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Oxytocin (OT), a neuropeptide involved in affiliation has been shown to enhance social skills in patients with autism spectrum disorders (ASD). Nevertheless, OT improvements seem ephemeral. Animal research has demonstrated OT action on serotonin (5-HT), an interaction that we also found in the healthy human brain. Whether such synaptic interplay also occurs in ASD patients is unknown. To address this issue, we mapped the effects of intranasal OT on 5-HT in 18 patients with ASD and 24 healthy controls (HC) in a double blind, placebo controlled, within subject PET-scan experiment. Each participant underwent two scans: baseline and spray (OT or placebo). Using the radiotracer [18 F]MPPF, marking the 5-HT 1A receptor (5-HT1AR), we measured MPPF-Binding Potential (BP) as an index of OT-induced serotonin functional modulation. At baseline ASD patients did not differ from controls for 5-HT1AR concentration and distribution. However, while OT significantly increased MPPF BP in several brain regions of HC, no changes were observed in the ASD group. Serotonin serum concentration analysis corroborated these results. Our findings suggest a disturbed OT-serotonin interaction in autism. This may limit the potential benefits of OT in these patients and open the ways to investigate combined OT-serotonin treatments.

Although structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, the differences in the processing of child sexual stimuli between men attracted to children and those attracted to adults remain unclear. Here, our purpose was to identify through positron emission tomography the brain responses of 15 male outpatients with pedophilic disorder to validated visual sexual stimuli depicting children (VSSc) and to compare them with 15 male healthy controls matched for sexual orientation (to female or male adults), age, and handedness. The patients' sample comprised both offenders and non-offenders. In response to VSSc, the between-groups analysis showed that activation in the right inferior temporal cortex [Brodmann area (BA) 20] was lower in patients than in controls. Moreover, in patients but not in controls, the presentation of VSSc induced an activation in a more caudal region of the right inferior temporal gyrus (BA 37) and in the left middle occipital gyrus (BA 19). In addition, in patients the level of activation in the caudal right inferior temporal gyrus was positively correlated with ratings of sexual arousal elicited by VSSc, whereas this correlation was negative in BA 20. These results implicate the right inferior temporal gyrus as a possible candidate area mediating sexual arousal in patients with pedophilic disorder and suggest that two of its areas play opposite, i.e., activating and inhibitory, roles., Highlights • Images of children activate the pedophilic patients' right Brodmann area (BA) 37. • Images of children (IC) activate the pedophilic patients' left BA 19. • Right BA37 activation correlates with pedophilic patients' rating of sexual arousal. • IC induce lower right BA 20 activation in pedophilic patients than in controls.

Purpose The opioid system role in anorexia nervosa (AN) pathophysiology is still unclear since conflicting results were reported on peripheral and cerebrospinal fluid opioids levels. The study main aim was to evaluate cerebral AN opiate receptor availability by using [11C] diprenorphine, a ligand with non-selective binding. Methods In vivo [11C]diprenorphine cerebral non-displaceable binding potential (BPND) evaluated by PET imaging was compared between three groups : 17 undernourished restrictive-type AN patients (LeanAN), 15 AN patients having regained normal weight (RecAN) and 15 controls. A lower BPND may account for an increased opioid tone and vice versa. Serum hormones and endogenous opioids levels, eating-related and unspecific psychological traits were also evaluated. Results Compared to controls, LeanAN and RecAN patients had decreased [11C]diprenorphine BPND in middle frontal gyrus, temporo-parietal cortices, anterior cingulate cortex and in left accumbens nucleus. Hypothalamo-pituitary (H-P), left amygdala and insula BPND was found decreased only in LeanAN and that of putamen only in RecAN. LeanAN presented higher dynorphin A and enkephalin serum levels than in controls or RecAN. Inverse correlations were found in total group between : 24 h mean serum cortisol levels and anterior cingulate gyrus or insula BPND; eating concern score and left amygdala BPND. Positive correlation were found between leptin and hypothamus BPND; LH and pituitary BPND. Conclusions Low opiate receptor availability may be interpreted as an increased opioid tone in areas associated with both reward/aversive system in both AN groups. The relationship between the opioid receptors activity and hypercorticism or specific psychometric scores in some of these regions suggests adaptive mechanisms facing anxiety but also may play a role in the disease perpetuation.

