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

Abstract

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.

Prefrontal and Striatal Gamma-Aminobutyric Acid Levels and the Effect of Antipsychotic Treatment in First-Episode Psychosis Patients

“…In the second study, which was conducted in drug-naive subjects at UHR for psychosis (17) and measured GABA levels in the MPFC and dorsal caudate, significant elevations compared to control subjects were found in both regions. However, there appears to be a regional specificity to the GABA elevations in unmedicated patients, since prior studies found no group differences in the dorsolateral prefrontal cortex (8), in the dorsal anterior cingulate cortex (12), or in the occipital cortex (15) despite having studied unmedicated patients. In addition, although at baseline in the present study we found elevated MPFC GABA levels in five non-responders compared to responders, suggesting that the elevations observed in unmedicated patients at baseline may be driven by the non-responders, this interpretation must be viewed as preliminary since it is based on a small sample size.…”

“…GABAergic neurotransmission plays a critical role in the coordination of pyramidal cell activity, and its abnormalities have been linked to neurocognitive deficits in schizophrenia (5). Neuroimaging studies using proton magnetic resonance spectroscopy ( 1 H MRS) to measure GABA levels in vivo in schizophrenia have yielded variable results, with most studies in antipsychotic-treated, stable schizophrenia patients showing lower or normal GABA levels in the anterior cingulate cortex (6), the medial prefrontal cortex (MPFC) (7–11), the dorsolateral prefrontal cortex (8), the dorsal anterior cingulate cortex (9, 12), parieto-occipital cortices (7, 11, 13, 14), and the basal ganglia (7, 14) compared to healthy subjects, while studies in antipsychotic-free patients found lower GABA levels in the occipital cortex (15), normal levels in the dorsal anterior cingulate (12), or elevations in the ventromedial prefrontal cortex (16) and in the MPFC (8). Moreover, in the first study that measured GABA levels in both the MPFC and the dorsolateral prefrontal cortex of the same antipsychotic-free and antipsychotic-treated patients (8), GABA elevations were found in the MPFC of antipsychotic-free patients compared to both the medicated patients and control subjects, while no differences were found among the three groups in the dorsolateral prefrontal cortex.…”

Retrospective correction of frequency drift in spectral editing: The GABA editing example

“…Changes in GABA concentrations in many mental illnesses can be very subtle . This places stringent requirements on the reproducibility of the GABA editing sequence.…”

“…One hundred and thirty‐five healthy volunteers participated in Institutional Review Board‐approved protocols 95‐M‐0150 and 00‐M‐0085 between February 2008 and January 2015 . The volunteers were scanned on a 3‐T whole‐body scanner (GE, Milwaukee, WI, USA; 14 M4 platform) with a quadrature single‐channel transmit/receive radiofrequency (RF) coil (IGC Medical Advances, Milwaukee, WI, USA).…”

Magnetic Resonance Spectroscopy and its Clinical Applications: A Review

“…MRS and, recently, 31P-MRS studies demonstrated the changes that happen in membrane phospholipid characteristics, pH, and bioenergetic status. Also, 1H-MRS can be applied to map local NAA variations and the treatment effects [159][160][161][162][163][164][165][166][167][168].…”