GABAergic inhibition shapes behavior and neural dynamics in human visual working memory.

Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.

The predictive value of hypometabolism in focal epilepsy: a prospective study in surgical candidates.

PURPOSE: FDG PET is an established tool in presurgical epilepsy evaluation, but it is most often used selectively in patients with discordant MRI and EEG results. Interpretation is complicated by the presence of remote or multiple areas of hypometabolism, which leads to doubt as to the true location of the seizure onset zone (SOZ) and might have implications for predicting the surgical outcome. In the current study, we determined the sensitivity and specificity of PET localization prospectively in a consecutive unselected cohort of patients with focal epilepsy undergoing in-depth presurgical evaluation. METHODS: A total of 130 patients who underwent PET imaging between 2006 and 2015 matched our inclusion criteria, and of these, 86 were operated on (72% with a favourable surgical outcome, Engel class I). Areas of focal hypometabolism were identified using statistical parametric mapping and concordance with MRI, EEG and intracranial EEG was evaluated. In the surgically treated patients, postsurgical outcome was used as the gold standard for correctness of localization (minimum follow-up 12 months). RESULTS: PET sensitivity and specificity were both 95% in 86 patients with temporal lobe epilepsy (TLE) and 80% and 95%, respectively, in 44 patients with extratemporal epilepsy (ETLE). Significant extratemporal hypometabolism was observed in 17 TLE patients (20%). Temporal hypometabolism was observed in eight ETLE patients (18%). Among the 86 surgically treated patients, 26 (30%) had hypometabolism extending beyond the SOZ. The presence of unilobar hypometabolism, included in the resection, was predictive of complete seizure control (p = 0.007), with an odds ratio of 5.4. CONCLUSION: Additional hypometabolic areas were found in one of five of this group of nonselected patients with focal epilepsy, including patients with "simple" lesional epilepsy, and this finding should prompt further in-depth evaluation of the correlation between EEG findings, semiology and PET. Hypometabolism confined to the epileptogenic zone as defined by EEG and MRI is associated with a favourable postoperative outcome in both TLE and ETLE patients.

Correlation of FDG-PET hypometabolism and SEEG epileptogenicity mapping in patients with drug-resistant focal epilepsy.

OBJECTIVE: Interictal [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) is used in the presurgical evaluation of patients with drug-resistant focal epilepsy. We aimed at clarifying its relationships with ictal high-frequency oscillations (iHFOs) shown to be a relevant marker of the seizure-onset zone. METHODS: We studied the correlation between FDG-PET and epileptogenicity maps in an unselected series of 37 successive patients having been explored with stereo-electroencephalography (SEEG). RESULTS: At the group level, we found a significant correlation between iHFOs and FDG-PET interictal hypometabolism only in cases of temporal lobe epilepsy. This correlation was found with HFOs, and the same comparison between FDG-PET and ictal SEEG power of lower frequencies during the same epochs did not show the same significance. SIGNIFICANCE: This finding suggests that interictal FDG-PET and ictal HFOs may share common underlying pathophysiologic mechanisms of ictogenesis in temporal lobe epilepsy, and combining both features may help to identify the seizure-onset zone.

Effects of aripiprazole, risperidone, and olanzapine on 5-HT1A receptors in patients with schizophrenia.

To investigate the impact of various antipsychotic drugs on the 5-HT1A serotoninergic system, we performed a [F]4-(2-methoxyphenyl)-1-[2-(N-2-pirydynyl)-p-luorobenzamido]-ethyl-piperazine PET study in 19 schizophrenic patients treated with either aripiprazole, which has a partial agonist activity at 5-HT1A receptors, or second-generation antipsychotics (SGA) (olanzapine or risperidone), which do not demonstrate such property. We used a simplified reference tissue model to generate parametric images of [F]MPPF-binding potential (BPND). A significant reduction of [F]MPPF BPND was found in treated schizophrenic patients compared to age- and sex-matched healthy subjects. These modifications were mainly localized in the frontal and orbitofrontal cortex and may reflect either the pathophysiology of schizophrenia or medication effects. The schizophrenic patients treated with aripiprazole showed a reduction of global [F]MPPF BPND compared with healthy subjects and schizophrenic patients with SGA treatment. In addition, compared with matched controls, the reduction of regional [F]MPPF BPND was more marked in the schizophrenic patients treated with aripiprazole compared with those receiving SGA treatment, possibly reflecting the partial agonist of aripiprazole activity at 5-HT1A receptors.

