GABA and glutamate in schizophrenia: A 7 T 1H-MRS study

Marsman, Anouk; Mandl, René C.W.; Klomp, Dennis W. J.; Bohlken, Marc M.; Boer, Vincent O.; Andreychenko, Anna; Cahn, Wiepke; Kahn, René S.; Luijten, Peter R.; Pol, Hilleke E. Hulshoff

doi:10.1016/j.nicl.2014.10.005

Cited by 135 publications

(131 citation statements)

References 69 publications

(102 reference statements)

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“…This ratio finding might be determined by the trend for creatine/water to be higher especially in untreated patients than in healthy controls (for effect sizes, see Table S6 in the data supplement). These data are generally consistent with several studies of GABA levels in the prefrontal cortex (10,11,15,17), in the occipital cortex (13,14,17), and in the hippocampal formation (12), which found GABA levels to be reduced or unchanged in patients with schizophrenia compared with healthy controls. However, our findings differ in directionality from those by Ongür et al (20) in the dorsal anterior cingulate and Kegeles et al (19) in the medial prefrontal cortex (see the Supplementary Discussion section in the data supplement).…”

Section: Discussionsupporting

confidence: 91%

“…While some studies (10)(11)(12) found no differences in patients with schizophrenia compared with healthy controls, others found reduced levels in the occipital (13,14) and prefrontal (15) cortices (including the dorsal anterior cingulate cortex in patients over 35 years of age [16]) and in the basal ganglia (17). In contrast, our preliminary data in a small group of patients who do not overlap with the ones presented here (18) showed elevated GABA levels in the dorsal anterior cingulate in treated patients with psychosis compared with healthy controls.…”

Section: Objectivementioning

confidence: 96%

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Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

Marenco¹,

Meyer²,

Kuo³

et al. 2016

AJP

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Objective:The authors sought to compare GABA levels in treated and untreated patients with psychosis with levels in their unaffected siblings and healthy control subjects, and to assess the effects of antipsychotic medications on GABA levels.Method: GABA+ levels (i.e., including signal from unrelated proteins or macromolecules) referenced to creatine or water were studied with J-edited proton spectroscopy in the dorsal anterior cingulate cortex of 289 individuals: 184 healthy control subjects, 83 treated patients with psychosis, 25 untreated patients, 31 unaffected siblings, and 17 patients studied both while off all medications and while on a single antipsychotic.Results: GABA+ levels in the dorsal anterior cingulate did not differ between untreated patients and healthy controls. For treated patients, levels were modestly lower for GABA+/ creatine but did not differ for GABA+/water compared with healthy controls. For both GABA+ measures, unaffected siblings had significantly lower levels compared with controls. GABA+/creatine showed a modest degree of familiality (intraclass correlation=0.36). Antipsychotic dosage was negatively correlated with GABA+ levels, but the on-off medication studies indicated no difference in GABA+ levels on antipsychotics compared with off antipsychotics.Conclusions: GABA+/creatine in the dorsal anterior cingulate may constitute an intermediate phenotype with low effect size for psychosis, but GABA+/water measures do not fully support this conclusion. Low GABA+ levels in unaffected siblings could suggest a genetic association, but the failure to find consistent evidence of this phenotype in the patients themselves weakens genetic inference on risk for psychosis. Replication in independent samples of siblings is warranted to confirm the potential genetic risk association.

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Section: Discussionsupporting

confidence: 91%

Section: Objectivementioning

confidence: 96%

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

Marenco¹,

Meyer²,

Kuo³

et al. 2016

AJP

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“…Consistent with this possibility, pharmacological models of SCZ often propose a distributed disruption in E/I across cortical circuits. This finding is supported by clinical magnetic resonance spectroscopy studies showing GABA and glutamate deficits across the cortex in SCZ (7,(82)(83)(84).…”

