Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study.

PURPOSE: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [11C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals. METHODS: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [11C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model. RESULTS: SV2A occupancies and VND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC50), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits. CONCLUSION: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy. CLINICAL TRIAL REGISTRATION: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.

Ictal and interictal SPECT with 99m Tc-HMPAO in presurgical epilepsy. II: Methodological considerations on hyper- and hypoperfusion.

OBJECTIVE: Single-photon emission computed tomography (SPECT) with the tracer 99m Tc-HMPAO is a method to visualize the cerebral hyperperfusion during an epileptic seizure and thus localize the epileptogenic zone and seizure propagation. Subtraction of interictal from Ictal SPECT Co-registered to MRI (SISCOM) visualizes areas with relative increases in cerebral blood flow. The purpose of this retrospective study is to explore the added value of visualizing areas of hypoperfusion as well as hyperperfusion, so-called reversed SISCOM. METHODS: Fifty-six patients operated for epilepsy who had been investigated with SISCOM were included in the analysis. The patients were divided into two groups based on seizure duration after tracer injection, above or below 30 s. The preoperative SISCOM description was compared to the area of resection and given a concordance score. The 56 SISCOM were recalculated visualizing also areas of hypoperfusion and again compared to the site of resection using the same scale of concordance. The reversed SISCOM were categorized into three subgroups: "Altered Conclusion," "Confirmed Conclusion," and "Adds Nothing." If an area of hyperperfusion had an area of hypoperfusion in close proximity, it was re-interpreted as noise, thus possibly altering the conclusion. If the areas of hypoperfusion were in the opposite hemisphere it was interpreted as confirming factor. Further the concordance scores from conventional SISCOM and reversed SISCOM was compared to surgical outcome to explore the difference in sensitivity, positive predictive value (PPV), and odds ratio. RESULTS: In approximately half of the cases reversed SISCOM added additional value, meaning either altered the conclusion or confirmed the conclusion. The sensitivity, PPV, and odds ratio was also better in the subgroup of long, >30 s seizure duration after injection, and got worse in the group with short, <30 s seizure duration after injection. SIGNIFICANCE: Adding reversed SISCOM performed better than conventional SISCOM at predicting good surgical outcome.

Text mining of electronic health records can validate a register-based diagnosis of epilepsy and subgroup into focal and generalized epilepsy.

OBJECTIVE: Combining population-based health registries and electronic health records offers the opportunity to create large, phenotypically detailed patient cohorts of high quality. In this study, we used text mining of clinical notes to confirm International Classification of Diseases, 10th Revision (ICD-10)-registered epilepsy diagnoses and classify patients according to focal and generalized epilepsy types. METHODS: Using the Danish National Patient Registry, we identified patients who between 2006 and 2016 received an ICD-10 diagnosis of epilepsy. To validate the epilepsy diagnosis and stratify patients into focal and generalized epilepsy types, we constructed dictionaries for text mining-based extraction of clinical notes. Two physicians manually reviewed the clinical notes for a total of 527 patients and assigned epilepsy diagnoses, which were compared with the text-mined diagnoses. RESULTS: We identified 23 632 patients with an ICD-10 diagnosis of epilepsy, of whom 50% were registered with an unspecified epilepsy diagnosis. In total, 11 211 patients were considered likely to have epilepsy by text mining, with an F1 measure ranging from 82% to 90%. Manual review of the electronic health records for 310 patients revealed a false discovery rate of 29%. This rate was decreased to 4% by the text mining algorithm. The weighted average F1 measure for text mining-assigned epilepsy types was 79% (82% for focal and 76% for generalized epilepsy). Text mining successfully assigned a focal or generalized epilepsy type to 92% of the text mining-eligible patients registered with unspecified epilepsy. SIGNIFICANCE: Text mining of electronic health records can be used to establish a patient cohort with much higher likelihood of having a diagnosis of epilepsy and a focal or generalized epilepsy type compared to the cohort created from ICD-10 epilepsy codes alone. We believe the concept will be essential for future genome-wide and phenome-wide association studies and subsequently the development of precision medicine for epilepsy patients.

Ictal and interictal SPECT with 99m Tc-HMPAO in presurgical epilepsy. I: Predictive value and methodological considerations.

