Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle.

Sleep and brain glutamatergic signaling are homeostatically regulated. Recovery sleep following prolonged wakefulness restores efficient functioning of the brain, possibly by keeping glutamatergic signaling in a homeostatic range. Evidence in humans and mice suggested that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain's coping mechanisms with sleep deprivation. Here, proton magnetic resonance spectroscopy in 31 healthy men was used to quantify the levels of glutamate (Glu), glutamate-to-glutamine ratio (GLX), and γ-amino-butyric-acid (GABA) in basal ganglia (BG) and dorsolateral prefrontal cortex on 3 consecutive days, after ~8 (baseline), ~32 (sleep deprivation), and ~8 hours (recovery sleep) of wakefulness. Simultaneously, mGluR5 availability was quantified with the novel radioligand for positron emission tomography, [18F]PSS232, and the blood levels of the mGluR5-regulated proteins, fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) were determined. The data revealed that GLX (p = 0.03) in BG (for Glu: p < 0.06) and the serum concentration of FMRP (p < 0.04) were increased after sleep loss. Other brain metabolites (GABA, N-acetyl-aspartate, choline, glutathione) and serum BDNF levels were not altered by sleep deprivation (pall > 0.6). By contrast, the night without sleep enhanced whole-brain, BG, and parietal cortex mGluR5 availability, which was normalized by recovery sleep (pall < 0.05). The findings provide convergent multimodal evidence that glutamatergic signaling is affected by sleep deprivation and recovery sleep. They support a role for mGluR5 and FMRP in sleep-wake regulation and warrant further studies to investigate their causality and relevance for regulating human sleep in health and disease. Clinical Trial Registration: www.clinicaltrials.gov (study identifier: NCT03813082).

Diurnal changes in human brain glutamate + glutamine levels in the course of development and their relationship to sleep.

Sleep slow waves during non-rapid eye movement (NREM) sleep play a crucial role in maintaining cortical plasticity, a process that is especially important in the developing brain. Children show a considerably larger overnight decrease in slow wave activity (SWA; the power in the EEG frequency band between 1 and 4.5 â€‹Hz during NREM sleep), which constitutes the primary electrophysiological marker for the restorative function of sleep. We previously demonstrated in adults that this marker correlates with the overnight reduction in cortical glutamate â€‹+ â€‹glutamine (GLX) levels assessed by magnetic resonance spectroscopy (MRS), proposing GLX as a promising biomarker for the interplay between cortical plasticity and SWA. Here, we used a multimodal imaging approach of combined MRS and high-density EEG in a cross-sectional cohort of 46 subjects from 8 to 24 years of age in order to examine age-related changes in GLX and its relation to SWA. Gray matter volume, GLX levels and SWA showed the expected age-dependent decrease. Unexpectedly, the overnight changes in GLX followed opposite directions when comparing children to adults. These age-related changes could neither be explained by the overnight decrease in SWA nor by circadian factors.

Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples.

OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Beyond Dopamine: GABA, Glutamate, and the Axial Symptoms of Parkinson Disease.

Introduction: The axial symptoms of Parkinson disease (PD) include difficulties with balance, posture, speech, swallowing, and locomotion with freezing of gait, as well as axial rigidity. These axial symptoms impact negatively on quality of life for many patients, yet remain poorly understood. Dopaminergic treatments typically have little effect on the axial symptoms of PD, suggesting that disruptions in other neurotransmitter systems beyond the dopamine system may underlie these symptoms. The purpose of the present study was to examine the relationship between the axial symptoms of PD and GABA and glutamate levels quantified with magnetic resonance spectroscopy. Methods: The participant group included 20 patients with PD and 17 healthy control participants. Water-scaled GABA and Glx (glutamate + glutamine) concentrations were derived from GABA-edited MEGA-PRESS spectra acquired from the left basal ganglia and prefrontal cortex, and additional water-scaled Glx concentrations were acquired from standard PRESS spectra acquired from the pons. Spectra were analyzed with LCModel. The axial symptoms of PD were evaluated from subscales of the Unified Parkinson's Disease rating scale (MDS-UPDRS). Results: PD patients demonstrated significantly higher GABA levels in the basal ganglia, which correlated with the degree of gait disturbance. Basal ganglia Glx levels and prefrontal GABA and Glx levels did not differ significantly between patient and control groups, but within the PD group prefrontal Glx levels correlated negatively with difficulties turning in bed. Results from an exploratory subgroup analysis indicate that the associations between GABA, Glx, and axial symptoms scores are typically more prominent in akinetic-rigid patients than in tremor-dominant patients. Conclusion: Alterations in GABAergic and glutamatergic neurotransmission may contribute to some of the axial symptoms of PD.

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

INTRODUCTION: While 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. METHODS: Magnetic 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. RESULTS: Basal 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. CONCLUSION: GABAergic and glutamatergic neurotransmission is altered in PD, and glutamatergic activity in particular may influence outcome post-surgery.