Measuring NMDA receptors in vivo using [¹⁸F]GE-179 PET in health and disease

Background: N-methyl-D-aspartate receptors (NMDAR) are important glutamatergic ion channels in the brain. Studying the functional activation of NMDAR in vivo in humans has not been possible until recently. / Methods: We used positron emission tomography (PET) with [18F]GE-179, a novel radioligand binding inside the open NMDAR channel, to assess the in vivo activation of NMDAR. We developed methodology for quantification of ligand binding (Project 1) that did not require arterial sampling and was then applied to study NMDAR activation in aging (n=29, Project 2), epilepsy (n=26, Project 3), and Anti-NMDAR encephalitis (n=5, Project 4). / Results: In Project 1, we validated a method for kinetic modelling using an imagederived input function and serial venous samples. This approach provided unbiased estimates of ligand volume of distribution (VT) that were highly correlated (r=0.95, p<0.001) with the gold standard, an arterial input function. In Project 2, we observed increased tracer uptake related to aging in healthy individuals (VT increase of 0.6 per 10 years, p=0.04), particularly in bilateral hippocampi, temporo-parieto-occipital junctions, dorsolateral prefrontal cortex, and striata. In people with epilepsy, the age-related increase in VT (1.4 per 10 years, p=0.006) was most pronounced in the striatum and thalamus. In Project 3, we found reduced interictal ligand uptake in epilepsy that was related to longer disease duration (VT decrease of 1.6 per 10 years, p=0.004), spatially widespread and bihemispheric. Regional uptake was increased in those taking lacosamide and after anterior temporal lobe resection. In Project 4, we observed decreased ligand uptake in Anti-NMDAR encephalitis with persisting Anti-GluN1-antibodies (mean VT 6.2 in cases vs. 8.8 in healthy volunteers, p=0.02), particularly in bilateral anterior temporal and superior parietal lobes. / Conclusions: [18F]GE-179 PET is useful to detect altered NMDAR function. We observed increased NMDAR activation in aging and decreased activation in interictal epilepsy and antibody-positive Anti-NMDAR encephalitis

Amygdala dismantled: the role of amygdala subregions in epilepsy.

This scientific commentary refers to: 'Amygdala subnuclear volumes in temporal lobe epilepsy with hippocampal sclerosis and in non-lesional patients' by Ballerini et al. (https://doi.org/10.1093/braincomms/fcac225)

New-onset refractory status epilepticus due to autoimmune encephalitis after vaccination against SARS-CoV-2: First case report

BACKGROUND Vaccination against SARS-CoV-2 has been conducted frequently to limit the pandemic but may rarely be associated with postvaccinal autoimmune reactions or disorders. CASE PRESENTATION We present a 35-year-old woman who developed fever, skin rash, and headache 2 days after the second SARS-CoV-2 vaccination with BNT162b2 (Pfizer/Biontech). Eight days later, she developed behavioral changes and severe recurrent seizures that led to sedation and intubation. Cerebral magnetic resonance imaging showed swelling in the (para-) hippocampal region predominantly on the left hemisphere and bilateral subcortical subinsular FLAIR hyperintensities. Cerebrospinal fluid analysis revealed a lymphocytic pleocytosis of 7 cells/μl and normal protein and immunoglobulin parameters. Common causes of encephalitis or encephalopathy such as viral infections, autoimmune encephalitis with well-characterized autoantibodies, paraneoplastic diseases, and intoxications were ruled out. We made a diagnosis of new-onset refractory status epilepticus (NORSE) due to seronegative autoimmune encephalitis. The neurological deficits improved after combined antiepileptic therapy and immunomodulatory treatment including high-dose methylprednisolone and plasma exchange. CONCLUSIONS Although a causal relationship cannot be established, the onset of symptoms shortly after receiving the SARS-CoV-2 vaccine suggests a potential association between the vaccination and NORSE due to antibody-negative autoimmune encephalitis. After ruling out other etiologies, early immunomodulatory treatment may be considered in such cases

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization

Seizures and Epilepsy After Stroke: Epidemiology, Biomarkers and Management

Convulsions; Farmacodinàmica; ElectroencefalogramaConvulsiones; Farmacodinámica; ElectroencefalogramaSeizures; Pharmacodynamics; Electroencephalogram[Galovic M] Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. Chalfont Centre for Epilepsy, Chalfont St Peter, UK. [Ferreira-Atuesta C] Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. Chalfont Centre for Epilepsy, Chalfont St Peter, UK. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA. [Abraira L] Unitat d’Epilèpsia, Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Döhler N] Specialist Clinic for Neurorehabilitation, Kliniken Beelitz, Beelitz-Heilstätten, Germany. [Sinka L] Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. [Brigo F] Division of Neurology, “Franz Tappeiner” Hospital, Merano, ItalyOpen Access funding provided by Universität Zürich. No sources of funding were used to conduct this study or prepare this manuscript

Altered activation and connectivity of the supplementary motor cortex at motor initiation in Parkinson's disease patients with freezing

OBJECTIVE Motor initiation failure is a key feature of freezing of gait (FOG) due to Parkinson's disease (PD). The supplementary motor cortex (SMC) plays a central role in its pathophysiology. We aimed at investigating SMC activation, connectivity and plasticity with regard to motor initiation in FOG. METHODS Twelve patients with FOG and eleven without FOG underwent a multimodal electrophysiological evaluation of SMC functioning including the Bereitschaftspotential and movement-related desynchronisation of cortical beta oscillations. SMC plasticity was modulated by intermittent theta burst stimulation (iTBS) and its impact on gait initiation was assessed by a three-dimensional gait analysis. RESULTS Prior to volitional movements the Bereitschaftspotential was smaller and beta power was less strongly attenuated over the SMC in patients with FOG compared to those without. Pre-motor coherence between the SMC and the primary motor cortex in the beta frequency range was also stronger in patients with FOG. iTBS resulted in a relative deterioration of gait initiation. CONCLUSIONS Reduced activation of the SMC along with increased SMC connectivity in the beta frequency range hinder a flexible shift of the motor set as it is required for gait initiation. SIGNIFICANCE Altered SMC functioning plays an important role for motor initiation failure in PD-related FOG

Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of ASM withdrawal were focal non motor-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients