Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.
ABSTRACT: There is increasing evidence that abnormalities in glutamate signalling may contribute to the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Proton magnetic resonance spectroscopy ([1H]MRS) can be used to measure glutamate, and also its metabolite glutamine, in vivo. However, few studies have investigated glutamate in the brain of adults with ADHD naive to stimulant medication. Therefore, we used [1H]MRS to measure the combined signal of glutamate and glutamine (Glu+Gln; abbreviated as Glx) along with other neurometabolites such as creatine (Cr), N-acetylaspartate (NAA) and choline. Data were acquired from three brain regions, including two implicated in ADHD-the basal ganglia (caudate/striatum) and the dorsolateral prefrontal cortex (DLPFC)-and one 'control' region-the medial parietal cortex. We compared 40 adults with ADHD, of whom 24 were naive for ADHD medication, whereas 16 were currently on stimulants, against 20 age, sex and IQ-matched healthy controls. We found that compared with controls, adult ADHD participants had a significantly lower concentration of Glx, Cr and NAA in the basal ganglia and Cr in the DLPFC, after correction for multiple comparisons. There were no differences between stimulant-treated and treatment-naive ADHD participants. In people with untreated ADHD, lower basal ganglia Glx was significantly associated with more severe symptoms of inattention. There were no significant differences in the parietal 'control' region. We suggest that subcortical glutamate and glutamine have a modulatory role in ADHD adults; and that differences in glutamate-glutamine levels are not explained by use of stimulant medication.
Project description:Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([(1)H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [(1)H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease.
Project description:Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia.We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC).The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr.We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.
Project description:Magnetic resonance spectroscopy has demonstrated metabolite changes in neurodegenerative disorders such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB); however, their pattern and relationship to clinical symptoms is unclear. To determine whether the spatial patterns of brain-metabolite changes in AD and DLB are regional or diffused, and to examine whether the key metabolite levels are associated with cognitive and non-cognitive symptoms, we acquired whole-brain spatially resolved 3T magnetic resonance spectroscopic imaging (MRSI) data from subjects with AD (N=36), DLB (N=35) and similarly aged controls (N=35). Voxel-wise measurement of N-acetylaspartate to creatine (NAA/Cr), choline to Cr (Cho/Cr), myo-inositol to Cr (mI/Cr) as well as glutamate and glutamine to Cr (Glx/Cr) ratios were determined using MRSI. Compared with controls, AD and DLB groups showed a significant decrease in most brain metabolites, with NAA/Cr, Cho/Cr and mI/Cr levels being reduced in posterior cingulate, thalamus, frontotemporal areas and basal ganglia. The Glx/Cr level was more widely decreased in DLB (posterior cingulate, hippocampus, temporal regions and caudate) than in AD (only in posterior cingulate). DLB was also associated with increased levels of Cho/Cr, NAA/Cr and mI/Cr in occipital regions. Changes in metabolism in the brain were correlated with cognitive and non-cognitive symptoms in the DLB but not in the AD group. The different patterns between AD and DLB may have implications for improving diagnosis, better understanding disease-specific neurobiology and targeting therapeutics. In addition, the study raised important questions about the role of occipital neuroinflammation and glial activation as well as the glutamatergic treatment in DLB.
Project description:Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder of childhood. Preliminary studies with proton magnetic resonance spectroscopy ((1)H-MRS) of the brain have reported differences in brain metabolite concentration-to-Cr ratios between individuals with ADHD and unaffected controls in several frontal brain regions including anterior cingulate cortex. Using multivoxel (1)H-MRS, we compared 14 individuals affected with ADHD to 20 individuals without ADHD from the same genetic isolate. After controlling by sex, age, and multiple testing, we found significant differences at the right posterior cingulate of the Glx/Cr ratio density distribution function between ADHD cases and controls (P < 0.05). Furthermore, we found several interactions of metabolite concentration-to-Cr ratio, age, and ADHD status: Ins/Cr and Glx/Cr ratios at the left posterior cingulate, and NAA/Cr at the splenius, right posterior cingulate, and at the left posterior cingulate. We also found a differential metabolite ratio interaction between ADHD cases and controls for Ins/Cr and NAA/Cr at the right striatum. These results show that: (1) NAA/Cr, Glx/Cr, and Ins/Cr ratios, as reported in other studies, exhibit significant differences between ADHD cases and controls; (2) differences of these metabolite ratios between ADHD cases and controls evolve in specific and recognizable patterns throughout age, a finding that replicates previous results obtained by structural MRI, where is demonstrated that brain ontogeny follows a different program in ADHD cases and controls; (3) Ins/Cr and NAA/Cr ratios, at the right striatum, interact in a differential way between ADHD cases and controls. As a whole, these results replicate previous 1H-MRS findings and add new intriguing differential metabolic and ontogeny patterns between ADHD cases and controls that warrant further pursue.