OBJECTIVE: This retrospective study investigates the predictive value of ictal subtraction single-photon emission computed tomography (SPECT) co-registered to magnetic resonance imaging (MRI) (SISCOM) for successful epilepsy surgery. METHODS: 57 patients examined with SISCOM as a part of epilepsy surgery evaluation were divided into two groups based on seizure duration after tracer injection (group 1: Seizure duration above or equal to 30 s, group 2: Seizure duration under 30 s). SISCOM was compared to the surgical site and categorized as good or poor concordance. Subsequently, Odds ratios (ORs) and positive predictive values (PPVs) were calculated for each group for good surgical outcome, freedom from disabling seizures. RESULTS: The PPVs and ORs for good surgical outcome was 74.1% and 5.71 for group 1 and 40% and 0.22 for group 2. SISCOM had a similar positive predictive value regardless of whether the focus was in the same or neighboring lobe, but same hemisphere as the resection. CONCLUSION: In conclusion, the implementation of a precise definition for a well-executed ictal SPECT scan with respect to seizure duration after injection enhances the positive predictive value (PPV) and odds ratio (OR) for successful surgical outcome, surpassing previous findings, whether the focus in resected lobe or the neighboring.

Differential Expression of the ß3 Subunit of Voltage-Gated Ca2+ Channel in Mesial Temporal Lobe Epilepsy.

The purpose of this study was to identify and validate new putative lead drug targets in drug-resistant mesial temporal lobe epilepsy (mTLE) starting from differentially expressed genes (DEGs) previously identified in mTLE in humans by transcriptome analysis. We identified consensus DEGs among two independent mTLE transcriptome datasets and assigned them status as "lead target" if they (1) were involved in neuronal excitability, (2) were new in mTLE, and (3) were druggable. For this, we created a consensus DEG network in STRING and annotated it with information from the DISEASES database and the Target Central Resource Database (TCRD). Next, we attempted to validate lead targets using qPCR, immunohistochemistry, and Western blot on hippocampal and temporal lobe neocortical tissue from mTLE patients and non-epilepsy controls, respectively. Here we created a robust, unbiased list of 113 consensus DEGs starting from two lists of 3040 and 5523 mTLE significant DEGs, respectively, and identified five lead targets. Next, we showed that CACNB3, a voltage-gated Ca2+ channel subunit, was significantly regulated in mTLE at both mRNA and protein level. Considering the key role of Ca2+ currents in regulating neuronal excitability, this suggested a role for CACNB3 in seizure generation. This is the first time changes in CACNB3 expression have been associated with drug-resistant epilepsy in humans, and since efficient therapeutic strategies for the treatment of drug-resistant mTLE are lacking, our finding might represent a step toward designing such new treatment strategies.

Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort.

BACKGROUND: Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. METHODS: All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. DISCUSSION: The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. TRIAL REGISTRATION: Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABAA receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach.

Divergent Cellular Energetics, Glutamate Metabolism, and Mitochondrial Function Between Human and Mouse Cerebral Cortex.

Disruptions of brain energy and neurotransmitter metabolism are associated with several pathological conditions including neurodegenerative diseases such as Alzheimer's disease. Transgenic rodent models, and in vitro preparations hereof, are often applied for studying pathological aspects of brain metabolism. However, despite the conserved cerebral development across mammalian species, distinct differences in cellular composition and structure may influence metabolism of the rodent and human brain. To address this, we investigated the metabolic function of acutely isolated brain slices and non-synaptic mitochondria obtained from the cerebral cortex of mice and neurosurgically resected neocortical tissue of humans. Utilizing dynamic isotope labeling with 13C-enriched metabolic substrates, we show that metabolism of glucose, acetate, ß-hydroxybutyrate, and glutamine operates at lower rates in human cerebral cortical slices when compared to mouse slices. In contrast, human cerebral cortical slices display a higher capacity for converting exogenous glutamate into glutamine, which subsequently supports neuronal GABA synthesis, whereas mouse slices primarily convert glutamate into aspartate. In line with the reduced metabolic rate of the human brain slices, isolated non-synaptic mitochondria of the human cerebral cortex have a lower oxygen consumption rate when provided succinate as substrate. However, when provided pyruvate and malate, human mitochondria display a higher coupled respiration and lower proton leak, signifying a more efficient mitochondrial coupling compared to mouse mitochondria. This study reveals key differences between mouse and human brain metabolism concerning both neurons and astrocytes, which must be taken into account when applying in vitro rodent preparations as a model system of the human brain.

