Motor cortex functional connectivity is associated with underlying neurochemistry in ALS.

OBJECTIVE: To identify structural and neurochemical properties that underlie functional connectivity impairments of the primary motor cortex (PMC) and how these relate to clinical findings in amyotrophic lateral sclerosis (ALS). METHODS: 52 patients with ALS and 52 healthy controls, matched for age and sex, were enrolled from 5 centres across Canada for the Canadian ALS Neuroimaging Consortium study. Resting-state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy data were acquired. Functional connectivity maps, diffusion metrics and neurometabolite ratios were obtained from the analyses of the acquired multimodal data. A clinical assessment of foot tapping (frequency) was performed to examine upper motor neuron function in all participants. RESULTS: Compared with healthy controls, the primary motor cortex in ALS showed reduced functional connectivity with sensory (T=5.21), frontal (T=3.70), temporal (T=3.80), putaminal (T=4.03) and adjacent motor (T=4.60) regions. In the primary motor cortex, N-acetyl aspartate (NAA, a neuronal marker) ratios and diffusion metrics (mean, axial and radial diffusivity, fractional anisotropy (FA)) were altered. Within the ALS cohort, foot tapping frequency correlated with NAA (r=0.347) and white matter FA (r=0.537). NAA levels showed associations with disturbed functional connectivity of the motor cortex. CONCLUSION: In vivo neurochemistry may represent an effective imaging marker of impaired motor cortex functional connectivity in ALS.

Prospective Investigation of Glutamate Levels and Percentage Gray Matter in the Medial Prefrontal Cortex in Females at Risk for Postpartum Depression.

BACKGROUND: The substantial female hormone fluctuations associated with pregnancy and postpartum have been linked to a greater risk of developing depressive symptoms, particularly in high-risk women (HRW), i.e. those with histories of mood sensitivity to female hormone fluctuations. We have shown that glutamate (Glu) levels in the medial prefrontal cortex (MPFC) decrease during perimenopause, a period of increased risk of developing a major depressive episode. Our team has also demonstrated that percentage gray matter (%GM), another neural correlate of maternal brain health, decreases in the MPFC during pregnancy. OBJECTIVE: To investigate MPFC Glu levels and %GM from late pregnancy up to 7 weeks postpartum in HRW and healthy pregnant women (HPW). METHODS: Single-voxel spectra were acquired from the MPFC of 41 HPW and 22 HRW using 3- Tesla in vivo proton magnetic resonance spectroscopy at five different time points. RESULTS: We observed a statistically significant interaction between time and group for the metabolite Glu, with Glu levels being lower for HRW during pregnancy and early postpartum (p<0.05). MPFC %GM was initially lower during pregnancy and then significantly increased over time in both groups (p<0.01). CONCLUSION: This investigation suggests that the vulnerability towards PPD is associated with unique fluctuations of MPFC Glu levels during pregnancy and early postpartum period. Our results also suggest that the decline in MPFC %GM associated with pregnancy seems to progressively recover over time. Further investigations are needed to determine the specific role that female hormones play on the physiological changes in %GM during pregnancy and postpartum.

Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study.

OBJECTIVE: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS. METHODS: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios. RESULTS: Patients with ALS had reduced NAA ratios in the motor cortex at baseline (p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing (p < 0.01) and high UMN burden (p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (p < 0.05); prefrontal cortex metabolites did not change over time. CONCLUSIONS: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02405182.

Rapid acquisition diffusion MR spectroscopy of metabolites in human brain.

Few studies have focused on metabolite diffusion in the human brain using 1 H-MRS due to significant technical challenges. Moreover, such studies have required lengthy acquisition times and are therefore impractical to implement clinically. By first characterizing and then minimizing the effects of linear and oscillating eddy currents, which arise from the diffusion gradients, and by implementing phase-cycle and slice-order strategies, as well as introducing a new phase-alignment methodology, we report a method that allows data acquisition requiring 20 seconds per spectrum. This remained feasible, even for b-values >8000 s/mm2 , with a rapid acquisition diffusion MRS methodology. It has allowed the nonlinear characterization of signal intensity with multiple b-values, and has improved the measurement of rotationally invariant diffusion parameters via six-direction, six b-value diffusion tensor spectroscopy (DTS) in 12 minutes at 4.7 T. The shorter DTS acquisition will enable its application to white matter regions not aligned with the gradients and permit clinical studies in a feasible time.

Spectroscopic markers of neurodegeneration in the mesial prefrontal cortex predict survival in ALS.

