Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia

Abstract Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their “voices” through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.

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Dissociable brain correlates for depression, anxiety, dissociation, and somatization in depersonalization-derealization disorder

CNS Spectrums ◽

10.1017/s1092852913000588 ◽

2013 ◽

Vol 21 (1) ◽

pp. 35-42 ◽

Cited By ~ 13

Author(s):

Erwin Lemche ◽

Simon A. Surguladze ◽

Michael J. Brammer ◽

Mary L. Phillips ◽

Mauricio Sierra ◽

...

Keyword(s):

Inferior Frontal Gyrus ◽

Superior Temporal Gyrus ◽

Brain Regions ◽

Self Report ◽

Parahippocampal Gyrus ◽

Left Inferior Frontal Gyrus ◽

Symptoms Of Depression ◽

Caudate Head ◽

Brain Correlates ◽

The Right

ObjectiveThe cerebral mechanisms of traits associated with depersonalization-derealization disorder (DPRD) remain poorly understood.MethodHappy and sad emotion expressions were presented to DPRD and non-referred control (NC) subjects in an implicit event-related functional magnetic resonance imaging (fMRI) design, and correlated with self report scales reflecting typical co-morbidities of DPRD: depression, dissociation, anxiety, somatization.ResultsSignificant differences between the slopes of the two groups were observed for somatization in the right temporal operculum (happy) and ventral striatum, bilaterally (sad). Discriminative regions for symptoms of depression were the right pulvinar (happy) and left amygdala (sad). For dissociation, discriminative regions were the left mesial inferior temporal gyrus (happy) and left supramarginal gyrus (sad). For state anxiety, discriminative regions were the left inferior frontal gyrus (happy) and parahippocampal gyrus (sad). For trait anxiety, discriminative regions were the right caudate head (happy) and left superior temporal gyrus (sad).DiscussionThe ascertained brain regions are in line with previous findings for the respective traits. The findings suggest separate brain systems for each trait.ConclusionOur results do not justify any bias for a certain nosological category in DPRD.

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A Cortical Network Sensitive to Stimulus Salience in a Neutral Behavioral Context Across Multiple Sensory Modalities

Journal of Neurophysiology ◽

10.1152/jn.00636.2001 ◽

2002 ◽

Vol 87 (1) ◽

pp. 615-620 ◽

Cited By ~ 347

Author(s):

Jonathan Downar ◽

Adrian P. Crawley ◽

David J. Mikulis ◽

Karen D. Davis

Keyword(s):

Response Selection ◽

Inferior Frontal Gyrus ◽

Superior Temporal Gyrus ◽

Brain Regions ◽

Anterior Cingulate ◽

Behavioral Context ◽

General Role ◽

Sensory Stimuli ◽

Tactile Stimuli ◽

Stimulus Salience

Stimulus salience depends both on behavioral context and on other factors such as novelty and frequency of occurrence. The temporo-parietal junction (TPJ) responds preferentially to behaviorally relevant stimuli and is thought to play a general role in detecting salient stimuli. If so, it should respond preferentially to novel or infrequent events, even in a neutral behavioral context. To test this hypothesis, we used event-related functional magnetic resonance imaging (fMRI) to identify brain regions sensitive to the novelty of visual, auditory, and tactile stimuli during passive observation. Cortical regions with a greater response to novel than familiar stimuli across all modalities were identified at two sites in the TPJ region: the supramarginal gyrus (SMG) and superior temporal gyrus. The right inferior frontal gyrus (IFG), right anterior insula, left anterior cingulate cortex (ACC), and left inferior temporal gyrus also showed sensitivity to novelty. The novelty-sensitive TPJ activation in SMG overlaps a region previously identified as sensitive behavioral context. This region may play a general role in identifying salient stimuli, whether the salience is due to the current behavioral context or not. The IFG activation overlaps regions previously identified as responsive to nonnovel sensory events regardless of behavioral context. The IFG may therefore play a general role in stimulus evaluation rather than a specific role in identifying novel stimuli. The ACC activation lies in a region active during complex response-selection tasks, suggesting a general role in detecting and/or planning responses to salient events. A frontal-parietal-cingulate network may serve to identify and evaluate salient sensory stimuli in general.