Accuracy of high-density EEG electrode position measurement using an optical scanner compared with the photogrammetry method.

Objective: To determine the feasibility and accuracy of a handheld optical scanner to measure the three-dimensional (3D) EEG electrode coordinates in a high-density array of 256 electrodes. Methods: We compared the optical scanning with a previously validated method, based on photogrammetry. Electrode coordinates were co-registered with the MRI of the patients, and mean distance error relative to the three-dimensional MRI reconstruction was determined for each patient. We included 60 patients: 30 were measured using the photogrammetry method, and 30 age and gender matched patients were measured with the optical scanner. Results: Using the optical scanner, the mean distance error was 1.78 mm (95% confidence interval: 1.59-1.98 mm) which was significantly lower (p < 0.001) compared with the photogrammetry method (mean distance error: 2.43 mm; 95% confidence interval: 2.28-2.57 mm). The real-time scanning took 5-10 min per patient. Conclusions: The handheld optical scanner is more accurate and feasible, compared to the photogrammetry method. Significance: Measuring EEG electrode positions in high-density array, using the optical scanner is suitable for clinical implementation in EEG source imaging for presurgical evaluation.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: EEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. METHODS: We have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. RESULTS: We analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66-85.37%). CONCLUSIONS: Automated ictal ESI has a high accuracy for localizing the seizure onset zone. SIGNIFICANCE: Automating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease.

The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important nitrogen donors for synthesis of glutamate, the main excitatory neurotransmitter in the brain. The glutamate carbon skeleton originates from the tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate, while the amino group is derived from nitrogen donors such as the BCAAs. Disturbances in neurotransmitter homeostasis, mainly of glutamate, are strongly implicated in the pathophysiology of Alzheimer's disease (AD). The divergent BCAA metabolism in different cell types of the human brain is poorly understood, and so is the involvement of astrocytic and neuronal BCAA metabolism in AD. The goal of this study is to provide the first functional characterization of BCAA metabolism in human brain tissue and to investigate BCAA metabolism in AD pathophysiology using astrocytes and neurons derived from human-induced pluripotent stem cells (hiPSCs). Mapping of BCAA metabolism was performed using mass spectrometry and enriched [15N] and [13C] isotopes of leucine, isoleucine, and valine in acutely isolated slices of surgically resected cerebral cortical tissue from human brain and in hiPSC-derived brain cells carrying mutations in either amyloid precursor protein (APP) or presenilin-1 (PSEN-1). We revealed that both human astrocytes of acutely isolated cerebral cortical slices and hiPSC-derived astrocytes were capable of oxidatively metabolizing the carbon skeleton of BCAAs, particularly to support glutamine synthesis. Interestingly, hiPSC-derived astrocytes with APP and PSEN-1 mutations exhibited decreased amino acid synthesis of glutamate, glutamine, and aspartate derived from leucine metabolism. These results clearly demonstrate that there is an active BCAA metabolism in human astrocytes, and that leucine metabolism is selectively impaired in astrocytes derived from the hiPSC models of AD. This impairment in astrocytic BCAA metabolism may contribute to neurotransmitter and energetic imbalances in the AD brain.

A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABAA receptors.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. For decades, several in vivo and ex vivo techniques have been used to highlight the mechanisms of the GABA system, however, no studies have currently combined the techniques to create a high-resolution multimodal view of the GABA system. Here, we present a quantitative high-resolution in vivo atlas of the human brain benzodiazepine receptor sites (BZR) located on postsynaptic ionotropic GABAA receptors (GABAARs), generated on the basis of in vivo [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on ex vivo autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association between BZR protein density and ex vivo mRNA expression for the 19 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein. This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAAR and the BZR density at each location in the brain.

7T Epilepsy Task Force Consensus Recommendations on the Use of 7T MRI in Clinical Practice.