Background and objective: N-acetylaspartate (NAA) and myo-inositol (mIns) are spectroscopic markers of neuronal integrity and astrogliosis, respectively. We performed a survival analysis to determine the prognostic value of the NAA/mIns metabolite ratio in ALS after a period of two and five years. Methods: Twenty-four patients with ALS (two with ALS-FTD) were recruited to participate in a high-field MR spectroscopy study of the mesial prefrontal cortex. Univariate and multivariate Cox proportional hazards analyses were used to assess NAA/mIns as a predictor of survival alongside other demographic and clinical measures. Census dates were set at two and five years after the time of MR scan for each patient. Survival curves were calculated using the Kaplan-Meier method. Results: After a five-year observation period, 19 patients had died and five were still alive. Median survival time from date of scan was 1.95 years. Univariate and multivariate Cox analysis showed NAA/mIns to be a significant independent predictor of survival at two years after scanning, but not at five years. Conclusion: Cerebral degeneration in the mesial prefrontal cortex as detected by the NAA/mIns metabolite ratio is predictive of survival in ALS in a time-dependent manner.

Cerebral degeneration in amyotrophic lateral sclerosis: A prospective multicenter magnetic resonance spectroscopy study.

BACKGROUND: We investigated cerebral degeneration and neurochemistry in patients with amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS). METHODS: We prospectively studied 65 patients and 43 age-matched healthy controls. Participants were recruited from 4 centers as part of a study in the Canadian ALS Neuroimaging Consortium. All participants underwent single-voxel proton MRS using a protocol standardized across all sites. Metabolites reflecting neuronal integrity (total N-acetyl aspartyl moieties [tNAA]) and gliosis (myo-inositol [Ino]), as well as creatine (Cr) and choline (Cho), were quantified in the midline motor cortex and midline prefrontal cortex. Comparisons were made between patients with ALS and healthy controls. Metabolites were correlated with clinical measures of upper motor neuron dysfunction, disease progression rate, and cognitive performance. RESULTS: In the motor cortex, tNAA/Cr, tNAA/Cho, and tNAA/Ino ratios were reduced in the ALS group compared with controls. Group differences in tNAA/Cr and tNAA/Cho in the prefrontal cortex displayed reduced ratios in ALS patients; however, these were not statistically significant. Reduced motor cortex ratios were associated with slower foot tapping rate, whereas only motor tNAA/Ino was associated with finger tapping rate. Disease progression rate was associated with motor tNAA/Cho. Verbal fluency, semantic fluency, and digit span forwards and backwards were associated with prefrontal tNAA/Cr. CONCLUSIONS: This study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia.

Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age- and sex-matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1-weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss.

Considerations for measuring the fractional anisotropy of metabolites with diffusion tensor spectroscopy.

Diffusion tensor spectroscopy of metabolites in brain is challenging because of their lower diffusivity (i.e. less signal attenuation for a given b value) and much poorer signal-to-noise ratio relative to water. Although diffusion tensor acquisition protocols have been studied in detail for water, they have not been evaluated systematically for the measurement of the fractional anisotropy of metabolites such as N-acetylaspartate, creatine and choline in the white and gray matter of human brain. Diffusion tensor spectroscopy was performed in vivo with variable maximal b values (1815 or 5018 s/mm(2)). Experiments were also performed on simulated spectra and isotropic alcohol phantoms of various diffusivities, ranging from approximately 0.54 × 10(-3) to 0.13 × 10(-3) mm(2)/s, to assess the sensitivity of diffusion tensor spectroscopic parameters to low diffusivity, noise and b value. The low maximum b value of 1815 s/mm(2) yielded elevated fractional anisotropy (0.53-0.60) of N-acetylaspartate in cortical gray matter relative to the more isotropic value (0.25-0.30) obtained with a higher b value of 5018 s/mm(2); in contrast, the fractional anisotropy of white matter was consistently anisotropic with the different maximal b values (i.e. 0.43-0.54 for b = 1815 s/mm(2) and 0.47-0.51 for b = 5018 s/mm(2)). Simulations, phantoms and in vivo data indicate that greater signal attenuation, to a degree, is desirable for the accurate quantification of diffusion-weighted spectra for slowly diffusing metabolites.

Combined structural and neurochemical evaluation of the corticospinal tract in amyotrophic lateral sclerosis.

Our objective was to characterize the structural and metabolic changes of the corticospinal tract (CST) in ALS patients using combined diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI). Fourteen patients (male:female, 6:8; mean age, 54 years) and 14 controls (male:female, 8:6; mean age, 53 years) underwent imaging. Four regions of the CST were evaluated: precentral gyrus, corona radiata, posterior limb of the internal capsule, and cerebral peduncle. DTI and MRSI indices tested included fractional anisotropy (FA), apparent diffusion coefficient (ADC), and the ratio of N-acetylaspartate to choline (NAA/Cho) and creatine (NAA/Cr). In the precentral gyrus, NAA/Cho was reduced 18% (p<0.001), NAA/Cr was reduced 9% (p=0.01), and FA was reduced 3% (p=0.02). NAA/Cho and NAA/Cr were reduced in the corona radiata (p<0.001). Reduced NAA/Cho in the precentral gyrus correlated with shorter symptom duration (r=0.66, p=0.02) and faster disease progression (r=-0.65, p=0.008). Increased spasticity correlated with higher ADC in the precentral gyrus (R=0.52, p=0.005). In conclusion, both MRSI and DTI provided in vivo evidence of intracranial degeneration of the CST in ALS that was most prominent rostrally in the precentral gyrus.