OBJECTIVE Chronic kidney disease is associated with higher morbidity and mortality in patients with diabetes. A low-protein diet is recommended to slow diabetic nephropathy progression because each protein load leads to renal hemodynamic variations. The aim of our study was to evaluate whether the advanced glycation end products (AGE) content of a protein load is responsible for the protein-induced renal hemodynamic variations in humans. RESEARCH DESIGN AND METHODS Ten healthy subjects were assigned to a high-protein (1 g/kg) low-AGE (3,000 kU AGE) versus high-AGE (30,000 kU AGE) meal. Renal perfusion, oxygen consumption, and oxygen content were measured before and 120 min after each meal. RESULTS Renal perfusion (3.2 ± 0.5 vs. 3.8 ± 0.4 mL/min/g; P = 0.0002) and oxygen consumption (0.3 ± 0.04 vs. 0.4 ± 0.08 min−1; P = 0.005) increased significantly after the high-AGE meal compared with the low-AGE meal. CONCLUSIONS Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content.

A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.

Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. We asked whether these chemical messengers interact in the regulation of emotion-based behavior by administering OXT or placebo to 24 healthy subjects and mapping cerebral 5-HT system by using 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), an antagonist of 5-HT1A receptors. OXT increased [(18)F]MPPF nondisplaceable binding potential (BPND) in the dorsal raphe nucleus (DRN), the core area of 5-HT synthesis, and in the amygdala/hippocampal complex, insula, and orbitofrontal cortex. Importantly, the amygdala appears central in the regulation of 5-HT by OXT: [(18)F]MPPF BPND changes in the DRN correlated with changes in right amygdala, which were in turn correlated with changes in hippocampus, insula, subgenual, and orbitofrontal cortex, a circuit implicated in the control of stress, mood, and social behaviors. OXT administration is known to inhibit amygdala activity and results in a decrease of anxiety, whereas high amygdala activity and 5-HT dysregulation have been associated with increased anxiety. The present study reveals a previously unidentified form of interaction between these two systems in the human brain, i.e., the role of OXT in the inhibitory regulation of 5-HT signaling, which could lead to novel therapeutic strategies for mental disorders.

Summary Objective Tuberous sclerosis complex (TSC) is often associated with cerebral tubers and medically intractable epilepsy. We reevaluated whether increased uptake of α-[11C]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-[11C]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.

See Schrag and Politis (doi:[10.1093/aww190][1]) for a scientific commentary on this article . Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinson’s disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinson’s disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ −21) and 15 non-apathetic (−36 ≤ Lille Apathy Rating Scale scores ≤ −22) drug-naive de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [11C- N -(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] ( n = 29) and serotonergic [11C- N , N -dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] ( n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression ( P = 0.0004) and anxiety ( P = 0.004) scores – as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively – compared to the non-apathetic ones – who were not different from the age-matched healthy subjects ( n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation ( n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation ( n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic ( n = 15) and serotonergic ( n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra–ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinson’s disease. * Abbreviations : ACC : anterior cingulate cortex BDI : Beck Depression Inventory BPND : non-displaceable binding potential DASB : N , N -dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine DAT : dopaminergic transporter GPe : globus pallidus pars externa or external pallidum LARS : Lille Apathy Rating Scale MDS-UPDRS : Movement Disorders Society Unified Parkinson’s Disease Rating Scale OFC : orbitofrontal cortex PE2I : N -(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane SERT : serotonergic transporter SN-VTA : substantia nigra–ventral tegmental area STAI-YB : State-Trait Anxiety Inventory part B [1]: /lookup/doi/10.1093/brain/aww190

