Glx Levels Research Articles

1H MRS spectroscopy in preclinical autosomal dominant Alzheimer disease.

1H magnetic resonance spectroscopy (MRS) can reveal changes in brain biochemistry in vivo in humans and has been applied to late onset Alzheimer disease (AD). Carriers of mutations for autosomal dominant Alzheimer disease (ADAD) may show changes in levels of metabolites prior to the onset of clinical symptoms. Proton MR spectra were acquired at 1.5T for 16 cognitively asymptomatic or mildly symptomatic mutation carriers (CDR < 1) and 11 non-carriers as part of a comprehensive cross-sectional study of preclinical ADAD. Levels of N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (NAA), glutamate/glutamine (Glx), creatine/phosphocreate (Cr), choline (Cho), and myo-inositol (mI) in the left and right anterior cingulate and midline posterior cingulate and precuneus were compared between mutation carriers (MCs) and non-carriers (NCs) using multivariate analysis of variance with age as a covariate. Among MCs, correlations between metabolite levels and time until expected age of dementia diagnosis were calculated. MCs had significantly lower levels of NAA and Glx in the left pregenual anterior cingulate cortex, and lower levels of NAA and higher levels of mI and Cho in the precuneus compared to NCs. Increased levels of mI were seen in these regions in association with increased proximity to expected age of dementia onset. MRS shows effects of ADAD similar to those seen in late onset AD even during the preclinical period including lower levels of NAA and higher levels of mI. These indices of neuronal and glial dysfunction might serve as surrogate outcome measures in prevention studies of putative disease-modifying agents.

Effect of monolingualism and bilingualism in the anterior cingulate cortex: a proton magnetic resonance spectroscopy study in two centers

Reports of an advantage of bilingualism on brain structure in young adult participants are inconsistent. Abutalebi et al. (2012) reported more efficient monitoring of conflict during the Flanker task in young bilinguals compared to young monolingual speakers. The present study compared young adult (mean age = 24) Cantonese-English bilinguals in Hong Kong and young adult monolingual speakers. We expected (a) differences in metabolites in neural tissue to result from bilingual experience, as measured by 1H-MRS at 3T, (b) correlations between metabolic levels and Flanker conflict and interference effects (c) different associations in bilingual and monolingual speakers. We found evidence of metabolic differences in the ACC due to bilingualism, specifically in metabolites Cho, Cr, Glx and NAA. However, we found no significant correlations between metabolic levels and conflict and interference effects and no significant evidence of differential relationships between bilingual and monolingual speakers. Furthermore, we found no evidence of significant differences in the mean size of conflict and interference effects between groups i.e. no bilingual advantage. Lower levels of Cho, Cr, Glx and NAA in bilingual adults compared to monolingual adults suggest that the brains of bilinguals develop greater adaptive control during conflict monitoring because of their extensive bilingual experience.***Efeito do monolinguismo e do bilinguismo no córtex anterior cingulado: um estudo de espectroscopia de ressonância magnética de prótons em dois centros***Relatos de uma vantagem do bilinguismo na estrutura cerebral em jovens participantes adultos são inconsistentes. Abutalebi et al. (2012) relataram uma monitorização mais eficiente do conflito durante a tarefa de Flanker em jovens bilíngues comparados com jovens monolíngues. O presente trabalho comparou jovem adultos (idade média = 24) bilíngues em Cantonês-Inglês de Hong Kong e jovens monolíngues adultos. Estávamos a contar com (a) diferenças em metabólitos no tecido neural como resultado de uma experiência bilíngue, medido pelo 3T 1H-MRS, (b) correlações entre os níveis metabólicos, conflito Flanker e efeitos de interferência (c) diferentes associações em falantes monolíngues e bilíngues. Encontramos evidências de diferenças metabólicas no ACC devido ao bilinguismo, especificamente nos metabólitos Cho, Cr, Gly e NAA. Porém, não constatamos correlações significativas entre os níveis metabólicos e efeitos de conflito e interferência e nenhuma evidência significativa de relações diferenciais entre falantes monolíngues e bilíngues. Além disso, não encontramos nenhuma evidência de diferenças significativas no tamanho médio dos efeitos do conflito e interferência entre os grupos, ou seja, nenhuma vantagem bilíngue. Níveis inferiores de Cho, Cr, Gly em adultos bilíngues em comparação com adultos monolíngues sugerem que o cérebro dos bilíngues desenvolve maior controle adaptativo durante a monitorização do conflito por causa da sua extensa experiência bilíngue.

Lower Choline and Myo-Inositol in Temporo-Parietal Cortex Is Associated With Apathy in Amnestic MCI.

Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer’s disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy (1H-MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy.