Positron emission tomography with α-[11C]methyl-L-tryptophan in tuberous sclerosis complex-related epilepsy.

OBJECTIVE: Tuberous sclerosis complex (TSC) is often associated with cerebral tubers and medically intractable epilepsy. We reevaluated whether increased uptake of α-[(11) C]methyl-l-tryptophan (AMT) in cerebral tubers is associated with tuber epileptogenicity. METHODS: We included 12 patients (six male, 4-53 years old) with TSC and refractory seizures who were evaluated for epilepsy surgery in our center, including video-electroencephalographic (EEG) monitoring, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI), and positron emission tomography (PET) with α-[(11) C]methyl-l-tryptophan (AMT-PET). Nine of these 12 patients also underwent intracerebral EEG recording. AMT uptake in each tuber was visually evaluated on PET coregistered with MRI. An AMT uptake index based on lesional/healthy cortex ratio was also calculated. Sensitivity and specificity values of AMT-PET in the detection of epileptogenic lesions were obtained, using the available electroclinical and neuroimaging evidence as the gold standard for epileptogenicity. RESULTS: A total of 126 tubers were identified. Two of 12 patients demonstrated a tuber with clearly increased AMT uptake, one of whom also showed a subtle increased AMT uptake in another contralateral tuber. Four other patients showed only subtle increased AMT uptake. The only two tubers with clearly increased AMT uptake proved to be epileptogenic based on intracerebral EEG data, whereas none of the tubers associated with subtle increased AMT uptake were involved at ictal onset. In a per-patient approach, this yielded a sensitivity of clearly increased AMT uptake in detecting tuber epileptogenicity of 17% (2/12 patients), whereas the per-lesion sensitivity and specificity were 12% (95% confidence interval [CI]: 3-34%) and 100% (95% CI: 97-100%), respectively. SIGNIFICANCE: AMT-PET is a specific neuroimaging technique in the identification of epileptogenic tubers in TSC. Despite its low sensitivity, the clinical usefulness of AMT-PET still deserves to be considered according to the challenging complexity of epilepsy surgery in tuberous sclerosis.

Single subanesthetic dose of ketamine produces delayed impact on brain [18F]FDG PET imaging and metabolic connectivity in rats.

Introduction: Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact. Methods: We explored the glucose metabolism with [18F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [18F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs. Results: No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline. Discussion: This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.

Deep-learning predicted PET can be subtracted from the true clinical fluorodeoxyglucose PET co-registered to MRI to identify the epileptogenic zone in focal epilepsy.

OBJECTIVE: Normal interictal [18 F]FDG-PET can be predicted from the corresponding T1w MRI with Generative Adversarial Networks (GANs). A technique we call SIPCOM (Subtraction Interictal PET Co-registered to MRI) can then be used to compare epilepsy patients' predicted and clinical PET. We assessed the ability of SIPCOM to identify the Resection Zone (RZ) in patients with drug-resistant epilepsy (DRE) with reference to visual and statistical parametric mapping (SPM) analysis. METHODS: Patients with complete presurgical work-up and subsequent SEEG and cortectomy were included. RZ localisation, the reference region, was assigned to one of eighteen anatomical brain regions. SIPCOM was implemented using healthy controls to train a GAN. To compare, the clinical PET coregistered to MRI was visually assessed by two trained readers, and a standard SPM analysis was performed. RESULTS: Twenty patients aged 17-50 (32 ± 7.8) years were included, 14 (70%) with temporal lobe epilepsy (TLE). Eight (40%) were MRI-negative. After surgery, 14 patients (70%) had a good outcome (Engel I-II). RZ localisation rate was 60% with SIPCOM vs 35% using SPM (P = 0.015) and vs 85% using visual analysis (P = 0.54). Results were similar for Engel I-II patients, the RZ localisation rate was 64% with SIPCOM vs 36% with SPM. With SIPCOM localisation was correct in 67% in MRI-positive vs 50% in MRI-negative patients, and 64% in TLE vs 43% in extra-TLE. The average number of false-positive clusters was 2.2 ± 1.3 using SIPCOM vs 2.3 ± 3.1 using SPM. All RZs localized with SPM were correctly localized with SIPCOM. In one case, PET and MRI were visually reported as negative, but both SIPCOM and SPM localized the RZ. SIGNIFICANCE: SIPCOM performed better than the reference computer-assisted method (SPM) for RZ detection in a group of operated DRE patients. SIPCOM's impact on epilepsy management needs to be prospectively validated.

Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons.

Erythropoietin receptor (EpoR) binding mediates neuroprotection by endogenous Epo or by exogenous recombinant human (rh)Epo. The level of EpoR gene expression may determine tissue responsiveness to Epo. Thus, harnessing the neuroprotective power of Epo requires an understanding of the Epo-EpoR system and its regulation. We tested the hypothesis that neuronal expression of EpoR is required to achieve optimal neuroprotection by Epo. The ventral limbic region (VLR) in the rat brain was used because we determined that its neurons express minimal EpoR under basal conditions, and they are highly sensitive to excitotoxic damage, such as occurs with pilocarpine-induced status epilepticus (Pilo-SE). We report that (i) EpoR expression is significantly elevated in nearly all VLR neurons when rats are subjected to 3 moderate hypoxic exposures, with each separated by a 4-day interval; (ii) synergistic induction of EpoR expression is achieved in the dorsal hippocampus and neocortex by the combination of hypoxia and exposure to an enriched environment, with minimal increased expression by either treatment alone; and (iii) rhEpo administered after Pilo-SE cannot rescue neurons in the VLR, unless neuronal induction of EpoR is elicited by hypoxia before Pilo-SE. This study thus demonstrates using environmental manipulations in normal rodents, the strict requirement for induction of EpoR expression in brain neurons to achieve optimal neuroprotection. Our results indicate that regulation of EpoR gene expression may facilitate the neuroprotective potential of rhEpo.

CERMEP-IDB-MRXFDG: a database of 37 normal adult human brain [18F]FDG PET, T1 and FLAIR MRI, and CT images available for research.

We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG). Thirty-nine participants underwent static [18F]FDG PET/CT and MRI, resulting in [18F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants' individual demographics (mean age 38 ± 11.5 years, range 23-65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts. The database is stored in three different formats, following the BIDS common specification: (1) DICOM (data not processed), (2) NIFTI (multimodal images coregistered to PET subject space), (3) NIFTI normalized (images normalized to MNI space). Bona fide researchers can request access to the database via a short form.

5-HT1A gene promoter polymorphism and [18F]MPPF binding potential in healthy subjects: a PET study.

BACKGROUND: Previous Positron Emission Tomography (PET) studies of 5-HT1A receptors have shown an influence of several genetic factors, including the triallelic serotonin transporter gene-linked polymorphic region on the binding potential (BPND) of these receptors. The aim of our study was to investigate the relationship between a 5-HT1A promoter polymorphism and the binding potential of another selective 5-HT1A receptor antagonist, [18F]MPPF, in healthy subjects. METHODS: Thirty-five volunteers, including 23 women, underwent an [18F]MPPF scan and were genotyped for both the C(-1019)G 5-HT1A promoter polymorphism and the triallelic serotonin transporter gene-linked polymorphic region. We used a simplified reference tissue model to generate parametric images of BPND. Whole brain Statistical Parametric Mapping and raphe nuclei region of interest analyses were performed to look for an association of [18F]MPPF BPND with the C(-1019)G 5-HT1A promoter polymorphism. RESULTS: Among the 35 subjects, 5-HT1A promoter genotypes occurred with the following frequencies: three G/G, twenty-one G/C, and eleven C/C. No difference of [18F]MPPF BPND between groups was observed, except for two women who were homozygote carriers for the G allele and showed greater binding potential compared to other age-matched women over the frontal and temporal neocortex. However, the biological relevance of this result remains uncertain due to the very small number of subjects with a G/G genotype. These findings were not modified by excluding individuals carrying the S/S genotype of the serotonin transporter gene-linked polymorphic region. CONCLUSIONS: We failed to observe an association between the C(-1019)G 5-HT1A promoter polymorphism and [18F]MPPF binding in healthy subjects. However our data suggest that the small number of women homozygote for the G allele might have greater [18F]MPPF BPND relative to other individuals. This finding should be confirmed in a larger sample.

Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer's Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P.

BACKGROUND: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders. OBJECTIVE: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages. METHODS: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15). RESULTS: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011). CONCLUSION: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.

Preclinical validation of [18F]2FNQ1P as a specific PET radiotracer of 5-HT6 receptors in rat, pig, non-human primate and human brain tissue.

