Relationships between serotonin availability and frontolimbic response to fearful and threatening faces.

Serotonin is a critical neurotransmitter in the regulation of emotional behavior. Although emotion processing is known to engage a corticolimbic circuit, including the amygdala and prefrontal cortex, exactly how this brain system is modulated by serotonin remains unclear. Here, we hypothesized that serotonin modulates variability in excitability and functional connectivity within this circuit. We tested whether this modulation contributes to inter-individual differences in emotion processing. Using a multimodal neuroimaging approach with a simultaneous PET-3T fMRI scanner, we simultaneously acquired BOLD signal while participants viewed emotional faces depicting fear and anger, while also measuring serotonin transporter (SERT) levels, regulating serotonin functions. Individuals with higher activity of the medial amygdala BOLD in response to fearful or angry facial expressions, who were temperamentally more anxious, also exhibited lower SERT availability in the dorsal raphe nucleus (DRN). Moreover, higher connectivity of the medial amygdala with the left dorsolateral prefrontal and the anterior cingulate cortex was associated with lower levels of SERT availability in the DRN. These results demonstrate the association between the serotonin transporter level and emotion processing through changes in functional interactions between the amygdala and the prefrontal areas in healthy humans.

Quantitative longitudinal imaging of activated microglia as a marker of inflammation in the pilocarpine rat model of epilepsy using [11C]-( R)-PK11195 PET and MRI.

Inflammation may play a role in the development of epilepsy after brain insults. [11C]-( R)-PK11195 binds to TSPO, expressed by activated microglia. We quantified [11C]-( R)-PK11195 binding during epileptogenesis after pilocarpine-induced status epilepticus (SE), a model of temporal lobe epilepsy. Nine male rats were studied thrice (D0-1, D0 + 6, D0 + 35, D0 = SE induction). In the same session, 7T T2-weighted images and DTI for mean diffusivity (MD) and fractional anisotropy (FA) maps were acquired, followed by dynamic PET/CT. On D0 + 35, femoral arterial blood was sampled for rat-specific metabolite-corrected arterial plasma input functions (AIFs). In multiple MR-derived ROIs, we assessed four kinetic models (two with AIFs; two using a reference region), standard uptake values (SUVs), and a model with a mean AIF. All models showed large (up to two-fold) and significant TSPO binding increases in regions expected to be affected, and comparatively little change in the brainstem, at D0 + 6. Some individuals showed increases at D0 + 35. AIF models yielded more consistent increases at D0 + 6. FA values were decreased at D0 + 6 and had recovered by D0 + 35. MD was increased at D0 + 6 and more so at D0 + 35. [11C]-( R)-PK11195 PET binding and MR biomarker changes could be detected with only nine rats, highlighting the potential of longitudinal imaging studies.

Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study.

Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology.

Advanced [(18)F]FDG and [(11)C]flumazenil PET analysis for individual outcome prediction after temporal lobe epilepsy surgery for hippocampal sclerosis.

PURPOSE: We have previously shown that an imaging marker, increased periventricular [(11)C]flumazenil ([(11)C]FMZ) binding, is associated with failure to become seizure free (SF) after surgery for temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). Here, we investigated whether increased preoperative periventricular white matter (WM) signal can be detected on clinical [(18)F]FDG-PET images. We then explored the potential of periventricular FDG WM increases, as well as whole-brain [(11)C]FMZ and [(18)F]FDG images analysed with random forest classifiers, for predicting surgery outcome. METHODS: Sixteen patients with MRI-defined HS had preoperative [(18)F]FDG and [(11)C]FMZ-PET. Fifty controls had [(18)F]FDG-PET (30), [(11)C]FMZ-PET (41), or both (21). Periventricular WM signal was analysed using Statistical Parametric Mapping (SPM8), and whole-brain image classification was performed using random forests implemented in R (http://www.r-project.org). Surgery outcome was predicted at the group and individual levels. RESULTS: At the group level, non-seizure free (NSF) versus SF patients had periventricular increases with both tracers. Against controls, NSF patients showed more prominent periventricular [(11)C]FMZ and [(18)F]FDG signal increases than SF patients. All differences were more marked for [(11)C]FMZ. For individuals, periventricular WM signal increases were seen at optimized thresholds in 5/8 NSF patients for both tracers. For SF patients, 1/8 showed periventricular signal increases for [(11)C]FMZ, and 4/8 for [(18)F]FDG. Hence, [(18)F]FDG had relatively poor sensitivity and specificity. Random forest classification accurately identified 7/8 SF and 7/8 NSF patients using [(11)C]FMZ images, but only 4/8 SF and 6/8 NSF patients with [(18)F]FDG. CONCLUSION: This study extends the association between periventricular WM increases and NSF outcome to clinical [(18)F]FDG-PET, but only at the group level. Whole-brain random forest classification increases [(11)C]FMZ-PET's performance for predicting surgery outcome.

Brainstem changes in 5-HT1A receptor availability during migraine attack.

BACKGROUND: Among serotonin receptors, 5-HT(1A) receptors are implicated in the regulation of central serotoninergic tone and could be involved in the abnormal brain 5-HT turnover suspected in migraineurs. The aim of this study was to investigate 5-HT(1A) receptors' availability during migraine attacks. METHODS: Ten patients suffering from odor-triggered migraine attacks and 10 control subjects were investigated using positron emission tomography (PET) and [(18)F]MPPF PET tracer, a selective 5-HT(1A) antagonist. All subjects underwent calibrated olfactory stimulations prior to the PET study. RESULTS: Four patients developed a migraine attack during the PET study. In these patients, statistical parametrical mapping and region of interest analyses showed an increased [(18)F]MPPF binding potential (BP(ND)) in the pontine raphe when compared to headache-free migraineurs and control subjects. This ictal change was confirmed at the individual level in each of the four affected patients. In comparison with the headache-free migraineurs, patients with a migraine attack also showed significantly increased [(18)F]MPPF BP(ND) in the left orbitofrontal cortex, precentral gyrus and temporal pole. No significant change in [(18)F]MPPF BP(ND) was observed between headache-free migraineurs and controls. CONCLUSIONS: Our results emphasize the role of 5HT(1A) receptors in the pontine raphe nuclei during the early stage of migraine attacks.

Comorbidity between temporal lobe epilepsy and depression: a [18F]MPPF PET study.

Brain and brainstem changes of serotoninergic 5-hydroxytryptophan (5-HT)(1A) receptor density have been reported in patients with major depressive disorder as well as in patients with temporal lobe epilepsy (TLE), using PET and the selective antagonist radiotracers [(11)C]WAY-100635 or [(18)F]FC-WAY. We used a distinct 5-HT(1A) antagonist, [(18)F]MPPF, whose binding potential depends on both receptor density and extracellular serotonin concentration, in 24 patients with drug-resistant TLE and MRI evidence of hippocampal sclerosis but without prior antidepressant exposure. Their Beck Depression Inventory (BDI-2) score ranged from 0 to 34, with nine patients having a score >11. We used a simplified reference tissue model, statistical parametric mapping and anatomical regions of interest (ROIs) to correlate parametric images of [(18)F]MPPF BP with the total BDI score and its four subclasses. The total BDI score, as well as symptoms of psychomotor anhedonia and negative cognition, correlated positively with [(18)F]MPPF BP in the raphe nuclei and in the insula contralateral to seizure onset, whereas somatic symptoms correlated positively with [(18)F]MPPF binding potential in the hippocampal/parahippocampal region ipsilateral to seizure onset, the left mid-cingulate gyrus and the inferior dorsolateral frontal cortex, bilaterally. We confirm an association of depressive symptoms in TLE patients with changes of the central serotoninergic pathways, in particular within the raphe nuclei, insula, cingulate gyrus and epileptogenic hippocampus. These changes are likely to reflect lower extracellular serotonin concentration in more depressed patients, with an upregulation of receptors a less likely alternative.