F14. REDUCED DURATION MISMATCH NEGATIVITY ASSOCIATED WITH DECREASED GLUTAMATE+GLUTAMINE LEVEL IN SUBJECTS AT CLINICAL HIGH-RISK FOR PSYCHOSIS

BackgroundAbnormal mismatch negativity (MMN), thought to be a putative marker of glutamatergic function, has been reported in non-Asian, first episode schizophrenia and clinical high-risk for psychosis (CHR) individuals as indicative of impairments in pre-attentive processes. However, reports of abnormal MMN in Asian populations are sparse, as well as its relationships to glutamate and γ–aminobutyric acid (GABA) levels in medial prefrontal cortex. The present longitudinal study explored MMN differences between CHR subjects who will and who will not remit, and its relationships with prefrontal glutamate and GABA levels.MethodsAll subjects participated in the ShangHai At-Risk for Psychosis (SHARP) program. CHR subjects met the criteria defined by the Chinese version of the Structural Interview for Prodromal Syndromes (SIPS). From the SHARP sample, 76 CHR subjects (41 male, age 18.63 ± 5.02 years) and 53 HC (31 male, age 17.72 ± 3.18 years) completed both MMN test and proton magnetic resonance spectroscopy (1H MRS) scans using a MEGA-PRESS sequence at their initial visit. CHR subjects were divided into remitted (37) and non-remitted (34) individuals based on their clinical symptoms and functional scores at a one-year follow up. Duration MMN amplitude was measured at electrodes F1/2, Fz, FC1/2, FCz, C1/2 and Cz. Concentrations of glutamate+glutamine (Glx) and GABA in the medial prefrontal cortex (mPFC) were quantified using the LCModel software (version 6.3-0I).Repeated measures analysis of variance (ANOVA) with group (remitted CHR, non-remitted CHR and HC) as the between-group factor and electrodes (Fz, FCz and Cz) as the within-group factor were performed for the midline sites, and the ANOVA using F1/2, FC1/2 and C1/C2 with laterality (left and right hemisphere) as an additional within-group factor was performed for the lateral sites. Correlations of the dMMN amplitude (averaged over the 9 electrodes) and Glx and GABA concentrations were assessed by Pearson correlation tests for each group.ResultsThere was a significant main effect of group (F(2,121)=3.14, p<0.05) for the midline fronto-central dMMN amplitude. Post-hoc tests showed that non-remitted CHR subjects had lower baseline dMMN amplitude (-4.75 ± 0.37μv) than HC (-5.92 ± 0.30μv, p<0.05), whereas dMMN in remitted CHR (-5.22 ± 0.36μv, p=0.41) was comparable to dMMN in HC.The main effect of group was marginally significant at lateral sites (F(2,121)=2.83, p=0.06). DMMN amplitude in non-remitted CHR (-4.67 ± 0.37μv) tended to be lower than those in HC (-5.76 ± 0.29μv, p<0.1), while remitted CHR had dMMN amplitude (-5.11 ± 0.35μv, p=0.47) comparable to HC. There was no significant main effect of laterality or interaction of group × laterality.In non-remitted CHR subjects, dMMN amplitude was significantly correlated with Glx level (r=-0.47, p<0.01) and with GABA level (r=-0.38, p<0.05) in the mPFC. However, the correlation of dMMN amplitude with Glx or GABA levels was not significant among either HC or remitted CHR.DiscussionIn line with previous studies, reduced dMMN amplitude distinguished between remitted and non-remitted CHR subjects, with remitted CHR not different from HCs. Our finding further supports the idea that reduced dMMN amplitude could be a candidate biomarker for predicting outcome in CHR. More importantly, we linked the reduced dMMN amplitude in non-remitted CHR to their Glx and GABA levels in mPFC, the region identified as one of dMMN sources (responsible for attention switching) thus supporting the idea that NMDA-mediated disruptions may play a key role in predicting psychosis and functional outcome.

S16. GLUTAMATERGIC NEUROMETABOLITE LEVELS IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA: A CROSS-SECTIONAL 3T PROTON MRS STUDY

BackgroundIn terms of response to antipsychotic treatment, patients with schizophrenia can be classified into three groups; (1) treatment-resistant patients who are clozapine (CLZ)-resistant (ultra treatment-resistant schizophrenia [UTRS]), (2) treatment-resistant patients who are CLZ-responsive (TRS), and (3) patients who respond to non-CLZ antipsychotics (treatment non-resistant schizophrenia [TnRS]). The aim of this study was to examine glutamatergic neurometabolite levels in these three patient groups, along with healthy controls (HCs), using proton magnetic resonance spectroscopy (1H-MRS).MethodsGlutamate (Glu) and glutamate+glutamine (Glx) levels were assessed in the associative striatum (Str), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) using 3T 1H-MRS (PRESS, TE=35ms). Neurometabolite levels were corrected for cerebrospinal fluid proportion.ResultsA total of 100 participants (26 UTRS, 27 TRS, 21 TnRS, and 26 HCs) were included in this study. Patients with UTRS showed higher Glx levels in the ACC compared to HCs (p=0.038). When patients with UTRS and TRS were combined into one group, this subset of patients showed higher Glu and Glx levels in the ACC compared to HCs (p=0.028 and p=0.023, respectively). There were no significant group differences in the Str or DLPFC.DiscussionPrevious findings reporting higher glutamatergic levels in the ACC of patients with TRS may be mainly influenced by patients with CLZ non-responder. Higher ACC glutamatergic neurometabolite level may be a biological trait of resistance to the first-line antipsychotic treatment that is retained even after CLZ administration.

