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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., (© 2021 American Academy of Neurology.)

Background: There is a paucity of data connecting the metabolic and cognitive functioning of abstinent cocaine users. This is a pressing public health concern as approximately 1% of the Canadian population and 0.4% of the global population is estimated to have used cocaine in the past year., Methods: Our clinical study compared the in vivo neurochemical profiles in the prefrontal cortex to cognitive tests associated with the same region in 21 moderate term abstinent cocaine users (average 187days abstinent, range 15-1432days), and 30 healthy controls using 3T 1 H MRS., Results: The abstinent cocaine users exhibited a 10% decrease in N-acetylaspartate (NAA) relative to healthy control subjects (p<0.01, Cohen's d=1.15). When subdivided by method of administration, a significant decrease in glutamate levels in former crack smokers compared to healthy controls (p<0.05) was observed, this decrease was not present in powder users. Abstinent users were significantly worse than healthy controls on the Trail Making Test B (p<0.05), and performance on this task was inversely related to NAA levels (p<0.05). Abstinent cocaine users showed deficits in the Wisconsin card sorting test with failures to maintain set (p<0.01)., Conclusions: Our work suggests that there are subtle but important changes in the brain that remain even with the moderate term cessation of cocaine use., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Acute symptoms of methamphetamine-induced psychosis are similar to those of primary schizophrenia. Understanding similarities or differences in the biological substrate of these psychoses could lead to early differentiation of these two clinical conditions resulting in more efficient treatment strategies. Proton magnetic resonance spectroscopy was acquired from the medial prefrontal cortex in 29 unmedicated patients with first episode of psychosis (FEP), 29 abstinent methamphetamine-addicted people (METH) and 45 healthy controls (HCs) (age range 17.3 to 29.9years old). The METH group displayed robust reductions in concentration levels of glutamate (Glu) relative to FEP (Cohen's d=1.20) and HC (d=0.87). The METH group also displayed reduced levels of N-acetylaspartate (NAA) relative to FEP (d=0.53) and HC (d=0.76). The HC group displayed a positive association between levels of Glu and NAA, r(45)=0.52, p<0.001, while the two clinical groups failed to show this normal association. This suggests that the cellular metabolism is altered in both conditions. These data support the assumption that cellular abnormalities differ between primary schizophrenia and methamphetamine addiction despite the overlap in clinical presentation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The medial prefrontal cortex (MPFC) is a key brain area in depressive symptomatology; specifically, glutamate (Glu) has been reported to play a significant role in major depression (MD) in this area. MPFC Glu levels are sensitive to ovarian hormone fluctuations and pregnancy and the postpartum period are associated with the most substantial physiological alterations of female hormones. It is therefore logical to measure MPFC Glu levels in women with postpartum depression (PPD). Using in vivo magnetic resonance spectroscopy (MRS) at a field strength of 3 T, we acquired single-voxel spectra from the MPFC of 12 women with PPD and 12 healthy controls (HCs) matched for postpartum scan timing. Water-referenced MPFC Glu levels were measured using a MRS technique that allowed us to be specific for Glu with very little glutamine contamination. The concentrations of other water-quantified brain metabolites such as glycerophosphorylcholine plus phosphorylcholine, N-acetylaspartate (NAA), and creatine plus phosphocreatine were measured in the same MR spectra. MPFC Glu levels were higher in women with PPD (7.21±1.20) compared to matched HCs (6.04±1.21). There were no differences between groups for other brain metabolites measured. These findings suggest an association between Glu dysregulation in the MPFC and PPD. Whether the pathophysiology of PPD differs from the pathophysiology of MD remains to be determined. Further investigations are needed to determine the chronological associations between the occurrence of symptoms of PPD and the onset of changes in MPFC Glu levels.