INTRODUCTION: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [18F]2FNQ1P, a new PET radiotracer of 5-HT6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT6 receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target. METHODS: In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat. RESULTS: In all species, autoradiography data revealed high binding levels of [18F]2FNQ1P in cerebral regions with high 5-HT6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided KD and Bmax values of respectively 1.34 nM and 0.03 pmol·mg-1 in rat, 0.60 nM and 0.04 pmol·mg-1 in pig, 1.38 nM and 0.07 pmol·mg-1 in non-human primate, and 1.39 nM and 0.15 pmol·mg-1 in human caudate nucleus. In rat brain, the proportion of unmetabolized [18F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection). CONCLUSION: These radiopharmacological data confirm that [18F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT6 receptors and suggest that it could be used as a radiopharmaceutical in humans.

Association between triallelic polymorphism of the serotonin transporter and [18F]MPPF binding potential at 5-HT1A receptors in healthy subjects.

Previous [(11)C]WAY100-635 PET studies have demonstrated that the short (S) and long (L) alleles of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) were associated with distinct patterns of 5-HT(1A) receptor distribution in human. However, these studies reported discordant findings and did not take into account the recent description of two functional variants of the L allele (L(A)/L(G)). To further explore this issue, we investigated the triallelic functional polymorphism of the 5-HTTLPR in 38 healthy volunteers who underwent a [(18)F]MPPF PET study of 5-HT1A receptors. We used a simplified reference tissue model to generate parametric images of [(18)F]MPPF binding potential (BP(ND)), and compared these data among the different genotypes using statistical parametric mapping and region of interest of the raphe nuclei. Homozygote carriers of the S allele demonstrated greater [(18)F]MPPF BP(ND) than carriers of the L(A) allele, but this association was only found in women. Differences in [(18)F]MPPF BP(ND) between women with and without L(A) allele were observed over large clusters encompassing the right and left temporal lobes, cingulate and perisylvian regions, as well as the right precuneus and frontal dorso-lateral cortex, and the left orbitofrontal cortex. In contrast, no difference was found between groups in the raphe nuclei. The greater [(18)F]MPPF BP(ND) observed in women homozygote carriers of the S allele could either reflect a greater 5-HT1A receptor density or a lower extracellular concentration of 5-HT. Our data suggest that any future PET studies of 5-HT1A receptors should incorporate the 5-HTTLPR polymorphism status of the population studied.

Cognitive Deficits and Inflammatory Response Resulting from Mild-to-Moderate Traumatic Brain Injury in Rats Are Exacerbated by Repeated Pre-Exposure to an Innate Stress Stimulus.

Traumatic brain injury (TBI) is common in both military and civilian populations, and often results in neurobehavioral sequelae that impair quality of life in both patients and their families. Although individuals who are chronically exposed to stress are more likely to experience TBI, it is still unknown whether pre-injury stress influences the outcome after TBI. The present study tested whether behavioral and cognitive long-term outcome after TBI in rats is affected by prior exposure to an innate stress stimulus. Young adult male Sprague-Dawley rats were exposed to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) or to water (WAT); exposure was repeated eight times at irregular intervals over a 2-week period. Rats were subsequently subjected to either mild-to-moderate bilateral brain injury (lateral fluid percussion [LFP]) or sham surgery (Sham). Four experimental groups were studied: Sham-WAT, Sham-TMT, LFP-WAT and LFP-TMT. Compared with Sham-WAT rats, LFP-WAT rats exhibited transient locomotor hyperactivity without signs of anxiety, minor spatial learning acquisition and hippocampal long-term potentiation deficits, and lower baseline activity of the hypothalamic-pituitary-adrenal axis with slightly stronger reactivity to restraint stress. Exposure to TMT had only negligible effects on Sham rats, whereas it exacerbated all deficits in LFP rats except for locomotor hyperactivity. Early brain inflammatory response (8 h post-trauma) was aggravated in rats pre-exposed to TMT, suggesting that increased brain inflammation may sustain functional deficits in these rats. Hence, these data suggest that pre-exposure to stressful conditions can aggravate long-term deficits induced by TBI, leading to severe stress response deficits, possibly due to dysregulated inflammatory response.

Seizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: a [11C]flumazenil-PET study.