Project description:Muscle spasticity is a disability caused by damage to the pyramidal system. Standard treatments for spasticity include muscle stretching, antispastic medications, and tendon release surgeries, but treatment outcomes remain unsatisfactory. Anodal transcranial direct current stimulation (tDCS) in patients with muscle spasticity is known to result in significant improvement in spastic tone (p < 0.001). However, the mechanism of action by which tDCS treatment affects spasticity remains unclear. This pilot study aimed to investigate the effect of anodal tDCS upon brain metabolites in the left basal ganglia and ipsilateral primary motor cortex (M1) in children with spastic cerebral palsy (CP).This study consisted of three steps: a baseline evaluation, a treatment period, and a follow-up period. During the treatment period, patients were given 20 min of 1 mA anodal tDCS over the left M1 for five consecutive days. Outcomes were compared between pre- and immediate posttreatment in terms of brain metabolites, Tardieu scales, and the quality of upper extremity skills test.Ten patients with spastic CP were enrolled. Following tDCS, there were significant increases in the ratio of N-acetylaspartate (NAA)/creatine (Cr) (p = 0.030), choline (Cho)/Cr (p = 0.043), and myoinositol (mI)/Cr (p = 0.035) in the basal ganglia. Moreover, increased glutamine-glutamate (Glx)/Cr ratio in the left M1 (p = 0.008) was found. In addition, we also observed improvements in the extent of spasticity and hand function (p = 0.028).Five consecutive days of anodal tDCS over the left M1 appeared statistically to reduce the degree of spasticity and increase NAA, Cho, mI, and Glx. Future research studies, involving a larger sample size of spastic CP patients undergoing tDCS is now warranted.
Project description:BACKGROUND:Executive function deficits in children born very preterm (VPT) have been linked to anatomical abnormalities in white matter and subcortical brain structures. This study aimed to investigate how altered brain metabolism contributes to these deficits in VPT children at school-age. METHODS:Fifty-four VPT participants aged 8-13 years and 62 term-born peers were assessed with an executive function test battery. Brain metabolites were obtained in the frontal white matter and the basal ganglia/thalami, using proton magnetic resonance spectroscopy (MRS). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, glutamate?+?glutamine (Glx)/Cr, and myo-Inositol (mI)/Cr were compared between groups and associations with executive functions were explored using linear regression. RESULTS:In the frontal white matter, VPT showed lower Glx/Cr (mean difference: -5.91%, 95% CI [-10.50, -1.32]), higher Cho/Cr (7.39%, 95%-CI [2.68, 12.10]), and higher mI/Cr (5.41%, 95%-CI [0.18, 10.64]) while there were no differences in the basal ganglia/thalami. Lower executive functions were associated with lower frontal Glx/Cr ratios in both groups (??=?0.16, p?=?0.05) and higher mI/Cr ratios in the VPT group only (interaction: ??=?-0.17, p?=?0.02). CONCLUSION:Long-term brain metabolite alterations in the frontal white matter may be related to executive function deficits in VPT children at school-age. IMPACT:Very preterm birth is associated with long-term brain metabolite alterations in the frontal white matter. Such alterations may contribute to deficits in executive function abilities. Injury processes in the brain can persist for years after the initial insult. Our findings provide new insights beyond structural and functional imaging, which help to elucidate the processes involved in abnormal brain development following preterm birth. Ultimately, this may lead to earlier identification of children at risk for developing deficits and more effective interventions.
Project description:Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and ?-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. ¹H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.
Project description:The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1H-MRS) at 3?T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluid-corrected ACC metabolite concentrations were compared between healthy control (HC, n?=?16), depressed without SI (Dep/SI-, n?=?13), and depressed with SI (Dep/SI+, n?=?11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI-?and Dep/SI+?adolescents. Dep/SI+?adolescents had higher Glx than Dep/SI-?participants (padj?=?0.012) and had lower NAA/Glx than both Dep/SI-?(padj?=?0.002) and HC adolescents (padj?=?0.039). There were significant relationships between SI intensity and Glx (pFDR?=?0.026), SI severity and NAA/Glx (pFDR?=?0.012), and SI intensity and NAA/Glx (pFDR?=?0.004). ACC Glx and NAA/Glx discriminated Dep/SI-?from Dep/SI+?participants. Uncoupled NAA-glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.
Project description:Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T.We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects.In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms.Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.