S181. THE STATE OR TRAIT COMPONENT OF DOPAMINE AND GLUTAMATE DYSFUNCTION IN THE RISK FOR PSYCHOSIS: AN IN VIVO MULTIMODAL IMAGING STUDY OF INDIVIDUALS WITH 22Q11.2 DELETION

BackgroundDopaminergic and glutamatergic dysregulation are among the leading hypotheses for schizophrenia. Previous in vivo imaging studies have shown that increased striatal presynaptic dopamine synthesis capacity (DSC) predates the onset of psychosis and is associated with symptom severity. Recent meta-analysis in magnetic resonance spectroscopy studies in schizophrenia reported increased levels of glutamate and glutamine (Glx) in basal ganglia and medial frontal cortex in clinical high-risk groups for psychosis. Despite the evidence of alterations in both dopamine and glutamate in schizophrenia, the degree to which these alterations are trait markers linked to genetic risk for psychosis or reflects state changes is not clear from previous studies. Over the last fifteen years, it has been well established that 22q11 deletion is one of the most important genetic risk factors for the development of schizophrenia. Individuals with 22q11 deletion are at increased genetic risk for psychosis, reaching a prevalence 30% for psychotic disorder. The aims of our study were to investigate dopaminergic and glutamatergic function in individuals with 22q11.2 deletion.MethodsParticipants underwent 18F DOPA PET, MRI, as well as clinical measures.21 individuals with 22q11 deletion (14 females and 7 males, age (mean, SD): 26.1(7.72)) and 26 healthy volunteers (15 females and 11 males, age (mean, SD): 26.12(4.28)) took part in the 18F DOPA PET. Standardised ROIs was defined in the striatum, including limbic, associative and sensorimotor sub-regions, and the reference region, defined according to previous study. The ROI atlas was normalised to each individual PET dynamic image. A Patlak analysis was applied to calculate influx constants (Ki values) for the whole striatal ROI relative to uptake in the cerebellar reference region (Kicer [min-1]).In addition, 17 individuals with 22q11 deletion (11 females and 6 males, age (mean, SD): 26.39(7.7)) and 30 healthy controls (17 females and 13 males, age (mean, SD): 27.17(4.8)) had MRI. 1H-MRS voxels were placed on the anterior cingulate cortex and left striatum. Spectra were analyzed using LC Model version 6.3-1L. Poorly fitted metabolite peaks (Cramer–Rao minimum variance bounds >20% as reported by LC Model) were excluded from further analysis.ResultsDSC in the whole striatum was significantly increased in the individuals with 22q11 deletion compared to healthy controls (mean (Kicer [min-1] =0.0143; SD=0.001; mean Kicer [min-1] = 0.0127; SD=0.001, respectively; effect size (Cohen’s d= 1.47, p< 0.000). In addition, no difference was found between groups in Glx levels in anterior cingulate cortex (individuals with 22q11 deletion; mean=19.85; SD=3.17, healthy controls; mean= 21.04; SD=3.91) and left striatum (individuals with 22q11 deletion; mean=11.45; SD=2.88, healthy controls; mean=11.6;SD=2.74)(t(44) =-1.065; p=0.29, t(42)=-0.172;p=0.86, respectively).Psychopathology scales were not correlated with either dopaminergic or glutamatergic function in the group of 22q11 deletion.DiscussionOur findings provide evidence that dopamine synthesis capacity has a strong trait component and glutamatergic dysfunction may be most likely associated with disease status. Future studies with longitudinal design are warranted to further investigate the role of dopamine and glutamate in individuals with 22q11 deletion. Moreover, there is a clear need for studies utilizing higher field resonance strength and appropriate radiotracers to investigate glutamatergic function in this population. These will be crucial steps towards the development of new treatments, that can be applied in early stages of illness.