We have undertaken a test-re-test [11C]flumazenil (FMZ) PET study in 10 drug-resistant epileptic patients, including six with a mesiotemporal epilepsy (MTE), and 10 normal controls, in order to investigate seizure-related short-term plasticity of benzodiazepine (BZD) receptors. All subjects underwent two FMZ-PET scans at a 1 week interval. Patients benefited from a concurrent video-EEG monitoring which allowed determination of the duration of the interictal period (IP) preceding each PET. Test-re-test whole brain B'(max) variations, evaluated with a partial-saturation injection protocol, were similarly observed in patients and controls, suggesting a physiological modulation of BZD receptors. Five patients (50%), but no controls, also demonstrated clinically significant test-re-test FMZ-PET variations in the mesial temporal region. This was observed in all three patients with MTE and no hippocampal atrophy in whom only the PET study associated with the shortest IP correctly identified the epileptogenic zone. Statistical analysis revealed a significant effect of IP duration on BZD receptor B'(max) in MTE patients, suggesting that the shorter the IP, the lower the B'(max) in the epileptogenic hippocampus. FMZ-PET appears to be an interesting tool for investigating both normal and abnormal short-term modulations of the BZD receptor system, and should ideally be performed within a few days following a seizure in patients with MTE and a normal MRI.

Gamma oscillations in V1 are correlated with GABA(A) receptor density: A multi-modal MEG and Flumazenil-PET study.

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.

Accuracy of distinguishing between dysembryoplastic neuroepithelial tumors and other epileptogenic brain neoplasms with [¹¹C]methionine PET.

BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNTs) represent a prevalent cause of epileptogenic brain tumors, the natural evolution of which is much more benign than that of most gliomas. Previous studies have suggested that [(11)C]methionine positron emission tomography (MET-PET) could help to distinguish DNTs from other epileptogenic brain tumors, and hence optimize the management of patients. Here, we reassessed the diagnostic accuracy of MET-PET for the differentiation between DNT and other epileptogenic brain neoplasms in a larger population. METHODS: We conducted a retrospective study of 77 patients with focal epilepsy related to a nonrapidly progressing brain tumor on MRI who underwent MET-PET, including 52 with a definite histopathology. MET-PET data were assessed by a structured visual analysis that distinguished normal, moderately abnormal, and markedly abnormal tumor methionine uptake and by semiquantitative ratio measurements. RESULTS: Pathology showed 21 DNTs (40%), 10 gangliogliomas (19%), 19 low-grade gliomas (37%), and 2 high-grade gliomas (4%). MET-PET visual findings significantly differed among the various tumor types (P < .001), as confirmed by semiquantitative analyses (P < .001 for all calculated ratios), regardless of gadolinium enhancement on MRI. All gliomas and gangliogliomas were associated with moderately or markedly increased tumor methionine uptake, whereas 9/21 DNTs had normal methionine uptake. Receiver operating characteristics analysis of the semiquantitative ratios showed an optimal cutoff threshold that distinguished DNTs from other tumor types with 90% specificity and 89% sensitivity. CONCLUSIONS: Normal MET-PET findings in patients with an epileptogenic nonrapidly progressing brain tumor are highly suggestive of DNT, whereas a markedly increased tumor methionine uptake makes this diagnosis unlikely.

Can we increase the yield of FDG-PET in the preoperative work-up for epilepsy surgery?

PURPOSE: [(18)F] Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a semi-invasive, interictal method of localization of hypometabolic epileptic foci. FDG-PET can be useful in the clinical work-up prior to epilepsy surgery, especially in equivocal cases. We investigated whether we could increase the yield of presurgical FDG-PET in patients with difficult epilepsy requiring chronic subdural electrocorticography (ECoG). METHODS: We retrospectively studied patients with refractory focal epilepsy in whom there was uncertainty about the focus localization and who underwent FDG-PET and ECoG. Two experts (epileptologist and nuclear medicine radiologist) together systematically re-assessed the scans visually (PETRE), blinded to their initial reports. Scans were also re-analyzed by comparing them to a normal control dataset with Statistical Parametric Mapping (SPM), using a liberal (PETSPM1), and strict (PETSPM2) statistical threshold. Regions with hypometabolism and regions containing the seizure onset zone (SOZ) in ECoG were marked as positive anatomical regions (PARs). We compared the concordance of these PARs for the different PET re-assessments. We calculated the sensitivity, specificity and accuracy of the PET results for the SOZ. The added value of the re-assessments was evaluated with emphasis on scans initially reported as negative. RESULTS: 41 Patients (63% extra-temporal) were included. PETRE identified the SOZ best, with a sensitivity of 62% and specificity of 93%. PETSPM1 had a sensitivity of 62% and specificity 69%, for PETSPM2 this was 35% and 85% respectively. The overlap between PETRE vs. PETSPM1 and vs. PETSPM2 was 71% and 37%. Visual re-assessment and PETSPM1 identified the SOZ in four out of five scans that were initially reported as negative. CONCLUSIONS: Pre-surgical re-assessment of PET scans is worthwhile in epilepsy patients who undergo ECoG, especially when results were reported as negative before. Visual re-assessment itself has a higher combined specificity, sensitivity and accuracy than SPM analysis alone. SPM analysis could be used as a guide for visual (re-)assessment, because of its high sensitivity.