International audience; PURPOSE: Gastro-entero-pancreatic (GEP) endocrine tumours are a heterogenous group of tumours of variable localization and prognosis. It has been suggested that positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) may have a prognostic value and help to identify patients at risk of progression. [18F]fluoro-3'-deoxy-3'-L-fluorothymidine (18F-FLT) has been recently developed as a PET proliferation tracer. At present, there are no studies investigating its role in GEP. The aim of this prospective study was to assess the value of 18F-FLT-PET for the evaluation of GEP. MATERIALS AND METHODS: Ten patients with biopsy-proven locally advanced or metastasized, well-differentiated GEP neuroendocrine tumours were prospectively enrolled and scheduled for 18F-FDG and 18F-FLT-PET. Images were compared with other conventional diagnostic procedures, namely computed tomography, ultrasound, somatostatin receptor scintigraphy and with clinical and diagnostic follow-up. RESULTS: Evaluation criteria were interpreted in terms of assumed presence of tumoral tissue. According to the patient's status, FDG was positive in five out of the seven patients with stable disease and in two out of the three patients with progressive disease. No positive case was identified by 18F-FLT in either the primary or the metastatic tumour site, whatever the status of patients, and this was probably a reflection of the slow proliferation rate of tumours. CONCLUSION: These preliminary data suggest that 18F-FLT-PET is not a suitable tracer for the evaluation of advanced well-differentiated GEP tumours. FDG showed good diagnostic performance but does not help to identify patients at risk of progression.

This study aimed to characterize the neural networks involved in patients with chronic low-back pain during hypnoanalgesia. PET was performed in 2 states of consciousness, normal alertness and hypnosis. Two groups of patients received direct or indirect analgesic suggestion. The normal alertness state showed activations in a cognitive-sensory pain modulation network, including frontotemporal cortex, insula, somatosensory cortex, and cerebellum. The hypnotic state activated an emotional pain modulation network, including frontotemporal cortex, insula, caudate, accumbens, lenticular nuclei, and anterior cingulate cortex (ACC). Direct suggestion activated cognitive processes via frontal, prefrontal, and orbitofrontal cortices, while indirect suggestion activated a widespread and more emotional network including frontal cortex, anterior insula, inferior parietal lobule, lenticular nucleus, and ACC. Confirmed by visual analog scale data, these results suggest that chronic pain modulation is greater with hypnosis, which enhances both activated networks.

Background— Despite the major role attributed to myocardial vagal activity in left ventricular arrhythmogenesis in chronic myocardial infarction, the impact of infarction on left ventricular muscarinic receptor density remains unknown. Methods and Results— Left ventricular muscarinic receptor density was measured in vivo by positron emission tomography using the specific antagonist [ 11 C]methylquinuclidinyl benzilate ([ 11 C]MQNB) in 11 patients 43�20 days after myocardial infarction and 9 healthy volunteers. The extent of myocardial damage was quantified by delayed contrast-enhanced MRI. Three short-axis slices from each subject were analyzed in matched positron emission tomography and MRI images. A 2-injection positron emission tomography protocol was used; [ 11 C]MQNB time-activity curves were obtained in 6 regions per slice and fitted to a 3-compartment ligand-receptor model. Four classes of myocardial regions were considered: normal (in volunteers); remote, supplied by healthy or 70% diameter reduction arteries and without signs of damage; and damaged, with damage. The muscarinic receptor density in remote (67�30 pmol/mL tissue; n=86) and potentially damaged (71�30 pmol/mL tissue; n=42) regions of patients was higher than in normal regions of volunteers (32�17 pmol/mL tissue; n=156; P P P =0.093). Conclusions— Vagal control in patients with chronic myocardial infarction involves muscarinic receptor upregulation in remote nondamaged left ventricular regions. Our results suggest that the receptor density remains within normal values in myocardial regions containing damaged tissue.

