Didier Le Bars

Brain processing of visual sexual stimuli in human males

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.

Neuroanatomical Correlates of Visually Evoked Sexual Arousal in Human Males

Brain areas activated in human male sexualbehavior have not been characterized precisely. For thefirst time, positron emission tomography (PET) was usedto identify the brain areas activated in healthy males experiencing visually evoked sexualarousal. Eight male subjects underwent six measurementsof regional brain activity following the administrationof [15O]H2O as they viewedthree categories of film clips: sexually explicit clips,emotionally neutral control clips, and humorous controlclips inducing positive but nonsexual emotions.Statistical Parametric Mapping was used to identifybrain regions demonstrating an increased activity associatedwith the sexual response to the visual stimulus.Visually evoked sexual arousal was characterized by athreefold pattern of activation: the bilateralactivation of the inferior temporal cortex, a visualassociation area; the activation of the right insula andright inferior frontal cortex, which are two paralimbicareas relating highly processed sensory information with motivational states; and the activation ofthe left anterior cingulate cortex, another paralimbicarea known to control autonomic and neuroendocrinefunctions. Activation of some of these areas was positively correlated with plasma testosteronelevels. Although this study should be consideredpreliminary, it identified brain regions whoseactivation was correlated with visually evoked sexualarousal in males.

Functional Anatomy of Perceptual and Semantic Processing for Odors

The functional anatomy of perceptual and semantic processings for odors was studied using positron emission tomography (PET). The first experiment was a pretest in which 71 normal subjects were asked to rate 185 odorants in terms of intensity, familiarity, hedonicity, and comestibility and to name the odorants. This pretest was necessary to select the most appropriate stimuli for the different cognitive tasks of the second experiment. The second one was a PET experiment in which 15 normal subjects were scanned using the water bolus method to measure regional cerebral blood flow (rCBF) during the performance in three conditions. In the first (perceptual) condition, subjects were asked to judge whether an odor was familiar or not. In the second (semantic) condition, subjects had to decide whether an odor corresponded to a comestible item or not. In the third (detection) condition, subjects had to judge whether the perceived stimulus was made of an odor or was just air. It was hypothetized that the three tasks were hierarchically organized from a superficial detection level to a deep semantic level. Odorants were presented with an air-flow olfactometer, which allowed the stimulations to be synchronized with breathing. Subtraction of activation images obtained between familiarity and control judgments revealed that familiarity judgments were mainly associated with the activity of the right orbito-frontal area, the subcallosal gyrus, the left inferior frontal gyrus, the left superior frontal gyrus, and the anterior cingulate (Brodmanns areas 11, 25, 47, 9, and 32, respectively). The comestibility minus familiarity comparison showed that comestibility judgments selectively activated the primary visual areas. In contrast, a decrease in rCBF was observed in these same visual areas for familiarity judgments and in the orbitofrontal area for comestibility judgments. These results suggest that orbito-frontal and visual regions interact in odor processing in a complementary way, depending on the task requirements.

A controlled positron emission tomography study of obsessive and neutral auditory stimulation in obsessive-compulsive disorder with checking rituals

Ten nondepressed patients with obsessive-compulsive disorder (OCD) who were characterized by predominant checking rituals were compared with 10 age- and sex-matched control subjects. Hemispheric and regional cerebral blood flow levels (rCBF) were measured with positron emission tomography (H2 15O) across four conditions: rest, auditory stimulation with idiosyncratic normal or abnormal obsession, auditory stimulation with neutral verbal stimuli, and rest. Order of neutral and obsessive stimulation was randomized. Higher subjective responses to obsessive than to neutral stimulation were found in both groups; subjective response was higher in OCD patients when obsessive stimulation was presented first. A four-way analysis of variance (group x stimulation order x hemisphere x condition [neutral or obsessive stimulation]) was performed on stimulation minus rest normalized rCBF values. Control subjects had significantly higher rCBF in the thalamus and putamen. A trend toward higher rCBF in OCD patients was found in the superior temporal regions. When neutral stimulation was presented first, rCBF was significantly higher in the caudate region of control subjects. Obsessive stimulation was associated with higher rCBF than neutral stimulation in orbitofrontal regions in both groups of subjects. Under obsessive stimulation, superior temporal and orbitofrontal activities were correlated in OCD patients but not in control subjects. Our study suggests specific abnormalities of information processing in the basal ganglia and temporal structures of compulsive checkers.

Brain processing of visual sexual stimuli in men with hypoactive sexual desire disorder

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.