Spectral editing of weakly coupled spins using variable flip angles in PRESS constant echo time difference spectroscopy: application to GABA.

A general in vivo magnetic resonance spectroscopy editing technique is presented to detect weakly coupled spin systems through subtraction, while preserving singlets through addition, and is applied to the specific brain metabolite gamma-aminobutyric acid (GABA) at 4.7 T. The new method uses double spin echo localization (PRESS) and is based on a constant echo time difference spectroscopy approach employing subtraction of two asymmetric echo timings, which is normally only applicable to strongly coupled spin systems. By utilizing flip angle reduction of one of the two refocusing pulses in the PRESS sequence, we demonstrate that this difference method may be extended to weakly coupled systems, thereby providing a very simple yet effective editing process. The difference method is first illustrated analytically using a simple two spin weakly coupled spin system. The technique was then demonstrated for the 3.01 ppm resonance of GABA, which is obscured by the strong singlet peak of creatine in vivo. Full numerical simulations, as well as phantom and in vivo experiments were performed. The difference method used two asymmetric PRESS timings with a constant total echo time of 131 ms and a reduced 120 degrees final pulse, providing 25% GABA yield upon subtraction compared to two short echo standard PRESS experiments. Phantom and in vivo results from human brain demonstrate efficacy of this method in agreement with numerical simulations.

Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism.

OBJECTIVES: To determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients. DESIGN: Forty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinson's Disease Rating Scale, separated into dopamine responsive and dopamine non-responsive signs) and neuropsychological testing (memory: California Verbal Learning Test (CVLT)) and a composite of index of executive function (EF): Stroop Interference, Trail Making Test Part B, and digit ordering. All underwent volumetric MRI scans analyzed using voxel-based morphometry (VBM). Group comparisons, and the correlations between MRI gray and white matter volume and motor and cognitive measures were controlled for age, sex and intracranial volume. Cerebellar volume was independently measured using a validated extraction method. RESULTS: Patients and controls were matched for demographics and global cognitive measures. VBM indicated significant gray matter (GM) atrophy in the cerebellum in PD and was confirmed independently. Poor memory was associated with GM atrophy in the left (uncus, middle temporal and fusiform gyri) and right temporal lobes and left putamen. Dopamine non-responsive motor signs and EF were associated with caudate atrophy. EF was also associated with GM atrophy in the middle temporal gyri, the left precuneus and cerebellum. CONCLUSIONS: Cortical and striatal atrophy were associated with dopamine non-responsive motor signs and cognitive impairment and provide a morphologic correlate for progression of PD. Cerebellar atrophy was found in older PD patients.

Acute dextro-amphetamine administration does not alter brain myo-inositol levels in humans and animals: MRS investigations at 3 and 18.8 T.

The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75 min after receiving a 25 mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0 Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1 h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8 T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations.

Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder.

BACKGROUND: Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). METHODS: Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. RESULTS: A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. CONCLUSIONS: The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

Anisotropic diffusion of metabolites in peripheral nerve using diffusion weighted magnetic resonance spectroscopy at ultra-high field.

Although the diffusivity and anisotropy of water has been investigated thoroughly in ordered axonal systems (i.e., nervous tissue), there have been very few studies on the directional dependence of diffusion of metabolites. In this study, the mean apparent diffusion coefficient (Trace/3 ADC) and fractional anisotropy (FA) values of the intracellular metabolites N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), choline (Cho), taurine (Tau), and glutamate and glutamine (Glx) were measured parallel and perpendicular to the length of excised frog sciatic nerve using a water suppressed, diffusion-weighted, spin-echo pulse sequence at 18.8T. The degree of anisotropy (FA) of NAA (0.41+/-0.09) was determined to be less than tCr (0.59+/-0.07) and Cho (0.61+/-0.11), which is consistent with previously reported human studies of white matter. In contrast, Glx diffusion was found to be almost isotropic with an FA value of 0.20+/-0.06. The differences of FA between the metabolites is most likely due to their differing micro-environments and could be beneficial as an indicator of compartment specific changes with disease, information not readily available with water diffusion.

The relation between peripheral and central glutamate and glutamine in healthy male volunteers.