Identifying a structural brain lesion on MRI has important implications in epilepsy and is the most important factor that correlates with seizure freedom after surgery in patients with drug-resistant focal onset epilepsy. However, at conventional magnetic field strengths (1.5 and 3T), only approximately 60%-85% of MRI examinations reveal such lesions. Over the last decade, studies have demonstrated the added value of 7T MRI in patients with and without known epileptogenic lesions from 1.5 and/or 3T. However, translation of 7T MRI to clinical practice is still challenging, particularly in centers new to 7T, and there is a need for practical recommendations on targeted use of 7T MRI in the clinical management of patients with epilepsy. The 7T Epilepsy Task Force-an international group representing 21 7T MRI centers with experience from scanning over 2,000 patients with epilepsy-would hereby like to share its experience with the neurology community regarding the appropriate clinical indications, patient selection and preparation, acquisition protocols and setup, technical challenges, and radiologic guidelines for 7T MRI in patients with epilepsy. This article mainly addresses structural imaging; in addition, it presents multiple nonstructural MRI techniques that benefit from 7T and hold promise as future directions in epilepsy. Answering to the increased availability of 7T MRI as an approved tool for diagnostic purposes, this article aims to provide guidance on clinical 7T MRI epilepsy management by giving recommendations on referral, suitable 7T MRI protocols, and image interpretation.

Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19869-5.

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.

Distinct effects on cAMP signaling of carbamazepine and its structural derivatives do not correlate with their clinical efficacy in epilepsy.

The antiepileptic sodium channel blocker, carbamazepine, has long been known to be able to attenuate cAMP signals. This could be of clinical importance since cAMP signaling has been shown to be involved in epileptogenesis and seizures. However, no information on the ability to affect cAMP signaling is available for the marketed structural derivatives, oxcarbazepine and eslicarbazepine acetate or their dominating metabolite, licarbazepine. Thus, we employed a HEK293 cell line stably expressing a cAMP biosensor to assess the effect of these two drugs on cAMP accumulation. We find that oxcarbazepine does not affect cAMP accumulation whereas eslicarbazepine acetate, surprisingly, is able to enhance cAMP accumulation. Since the transcription of ADCY8 (adenylyl cyclase isoform 8; AC8) has been found to be elevated in epileptic tissue from patients, we subsequently expressed AC8 in the HEK293 cells. In the AC8-expressing cells, oxcarbazepine was now able to attenuate whereas eslicarbazepine maintained its ability to increase cAMP accumulation. However, at all concentrations tested, licarbazepine demonstrated no effect on cAMP accumulation. Thus, we conclude that the effects exerted by carbamazepine and its derivatives on cAMP accumulation do not correlate with their clinical efficacy in epilepsy. However, this does not disqualify cAMP signaling per se as a potential disease-modifying drug target for epilepsy since more potent and selective inhibitors may be of therapeutic value.

Striatal Volume Increase After Six Weeks of Selective Dopamine D2/3 Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients.

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D2/3 receptor (D2/3R) blockade. Separating the effects of disease from medication is challenging due to the lack of a proper placebo-group. To address this, we conducted a longitudinal study of antipsychotic-naïve, first-episode schizophrenia patients to test the hypothesis that selective blockade of D2/3R would induce a dose-dependent striatal volume increase. Twenty-one patients underwent structural magnetic resonance imaging (sMRI), single-photon emission computed tomography (SPECT), and symptom severity ratings before and after six weeks of amisulpride treatment. Twenty-three matched healthy controls underwent sMRI and baseline SPECT. Data were analyzed using repeated measures and multiple regression analyses. Correlations between symptom severity decrease, volume changes, dose and receptor occupancy were explored. Striatal volumes did not differ between patients and controls at baseline or follow-up, but a significant group-by-time interaction was found (p = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens d = 0.45). Striatal increase was predicted by amisulpride dose, but not by either D2/3R occupancy or baseline symptom severity. A significant reduction in symptom severity was observed at a mean dose of 233.3 (SD = 109.9) mg, corresponding to D2/3R occupancy of 44.65%. Reduction in positive symptoms correlated significantly with striatal volume increase, driven by reductions in hallucinations. Our data demonstrate a clear link between antipsychotic treatment and striatal volume increase in antipsychotic-naïve schizophrenia patients. Moreover, the treatment-induced striatal volume increase appears clinically relevant by correlating to reductions in core symptoms of schizophrenia.