Interictal brain 5-HT1A receptors binding in migraine without aura: a 18F-MPPF-PET study.

In this study we aimed to assess the brain distribution of 5-HT(1A) receptors in migraine patients without aura. Ten female migraine patients and 24 female healthy volunteers underwent magnetic resonance imaging and positron emission tomography using a radioligand antagonist of 5-HT(1A) receptors [4-(2'-methoxyphenyl)-1-[2'-(N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine ((18)F-MPPF)]. A simplified reference tissue model was used to generate parametric images of 5-HT(1A) receptor binding potential (BP) values. Statistical Parametrical Mapping (SPM) analysis showed increased MPPF BP in posterior cortical areas and hippocampi bilaterally in patients compared with controls. Region of interest (ROI) analysis showed a non-significant trend in favour of a BP increase patients in cortical regions identified by the SPM analysis except in hippocampi, left parietal areas and raphe nuclei. During the interictal period of migraine patients without aura, the increase of MPPF BP in posterior cortical and limbic areas could reflect an increase in receptor density or a decrease of endogenous serotonin, which could explain their altered cortical excitability.

A distinct [18F]MPPF PET profile in amnestic mild cognitive impairment compared to mild Alzheimer's disease.

To date, two positron emission tomography (PET) studies have explored 5-HT(1A) receptor density in the hippocampus of Alzheimer's disease (AD) patients. They showed early changes of 5-HT(1A) receptors in this brain region, known to have a dense serotonergic innervation. These studies only reported measurements in hippocampus. In the present PET study, we used an antagonist of 5-HT(1A) receptors, the [(18)F]MPPF (1) to explore 5-HT(1A) receptor density in the whole brain of AD patients at a mild stage of dementia and amnestic mild cognitive impairment (aMCI) patients compared to a control population; (2) to explore more precisely the 5-HT(1A) receptor density in the limbic brain regions of AD patients and aMCI patients compared to controls. Voxel-based analyses were performed to assess differences in the [(18)F]MPPF binding potential (BP) between AD patients and aMCI patients compared to controls. Analyses of whole-brain [(18)F]MPPF BP showed a global decrease in AD brains in contrast with a global increase in aMCI brains. In AD brains, a significant decrease of BP was detected in hippocampus and parahippocampal gyrus, whereas a significant increase of BP was observed in the inferior occipital gyrus in aMCI brains. These whole brain results are in accordance to hippocampal data reported in a previous study, showing an increase of [(18)F]MPPF binding in the aMCI group contrasting with a decrease in the AD group. Altogether, these results suggest the implication of a compensatory mechanism illustrated by an up regulation of serotonergic metabolism at the aMCI stage before a breakdown of this mechanism at the AD stage. This difference of serotonergic receptor labeling allows to distinguish the groups of aMCI patients from mild AD patients with specific [(18)F]MPPF PET profiles for each patient group.

Motor cortex stimulation for pain control induces changes in the endogenous opioid system.

BACKGROUND: Motor cortex stimulation (MCS) for neuropathic pain control induces focal cerebral blood flow changes involving regions with high density of opioid receptors. We studied the possible contribution of the endogenous opioid system to MCS-related pain relief. METHODS: Changes in opioid receptor availability induced by MCS were studied with PET scan and [(11)C]diprenorphine in eight patients with refractory neuropathic pain. Each patient underwent two preoperative (test-retest) PET scans and one postoperative PET scan acquired after 7 months of chronic MCS. RESULTS: The two preoperative scans, performed at 2 weeks interval, did not show significant differences. Conversely, postoperative compared with preoperative PET scans revealed significant decreases of [(11)C]diprenorphine binding in the anterior middle cingulate cortex (aMCC), periaqueductal gray (PAG), prefrontal cortex, and cerebellum. Binding changes in aMCC and PAG were significantly correlated with pain relief. CONCLUSION: The decrease in binding of the exogenous ligand was most likely explained by receptor occupancy due to enhanced secretion of endogenous opioids. Motor cortex stimulation (MCS) may thus induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain. Correlation of this effect with pain relief in at least two of these structures supports the role of the endogenous opioid system in pain control induced by MCS.