Background: Fronto-limbic dysregulation in major depressive disorder (MDD) may be influenced by early life stress and antidepressant treatment. The present structural MRI study aimed to determine the relationship between amygdala, cingulate and subgenual prefrontal cortex volumes in MDD and their associations with child abuse and antidepressants., Methods: Right-handed subjects (21-50 years), meeting DSM-IV criteria for MDD, either with (n=19) or without (n=20) childhood sexual or physical abuse. Healthy controls (n=34) were matched for age, sex, education and smoking. 3D-MPRAGE images with a spatial resolution of 1.5 mm×1.0 mm×1.0 mm were acquired with a Siemens Sonata 1.5 T system. Volumes of subgenual prefrontal cortex, amygdala and affective, cognitive, superior and posterior divisions of cingulate cortex were analyzed using DISPLAY software using reliable volumetric protocols. Groups were compared using ANCOVA, with intracranial volume as a covariate., Results: MDD subjects had low cingulate (cognitive division) and high amygdala volumes. Low cingulate volume was related to abuse and treatment history. Amygdala volume was predicted by subgenual prefrontal and cingulate (cognitive division) volumes and the presence of paracingulate cortex., Limitations: This study was cross sectional and the sample size was limited for subgroup and correlational analyses., Summary: Our data suggest that MDD may be associated with alterations in anterior cingulate cortex and amygdala. Morphological variation, early stress and stress-protective factors may contribute to differences in fronto-limbic structures in MDD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Previous diffusion tensor imaging (DTI) studies confirmed the vulnerability of frontal callosal fibers to normal aging. The present study extended this examination systematically to other prefrontal white matter regions. Structural magnetic resonance imaging and DTI datasets were acquired from 69 healthy subjects aged 22-84 years. The prefrontal white matter was parcellated into several anatomical sub-regions: medial and lateral orbitofrontal white matter, dorsolateral prefrontal white matter, and medial prefrontal white matter, using reliable DTI-tractography protocols. Tract-specific characteristics were calculated using Matlab. Regression models were used to determine the relationship between age and structural integrity of white matter tracts. The results of our study demonstrate regional age-related changes in the prefrontal white matter tracts of the human brain. This study was cross-sectional and therefore additional longitudinal studies are needed to confirm our findings., (© Springer-Verlag 2011)

The search for genes conferring liability for schizophrenia may be aided by the identification of endophenotypes. Response selection is a heritable cognitive function that is impaired in patients with schizophrenia and their unaffected siblings. The abnormalities in cerebral function that presumably underlie the deficit in patients and unaffected siblings remain to be elucidated. Cerebral neurophysiology during performance of a 4-choice reaction time (CRT) task in 25 patients with schizophrenia (15 medication free first episode (FEP) and 10 chronic patients), 32 controls, and 12 unaffected siblings of individuals with schizophrenia was investigated using fMRI. CRT was impaired in both medication free FEP and chronic patients with schizophrenia, and unaffected siblings. FEP patients, chronic patients, and unaffected siblings demonstrated greater BOLD response in the right dorsolateral prefrontal cortex (dlPFC) during CRT task blocks. The nature of the altered activation in the dlPFC was further examined using functional connectivity analysis. This revealed marked reductions in connectivity between the right dlPFC and multiple brain regions in both patient groups and, to a lesser degree, unaffected siblings. The magnitude of connectivity between right dlPFC and inferior parietal lobule correlated with task performance in the combined patient/unaffected siblings group, but not controls suggesting that the network of brain regions recruited to perform the task differed as a function of genetic liability for schizophrenia. The findings suggest that altered activity and connectivity of the right dlPFC appears to be related to genetic vulnerability for schizophrenia and may represent a potential endophenotype of the 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.

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.

Objective Perimenopause is associated with an increased risk of developing a major depressive (MD) episode. A significant number of women develop their first MD episode during perimenopause, suggesting a unique pathophysiology of perimenopausal (PM) depression. Previous research has shown that depression is associated with decreased gamma-aminobutyric acid (GABA) levels in the medial prefrontal cortex (MPFC) of MD patients. The objective of this study was to compare MPFC GABA+ levels in healthy reproductive-aged (RD) and PM women. Methods A total of 18 healthy PM and 20 RD women were included in the study. MPFC GABA+ levels, which include homocarnosine and macromolecules, were measured via magnetic resonance spectroscopy using a 3 Tesla magnet. MPFC GABA+ levels were referenced to creatine + phosphocreatine (Cr+PCr). Absence of current or past psychiatric diagnosis was confirmed via a structured interview. RD participants were scanned during the early follicular phase of the menstrual cycle. PM women were scanned outside of ovulatory cycles. Results Mean MPFC GABA+ concentrations (relative to Cr+PCr) were decreased in the PM group compared with the RD group (PM mean = 0.08 ± 0.02, RD mean = 0.09 ± 0.02, t  = −2.03, df  = 36, P  = .05) even after correcting for in percentage in gray matter (GM). Because PM women were inherently older than RD women (aged 48.8 ± 3.55 and 31.5 ± 9.66 years, respectively), the age difference between the 2 groups was statistically significant (P  < .001). When age was treated as an independent covariate and included in the model, the difference in GABA+ between PM and RD women was no longer significant (P  = .092). Conclusion Perimenopause is associated with decreased MPFC GABA+/Cr+PCr levels, which may contribute to the increased risk of experiencing a MD episode during PM. [ABSTRACT FROM AUTHOR]

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The role played by medial prefrontal cortex (MPFC) glutamate (Glu) and gamma-aminobutyric acid (GABA) in the pathophysiology and the treatment of major depression (MD) is increasingly recognized. Although measurements of MPFC GABA and Glu have been shown to be sensitive to physiological fluctuations of female hormones, none of the magnetic resonance spectroscopy (MRS) investigations of MPFC Glu and GABA in MD have controlled for possible bias effect of the reproductive stage of the women included. MPFC Glu and GABA+ (which include homocarnosine and macromolecules) referenced to creatine and phosphocreatine, were measured via magnetic resonance spectroscopy (MRS) using a 3-Tesla magnet in 24 women with MD and 24 healthy women paired for reproductive status. All participants were unmedicated. There were no statistical differences in either MPFC Glu [95 % CI: (−0.025, 0.034)] or MPFC GABA+ [95 % CI: (−0.005, 0.017)] between women with MD and healthy controls. Our investigation does not support abnormalities in measurement of MPFC Glu and GABA in MD women when stringent control for reproductive status is performed. As a result of the inherent limitations of MRS methodology, our results do not preclude glutamatergic and GABAergic dysregulations in the MPFC of women with MD. • A stringent control for reproductive status was performed for healthy females and females experiencing depression. • All participants were age and sex matched. • MPFC Glu and GABA+ were not significantly different between groups when reproductive status was controlled. [ABSTRACT FROM AUTHOR]

Abstract: Diffusion tensor imaging (DTI) provides the opportunity to study white matter tracts in vivo. The goal was to estimate the reliability of DTI tractography for the analysis of limbic and paralimbic white matter. Normative data from 24 healthy subjects and reliability data from four healthy and four depressed subjects were acquired at 1.5 Tesla, using twice-refocused spin-echo, echoplanar DTI and Fluid-Attenuated Inversion Recovery (FLAIR) DTI sequences. Fiber tracking was performed using the Fiber Assignment by Continuous Tracking algorithm. Fractional Anisotropy (FA), trace Apparent Diffusion Coefficient and tract volumes were calculated. The inter-rater (and intra-rater) intraclass correlation coefficients for FA values were as follows: rostral cingulum 0.89 (0.87), dorsal cingulum 0.85 (0.90), parahippocampal cingulum 0.85 (0.95), uncinate fasciculus 0.85 (0.87), medial prefrontal white matter 0.97 (0.99), ventromedial prefrontal white matter 0.92 (0.93), crus of fornix 0.80 (0.81). The reported DTI protocol provides a reliable method to analyze limbic and paralimbic white matter tracts relevant to psychiatric disorders. [Copyright &y& Elsevier]

Abstract: 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 75min after receiving a 25mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0Tesla (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 1h 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 18.8T 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. [Copyright &y& Elsevier]