GABA deficiency in NF1: A multimodal [11C]-flumazenil and spectroscopy study.
Ontology highlight
ABSTRACT: Objective
To provide a comprehensive investigation of the γ-aminobutyric acid (GABA) system in patients with neurofibromatosis type 1 (NF1) that allows understanding the nature of the GABA imbalance in humans at pre- and postsynaptic levels.Methods
In this cross-sectional study, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [(11)C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). Fourteen adult patients with NF1 and 13 matched controls were included in the study. MRS was performed in the occipital cortex and in a frontal region centered in the functionally localized frontal eye fields. PET and MRS acquisitions were performed in the same day.Results
Patients with NF1 have reduced concentration of GABA+ in the occipital cortex (p = 0.004) and frontal eye fields (p = 0.026). PET results showed decreased binding of GABAA receptors in patients in the parieto-occipital cortex, midbrain, and thalamus, which are not explained by decreased gray matter levels.Conclusions
Abnormalities in the GABA system in NF1 involve both GABA concentration and GABAA receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement.
SUBMITTER: Violante IR
PROVIDER: S-EPMC5035153 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [(18)F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders.
| S-EPMC6869063 | biostudies-literature
Project description:BackgroundDeficiency of 4-aminobutyrate aminotransferase (GABA-T) is a rare disorder of GABA catabolism, with only a single sibship reported. We report on a third case, a Japanese female infant with severe psychomotor retardation and recurrent episodic lethargy with intractable seizures, with the diagnosis facilitated by proton magnetic resonance (MR) spectroscopy ((1)H-MRS).MethodsNeuroimaging was performed at the first episode of lethargy. For (1)H-MRS, locations were placed in the semioval center and the basal ganglia. Quantification of metabolite concentrations were derived using the LCModel. We confirmed the diagnosis subsequently by enzyme and molecular studies, which involved direct DNA sequence analysis and the development of a novel multiplex ligation-dependent probe amplification test.Results(1)H-MRS analysis revealed an elevated GABA concentration in the basal ganglia (2.9 mmol/l). Based on the results of quantitative (1)H-MRS and clinical findings, GABA-T deficiency was suspected and confirmed in cultured lymphoblasts. Molecular studies of the GABA-T gene revealed compound heterozygosity for a deletion of one exon and a missense mutation, 275G>A, which was not detected in 210 control chromosomes.ConclusionsOur results suggest that excessive prenatal GABA exposure in the central nervous system (CNS) was responsible for the clinical manifestations of GABA transaminase deficiency. Our findings suggest the dual nature of GABA as an excitatory molecule early in life, followed by a functional switch to an inhibitory species later in development. Furthermore, quantitative (1)H-MRS appears to be a useful, noninvasive tool for detecting inborn errors of GABA metabolism in the CNS.
| S-EPMC2828554 | biostudies-literature
Project description:High-frequency oscillations in the gamma-band reflect rhythmic synchronization of spike timing in active neural networks. The modulation of gamma oscillations is a widely established mechanism in a variety of neurobiological processes, yet its neurochemical basis is not fully understood. Modeling, in-vitro and in-vivo animal studies suggest that gamma oscillation properties depend on GABAergic inhibition. In humans, search for evidence linking total GABA concentration to gamma oscillations has led to promising -but also to partly diverging- observations. Here, we provide the first evidence of a direct relationship between the density of GABA(A) receptors and gamma oscillatory gamma responses in human primary visual cortex (V1). By combining Flumazenil-PET (to measure resting-levels of GABA(A) receptor density) and MEG (to measure visually-induced gamma oscillations), we found that GABA(A) receptor densities correlated positively with the frequency and negatively with amplitude of visually-induced gamma oscillations in V1. Our findings demonstrate that gamma-band response profiles of primary visual cortex across healthy individuals are shaped by GABA(A)-receptor-mediated inhibitory neurotransmission. These results bridge the gap with in-vitro and animal studies and may have future clinical implications given that altered GABAergic function, including dysregulation of GABA(A) receptors, has been related to psychiatric disorders including schizophrenia and depression.