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.

The aim of this study was to assess the reliability of 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF) PET binding parameter9s quantification via a test–retest study over a long-term period. Methods: Ten healthy volunteers underwent 2 dynamic 18F-MPPF PET scans in an interval of 6 mo. As a methodologic control, 10 simulated datasets, including interindividual functional and anatomic variabilities, were also used to assess the measurement variations in the absence of intraindividual variability. Indices of tracer binding were computed using 2 different models: (a) the simplified reference tissue model (SRTM) and (b) the Logan graphical model. The SRTM allows computing the binding potential (BP) index and plasma-to-brain transport constants (R1, k2). The Logan model evaluates the distribution volume (DV). For both methods, cerebellum was taken as the reference region. From both models, binding indices were calculated with time–activity curves extracted from regions of interest, on one hand, and for each voxel to perform parametric images on the other hand. Results: Reliability indices—that is, bias, variability, and intraclass correlation (ICC)—indicated a good reproducibility: the BP percentage change in mean between test and retest is close to 1% in rich regions and 2% in poor regions. The typical error is around 7%. Mean ICC is over 0.70. The DV percentage change in the mean is ±2.5%, with a typical error close to 6% and an ICC over 0.60. Conclusion: Our results show a good reliability, with a reasonable level of intraindividual biologic variability that allows crossover studies with 18F-MPPF in which small percentage changes are expected between test and retest measurements, in group studies and for single subject assessment.

Experimental data in animals show that 5-HT(1A) receptors are predominantly located in limbic areas and suggest that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In this PET study, we used an antagonist of the 5-HT(1A) receptor, [(18)F]MPPF, to assess the extent of 5-HT(1A) receptor binding changes in a group of seven temporal lobe epilepsy (TLE) patients with hippocampal ictal onset demonstrated by intracerebral EEG recording. On the basis of MRI-measured hippocampal volumes (HV), patients were classified into "normal HV" or "hippocampal atrophy" (HA). Voxel-based analyses (SPM99) were performed to objectively assess the differences in [(18)F]MPPF binding potential (BP) between patients (taken as a group or as individuals) and a database of 48 controls subjects. In the full group of patients, a significant decreased BP was detected ipsilateral to the epileptogenic zone in the hippocampus, temporal pole, insula, and temporal neocortex. This result was confirmed in the subgroup of patients with HA. In patients with normal HV, the BP decrease was restricted to the temporal pole. TLE patients also demonstrated an increased BP in various regions contralateral to the epileptogenic zone. These data suggest that in TLE patients with hippocampal seizure onset, the decrease in 5-HT(1A) receptor binding partly reflects hippocampal neuronal loss, but is also observed in various regions involved in temporo-limbic epileptogenic networks that appeared normal on MRI. Further studies are warranted to evaluate the clinical usefulness of [(18)F]MPPF-PET as compared to other established PET tracers in drug resistant TLE.

The aim of our study was to assess abnormalities in 5-hydroxytryptamine-1A (5-HT1A) receptor density in patients suffering from refractory temporal lobe epilepsy (TLE). Experimental data in animals show that 5-HT1A receptors are predominantly located in limbic areas, and that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In TLE patients, we quantified 5-HT1A receptor density in epileptogenic and non-epileptogenic areas, as defined by intracranial recordings with stereo-electroencephalography (SEEG). Nine TLE patients and 53 control subjects were studied by PET using a 5-HT1A receptor antagonist ([18F]MPPF). Anatomical regions of interest (ROIs) were drawn on patient and control MRIs co-registered with PET. PET data were quantified using a simplified model to assess binding potential (BP) values in each ROI, with cerebellum as reference. For each patient, a normalized percentage BP change was calculated as the relative variation of BP in each ROI compared with the corresponding ROI in control subjects. In patients, ROIs explored by SEEG were categorized according to their degree of epileptic activity (ictal onset, ictal spreading, interictal spikes, no epileptic activity) and according to their lesional aspect and volume (lesional with volume loss, lesional without volume loss, non-lesional). Compared with control values, the binding to 5-HT1A receptors in TLE patients was decreased in the epileptogenic temporal lobe. BP decrease was significantly greater in: (i) regions involved in the seizure onset than regions where only interictal paroxysms or no epileptic activity was recorded; and (ii) regions where the discharge propagated than regions where only interictal paroxysms or no epileptic activity was recorded. BP decrease was shown to be significantly influenced by the existence of a lesion on MRI. However, in the group of ROIs with normal quantitative and qualitative MRI aspect, BP decrease remained strongly correlated to the degree of epileptic activity. This study shows that in vivo availability of 5-HT1A receptors is decreased in epileptic patients compared with normal subjects. This decrease is highly correlated to the degree of epileptogenicity of cortical areas explored by intracerebral recordings, and does not reflect only pathological changes or neuronal loss in the epileptic focus.