A phantom and animal study of temperature changes during fMRI with intracerebral depth electrodes.

BACKGROUND: MRI is routinely used in patients undergoing intracerebral electroencephalography (icEEG) in order to precisely locate the position of intracerebral electrodes. In contrast, fMRI has been considered unsafe due to suspected greater risk of radiofrequency-induced (RF) tissue heating at the vicinity of intracerebral electrodes. We determined the possible temperature change at the tip of such electrodes during fMRI sessions in phantom and animals. METHODS: A human-shaped torso phantom and MRI-compatible intracerebral electrodes approved for icEEG in humans were used to mimic a patient with four intracerebral electrodes (one parasagittal and three coronal). Six rabbits were implanted with one or two coronal electrodes. MRI-induced temperature changes at the tip of electrodes were measured using a fibre-optic thermometer. All experiments were performed on Siemens Sonata 1.5T scanner. RESULTS: For coronally implanted electrodes with wires pulled posteriorly to the magnetic bore, temperature increase recorded during EPI sequences reached a maximum of 0.6°C and 0.9°C in phantom and animals, respectively. These maximal figures were decreased to 0.2°C and 0.5°C, when electrode wires were connected to cables and amplifier. When electrode wires were pulled anteriorly to the magnetic bore, temperature increased up to 1.3°C in both phantom and animals. Greater temperature increases were recorded for the single electrode implanted parasagitally in the phantom. CONCLUSION: Variation of the temperature depends on the electrode and wire position relative to the transmit body coil and orientation of the constant magnetic field (B0). EPI sequence with intracerebral electrodes appears as safe as standard T1 and T2 sequence for implanted electrodes placed perpendicular to the z-axis of the magnetic bore, using a 1.5T MRI system, with the free-end wires moving posteriorly, in phantom and animals.

Periventricular [(11)C]flumazenil binding for predicting postoperative outcome in individual patients with temporal lobe epilepsy and hippocampal sclerosis.

A third of patients with intractable temporal lobe epilepsy and hippocampal sclerosis (HS) are not seizure free (NSF) after surgery. Increased periventricular [(11)C]flumazenil (FMZ) binding, reflecting heterotopic neuron concentration, has been described as one predictor of NSF outcome at the group level. We aimed to replicate this finding in an independent larger cohort and investigated whether NSF outcome can be predicted in individuals. Preoperative [(11)C]FMZ summed radioactivity images were available for 16 patients with HS and 41 controls. Images were analyzed using SPM8, explicitly including the white matter, and correction for global radioactivity via group-specific ANCOVA. Periventricular increases were assessed with a mask and different cutoffs for distinguishing NSF and seizure free (SF) patients. NSF patients had increased [(11)C]FMZ binding around the posterior horn of the ventricles ipsilaterally (z = 2.53) and contralaterally (z = 4.44) to the seizure focus compared with SF patients. Compared with controls, SF patients had fewer periventricular increases (two clusters, total volume 0.87 cm(3), zmax = 3.8) than NSF patients (two ipsilateral and three contralateral clusters, 6.15 cm(3), zmax = 4.8). In individuals and at optimized cutoffs, five (63%) of eight NSF patients and one (13%) of eight SF patients showed periventricular increases compared with controls (accuracy 75%). Only one (2%) of the 41 controls had increases at the same cutoff. The association between periventricular [(11)C]FMZ increases and NSF outcome after temporal lobe resection for HS has been confirmed in an independent cohort on simple summed activity images. [(11)C]FMZ-PET may be useful for individual preoperative counseling with clinically relevant accuracy.