F209. TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) IN A NON-CLINICAL POPULATION AS A MODEL FOR TREATMENT OF AUDITORY VERBAL HALLUCINATIONS IN SCHIZOPHRENIA

BackgroundWe used transcranial direct current stimulation (tDCS) in a non-clinical population to simulate a model of tDCS-treatment for auditory verbal hallucinations (AVH) in schizophrenia. In tDCS, a low current is induced via two electrodes attached to the scalp. The anode and cathode typically up- and downregulate neuronal activity, respectively. It was suggested that AVH arise due to two main neuronal pathways: hyper-activity in the language areas in the temporo-parietal cortex and hypo-activity of the cognitive control areas in the dorsolateral prefrontal cortex. Accordingly, it was further hypothesized that by reducing activity in the temporo-parietal cortex through cathodal tDCS and simultaneously increasing neuronal activity in the dorsolateral prefrontal cortex with anodal tDCS, AVH could be reduced. Patients with schizophrenia, particularly those with AVH show additionally deficits on language and cognitive control tasks, which are known to draw on temporo-parietal and dorsolateral prefrontal cortex regions, respectively. In order to test the model we thus reversed the electrode montage in non-clinical participants and tested whether they would show similar deficits as schizophrenia patients. In addition, the healthy participants underwent magnetic resonance spectroscopy (MRS) to test whether, in accordance with the model, glutamate levels increase under the anode, and decrease under the cathode area.MethodsEighteen participants were recruited in a convenience sample (7 male/ 11 female) with a mean age of 26 years. They were tested twice with a mean interval of 8 days. In one session they received real 2mA tDCS for 20 min, while in an MRI scanner (GE 750, 3T). The other session was a sham stimulation control. The order of real/sham stimulation was counterbalanced and stimulation was double-blind. In each session, MRS was measured using a PRESS sequence (TE=35ms, 1500ms) before and after stimulation. MRS data were acquired from two voxels, one in the left dorsolateral prefrontal cortex (22ml) and one in the left temporo parietal cortex (25ml), right underneath anode and cathode electrodes, respectively. MRS data were analyzed using LCModel software; water-scaled estimates for glutamate and glutamine combined (Glx) are reported herein, with N-Acetylaspartate (NAA) and creatine (Cre) inspected to ensure stability of the Glx measure. Glx levels were subjected to a 2x2x2 ANOVA with the within-participant factors Stimulation (real vs sham), Stimulation area (dorsolateral prefrontal cortex versus temporo-parietal cortex), and Time (Pre and Post stimulation).ResultsTwo datasets where excluded from analysis due to poor spectral quality. As expected, NAA (F1,16=.809, p=.382) and Cre (F1,16=.005, p=.944) did not show significant changes. There was a trend for Glx to be higher during real as compared to sham stimulation (main effect Stimulation F1,16=3.867, p=.067) and for Glx to be higher after than before stimulation (main effect Time F1,16=1.396, p=.078).DiscussionGlx was increased during real compared to sham tDCS, and before compared to after stimulation. This could indicate that tDCS overall changes neuronal firing thresholds. However, we did not observe the expected three-way interaction of reduced glutamate levels in the dorsolateral prefrontal cortex and increased glutamate levels in the temporo-parietal cortex. This could be due to the relatively small sample. However, the present data analysis is preliminary and we aim to report findings for a larger dataset.

F159. NEUROMAGNETIC 40 HZ AUDITORY STEADY STATE RESPONSES AND AUDITORY CORTICAL GABA AND GLX IN CLINICAL HIGH RISK AND FIRST EPISODE OF PSYCHOSIS INDIVIDUALS

BackgroundRobust impairments in the power and phase of 40 Hz auditory steady state responses (ASSR) have been reported in chronic schizophrenia patients. This could reflect changes in the balance between inhibitory GABAergic and excitatory glutamatergic neurotransmission in auditory cortex. However, the direct link between the ASSR and alterations in these neurotransmitter systems has not been systematically explored. Furthermore, it remains unclear whether 40 Hz ASSR impairments are present in early and at-risk stages of psychosis. The current study aims to explore the 40 Hz ASSR in first-episode of psychosis patients and individuals at clinical high risk (CHR) of psychosis, and the possible relationship of deficits in gamma-band entrainment to a dysfunctional excitation inhibition balance, as reflected by alterations in cortical GABA and glutamate.MethodsData from 80 CHR, 11 FEP and 40 age-matched healthy control participants were collected as part of the MRC-funded Youth Mental Health Risk and Resilience study. MEG data were recorded on a 4D Neuroimaging Magnes 3600 Whole Head 248 Channel system, while participants were passively presented with a series of 1000 Hz carrier tones amplitude modulated at 40 Hz. Data were analysed at sensor and source-level in the frequency-domain for spectral power and intertrial phase-coherence (ITPC). For source-reconstruction, an eLoreta source-analysis algorithms was employed. Auditory regions of interest (ROIs) were defined using 98 nodes defined from the AAL-atlas. Levels of right auditory GABA and Glx (glutamate + glutamine) were measured using 1H-MRS at 3T and 2*2*2 cm voxels and were estimated relative to water. GABA levels were further corrected for grey and white matter and cerebrospinal fluid levels within the voxel. Finally, 40 Hz ASSR power in right auditory cortex was explored in relation to neurotransmitter levels in the same region.ResultsAcross groups, the ASSR stimulus activated temporal regions, including bilateral heschl’s gyrus and superior temporal cortex. A significant effect of hemisphere was found, reflecting higher 40 Hz ASSR power in the right hemisphere across groups. CHR and FEP participants showed attenuated 40 Hz ASSR power and ITPC compared to healthy control participants in right temporal regions, but an increase in spectral power in the left hemisphere. A moderate positive correlation was found between right auditory GABA and 40 Hz ASSR power in the right superior temporal gyrus in CHR, but not in controls.DiscussionThese results provide a link between MRS measures of GABA and 40 Hz ASSR power impairments in CHR individuals. Furthermore, these preliminary findings indicate that slight alterations in the 40 Hz ASSR are present in FEP patients and may arise already in the CHR stage, prior to the onset of psychosis.