Functional anatomy of the therapeutic effects of prism adaptation on left neglect.

OBJECTIVE: To investigate the anatomic substrates underlying the beneficial effect of prism adaptation in five patients with persistent left neglect following right stroke. METHODS: In a functional imaging PET study, we used a covariation analysis to examine linear changes of regional cerebral blood flow over sessions as a function of left neglect improvement. RESULTS: The network of significant brain regions associated with improvement of left neglect performance produced by prism adaptation involved the right cerebellum, the left thalamus, the left temporo-occipital cortex, the left medial temporal cortex, and the right posterior parietal cortex. CONCLUSION: Our results suggest that the realignment of visuomotor coordinates is processed by the cerebellum and that low level sensorimotor adaptation actively modulates cerebral areas, albeit now relying on intact cerebellocerebral connections. Hence, our data support the hypothesis that the beneficial effect of prism adaptation on the clinical presentation of left neglect derives from modulation of cortical regions implicated in spatial cognition.

Double dissociation in neural correlates of visual working memory: a PET study.

Using positron emission tomography (PET), we investigated the organisation of spatial versus object-based visual working memory in 11 normal human subjects. The paradigm involved a conditional colour-response association task embedded within two visual working memory tasks. The subject had to remember a position (spatial) or shape (object-based) and then use this to recover the colour of the matching element for the conditional association. Activation of the nucleus accumbens and the anterior cingulate cortex was observed during the conditional associative task, indicating a possible role of these limbic structures in associative memory. When the 2 memory tasks were contrasted, we observed activation of 2 distinct cortical networks: (1) The spatial task activated a dorsal stream network distributed in the right hemisphere in the parieto-occipital cortex and the dorsal prefrontal cortex, and (2) The non spatial task activated a ventral stream network distributed in the left hemisphere in the temporo- occipital cortex, the ventral prefrontal cortex and the striatum. These results support the existence of a domain-specific dissociation with dorsal and ventral cortical systems involved respectively in spatial and non spatial working memory functions.

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease--A [(11)C]-raclopride PET study.

CONTEXT: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. OBJECTIVE: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release. METHODS: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. RESULTS: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. CONCLUSION: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

Synthesis and cytotoxic activity of benzopyranoxanthone analogues of benz.

Condensation of 3-hydroxy-2-naphthalenecarboxylic acid with phloroglucinol afforded 1,3-dihydroxy-12H-benzo[b]xanthen-12-one. Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to a series of benzo[b]pyrano[2,3-i]xanthen-6-ones and benzo[b]pyrano[3,2-h]xanthen-7-ones related to psorospermine and benzo[b]acronycine. In contrast with what is observed in the pyridoacridone and benzopyridoacridone series, the linear benzo[b]-pyrano[2,3-i]xanthen-6-one derivatives were more potent than their angular benzo[b]pyrano[3,2-h]xanthen-7-one isomers. cis-3,4-Diacetoxy-5-methoxy-2,2-dimethyl-3,4-dihydro-2H,6H-benzo[b]pyrano[2,3-i]xanthen-6-one, the most active among the new compounds, was more potent than acronycine in inhibiting the proliferation of L1210 murine leukemia cells.

Functional neuroanatomy of different olfactory judgments.