| S-EPMC4647220 | biostudies-other
Project description:ObjectivesDisorders of consciousness (DoC)-that is, unresponsive wakefulness syndrome/vegetative state and minimally conscious state-are debilitating conditions for which no reliable markers of consciousness recovery have yet been identified. Evidence points to the GABAergic system being altered in DoC, making it a potential target as such a marker.Experimental designIn our preliminary study, we used [(11) C]Flumazenil positron emission tomography to establish global GABAA receptor binding potential values and the local-to-global (LTG) ratio of these for specific regions. These values were then compared between DoC patients and healthy controls. In addition, they were correlated with behavioral improvements for the patients between the time of scanning and 3 months later. Functional magnetic resonance imaging resting-state functional connectivity was also calculated and the same comparisons made.Principal observationslobal GABAA receptor binding was reduced in DoC, as was the LTG ratio in specifically the supragenual anterior cingulate. Both of these measures correlated with behavioral improvement after 3 months. In contrast to these measures of GABAA receptor binding, functional connectivity did not correlate with behavioral improvement.ConclusionsOur preliminary findings point toward GABAA receptor binding being a marker of consciousness recovery in DoC.
| S-EPMC6869690 | biostudies-literature
Project description:ObjectiveWe report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype.MethodsCase ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil.ResultsAll patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued.ConclusionsGABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.
| S-EPMC5444310 | biostudies-literature
Project description:Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, most NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study were to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of the ?-aminobutyric acid type A (GABAA)-benzodiazepine radiotracer (11)C-flumazenil under anesthetized and awake conditions. We hypothesized that (11)C-flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys.The small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning, which required acclimation of the animals to the chair, touch-screen tasks, intravenous catheter insertion, and tilting. For PET studies, the bolus-plus-constant infusion method was used for (11)C-flumazenil administration. Two rhesus monkeys were scanned under the awake (n = 6 scans) and isoflurane-anesthetized (n = 4 scans) conditions. An infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min after injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n = 4) and the awake (n = 5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. The percentage change per minute in radioactivity concentration was calculated in high- and low-binding regions to assess the quality of equilibrium.The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND (awake) = 0.94 BPND (anesthetized) + 0.36 (r(2) = 0.95). Cortisol levels were significantly higher under the awake condition (P < 0.05).We successfully performed awake NHP imaging with minimal head restraint. There was close agreement in (11)C-flumazenil BPND values between awake and anesthetized conditions.
| S-EPMC3857935 | biostudies-literature
Project description:SummaryGABA serves as a major neurotransmitter of the brain and functions mainly to inhibit neural excitatory activity. Disruption of the GABAergic processes appears to occur in various neurologic and psychiatric conditions, including epilepsy, mood disorders, motor disorders such as focal dystonia and stiff-person syndrome, sleep disorders, neuroplasticity, and drug and alcohol dependence. These concentration differences may be ascertained by using MR spectroscopy to provide information on the concentration of different metabolites. This review briefly discusses advances in MR spectroscopy methods and explores the application of this technique to detect changes in GABA due to disease processes and medication-induced effects.
| S-EPMC7965110 | biostudies-literature
Project description:Metabolite-specific, scalar spin-spin coupling constant (J)-editing 1H MRS methods have become gold-standard for measuring brain ?-amino butyric acid (GABA) levels in human brain. Localized, two-dimensional (2D) 1H MRS technology offers an attractive alternative as it significantly alleviates the problem of severe metabolite signal overlap associated with standard 1D MRS and retains spectroscopic information for all MRS-detectable species. However, for metabolites found at low concentration, a direct, in vivo, comprehensive methods comparison is challenging and has not been reported to date. Here, we document an assessment of comparability between 2D 1H MRS and J-editing methods for measuring GABA in human brain. This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout. We report a qualitative and quantitative comparison between these two measurement techniques. In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D 1H MRS time courses. The data presented are particularly encouraging considering recent 2D 1H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping.
| S-EPMC6123452 | biostudies-literature
Project description:BACKGROUND:Mesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D2/D3 receptor availability in MDD. METHODS:Twenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D3-preferring ligand [11C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks. RESULTS:MDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (?BPND) (-34% vs. -30%; p = .072, d = 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND were not significantly associated with blood oxygen level-dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response rate = 72.7%). CONCLUSIONS:[11C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D2/D3 availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.
| S-EPMC6347467 | biostudies-literature
Project description:Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter ?-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.
| S-EPMC5700835 | biostudies-literature