The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2' -methoxyphenyl)-1-[2' -(N-2“-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.

International audience; 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 [11C]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.

Vagal innervation modulates the electrical stability of the left ventricle (LV) during ischemia. Thus, abnormal parasympathetic activity in myocardial infarction (MI) patients with primary ventricular fibrillation (FV) can account for their arrhythmic disorders. We evaluated LV muscarinic receptor density (B max) after MI in patients with (FVG, n = 11) or without (nFVG, n = 12) primary FV. The B max was measured by positron emission tomography and the specific antagonist [11C]methylquinuclidinyl benzilate ([11C]MQNB) in 23 patients 39 ± 19 days post-MI, and 10 volunteers. Myocardial damage was quantified by delayed contrast-enhanced magnetic resonance imaging. Three short-axis slices per subject were analyzed and six time-activity curves per slice were fitted to a 3-compartment ligand-receptor model. The B max in remote regions of the 23 patients (67 ± 36 pmol/mL · tissue; n = 139) was higher than in normal regions of volunteers (33 ± 16 pmol/mL · tissue; n = 171; P = .01). Receptor density in remote regions was similarly upregulated in nFVG (69 ± 31 pmol/mL · tissue, n = 73) and FVG (66 ± 40 pmol/mL · tissue, n = 66; P = .72). In damaged regions, the B max was reduced in both patient groups (44 pmol/mL · tissue). Chronically infarcted patients with or without primary FV share similar patterns of ventricular muscarinic receptor remodeling, characterized by receptor upregulation, in remote non-damaged territories.

International audience; Depression is frequent in Parkinson's disease, but its pathophysiology remains unclear. Two recent studies have investigated the role of serotonergic system at the presynaptic level. The objective of the present study was to use positron emission tomography and [18F]MPPF to investigate the role of postsynaptic serotonergic system dysfunction in the pathophysiology of depression in Parkinson's disease. Four parkinsonian patients with depression and 8 parkinsonian patients without depression were enrolled. Each patient underwent a scan using [18F]MPPF, a selective serotonin 1A receptor antagonist. Voxel‐by‐voxel statistical comparison of [18F]MPPF uptake of the 2 groups of parkinsonian patients and with 7 matched normal subjects was made using statistical parametric mapping (P uncorrected < .001). Compared with nondepressed parkinsonian patients, depressed patients exhibited reduced tracer uptake in the left hippocampus, the right insula, the left superior temporal cortex, and the orbitofrontal cortex. Compared with controls, nondepressed parkinsonian patients presented reduced [18F]MPPF uptake bilaterally in the inferior frontal cortex as well as in the right ventral striatum and insula. Compared with controls, [18F]MPPF uptake was decreased in depressed parkinsonian patients in the left dorsal anterior cingulate and orbitofrontal cortices, in the right hippocampic region, and in the temporal cortex. The present imaging study suggests that abnormalities in serotonin 1A receptor neurotransmission in the limbic system may be involved in the neural mechanisms underlying depression in patients with Parkinson's disease.