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Progressive changes in glutamate concentration in early stages of schizophrenia: A longitudinal 7-Tesla MRS study

10.1101/2020.08.11.20172841 ◽

2020 ◽

Author(s):

Peter Jeon ◽

Roberto Limongi ◽

Sabrina Ford ◽

Michael MacKinley ◽

Kara Dempster ◽

...

Keyword(s):

Anterior Cingulate ◽

7 Tesla ◽

Resonance Spectroscopy ◽

Healthy Controls ◽

Dorsal Anterior Cingulate Cortex ◽

1H Mrs ◽

Glutamate Concentration ◽

Early Stages ◽

Time Interaction ◽

Cortical Maturation

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at the dorsal anterior cingulate cortex in 21 participants with a median lifetime antipsychotic exposure of less than 3 days and followed them up after 6 months of treatment. Healthy controls were also scanned at two time points. While patients had significantly lower overall glutamate levels than healthy controls (F(1,27) = 5.23, p = 0.03), we did not observe a progressive change of glutamate concentration in patients (F(1,18) = 0.47, p = 0.50), and the group by time interaction was not significant (F(1,27) = 0.86, p = 0.36). On average, patients with early psychosis receiving treatment showed a 0.02 mM/year increase, while healthy controls showed a 0.06 mM/year reduction of MRS glutamate levels. Bayesian analysis of our observations does not support early, post-onset glutamate loss in schizophrenia. Interestingly, it provides evidence in favour of a lack of progressive glutamate change in our schizophrenia sample indicating that the glutamatergic level at the onset of illness was the best predictor of the levels 6 months after treatment. A more nuanced view of glutamatergic physiology, linked to early cortical maturation, may be required to understand glutamatergic dynamics in schizophrenia.

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Metabolite Alterations in Adults With Schizophrenia, First Degree Relatives, and Healthy Controls: A Multi-Region 7T MRS Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.656459 ◽

2021 ◽

Vol 12 ◽

Author(s):

S. Andrea Wijtenburg ◽

Min Wang ◽

Stephanie A. Korenic ◽

Shuo Chen ◽

Peter B. Barker ◽

...

Keyword(s):

Prefrontal Cortex ◽

Dorsolateral Prefrontal Cortex ◽

Brain Regions ◽

Anterior Cingulate ◽

Resonance Spectroscopy ◽

Healthy Controls ◽

Centrum Semiovale ◽

Illness Duration ◽

First Degree Relatives ◽

Dorsolateral Prefrontal

Proton magnetic resonance spectroscopy (MRS) studies in schizophrenia have shown altered GABAergic, glutamatergic, and bioenergetic pathways, but if these abnormalities are brain region or illness-stage specific is largely unknown. MRS at 7T MR enables reliable quantification of multiple metabolites, including GABA, glutamate (Glu) and glutamine (Gln), from multiple brain regions within the time constraints of a clinical examination. In this study, GABA, Glu, Gln, the ratio Gln/Glu, and lactate (Lac) were quantified using 7T MRS in five brain regions in adults with schizophrenia (N = 40), first-degree relatives (N = 11), and healthy controls (N = 38). Metabolites were analyzed for differences between groups, as well as between subjects with schizophrenia with either short (<5 years, N = 19 or long (>5 years, N = 21) illness duration. For analyses between the three groups, there were significant glutamatergic and GABAergic differences observed in the anterior cingulate, centrum semiovale, and dorsolateral prefrontal cortex. There were also significant relationships between anterior cingulate cortex, centrum semiovale, and dorsolateral prefrontal cortex and cognitive measures. There were also significant glutamatergic, GABAergic, and lactate differences between subjects with long and short illness duration in the anterior cingulate, centrum semiovale, dorsolateral prefrontal cortex, and hippocampus. Finally, negative symptom severity ratings were significantly correlated with both anterior cingulate and centrum semiovale metabolite levels. In summary, 7T MRS shows multi-region differences in GABAergic and glutamatergic metabolites between subjects with schizophrenia, first-degree relatives and healthy controls, suggesting relatively diffuse involvement that evolves with illness duration. Unmedicated first-degree relatives share some of the same metabolic characteristics as patients with a diagnosis of schizophrenia, suggesting that these differences may reflect a genetic vulnerability and are not solely due to the effects of antipsychotic interventions.