Extensive astrocyte metabolism of γ-aminobutyric acid (GABA) sustains glutamine synthesis in the mammalian cerebral cortex.

Synaptic transmission is closely linked to brain energy and neurotransmitter metabolism. However, the extent of brain metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and the relative metabolic contributions of neurons and astrocytes, are yet unknown. The present study was designed to investigate the functional significance of brain GABA metabolism using isolated mouse cerebral cortical slices and slices of neurosurgically resected neocortical human tissue of the temporal lobe. By using dynamic isotope labeling, with [15 N]GABA and [U-13 C]GABA as metabolic substrates, we show that both mouse and human brain slices exhibit a large capacity for GABA metabolism. Both the nitrogen and the carbon backbone of GABA strongly support glutamine synthesis, particularly in the human cerebral cortex, indicative of active astrocytic GABA metabolism. This was further substantiated by pharmacological inhibition of the primary astrocytic GABA transporter subtype 3 (GAT3), by (S)-SNAP-5114 or 1-benzyl-5-chloro-2,3-dihydro-1H-indole-2,3-dione (compound 34), leading to significant reductions in oxidative GABA carbon metabolism. Interestingly, this was not the case when tiagabine was used to specifically inhibit GAT1, which is predominantly found on neurons. Finally, we show that acute GABA exposure does not directly stimulate glycolytic activity nor oxidative metabolism in cultured astrocytes, but can be used as an additional substrate to enhance uncoupled respiration. These results clearly show that GABA is actively metabolized in astrocytes, particularly for the synthesis of glutamine, and challenge the current view that synaptic GABA homeostasis is maintained primarily by presynaptic recycling.

Diagnostic added value of electrical source imaging in presurgical evaluation of patients with epilepsy: A prospective study.

OBJECTIVE: To investigate the diagnostic added value of electrical source imaging (ESI) in presurgical evaluation of patients with drug resistant focal epilepsy. METHODS: Eighty-two consecutive patients were included. We analyzed both low density (LD) and high density (HD) EEG recordings. LD ESI was done on interictal and ictal signals recorded during long-term video-EEG monitoring (LTM), with standard 25 electrodes and age-matched template head models. HD ESI was done on shorter recordings (90-120 min), with 256 electrodes, using individual head model. The multidisciplinary team made decisions first blinded to ESI (based on all other modalities) and then discussed the results of the ESI. We considered that ESI had diagnostic added value, when it provided non-redundant information that changed the patients management plan. RESULTS: ESI had diagnostic added value in 28 patients (34%). In most cases (85.7%), these changes were related to planning of the invasive recordings. In nine out of 13 patients, invasive recordings confirmed the localization. Out of eight patients in whom the ESI source was resected, six became seizure-free. CONCLUSIONS: ESI provides non-redundant information in one third of the patients undergoing presurgical evaluation. SIGNIFICANCE: This study provides evidence for the diagnostic added value of ESI in presurgical evaluation.

Aspects of cAMP Signaling in Epileptogenesis and Seizures and Its Potential as Drug Target.

Epilepsy is one of the most common chronic neurological conditions. Today, close to 30 different medications to prevent epileptic seizures are in use; yet, far from all patients become seizure free upon medical treatment. Thus, there is a need for new pharmacological approaches including novel drug targets for the management of epilepsy. Despite the fact that a role for cAMP signaling in epileptogenesis and seizures was first suggested some four decades ago, none of the current medications target the cAMP signaling system. The reasons for this are probably many including limited knowledge of the underlying biology and pathology as well as difficulties in designing selective drugs for the different components of the cAMP signaling system. This review explores selected aspects of cAMP signaling in the context of epileptogenesis and seizures including cAMP response element binding (CREB)-mediated transcriptional regulation. We discuss the therapeutic potential of targeting cAMP signaling in epilepsy and point to an increased knowledge of the A-kinase anchoring protein-based signaling hubs as being of seminal importance for future drug discovery within the field. Further, in terms of targeting CREB, we argue that targeting upstream cAMP signals might be more fruitful than targeting CREB itself. Finally, we point to astrocytes as cellular targets in epilepsy since cAMP signals may regulate astrocytic K+ clearance affecting neuronal excitability.