Background Serotonin (5-HT) pathway abnormalities were demonstrated in anorexia nervosa (AN). Brain imaging studies on 5-HT receptors support this evidence. 4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine ([ 18 F]MPPF) is a selective 5-HT 1A receptor antagonist with an affinity close to that of endogenous 5-HT. Methods In 24 subjects including 8 lean restrictive-type AN patients, 9 recovered from restrictive-type AN subjects and 7 age-matched control subjects, we assessed in vivo brain [ 18 F]MPPF binding by positron emission tomography and eating-related psychopathological traits. Inter-groups differences in [ 18 F]MPPF binding were evaluated by voxel-based analyses. Results Restrictive AN patients presented increased [ 18 F]MPPF binding in a selective area of the right cortex including part of the superior temporal gyrus, inferior frontal gyrus, parietal operculum, and temporoparietal junction. Striking regional similarities of increased [ 18 F]MPPF binding were found in recovered from AN subjects. Most of the psychiatric scores were increased in restrictive AN patients, and elevated perfectionism and interpersonal distrust scores were noticed in subjects recovered from AN. Conclusions The persistent increased 5-HT 1A receptor binding in frontotemporal region of recovered AN concomitantly with specific psychopathological traits support the hypothesis of an organic dysfunction of this area and corroborates with previous literature reports of AN cases induced by temporal lesions.

Tardive dystonia (TD) is a disabling disorder induced by neuroleptics. Internal globus pallidus (GPi) stimulation can dramatically improve TD. The present positron emission tomography and H215O study aimed to characterize the abnormalities of brain activation of TD and the impact of GPi stimulation on these abnormalities in five TD patients treated with GPi stimulation and eight controls. Changes of regional cerebral blood flow (rCBF) were determined: (i) at rest; (ii) when moving a joystick with the right hand in three freely chosen directions in on and off bilateral GPi stimulation. A significant increase of rCBF was found in TD patients in off-stimulation condition compared to controls: (1) during motor execution in the prefrontal, premotor lateral, and anterior cingulate cortex; (2) at rest, in the prefrontal and anterior cingulate cortex and the cerebellum. Internal globus pallidus stimulation led to a reduction of rCBF (1) during motor execution, in the primary motor and prefrontal cortex and the cerebellum; (2) at rest, in the primary motor and anterior cingulate cortex and supplementary motor area. The results are as follows: (1) TD is related to an excess of brain activity notably in the prefrontal and premotor areas; (2) GPi stimulation reduces the activation of motor, premotor, and prefrontal cortex as well as cerebellum.

International audience; This PET H 2 15 O study uses a reaching task to determine the neural basis of the unconscious motor speed up observed in the context of urgency in healthy subjects. Three conditions were considered: self-initiated (produce the fastest possible movement toward a large plate, when ready), externally-cued (same as self-initiated but in response to an acoustic cue) and temporally-pressing (same as externally-cued with the plate controlling an electromagnet that prevented a rolling ball from falling at the bottom of a tilted ramp). Results show that: (1) Urgent responses (Temporally-pressing versus Externally-cued) engage the left parasagittal and lateral cerebellar hemisphere and the sensorimotor cortex (SMC) bilaterally; (2) Externally-driven responses (Externally-cued versus Self-initiated) recruit executive areas within the contralateral SMC; (3) Volitional responses (Self-initiated versus Externally-cued) involve prefrontal cortical areas. These observations are discussed with respect to the idea that neuromuscular energy is set to a submaximal threshold in self-determined situations. In more challenging tasks, this threshold is raised and the first answer of the nervous system is to optimize the response of the lateral (i.e. crossed) corticospinal tract (contralateral SMC) and ipsilateral cerebellum. In a second step, the anterior (i.e. uncrossed) corticospinal tract (ipsilateral SMC) and the contralateral cerebellum are recruited. This recruitment is akin to the strategy observed during recovery in patients with brain lesions.

