflammation, which could be ass... more 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.
Background: Quantitative measurement is a routine, defining feature of every clinical science exc... more Background: Quantitative measurement is a routine, defining feature of every clinical science except for psychiatry. Multiple research groups have shown that cross-sectional and longitudinal measures of speech and facial features predict common clinical measures and could supplement the classic mental status exam. Here, we report the feasibility of feature generation from longitudinal data collected in an active inpatient psychiatric unit. Methods: Eight inpatients were voluntarily recorded with consumer-grade camera and microphone equipment in sterile interview rooms over 41 conversations averaging 4 minutes each. Facial features were generated using OpenFace; acoustic voice features with Praat and OpenSmile; transcribed speech content with LIWC, and GloVe. Results: Automated facial feature generation was 99.1% successful, with an overall mean confidence for successful frames of 95.25%. In a patient recovering from mania features for gaze density tightened on the clinician, pause duration increased as speech pressure decreased, and LIWC category weight reflecting perseveration declined. Conclusions: We found relevant, quantitative features could be generated from audio and video collected with inexpensive technology in an inpatient unit using minimal computational resources. These features quantified phenomena in a preliminary cohort that would otherwise be reflected only in high level instrument scores or not captured at all.
Objectives-To compare testicular metabolite concentrations between fertile control subjects and i... more Objectives-To compare testicular metabolite concentrations between fertile control subjects and infertile men. Materials and Methods-Single voxel 1 H-MRS was performed in the testes with and without water suppression at 3T in 9 fertile control subjects and 9 infertile patients (8 with azoospermia and 1 with oligospermia). In controls only, the T1 and T2 values of water and metabolites were also measured. Absolute metabolite concentrations were calculated using the unsuppressed water signal as a reference and correcting for the relative T1 and T2 weighting of the water and metabolite signals. Results-Testicular T1 values of water, total choline and total creatine were 2028 ± 125 ms, 1164 ± 105 ms and 1421 ± 314 ms respectively (mean ± standard deviation). T2 values were 154 ± 11 ms, 342 ± 53 ms and 285 ± 167 ms respectively. Total choline concentration was lower in patients (mean 1.5mM, range 0.9-2.1mM) than controls (mean 4.4mM, range 3.2-5.7mM), p = 4 x 10 −5. Total creatine concentration was likewise reduced in patients (mean 1.1mM, range: undetectable-2.7mM) compared to controls (mean 3.6mM, range 2.5-4.7mM), p = 1.6 x 10 −4. The myo-inositol signal normalized to the water reference was also lower in patients than controls (p = 4 x 10 −5). Conclusions-Testicular metabolite concentrations, measured by proton spectroscopy at 3T, may be valuable as noninvasive biomarkers of spermatogenesis.
For the spectroscopic assessment of brain disorders that require large-volume coverage, the requi... more 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 frontoparietal regions, and a contiguous parallel two-slice Hadamard-encoded acquisition to cover the temporal-occipital region, both with T R /T E = 2000/40 ms and matched acquisition times. With restricted (static, first/second-order) B 0 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 temporaloccipital regions. We applied these acquisitions at a nominal 400 mm 3 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 postsurgical outcome. This finding suggests that a larger burden of metabolic dysfunction is seen in patients with poorer post-surgical seizure control.
Introduction The purpose of this study is to investigate brain metabolic changes in patients with... more Introduction The purpose of this study is to investigate brain metabolic changes in patients with amnestic mild cognitive impairment (aMCI) using multivoxel proton MR spectroscopy (1 H-MVS). Methods Fourteen aMCI patients and fifteen healthy control subjects participated in this experiment. All MR measurements were acquired using a 1.5-T GE scanner. 1 H-MVS point resolved spectroscopy (2D PROBE-CSI PRESS) pulse sequence (TE= 35 ms; TR = 1,500 ms; phase×frequency, 18×18) was used for acquiring MRS data. All data were post-processed using Spectroscopy Analysis by General Electric software and linear combination of model (LCModel). The absolute concentrations of N-acetylaspartate (NAA), choline (Cho), myoinositol (MI), creatine (Cr), and the metabolite ratios of NAA/Cr, Cho/Cr, MI/Cr, and NAA/MI were measured bilaterally in the posterior cingulate gyrus (PCG), inferior precuneus (Pr), paratrigonal white matter (PWM), dorsal thalamus (DT), and lentiform nucleus (LN). Results Patients with aMCI displayed significantly lower NAA levels in the bilateral PCG (p<0.01), PWM (p<0.05), and left inferior Pr (p<0.05). The metabolite ratio of NAA/ MI was decreased in the bilateral PCG (p<0.01) and PWM (p<0.05) and in the left DT (p<0.01). NAA/Cr was decreased in the left PCG (p<0.01), DT (p<0.05), right PWM (p<0.05), and LN (p<0.05). However, MI/Cr was elevated in the right PCG (p<0.01) and left PWM (p<0.05). Significantly increased Cho level was also evident in the left PWM (p<0.05). Conclusions Our observations of decreased NAA, NAA/Cr, and NAA/MI, in parallel with increased Cho and MI/Cr might be characteristic of aMCI patients.
BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural ... more BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used 1 H-MR spectroscopy to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS: Nineteen patients with schizophrenia (11 men; mean age, 40.6 Ϯ 10.1 years; mean disease duration, 19.5 Ϯ 10.5 years) and 11 matched healthy controls (5 men; mean age, 33.7 Ϯ 10.1 years) underwent MR imaging and multivoxel point-resolved spectroscopy (TE/TR, 35/1400 ms) 1 H-MRS at 3T to obtain their hippocampal GM absolute NAA, Cr, Cho, and mIns concentrations. Unequal variance t tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared by using unequal variance t tests. RESULTS: Patients' average hippocampal GM Cr concentrations were 19% higher than that of controls, 8.7 Ϯ 2.2 versus 7.4 Ϯ 1.2 mmol/L (P Ͻ .05); showing no differences, concentrations in NAA were 8.8 Ϯ 1.6 versus 8.7 Ϯ 1.2 mmol/L; in Cho, 2.3 Ϯ 0.7 versus 2.1 Ϯ 0.3 mmol/L; and in mIns, 6.1 Ϯ 1.5 versus 5.2 Ϯ 0.9 (all P Ͼ .1). There was a positive correlation between mIns and Cr in patients (r ϭ 0.57, P ϭ .05) but not in controls. The mean bilateral hippocampal volume was ϳ10% lower in patients: 7.5 Ϯ 0.9 versus 8.4 Ϯ 0.7 cm 3 (P Ͻ .05). CONCLUSIONS: These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1 H-MR spectroscopy reports. Elevated Cr is consistent with hippocampal hypermetabolism, and its correlation with mIns may also suggest an inflammatory process affecting some cases; these findings may suggest treatment targets and markers to monitor them. ABBREVIATIONS: CSI ϭ chemical shift imaging; 1 H-MRSI ϭ 3D multivoxel 1 H-MRS imaging; SZ ϭ schizophrenia
Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but ... more Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but lacking. Objective: To test whether the MS Severity Scale (MSSS) and global neuronal viability, assessed through the quantification of the whole-brain N-acetylaspartate concentration (WBNAA), concur or complement the assessment of individual patients’ disease course. Methods: The MSSS and average WBNAA loss rate (ΔWBNAA, extrapolated based on one current measurement and the assumption that at disease onset neural sparing was similar to healthy controls, obtained with proton magnetic resonance (MR) spectroscopy and magnetic resonance imaging (MRI)) from 61 patients with MS (18 male and 43 female) with long disease duration (15 years or more) were retrospectively examined. Some 27 patients exhibited a ‘benign’ disease course, characterized by an Expanded Disability Status Scale score (EDSS) of 3.0 or less, and 34 were ‘non-benign’: EDSS score higher than 3.0. Results: The two cohorts were ...
To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhib... more To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-l-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials.
Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total chol... more Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS ((1) H-MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%-65% of the brain. Here we wish to demonstrate that non-localized, whole-head (WH) (1) H-MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T1 -weighted MRI for tissue segmentation, non-localizing, approximately 3 min WH (1) H-MRS (TE /TR /TI = 5/10/940 ms) and 30 min (1) H-MR spectroscopic imaging (MRSI) (TE /TR = 35/2100 ms) in a 360 cm(3) volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The m...
Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total chol... more Total N-acetyl-aspartate + N-acetyl-aspartate-glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS ((1) H-MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%-65% of the brain. Here we wish to demonstrate that non-localized, whole-head (WH) (1) H-MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T1 -weighted MRI for tissue segmentation, non-localizing, approximately 3 min WH (1) H-MRS (TE /TR /TI = 5/10/940 ms) and 30 min (1) H-MR spectroscopic imaging (MRSI) (TE /TR = 35/2100 ms) in a 360 cm(3) volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The m...