Humans routinely make judgments about olfactory stimuli. However, few studies have examined the functional neuroanatomy underlying the cognitive operations involved in such judgments. In order to delineate this functional anatomy, we asked 12 normal subjects to perform different judgments about olfactory stimuli while regional cerebral blood flow (rCBF) was measured with PET. In separate conditions, subjects made judgments about the presence (odor detection), intensity, hedonicity, familiarity, or edibility of different odorants. An auditory task served as a control condition. All five olfactory tasks induced rCBF increases in the right orbitofrontal cortex (OFC), but right OFC activity was highest during familiarity judgments and lowest during the detection task. Left OFC activity increased significantly during hedonic and familiarity judgments, but not during other odor judgments. Left OFC activity was significantly higher during hedonicity judgments than during familiarity or other olfactory judgments. These data demonstrate that aspects of odor processing in the OFC are lateralized depending on the type of olfactory task. They support a model of parallel processing in the left and right OFC in which the relative level of activation depends on whether the judgment involves odor recognition or emotion. Primary visual areas also demonstrated a differential involvement in olfactory processing depending on the type of olfactory task: significant rCBF increases were observed in hedonic and edibility judgments, whereas no significant rCBF increases were found in the other three judgments. These data indicate that judgments of hedonicity and edibility engage circuits involved in visual processing, but detection, intensity, and familiarity judgments do not.

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, orbito-frontal 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.

Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: a positron emission tomography study.

Neural correlates of responses to emotionally valenced olfactory, visual, and auditory stimuli were examined using positron emission tomography. Twelve volunteers were scanned using the water bolus method. For each sensory modality, regional cerebral blood flow (rCBF) during presentation of both pleasant and unpleasant stimuli was compared with that measured during presentation of neutral stimuli. During the emotionally valenced conditions, subjects performed forced-choice pleasant and unpleasant judgments. During the neutral conditions, subjects were asked to select at random one of a two key-press buttons. All stimulations were synchronized with inspiration, using an airflow olfactometer, to present the same number of stimuli for each sensory modality. A no-stimulation control condition was also performed in which no stimulus was presented. For all three sensory modalities, emotionally valenced stimuli led to increased rCBF in the orbitofrontal cortex, the temporal pole, and the superior frontal gyrus, in the left hemisphere. Emotionally valenced olfactory and visual but not auditory stimuli produced additional rCBF increases in the hypothalamus and the subcallosal gyrus. Only emotionally valenced olfactory stimuli induced bilateral rCBF increases in the amygdala. These findings suggest that pleasant and unpleasant emotional judgments recruit the same core network in the left hemisphere, regardless of the sensory modality. This core network is activated in addition to a number of circuits that are specific to individual sensory modalities. Finally, the data suggest a superior potency of emotionally valenced olfactory over visual and auditory stimuli in activating the amygdala.

Synthesis and cytotoxic and antitumor activity of benzo[b]pyrano[3, 2-h]acridin-7-one analogues of acronycine.

Benzo¿bacronycine (6-methoxy-3,3,14-trimethyl-3, 14-dihydro-7H-benzo¿bpyrano¿3,2-hacridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1, 2-dihydroxy-1,2-dihydrobenzo¿bacronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.

The effects of learning and intention on the neural network involved in the perception of meaningless actions.

PET was used to explore the neural network involved in the perception of meaningless action. In two conditions, subjects observed learned and unknown meaningless actions without any purpose. In two other conditions, subjects observed the same type of stimuli for later imitation. The control condition, which consisted of the presention of stationary hands, served as a baseline. Unsurprisingly, a common network that forms part of the dorsal pathway was engaged in all conditions when compared with stationary hands, and this was interpreted as being devoted to the analysis of hand movements. One of the most striking results of the present study was that some brain areas were strongly modulated by the learning level, independent of the subject's intention. Two different effects were observed: a reduced activity in posterior regions within the common network, which correlated with specific increases in the frontopolar area 10 and in the angular gyrus during the perception of learned meaningless actions compared with the perception of unknown actions. Finally, the major effect of the subject's intention to imitate was a strong increase in the dorsal pathway extending to the lateral premotor cortex and to the dorsolateral prefrontal cortex, which reflects the information processing needed for prospective action. Overall, our results provide evidence for both an effect of the visuomotor learning level and of the subject's intention on the neural network involved during the perception of human meaningless actions.