O3.7. EFFECT OF N-ACETYLCYSTEINE ON BRAIN GLUTAMATE LEVELS AND RESTING PERFUSION IN SCHIZOPHRENIA

BackgroundSchizophrenia may be associated with elevations in glutamate levels in the anterior cingulate cortex (ACC), and this may be particularly apparent in patients who have not responded well to conventional antipsychotic treatment (Egerton et al., 2012; Mouchliantis et al., 2016). This suggests that compounds that can decrease ACC glutamate levels may have therapeutic potential for this group. N-acetylcysteine (NAC) is one such compound, currently under investigation as an adjunctive therapy for schizophrenia. The effects of NAC on brain glutamate levels and physiology in schizophrenia have not been previously evaluated. The primary aim of this study was to examine whether a single oral dose of NAC can alter brain glutamate levels in schizophrenia. The secondary aim was to characterise the effects of NAC on regional brain perfusion.MethodsIn a double-blind placebo-controlled crossover study, twenty patients with a diagnosis of schizophrenia underwent two 3 Tesla MRI scans, performed one week apart, and following administration of a single oral dose of 2400mg NAC or matching placebo. Proton magnetic resonance spectroscopy (1H-MRS) was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling (pCASL) was used to measure the effects of NAC on resting cerebral blood flow (CBF) in the same regions. 1H-MRS spectra were analysed using LCModel version 6.3-0I using a standard basis set. Individual CBF maps were pre-processed in the Automatic Software for ASL Processing (ASAP) toolbox running in SPM-8 in Matlab 6.5. The effects of NAC on 1H-MRS metabolite levels were determined using paired samples t-tests. Changes in rCBF were determined using within-subjects, second-level analysis implemented in SPM-8.ResultsIn the ACC, Glx/Cr was significantly reduced in the NAC compared to placebo condition (t(17) = 2.40; P = .03, d = 0.64). There was no significant effect of condition on Glu/Cr in the ACC, or on Glx/Cr or Glu/Cr in the right caudate nucleus, or on any of the other metabolites quantifiable from the 1H-MRS spectra. There were no significant differences in CBF in the ACC (mean (SD) placebo = 47.22 (8.81); NAC = 46.83 (7.29); t(18) = .349, P = .73) or in the right caudate nucleus (mean (SD) placebo = 37.51 (7.48); NAC = 37.77 (6.71); t(18) -.310, P = .76) in the NAC compared to placebo condition. There was also no significant difference in global CBF between conditions (mean (SD) placebo = 39.64 (10.02); NAC = 40.03 (9.13); t(18) = -.398, P = .70).DiscussionThese results provide preliminary evidence that NAC may reduce ACC glutamate metabolites in schizophrenia. Future studies will need to determine the extent to which reductions in glutamate metabolites following a single dose of a glutamatergic compound are indicative of longer-term efficacy in improving symptoms.

(321) - Auditory hypersensitivity in temporomandibular disorder is associated with perigenual anterior cingulate cortex metabolite levels

Previous research has shown that many chronic pain patients display hypersensitivity not only to noxious stimuli, but also to other sensory modalities like audition and vision. Still, the neural mechanisms underlying this generalized sensitivity have yet to be fully elucidated. The present study used a combination of quantitative sensory testing (QST), proton magnetic resonance spectroscopy (1H-MRS), and psychosocial questionnaires to compare a group of 12 temporomandibular disorder (TMD) patients (age = 32.7 ± 10.6 years) with 10 pain-free controls (41.4 ± 15.7). Subjects rated the perceived loudness and unpleasantness (0–100 scales) of 3-sec, 2,000 Hz, binaural tones that were presented pseudorandomly at amplitudes ranging from 40–90 dB SPL. Participants also completed the 2011 ACR Fibromyalgia Survey Criteria as a surrogate measure of pain centralization, and a median split was performed to separate patients into low and high centralization. Brain metabolite concentrations were acquired using a point resolved spectroscopy sequence (PRESS) in a 3T GE Signa scanner, in a 2x2x2 cm voxel positioned in the perigenual anterior cingulate cortex (pgACC). 1H-MRS data were processed using LCModel and were corrected for CSF and age. Statistical tests were conducted in SPSS v24 with an α level of p < .05. The TMD patients with high centralization perceived the tones to be significantly more unpleasant (33.0/100) than the patients with low FM scores combined with controls (15.8/100; p = .029). In TMD patients, pgACC Glx (i.e. glutamate + glutamine) levels were positively correlated with perceived loudness of the tones (r = .71,p = .009) and with current TMD pain (r = .65, p = .021). Choline levels were positively correlated with perceived loudness (r = .69, p < .001) and unpleasantness (r = .51, p = .02) of the tones in all subjects. Given the known excitatory role of glutamate and the idea that choline levels reflect membrane turnover and cellular metabolism, these results suggest that auditory hypersensitivity in chronic pain may be related to increased excitatory tone in the pgACC.