Brain processing of visual sexual stimuli in treated and untreated hypogonadal patients

OBJECTIVE Although various brain regions have been shown to respond to the presentation of visual sexual stimuli (VSS), whether these regions are specifically mediating sexual arousal or whether they mediate general emotional or motivational arousal is unknown. To clarify this issue, our purpose was to map the regions where the response to VSS was related to plasma testosterone. Specific objectives were (i) to identify regions that respond differentially to VSS in untreated hypogonadal patients compared with healthy controls and (ii) to identify in hypogonadal patients the regions that respond differentially to VSS as a function of therapeutically induced increased testosterone levels. METHOD In nine male hypogonadal patients, in the same patients under treatment, and in eight healthy males, we used Positron Emission Tomography to investigate responses of regional cerebral blood flow to VSS. Statistical Parametric Mapping was used to locate regions that demonstrated a differential response. RESULTS Regions responding differentially both in untreated patients compared with controls and in untreated patients compared with themselves under treatment were the right orbitofrontal cortex, insula and claustrum, where the activation was higher in controls than in untreated patients and where activation increased under treatment, and the left inferior frontal gyrus, that demonstrated a deactivation only in controls and in patients under treatment. That these responses appear to depend on testosterone indicates that these regions mediate sexual arousal and not only a process of general emotional or motivational arousal.

Effect of endogenous serotonin on the binding of the 5-hT1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis.

By using a combination of an original β+‐sensitive␣intracerebral probe and microdialysis, the effect of increased endogenous serotonin on specific binding of 18F‐MPPF [4‐(2′‐methoxyphenyl)‐1‐[2′‐[N‐(2′′‐pyridinyl)‐p‐fluorobenzamido]ethyl]piperazine] to the serotonin‐1A (5‐HT1A) receptors was investigated in the hippocampus of the anaesthetized rat. Our β‐sensitive probe prototype was sensitive enough to obtain specific 18F‐MPPF time–activity curves in the rodent (hippocampus/cerebellum ratio ≈ 2). The serotonin neuronal release was pharmacologically enhanced using fenfluramine at three different doses (1, 2 and 10 mg/kg intravenous) multiplying by 2–15 the extracellular serotonin in the hippocampus. These extracellular variations of extracellular serotonin resulted in dose‐ranging decreases in 18F‐MPPF‐specific binding in the same rat. Our results showed for the first time that 18F‐MPPF binding could be modulated by modifications of extracellular serotonin in the rat hippocampus. These results were confirmed by the enhancement of extracellular radioactivity collected in dialysates after the displacement of 18F‐MPPF by fenfluramine. After modelization, 18F‐MPPF binding could constitute an interesting radiotracer for positron emission tomography in evaluating the serotonin endogenous levels in limbic areas of the human brain.

Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease.

Depression is frequent in Parkinsons 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 Parkinsons 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 Parkinsons disease.

Switching brain serotonin with oxytocin

Significance Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. Here we show that these chemical messengers interact in areas of the human brain important for the regulation of emotion-based behavior. By highlighting the role of OXT in the regulation of 5-HT signaling, our findings can lead to novel therapeutic strategies for mental disorders such as social anxiety, depression, and autism. 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-[18F]fluoro-benzamidoethylpiperazine ([18F]MPPF), an antagonist of 5-HT1A receptors. OXT increased [18F]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: [18F]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.

In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings

Our objective was to evaluate amyloid deposition in posterior cortical atrophy (PCA), using both cerebrospinal fluid (CSF) biomarker analysis and amyloid imaging. Five PCA patients, selected based on their neuropsychological profile and atrophic changes in posterior regions on MRI, underwent CSF analysis. CSF amyloid-beta 1–42, total tau, and phosphorylated tau at threonine 181 levels were determined. They also had positron emission tomography (PET) with Pittsburgh Compound B ([11C]PIB). [11C]PIB ratio images were assessed with visual, regional and voxel-based analyses and compared to eight typical Alzheimers disease (AD) patients and eight controls. The biological profile in the five PCA patients, resulting from CSF and [11C]PIB images analysis, was consistent with AD. Individual comparisons of PCA patients’ [11C]PIB images with the AD group with Statistical Parametric Mapping (SPM) revealed a distinctive posterior uptake in four out of the five patients showing increased amyloid deposition in occipital, temporal, and/or parietal regions. ROI group analysis showed a tendency for higher amyloid deposition in occipital and temporal regions. However, this pattern was not found with SPM group analysis when the global level of [11C]PIB uptake was used as a covariate. Our results indicate that amyloid burden can be demonstrated in vivo in PCA suggesting a diagnosis of AD. PCA patients may present a higher global amyloid load than AD that was not related to age at onset, disease severity, disease duration, or educational level in our study. Combined CSF and PET biomarkers seem helpful for in vivo diagnosis of this focal syndrome with underlying AD pathology.