Neurotransmission imaging studies require normative data for the statistical assessment of neurophysiologic dysfunctions. 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF) is a specific serotonin 5-HT1A antagonist PET tracer recently characterized, modeled, and used for clinical research to explore abnormalities in the serotoninergic system. Our study reports, to our knowledge, the first large normative imaging database of 18F-MPPF binding potential (BP) over aging, for both males and females.Fifty-three healthy volunteers (27 females, 26 males; age, 20-70 y) were selected to undergo structural MRI and single-injection 18F-MPPF multiframe dynamic PET. 18F-MPPF BP values were computed using a nonlinear modeling method with tissue reference. The statistical assessment of the effect of age and sex was performed both at the anatomic structure level, using regions of interest drawn manually on individual MR images, and at the voxel level, using normalized BP parametric images in different statistical parametric mapping designs.A negative linear correlation between age and 18F-MPPF binding (3.6% decrease by decade) was found in females but not in males and involved most of the limbic and paralimbic regions; on the other hand, males in their 30s showed decreased binding in most cerebral regions.A comparison of males and females revealed higher BP values independent of age in females in the right hemisphere and a different evolution of BP over aging. These results confirm the necessity of a database for further statistical analysis in individuals or groups with pathology.

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a β-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague–Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The β-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

Although hypoactive sexual desire disorder (HSDD) is a common condition and has long been hypothesized to result from malfunctions of the cerebral control mechanisms that adjust the level of sexual motivation, very little is known about the pathophysiology of this disorder. The primary objective was to identify in patients with HSDD brain regions where functional perturbations disrupt the regulation of sexual motivation. We used positron emission tomography to compare seven male patients with HSDD with eight healthy men on their regional cerebral blood flow responses to visual sexual stimuli (VSS) of graded intensity. Statistical Parametric Mapping was used to locate brain regions that demonstrated a differential activation (or deactivation) across the groups. Whereas in control subjects the medial orbitofrontal cortex showed a deactivation in response to VSS, in HSDD patients there was an abnormally maintained activity of this region, which has been implicated in the inhibitory control of motivated behavior. By contrast, the reverse pattern-activation in control subjects, deactivation or unchanged activity in patients-was found in the secondary somatosensory cortex and inferior parietal lobules, regions mediating emotional and motor imagery processes, as well as in those areas of the anterior cingulate gyrus and of the frontal lobes that are involved in premotor processes.

Background: Positron emission tomography (PET) is a functional imaging device that allows dynamic regional blood flow measurements. We performed a study to test whether PET could detect acute changes in renal blood flow (RBF) in patients with chronic renal failure (CRF). Methods: RBF was measured by means of PET (PET-RBF) using oxygen 15-labeled water (H 2 15 O) in eight men with hypertension and moderate CRF before and 5, 40, 80, and 120 minutes after the injection of quinaprilat (10 mg intravenously). Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured simultaneously by para-aminohippuric acid (PAH-ERPF) and inulin clearances before and 20, 60, 100, and 140 minutes after quinaprilat injection. Results: Baseline RBF and ERPF were decreased in all patients (221 ± 20 mL/min/100 g and 225 ± 38 mL/min/1.73 m 2 , respectively). PET-RBF increased significantly after quinaprilat injection (+15%, +26%, +19%, and +23% versus baseline; P P = 0.15). GFR (50.1 ± 8.9 mL/min/1.73 m 2 at baseline) did not change significantly after quinaprilat injection; however, filtration fraction (GFR-ERPF ratio) decreased significantly from 0.23% ± 0.02% to 0.20% ± 0.02% ( P = 0.0004). Mean arterial pressure decreased significantly after quinaprilat injection ( P Conclusion: This study dynamically measured RBF by means of PET in patients with CRF for the first time. It showed that RBF rapidly increased after quinaprilat injection. PET using H 2 15 O is a powerful method for the noninvasive measurement of dynamic changes in RBF that remain undetected by PAH clearance. Am J Kidney Dis 40:947-954. © 2002 by the National Kidney Foundation, Inc.