OBJECTIVE: High-field strength proton magnetic resonance spectroscopy ((1)H-MRS) and peripheral blood analyses reported in the literature reveal glutamate (Glu) and glutamine (Gln) abnormalities in schizophrenia. Given the relative ease and feasibility of using peripheral measures, the present study investigates the relation between peripheral and brain Glu and Gln levels. METHODS: We recruited healthy volunteers (n = 17, mean age 21.9 [standard deviation 2.9, range 18-29] yr) between May and December 2005. All participants underwent 3 Tesla (1)H-MRS analysis with segmentation (grey matter, white matter, cerebrospinal fluid) at the Nuclear Magnetic Resonance Centre at the University of Alberta Hospital to quantify medial prefrontal cortical (mPFC) Glu and Glx (i.e., combination of Glu and Gln). Within 1 week of (1)H-MRS analysis, we collected plasma from the same participants for Glu and Gln quantification, using high-performance liquid chromatography at the Neurochemical Research Unit at the University of Alberta. RESULTS: There was no correlation between plasma Glu and either medial prefrontal cortical Glu or Glx (R(1,15) = 0.019, p = 0.944 and R(1,15) = 0.081, p = 0.757, respectively). Similarly, there was no correlation between plasma Gln and either mPFC Glu or Glx (R(1,15) = 0.029, p = 0.911 and R(1,15) = 0.025, p = 0.925, respectively). CONCLUSION: Our findings support the use of (1)H-MRS, instead of peripheral blood analysis, for investigating glutamatergic dysfunction in the brain.

Diffusion tensor spectroscopy (DTS) of human brain.

The diffusion tensor of N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), and choline (Cho) was measured at 3T using a diffusion weighted STEAM (1)H-MRS sequence in the healthy human brain in 6 distinct regions (4 white matter and 2 cortical gray matter). The Trace/3 apparent diffusion coefficient (ADC) of each metabolite was significantly greater in white matter than gray matter. The Trace/3 ADC values of tCr and Cho were found to be significantly greater than NAA in white matter, whereas all 3 metabolites had similar Trace/3 ADC in cortical gray matter. Fractional anisotropy (FA) values for all 3 metabolites were consistent with water FA values in the 4 white matter regions; however, metabolite FA values were found to be higher than expected in the cortical gray matter. The principal diffusion direction derived for NAA was in good agreement with expected anatomic tract directions in the white matter.

Decreased prefrontal Myo-inositol in major depressive disorder.

BACKGROUND: Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. METHODS: Thirteen nonmedicated moderate-severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time=168 msec; mixing time=28 msec; repetition time=3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. RESULTS: Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94+/-.23) than control subjects (1.32+/-.37) [F(1,23)=6.9; p=.016]. CONCLUSIONS: These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD.

Trace apparent diffusion coefficients of metabolites in human brain using diffusion weighted magnetic resonance spectroscopy.

The rotationally invariant trace/3 apparent diffusion coefficients (ADC) of N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), and choline (Cho) were determined using a diffusion-weighted stimulated echo acquisition mode sequence at 3 T in three separate human brain regions, namely the subcortical white matter, occipital gray matter, and frontal gray matter. The measurement of the mean diffusivity eliminates the dependence of the measured ADC on the direction of the diffusion gradient relative to the tissue microstructure (i.e., anisotropy). Macroscopic brain motions induce phase errors that were compensated for by phasing (zero and first order) on the single average spectrum (zero order on the NAA peak) prior to summing the individual spectra. This method yielded reproducible trace/3 ADC values in the expected range without the use of cardiac gating. The mean diffusivity of NAA (0.14 +/- 0.03 x 10(-3) mm(2)/s) appears to be less than that of tCr (0.17 +/- 0.04 x 10(-3) mm(2)/s) and Cho (0.18 +/- 0.05 x 10(-3) mm(2)/s) in human brain.

3-T proton MRS investigation of glutamate and glutamine in adolescents at high genetic risk for schizophrenia.

OBJECTIVE: Glutamate and glutamine were examined in vivo in nonpsychotic adolescents at high genetic risk for schizophrenia by using 3-T proton magnetic resonance spectroscopy ((1)H-MRS). METHOD: Spectra from the right medial frontal lobe of 20 adolescents who had a parent with schizophrenia (high-risk group; mean age=16.4 years) were compared with spectra obtained from adolescent offspring of parents with no history of schizophrenia (low-risk group; mean age=16.7 years). RESULTS: Glutamate/glutamine was significantly higher in the adolescents at high genetic risk for schizophrenia than in the low-risk offspring. Age, premorbid adjustment scale scores, and other (1)H-MRS metabolites did not differ between groups. Global Assessment of Functioning Scale scores and socioeconomic status were lower in the high-risk group. DISCUSSION: The finding of glutamate/glutamine abnormalities in a group of subjects at high genetic risk for schizophrenia lends support for both the glutamate dysfunction and neurodevelopmental hypotheses for schizophrenia.