Section: Focal Vs Global Neuropathology Producing Preferential Assocsupporting

confidence: 56%

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

Yang

Murray

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

130

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Schizophrenia may involve an elevated excitation/inhibition (E/I) ratio in cortical microcircuits. It remains unknown how this regulatory disturbance maps onto neuroimaging findings. To address this issue, we implemented E/I perturbations within a neural model of large-scale functional connectivity, which predicted hyperconnectivity following E/I elevation. To test predictions, we examined restingstate functional MRI in 161 schizophrenia patients and 164 healthy subjects. As predicted, patients exhibited elevated functional connectivity that correlated with symptom levels, and was most prominent in association cortices, such as the fronto-parietal control network. This pattern was absent in patients with bipolar disorder (n = 73). To account for the pattern observed in schizophrenia, we integrated neurobiologically plausible, hierarchical differences in association vs. sensory recurrent neuronal dynamics into our model. This in silico architecture revealed preferential vulnerability of association networks to E/I imbalance, which we verified empirically. Reported effects implicate widespread microcircuit E/I imbalance as a parsimonious mechanism for emergent inhomogeneous dysconnectivity in schizophrenia.functional connectivity | schizophrenia | computational modeling S chizophrenia (SCZ) is a disabling psychiatric disease associated with widespread neural disturbances. These involve abnormal neurodevelopment (1-3), neurochemistry (4-7), neuronal gene expression (8-11), and altered microscale neural architecture (2). Such deficits are hypothesized to impact excitation-inhibition (E/I) balance in cortical microcircuits (12). Clinically, SCZ patients display a wide range of symptoms, including delusions, hallucinations (13, 14), higher-level cognitive deficits (15, 16), and lower-level sensory alterations (17). This display is consistent with a widespread neuropathology (18), such as the E/I imbalance suggested by the NMDA receptor (NMDAR) hypofunction model (19-21). However, emerging resting-state functional magnetic resonance imaging (rs-fMRI) studies implicate more networkspecific abnormalities in SCZ. Typically, these alterations are localized to higher-order association regions, such as the frontoparietal control network (FPCN) (18,22) and the default mode network (DMN) (23, 24), with corresponding disturbances in thalamo-cortical circuits connecting to association regions (25,26). It remains unknown how to reconcile widespread cellularlevel neuropathology in SCZ (20,21,27,28) with preferential association network disruptions (29,30).Currently a tension exists between two competing frameworks: global versus localized neural dysfunction in SCZ. Association network alterations in SCZ, identified via neuroimaging, may arise from a localized dysfunction (3,9,31,32). Alternatively, they may represent preferential abnormalities arising emergently from a nonspecific global microcircuit disruption (20, 33). Mechanistically, an emergent preferential effect could occur because of intrinsic differences between cortical ...

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“…GABA alterations in schizophrenia are also controversial [15, 21, 27, 28, 36–39]. Several studies have reported lower GABA levels in the ACC, bilateral calcarine sulci, and mPFC in chronic schizophrenia [15, 38, 39]. However, unchanged or elevated GABA levels in the ACC and mPFC have also been observed [15, 28, 37, 39].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have reported lower GABA levels in the ACC, bilateral calcarine sulci, and mPFC in chronic schizophrenia [15, 38, 39]. However, unchanged or elevated GABA levels in the ACC and mPFC have also been observed [15, 28, 37, 39]. Evidence of GABA alterations in first-episode schizophrenia remains limited [22].…”

Section: Introductionmentioning

confidence: 99%

Reducedγ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk

et al. 2016

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Altered γ-aminobutyric acid (GABA), glutamate (Glu) levels, and an imbalance between GABAergic and glutamatergic neurotransmissions have been involved in the pathophysiology of schizophrenia. However, it remains unclear how these abnormalities impact the onset and course of psychosis. In the present study, 21 drug-naïve subjects at ultrahigh risk for psychosis (UHR), 16 drug-naïve patients with first-episode schizophrenia (FES), and 23 healthy controls (HC) were enrolled. In vivo GABA and glutamate+glutamine (Glx) levels in the medial prefrontal cortex were measured using proton magnetic resonance spectroscopy. Medial prefrontal GABA and Glx levels in FES patients were significantly lower than those in HC and UHR, respectively. GABA and Glx levels in UHR were comparable with those in HC. In each group, there was a positive correlation between GABA and Glx levels. Reduced medial prefrontal GABA and Glx levels thus may play an important role in the early stages of schizophrenia.

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GABA and glutamate in schizophrenia: A 7 T 1H-MRS study

Cited by 135 publications

References 69 publications

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

Reducedγ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk

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