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N-Acetylaspartyl-Glutamate Metabolism in the Cingulated Cortices as a Biomarker of the Etiology in ASD: A 1H-MRS Model

Molecules ◽

10.3390/molecules26030675 ◽

2021 ◽

Vol 26 (3) ◽

pp. 675

Author(s):

Carmen Jiménez-Espinoza ◽

Francisco Marcano Serrano ◽

José Luis González-Mora

Keyword(s):

Developmental Stages ◽

Neurological Diseases ◽

Cingulate Cortex ◽

Brain Regions ◽

Posterior Cingulate Cortex ◽

Autism Spectrum ◽

Anterior Cingulate ◽

Resonance Spectroscopy ◽

Magnetic Studies ◽

1H Mrs

As brain functional resonance magnetic studies show an aberrant trajectory of neurodevelopment, it is reasonable to predict that the degree of neurochemical abnormalities indexed by magnetic resonance spectroscopy (1H-MRS) might also change according to the developmental stages and brain regions in autism spectrum disorders (ASDs). Since specific N-Acetyl-aspartate (NAA) changes in children’s metabolism have been found in the anterior cingulate cortex (ACC) but not in the posterior cingulate cortex (PCC), we analyzed whether the metabolites of ASD youths change between the cingulate cortices using 1H-MRS. l-glutamate (Glu) and l-Acetyl-aspartate (NAA) are products from the N-Acetyl-aspartyl-glutamate (NAAG) metabolism in a reaction that requires the participation of neurons, oligodendrocytes, and astrocytes. This altered tri-cellular metabolism has been described in several neurological diseases, but not in ASD. Compared to the typical development (TD) group, the ASD group had an abnormal pattern of metabolites in the ACC, with a significant increase of glutamate (12.10 ± 3.92 mM; p = 0.02); additionally, N-Acetyl-aspartyl-glutamate significantly decreased (0.41 ± 0.27 mM; p = 0.02) within ASD metabolism abnormalities in the ACC, which may allow the development of new therapeutic possibilities.

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Glutamate connectivity associations converge upon the salience network in schizophrenia and healthy controls

Translational Psychiatry ◽

10.1038/s41398-021-01455-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Robert A. McCutcheon ◽

Toby Pillinger ◽

Maria Rogdaki ◽

Juan Bustillo ◽

Oliver D. Howes

Keyword(s):

Functional Connectivity ◽

Frontal Cortex ◽

Network Connectivity ◽

Resonance Spectroscopy ◽

Salience Network ◽

Healthy Controls ◽

1H Mrs ◽

Before And After ◽

Functional Brain Networks ◽

The Relationship

AbstractAlterations in cortical inter-areal functional connectivity, and aberrant glutamatergic signalling are implicated in the pathophysiology of schizophrenia but the relationship between the two is unclear. We used multimodal imaging to identify areas of convergence between the two systems. Two separate cohorts were examined, comprising 195 participants in total. All participants received resting state functional MRI to characterise functional brain networks and proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate concentrations in the frontal cortex. Study A investigated the relationship between frontal cortex glutamate concentrations and network connectivity in individuals with schizophrenia and healthy controls. Study B also used 1H-MRS, and scanned individuals with schizophrenia and healthy controls before and after a challenge with the glutamatergic modulator riluzole, to investigate the relationship between changes in glutamate concentrations and changes in network connectivity. In both studies the network based statistic was used to probe associations between glutamate and connectivity, and glutamate associated networks were then characterised in terms of their overlap with canonical functional networks. Study A involved 76 individuals with schizophrenia and 82 controls, and identified a functional network negatively associated with glutamate concentrations that was concentrated within the salience network (p < 0.05) and did not differ significantly between patients and controls (p > 0.85). Study B involved 19 individuals with schizophrenia and 17 controls and found that increases in glutamate concentrations induced by riluzole were linked to increases in connectivity localised to the salience network (p < 0.05), and the relationship did not differ between patients and controls (p > 0.4). Frontal cortex glutamate concentrations are associated with inter-areal functional connectivity of a network that localises to the salience network. Changes in network connectivity in response to glutamate modulation show an opposite effect compared to the relationship observed at baseline, which may complicate pharmacological attempts to simultaneously correct glutamatergic and connectivity aberrations.