Despite its critical sociobiological importance, the brain processing of visual sexual stimuli has not been characterized precisely in human beings. We used Positron Emission Tomography (PET) to investigate responses of regional cerebral blood flow (rCBF) in nine healthy males presented with visual sexual stimuli of graded intensity. Statistical Parametric Mapping was used to locate brain regions whose activation was associated with the presentation of the sexual stimuli and was correlated with markers of sexual arousal. The claustrum, a region whose function had been unclear, displayed one of the highest activations. Additionally, activations were recorded in paralimbic areas (anterior cingulate gyrus, orbitofrontal cortex), in the striatum (head of caudate nucleus, putamen), and in the posterior hypothalamus. By contrast, decreased rCBF was observed in several temporal areas. Based on these results, we propose a model of the brain processes mediating the cognitive, emotional, motivational, and autonomic components of human male sexual arousal. Hum. Brain Mapping 11:162–177, 2000. © 2000 Wiley‐Liss, Inc.

We investigated the cerebral metabolic patterns associated with non-specific hyperintense T2-weighted image on Magnetic Resonance Imaging (MRI) in Temporal Lobe Epilepsy (TLE). Nineteen patients suffering from TLE with a normal CT scan underwent Positron Emission Tomography (PET) using 18F-fluorodeoxyglucose; 8 had hyperintense T2-weighted image on MRI in the epileptogenic temporal lobe and 11 had a normal MRI. Interictally, PET exhibited focal hypometabolism in all the patients with hyperintense T2-weighted image and in 8 of the 11 whose MRI was normal. The hypometabolic area was significantly more extensive in patients with hyperintense T2-weighted image in whom it always encompasses the site of the MRI abnormality. Moreover, these patients had higher metabolic asymmetry index in the temporal and parietal lobes than patients with a normal MRI. One patient with mesial temporal hyperintense T2-weighted image underwent an ictal PET, which showed that the focal hypermetabolism fitted remarkably with the site and size of the abnormal MR signal. Thus, non-specific hyperintense T2-weighted images are associated with particular interictal and ictal metabolic patterns which might suggest that these MRI abnormalities reflect an epileptogenic lesion.

Although mutations in cardiac sodium and potassium channel genes are associated with congenital long QT syndrome (LQTS), a “modifier” role of the sympathetic nervous system was proposed to explain the distinct severity of the disease. We evaluated cardiac sympathetic innervation using [11C]hydroxyephedrine ([11C]HED) and positron emission tomography (PET) in genotyped LQTS patients. H215O and [11C]HED PET studies were performed in 11 patients (5 symptomatic) and 8 controls. Perfusion and [11C]HED images were depicted as 36-sector polar maps. Sectorial values of perfusion (H2O%), absolute (HEDRet) and relative retention (HED%Ret) of [11C]HED, and the ratio of HED%Ret to H2O% (HED%Ret/H2O%) were calculated. Normal databases were obtained from controls. Sectorial values below 2SD database values were defined as “outside sectors.” Controls and patients showed similar sectorial perfusion. Sectorial HEDRet did not differ between groups, but means of HED%Ret were lower in three sectors for patients ( P < 0.05). Three sectors from 3 controls had HED%Ret below 2SD, whereas 36 sectors in 9 patients were outside sectors ( P < 0.01). In patients, average HED%Ret/H2O% was lower in 9 sectors ( P < 0.05 vs. controls); 2 outside sectors were found in controls, but 43 outside sectors were found in patients ( P < 0.01), 77% of them in the 5 symptomatic patients. Heterogeneous [11C]HED retention was localized in the septal, anterior, and lateral walls. Most LQTS patients showed a localized and decreased pattern of [11C]HED retention. The larger number of heterogeneous sectors in symptomatic patients suggests that sympathetic function could play an amplifier role for severity of the disease.