Neurotransmitter activity is linked to outcome following subthalamic deep brain stimulation in Parkinson's disease

IntroductionWhile the mechanisms underlying the therapeutic effects of deep brain stimulation (DBS) in Parkinson's Disease (PD) are not yet fully understood, DBS appears to exert a wide range of neurochemical effects on the network level, thought to arise from activation of inhibitory and excitatory pathways. The activity within the primary inhibitory (GABAergic) and excitatory (glutamatergic) neurotransmitter systems may therefore play an important role in the therapeutic efficacy of DBS in PD. The purpose of this study was to investigate abnormalities in GABA-ergic and glutamatergic neurotransmission in PD, and to examine the link between neurotransmitter levels and outcome following DBS. MethodsMagnetic resonance spectra were acquired from the pons and basal ganglia in sixteen patients with PD and sixteen matched control participants. GABA and glutamate levels were quantified with LCModel, an automated spectral fitting package. Fourteen patients subsequently underwent DBS, and PD symptoms were evaluated with the MDS-UPDRS at baseline and six months after surgery. The efficacy of DBS treatment was evaluated from the percentage improvement in MDS-UPDRS scores. ResultsBasal ganglia GABA levels were significantly higher in PD patients relative to control participants (p < 0.01), while pontine glutamate + glutamine (Glx) levels were significantly lower in patients with PD (p < 0.05). While GABA levels were not significantly related to outcome post-surgery, basal ganglia glutamate levels emerged as a significant predictor of outcome, suggesting a possible role for glutamatergic neurotransmission in the therapeutic mechanism of DBS. ConclusionGABAergic and glutamatergic neurotransmission is altered in PD, and glutamatergic activity in particular may influence outcome post-surgery.

Reduced insulin sensitivity may be related to less striatal glutamate: An 1H-MRS study in healthy non-obese humans

Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using 1H-MRS, we measured levels of several neurometabolites in the striatum and dorsolateral prefrontal cortex (DLPFC) of seventeen healthy non-obese persons (9 female, mean age: 28.35 ± 9.53). Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. We hypothesized that %S would be positively related with levels of Glu and Glu + glutamine (Glx) in the striatum. Exploratory analyses were also conducted between other fasting markers of metabolic health and neurometabolites measured with 1H-MRS. In the right striatum, %S was positively correlated with levels of Glu (r(15) = .49, p = .04) and Glx (r(15) = .50, p = .04). In the left striatum, there was a trend positive correlation between %S and Glu (r(15) = .46, p = .06), but not Glx levels (r(15) = .20, p = .44). The relationships between %S and striatal Glu levels remained after controlling for age, sex, and BMI (right: r(12) = .73, β = .52, t = 2.55, p = .03; left: (r(12) = .63, β = .53, t = 2.25, p = .04) These preliminary findings suggest that %S may be related to markers of glutamatergic functioning in the striatum of healthy non-obese persons. These findings warrant replication in larger samples and extension into neuropsychiatric populations where altered striatal DA, Glu, and %S are implicated.

Predictive value of 1H MR spectroscopy and 18F-FDG PET/CT for local control of advanced oropharyngeal and hypopharyngeal squamous cell carcinoma receiving chemoradiotherapy: a prospective study

PurposeTo determine whether pretreatment in vivo 1H magnetic resonance (MR) spectroscopy at 3 Tesla (T) and 18F-FDG PET/CT can offer predictive power regarding the local control of oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) patients.Materials and Methods1H MR spectroscopy was performed in addition to conventional MR imaging before definitive chemoradiotherapy in 58 patients with advanced OHSCC. The relationship of local control with the 1H MR spectroscopy and 18F-FDG PET/CT parameters was analyzed.ResultsWith a median follow-up of 17.6 months, 13 (22.4%) patients exhibited local failure; whereas the remaining 45 achieved local control. Kaplan-Meier analysis identified age > 60 years, creatine level on MRS ≦ 6.02 mM, glutamine and glutamate (Glx) level on MRS > 3.31 mM, and total lesion glycolysis (TLG) on 18F-FDG PET/CT > 217.18 g/mL × mL as significant adverse predictors for 2-year local control. Multivariate Cox regression analysis showed that age (p=0.017), Glx level on MRS (p=0.021), and TLG on 18F-FDG PET/CT (p=0.028) retained their independent prognostic significance. A scoring system was constructed based on the sum of these three factors. We found that patients with scores of 2–3 had significantly poorer local control rates than patients with scores of 0–1 (33.3% versus 86.8%, p=0.003).ConclusionWe conclude that Glx on 1H MR spectroscopy at 3 T was the independent prognostic factor for local control of OHSCC patients treated with chemoradiotherapy, and its combination with age and TLG may help identify a subgroup of patients at high risk for developing local failure.