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M146. NEUROCHEMICAL MODULATION OF AUDITORY CORTEX FUNCTIONAL CONNECTIVITY IN PATIENTS WITH AUDITORY VERBAL HALLUCINATIONS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.458 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S191-S191

Author(s):

Sarah Weber ◽

Helene Hjelmervik ◽

Alexander R Craven ◽

Erik Johnsen ◽

Rune Kroken ◽

...

Keyword(s):

Functional Connectivity ◽

Temporal Lobe ◽

Superior Temporal Gyrus ◽

Underlying Mechanism ◽

Auditory Hallucinations ◽

Anterior Cingulate ◽

Gamma Aminobutyric Acid ◽

Auditory Verbal Hallucinations ◽

Left And Right ◽

Neurochemical Correlates

Abstract Background Auditory hallucinations have been linked to aberrant functioning of the left superior temporal gyrus (STG) and are associated with impaired cognitive control regulated by areas in the prefrontal cortex. However, the mechanisms behind these dysfunctions are still unclear. Methods The current study combined resting state connectivity fMRI with MR spectroscopy (MRS) in a sample of 81 psychosis patients to explore how neurochemical correlates of auditory hallucinations modulate left STG functioning. The analyses were focused on glutamate (Glu) and gamma-aminobutyric acid (GABA), two neurotransmitters with excitatory and inhibitory functions, respectively, since these have previously been implicated in psychosis. Results Glu and GABA showed differential relationships with left STG connectivity in patients with and without hallucinations. Specifically, Glu concentration in the anterior cingulate cortex (ACC) was positively related to functional connectivity between the left and right temporal lobe in hallucinating patients only. In contrast, GABA concentration in the ACC was negatively related to connectivity between the left and right temporal lobe in non-hallucinating patients only. Discussion These findings support a recently proposed model of interhemispheric temporal lobe miscommunication in auditory hallucinations and indicate prefrontal neurochemical modulation as a potential underlying mechanism. The results can further be integrated with previously suggested excitatory/inhibitory imbalances as neurochemical modulators in AVH.

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Focal changes in brain energy and phospholipid metabolism in first-episode schizophrenia

The British Journal of Psychiatry ◽

10.1192/bjp.184.5.409 ◽

2004 ◽

Vol 184 (5) ◽

pp. 409-415 ◽

Cited By ~ 39

Author(s):

J. Eric Jensen ◽

Jodi Miller ◽

Peter C. Williamson ◽

Richard W J. Neufeld ◽

Ravi S. Menon ◽

...

Keyword(s):

Healthy Volunteers ◽

Imaging Techniques ◽

High Energy ◽

Brain Regions ◽

Anterior Cingulate ◽

First Episode ◽

Resonance Spectroscopy ◽

Membrane Breakdown ◽

First Episode Schizophrenia

BackgroundMembrane phospholipid and high-energy abnormalities measured with phosphorus magnetic resonance spectroscopy (31P-MRS) have been reported in patients with schizophrenia in several brain regions.AimsUsing improved imaging techniques, previously inaccessible brain regions were examined in patients with first-episode schizophrenia and healthy volunteers with 4.0 T 31P-MRS.MethodBrain spectra were collected in vivo from 15 patients with first-episode schizophrenia and 15 healthy volunteers from 15 cm3 effective voxels in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex and parieto-occipital cortex.ResultsPeople with first-episode schizophrenia showed increased levels of glycerophosphocholine in the anterior cingulate. Inorganic phosphate, phosphocreatine and adenosine triphosphate concentrations were also increased in the anterior cingulate in this group.ConclusionsThe increased phosphodiester and high-energy phosphate levels in the anterior cingulate of brains of people with first-episode schizophrenia may indicate neural overactivity in this region during the early stages of the illness, resulting in increased excitotoxic neural membrane breakdown.