To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophr... more To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophrenia are metabolically different from those in healthy control subjects. Materials and Methods: This institutional review board-approved study was HIPAA compliant, and all participants provided written informed consent. Twenty-two patients with schizophrenia (13 male, nine female; 39.4 years 6 10.6 [standard deviation]) and 11 age-and sex-matched control subjects (seven male, four female; 35.5 years 6 10.7) underwent magnetic resonance (MR) imaging and three-dimensional 3-T voxel proton MR spectroscopy to measure absolute rostral and caudal ACC N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) concentrations. Exact Mann-Whitney test was used to compare patient data with control data, paired-sample Wilcoxon signed rank test was used to compare subregions within groups, and receiver operating characteristic curve analysis was used to assess sensitivity and specifi city in diagnosis of schizophrenia. Results: There were no signifi cant metabolic differences between patients and control subjects or between ACC subregions in control subjects. In patients, rostral ACC NAA and Cr concentrations were signifi cantly lower than those in caudal ACC (6.2 mM 6 1.3 vs 7.1 mM 6 1.3, P , .01; 5.7 mmol/L 6 1.4 vs 6.3 mmol/L 6 1.6, P , .01; respectively); however, this did not hold true for Cho concentrations (1.7 mmol/L 6 0.5 vs 1.8 mmol/L 6 0.5). For individual differences between caudal and rostral measurements, only NAA in patients was different from that in control subjects (0.9 mmol/L 6 1.3 vs 2 0.1 mmol/L 6 0.5, P , .01), enabling prediction of schizophrenia with 68% sensitivity and 91% specifi city, for a difference of more than 0.4. Conclusion: Signifi cant differences between caudal and rostral NAA concentration are found in ACC of patients with schizophrenia but not in ACC of healthy control subjects, indicating that neuronal density or integrity differences between ACC subregions may be characteristic of the disease.
PURPOSE-The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnor... more PURPOSE-The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnormalities in the dentate granule cell layer (DGCL), but its small size (~100 micron thickness) has precluded in vivo human studies. We used ultra high field magnetic resonance imaging (MRI) to compare DGCL morphology of schizophrenic patients to matched controls'. METHOD-Bilateral hippocampi of 16 schizophrenia patients (10 male) 40.7±10.6 years old (mean ±standard deviation) were imaged at 7 Tesla MRI with heavily T 2 *-weighted gradient-echo sequence at 232 micron in-plane resolution (0.08 μL image voxels). Fifteen matched controls (8 male, 35.6±9.4 years old) and one ex vivo post mortem hippocampus (that also underwent histopathology) were scanned with same protocol. Three blinded neuroradiologists rated each DGCL on a qualitative scale of 1 to 6 (from "not discernible" to "easily visible, appearing dark gray or black") and mean left and right DGCL scores were compared using a non-parametric Mann-Whitney test. RESULTS-MRI identification of the DGCL was validated with histopathology. Mean right and left DGCL ratings in patients (3.2±1.0 and 3.5±1.2) were not statistically different from controls' (3.9±1.1 and 3.8±0.8), but patients' had a trend for lower right DGCL score (p=0.07), which was
The neuronal-marker, NAA, a quantitative metric for neurons' health and density, is currently obt... more The neuronal-marker, NAA, a quantitative metric for neurons' health and density, is currently obtained by integration of the manually defined peak in whole-head 1 H-MRS. Our goal was to develop a full spectral modeling approach for estimating automatically the whole-brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency-range peak integration approach previously employed. MRI and WBNAA 1 H-MRS from 18 healthy young were examined. Their non-localized, whole-head 1 H-MRS obtained at 3 T yielded the NAA peak area through both manually-defined frequency-range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T 1-weighted MRI) to yield the WBNAA. A paired sample t test was used to compare the WBNAA paradigms and a likelihood ratio test to compare their coefficients of variation. While the between-subject WBNAA means were nearly identical: 12.8±2.5 mM for integration, 12.8±1.4 mM for spectral modeling, the latter's standard deviation was significantly smaller (∼50%, p=0.026). The within-subject variability was 11.7% (1.3 mM) for integration, versus 7.0% (±0.8 mM) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer-Rao lower bounds ‹0.1% and vanishingly small (experiment-fit) residuals. Modeling the whole-head 1 H-MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality-control feedback. Together, these enhance the usefulness of the technique to monitor neurological disorders' diffuse progression and treatment response.
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Papers by Oded Gonen