Rehabilitation program based on sensorimotor recovery improves the static and dynamic balance and modifies the basal ganglia neurochemistry: A pilot 1H-MRS study on Parkinson's disease patients.

Rehabilitation interventions represent an alternative strategy to pharmacological treatment in order to slow or reverse some functional aspects of disability in Parkinson's disease (PD). To date, the neurophysiological mechanisms underlying rehabilitation-mediated improvement in PD patients are still poorly understood. Interestingly, growing evidence has highlighted a key role of the glutamate in neurogenesis and brain plasticity. The brain levels of glutamate, and of its precursor glutamine, can be detected in vivo and noninvasively as "Glx" by means of proton magnetic resonance spectroscopy (H-MRS). In the present pilot study, 7 PD patients with frequent falls and axial dystonia underwent 8-week rehabilitative protocol focused on sensorimotor improvement. Clinical evaluation and Glx quantification were performed before and after rehabilitation. The Glx assessment was focused on the basal ganglia in agreement with their key role in the motor functions. We found that the rehabilitation program improves the static and dynamic balance in PD patients, promoting a better global motor performance. Moreover, we observed that the levels of Glx within the left basal ganglia were higher after rehabilitation as compared with baseline. Thus, we posit that our sensorimotor rehabilitative protocol could stimulate the glutamate metabolism in basal ganglia and, in turn, neuroplasticity processes. We also hypothesize that these mechanisms could prepare the ground to restore the functional interaction among brain areas deputed to motor controls, which are affected in PD.

Occipital GABA levels in older adults and their relationship to visual perceptual suppression

Several studies have attributed certain visual perceptual alterations in older adults to a likely decrease in GABA (Gamma Aminobutyric Acid) concentration in visual cortex, an assumption based on findings in aged non-human primates. However, to our knowledge, there is no direct evidence for an age-related decrease in GABA concentration in human visual cortex. Here, we estimated visual cortical GABA levels and Glx (combined estimate of glutamate and glutamine) levels using magnetic resonance spectroscopy. We also measured performance for two visual tasks that are hypothesised to be mediated, at least in part, by GABAergic inhibition: spatial suppression of motion and binocular rivalry. Our results show increased visual cortical GABA levels, and reduced Glx levels, in older adults. Perceptual performance differed between younger and older groups for both tasks. When subjects of all ages were combined, visual cortical GABA levels but not Glx levels correlated with perceptual performance. No relationship was found between perception and GABA levels in dorsolateral prefrontal cortex. Perceptual measures and GABA were not correlated when either age group was considered separately. Our results challenge current assumptions regarding neurobiological changes that occur within the aging human visual cortex and their association with certain age-related changes in visual perception.

Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain 23Na-MRI and fast 1H-MRSI study

Background: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. Objective: To determine in vivo the metabolic counterpart of brain sodium accumulation. Materials/methods: Whole brain 23Na-MR imaging and 3D-1H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. Results: MS patients showed significant 23Na accumulations with lower choline and glutamate–glutamine (Glx) levels in GM; 23Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher 23Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. Conclusion: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.

The absolute quantitative analysis of cingulate cortex metabolites in preschool children with autism spectrum disorder using proton MR spectroscopy

Objective To investigate the metabolite changes in the preschool children with autism spectrum disorder (ASD) using MR spectroscopy (MRS) and explore the associations between image findings and clinical variables, which may provide a noninvasive brain biochemical method for the early diagnosis and prevention of autism. Methods Twenty one cases of preschool ASD children (3-6 years old) and age-and sex-matched 20 preschool healthy controls underwent single voxel short (SVS) short TE (TE=30 ms) MRS. The absolute metabolite concentrations in the anterior cingulate cortex (ACC), anterior middle anterior cingulate cortex (aMCC) and posterior cingulate (PCC) were quantitatively analyzed using LCModel software. Two independent sample t tests were used for analysis. The relationships between metabolite concentrations and diagnostic and statistical manual of mental disorders (DSM-IV), childhood autism rating scale (CARS) and autism behavior checklist (ABC) were analyzed by Pearson correlation analysis. Results Compared to control subjects, ASD patients had significantly lower N-acetylaspartate (NAA) values (4.35±0.80, 6.34±0.82, 8.04±0.97 mmol/L respectively) in ACC, aMCC and PCC (t=2.640, P=0.012; t=2.182, P=0.035; t=3.343, P=0.002), had significantly lower choline (Cho) 1.32±0.22 mmol/L (t=2.905, P=0.006) and glutamine and glutamate complex (Glx) 10.02±0.88 mmol/L (t=2.090, P=0.043) in PCC. Cho, total creatine (tCr), myo-Inositol (MI) and Glx levels did not differ between groups in other aforementioned regions (P>0.05). Negative correlations between the NAA ualues in the PCC and CARS (r=-0.504, P=0.020) were detected, and no significant correlation among DSM-IV, CARS, ABC and other metabolite values (P>0.05). Conclusions The biochemical changes in the preschool children with ASD in cingulate reflect the neuronal loss, structural or functional damage and cell membrane enzyme metabolic dysfunctions, may reveal the pathological basis of ASD. These results may provide noninvasive and quantitative methods for the diagnosis and prognosis evaluation of ASD child. Key words: Autism spectrum disorder; Magnetic resonance spectroscopy; Cingulate cortex; Child