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Framing and Self-Responsibility Modulate Brain Activities in Decision Escalation

10.21203/rs.2.24818/v4 ◽

2021 ◽

Author(s):

Ting-Peng Liang ◽

Yuwen Li ◽

Nai-Shing Yen ◽

Ofir Turel ◽

Sen-Mou Hsu

Keyword(s):

Anterior Cingulate Cortex ◽

Contextual Factors ◽

Inferior Frontal Gyrus ◽

Cingulate Cortex ◽

Brain Regions ◽

Anterior Cingulate ◽

Imaging Data ◽

Two Factors ◽

Human Decision

Abstract Background: Escalation of commitment is a common bias in human decision making. The present study examined (1) differences in neural recruitment for escalation and de-escalation decisions of prior investments, and (2) how the activations of these brain networks are modulated by two factors that are often argued to modulate the behavior: (i) self-responsibility, and (ii) framing of the success probabilities. Results: Imaging data were obtained from functional magnetic resonance imaging (fMRI) applied to 29 participants. A whole-brain analysis was conducted to compare brain activations between conditions. ROI analysis, then, was used to examine if these significant activations were modulated by two contextual factors. Finally, mediation analysis was applied to explore how the contextual factors affect escalation decisions through brain activations. The findings showed that (1) escalation decisions are faster than de-escalation decisions, (2) the corresponding network of brain regions recruited for escalation (anterior cingulate cortex, insula and precuneus) decisions differs from this recruited for de-escalation decisions (inferior and superior frontal gyri), (3) the switch from escalation to de-escalation is primarily frontal gyri dependent, and (4) activation in the anterior cingulate cortex, insula and precuneus were further increased in escalation decisions, when the outcome probabilities of the follow-up investment were positively framed; and activation in the inferior and superior frontal gyri in de-escalation decisions were increased when the outcome probabilities were negatively framed. Conclusions: Escalation and de-escalation decisions recruit different brain regions. Framing of possible outcomes as negative leads to escalation decisions through recruitment of the inferior frontal gyrus. Responsibility for decisions affects escalation decisions through recruitment of the superior (inferior) gyrus, when the decision is framed positively (negatively).

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Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

10.1101/2020.08.25.267419 ◽

2020 ◽

Author(s):

Min Wang ◽

Peter B. Barker ◽

Nicola Cascella ◽

Jennifer M. Coughlin ◽

Gerald Nestadt ◽

...

Keyword(s):

Young Adulthood ◽

Brain Regions ◽

First Episode Psychosis ◽

Anterior Cingulate ◽

7 Tesla ◽

First Episode ◽

Resonance Spectroscopy ◽

Invasive Approach ◽

Longitudinal Changes ◽

Episode Psychosis

AbstractObjective7 Tesla (T) longitudinal magnetic resonance spectroscopy (MRS) offers a precise measurment of metabolic levels in human brain via a non-invasive approach. Studying longitudinal changes in neurometabolites could help identify trait and state markers for diseases and understand inconsistent findings from different researchers due to differences in the age of study participants and duration of illness. This study is the first to report novel longitudinal patterns in young adulthood from both physiological and pathological viewpoints using 7T MRS.MethodsUtilizing a four-year longitudinal cohort with 38 first episode psychosis (FEP) patients (onset within 2 years) and 48 healthy controls (HC), the authors examined the annual percentage changes of 9 neurometabolites in 5 brain regions.ResultsBoth FEP patients and HC subjects were found to have significant longitudinal reductions in glutamate (Glu) in the anterior cingulate cortex (ACC). Only FEP patients were found to have a significant decrease over time in γ-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mI), and total choline (tCho: phosphocholine plus glycerophosphocholine) in the ACC. Uniquely, glutathione (GSH) was found to have a near zero annual percentage change in both FEP patients and HC subjects in all 5 brain regions over a four-year timespan in young adulthood.ConclusionsGSH could be a trait marker for diagnostic applications at least in young adulthood. Glu, GABA, NAA, mI, and tCho in the ACC are associated with the patient’s status and could be state markers for mechanistic studies of psychotic disorders, including those for progressive pathological changes and medication effects in young adulthood.

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