Dorsolateral prefrontal cortex GABA deficit in older adults with sleep-disordered breathing

Sleep-disordered breathing (SDB) is a common disorder in aging that is associated with cognitive decline, including significant executive dysfunction, for which the neurobiological underpinnings remain poorly understood. Using proton magnetic resonance spectroscopy (1H MRS), this study assessed whether dysregulation of the homeostatic balance of the major inhibitory and excitatory amino acid neurotransmitter systems of γ-aminobutyric acid (GABA) and glutamate, respectively, play a role in SDB. Levels of GABA and those of the combined resonances of glutamate and glutamine (Glx), were measured by 1H MRS in the left dorsolateral prefrontal cortex (l-DLPFC) and bilateral hippocampal regions of 19 older adults (age ± SD: 66.1 ± 1.9 years) with moderate to severe SDB, defined as having an Apnea-Hypopnea Index (AHI) greater than 15 as assessed by polysomnography, and in 14 older adults (age ± SD: 62.3 ± 1.3 years) without SDB (AHI < 5). In subjects with SDB, levels of l-DLPFC GABA, but not Glx, were significantly lower than in control subjects (P < 0.0002). Additionally, there was a negative correlation between l-DLPFC GABA levels, but not Glx, and SDB severity by AHI (r = -0.68, P < 0.0001), and a positive correlation between l-DLPFC GABA levels, but not Glx, and minimal oxygen saturation during sleep (r = 0.62, P = 0.0005). By contrast, no group differences or oxygenation associations were found for levels of GABA or Glx in right or left hippocampal region. These findings are interpreted in terms of a pathophysiological model of SDB in which hypoxia-mediated inhibitory neurotransmission deficit in DLPFC could lead to hyperexcitability and, potentially neuronal dysfunction and cognitive decline.

Anterior cingulate cortex \u03b3-aminobutyric acid deficits in youth with depression

Abnormally low γ-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty-four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12–21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder.

In vivo gamma-aminobutyric acid and glutamate levels in people with first-episode schizophrenia: A proton magnetic resonance spectroscopy study

BackgroundGamma-aminobutyric acid (GABA) dysfunction and its consequent imbalance are implicated in the pathophysiology of schizophrenia. Reduced GABA production would lead to a disinhibition of glutamatergic neurons and subsequently cause a disruption of the modulation between GABAergic interneurons and glutamatergic neurons. In this study, levels of GABA, Glx (summation of glutamate and glutamine), and other metabolites in the anterior cingulate cortex were measured and compared between first-episode schizophrenia subjects and healthy controls (HC). Diagnostic potential of GABA and Glx as upstream biomarkers for schizophrenia was explored. MethodsNineteen first-episode schizophrenia subjects and fourteen HC participated in this study. Severity of clinical symptoms of patients was measured with Positive and Negative Syndrome Scale (PANSS). Metabolites were measured using proton magnetic resonance spectroscopy, and quantified using internal water as reference. ResultsFirst-episode schizophrenia subjects revealed reduced GABA and myo-inositol (mI), and increased Glx and choline (Cho), compared to HC. No significant correlation was found between metabolite levels and PANSS scores. Receiver operator characteristics analyses showed Glx had higher sensitivity and specificity (84.2%, 92.9%) compared to GABA (73.7%, 64.3%) for differentiating schizophrenia patients from HC. Combined model of both GABA and Glx revealed the best sensitivity and specificity (89.5%, 100%). ConclusionThis study simultaneously showed reduction in GABA and elevation in Glx in first-episode schizophrenia subjects, and this might provide insights on explaining the disruption of modulation between GABAergic interneurons and glutamatergic neurons. Elevated Cho might indicate increased membrane turnover; whereas reduced mI might reflect dysfunction of the signal transduction pathway. In vivo Glx and GABA revealed their diagnostic potential for schizophrenia.