Paul Gravel

α-[11C]Methyl-l-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters

Low serotonin neurotransmission is thought to increase vulnerability to suicidal behavior. To test this hypothesis, we measured brain regional serotonin synthesis, as indexed by PET and alpha-[(11)C]methyl-L-tryptophan trapping, in 10 patients who had made a high-lethality suicide attempt and 16 healthy controls. Compared to healthy controls, suicide attempters had reduced normalized alpha-[(11)C]methyl-L-tryptophan trapping in orbital and ventromedial prefrontal cortex. alpha-[(11)C]Methyl-L-tryptophan trapping in these regions correlated negatively with suicide intent. Low serotonin synthesis in the prefrontal cortex might lower the threshold for suicidal behavior.

Where in-vivo imaging meets cytoarchitectonics: The relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET

MRI-based measurements of surface cortical thickness (SCT) have become a sensitive tool to quantify changes in cortical morphology. When comparing SCT to histological cortical thickness maps, a good correspondence can be found for many but not all human brain areas. Discrepancies especially arise in the sensory motor cortex, where histological cortical thickness is high, but SCT is very low. The aim of this study was to determine whether the relationship between cortical thickness and neuronal density is the same for different cytoarchitectonic areas throughout homo- and heterotypical isocortex. We assessed this relationship using high-resolution [(18)F]-labelled flumazenil (FMZ) PET and SCT-mapping. FMZ binds to the benzodiazepine GABA(A) receptor complex which is localized on axo-dendritic synapses, with a cortical distribution closely following the local density of neurons. SCT and voxelwise FMZ binding potential (BP(ND)) were assessed in ten healthy subjects. After partial volume correction, two subsets with a differential relationship between SCT and BP(ND) were identified: a fronto-parietal homotypical subset where neuronal density is relatively constant and mainly independent of SCT, and a subset comprising heterotypical and mainly temporal and occipital homotypical regions where neuronal density is negatively correlated with SCT. This is the first in-vivo study demonstrating a differential relationship between SCT, neuronal density and cytoarchitectonics in humans. These findings are of direct relevance for the correct interpretation of SCT-based morphometry studies, in that there is no simple relationship between apparent cortical thickness and neuronal density, here attributed to FMZ binding, holding for all cortical regions.

Acute prefrontal cortex TMS in healthy volunteers: Effects on brain 11C-αMtrp trapping

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) is a technique with purported efficacy as a treatment for major depression. Here, we assessed in vivo, in healthy volunteers, the effect of acute rTMS of the LDLPFC, relative to the stimulation of the left occipital cortex (LOC), on brain regional serotonin synthesis capacity, using the [(11)C]-alpha-methyl-tryptophan ((11)C-alphaMtrp)/PET method. Ten subjects were studied twice, once following rTMS of the LDLPFC and once following rTMS of the LOC in a randomized counterbalanced order. Three blocks of 15 trains of 10 Hz rTMS were delivered 10 min apart. Behavioural and autonomic measures were recorded before and after each rTMS session. Comparisons of TMS-related changes in regional normalized brain uptake and trapping of (11)C-alphaMtrp (K*) values were carried out using SPM99. Statistically significant regional differences were identified on the basis of an extent threshold of 50 voxels, with a peak threshold of p=0.005 uncorrected. Behavioural and autonomic measures were unaffected by rTMS. Relative to LOC stimulation, LDLPFC rTMS was associated with marked changes in normalized K* in limbic areas, with significantly lower values in the left parahippocampal gyrus (BA 28) and the right insula (BA 13), and higher values in the right cingulate gyrus (BA 31) and cuneus (BA 18). These findings indicate that acute rTMS of the LDLPFC in healthy volunteers modulates aspects of tryptophan/5-HT metabolism in limbic areas. Such adaptive changes may contribute to the mechanism of action of prefrontal rTMS in major depression.

Brain Serotonin Synthesis in Adult Males Characterized by Physical Aggression during Childhood: A 21-Year Longitudinal Study

Background Adults exhibiting severe impulsive and aggressive behaviors have multiple indices of low serotonin (5-HT) neurotransmission. It remains unclear though whether low 5-HT mediates the behavior or instead reflects a pre-existing vulnerability trait. Methodology/Principal Findings In the present study, positron emission tomography with the tracer alpha-[11C]methyl-L-tryptophan (11C-AMT) was used to compare 5-HT synthesis capacity in two groups of adult males from a 21-year longitudinal study (mean age ± SD: 27.1±0.7): individuals with a history of childhood-limited high physical aggression (C-LHPA; N = 8) and individuals with normal (low) patterns of physical aggression (LPA; N = 18). The C-LHPA males had significantly lower trapping of 11C-AMT bilaterally in the orbitofrontal cortex and self-reported more impulsiveness. Despite this, in adulthood there were no group differences in plasma tryptophan levels, genotyping, aggression, emotional intelligence, working memory, computerized measures of impulsivity, psychosocial functioning/adjustment, and personal and family history of mood and substance abuse disorders. Conclusions/Significance These results force a re-examination of the low 5-HT hypothesis as central in the biology of violence. They suggest that low 5-HT does not mediate current behavior and should be considered a vulnerability factor for impulsive-aggressive behavior that may or may not be expressed depending on other biological factors, experience, and environmental support during development.

Cocaine Cue-Induced Dopamine Release in Amygdala and Hippocampus: A High-Resolution PET ( 18 F)Fallypride Study in Cocaine Dependent Participants

Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [18F]fallypride. Twelve cocaine-dependent volunteers (mean age: 39.6±8.0 years; years of cocaine use: 15.9±7.4) underwent two [18F]fallypride high-resolution research tomography–PET scans, one with exposure to neutral cues and one with cocaine cues. [18F]Fallypride non-displaceable-binding potential (BPND) values were derived for five regions of interest (ROI; amygdala, hippocampus, ventral limbic striatum, associative striatum, and sensorimotor striatum). Subjective responses to the cues were measured with visual analog scales and grouped using principal component analysis. Drug cue exposure significantly decreased BPND values in all five ROI in subjects who had a high-, but not low-, craving response (limbic striatum: p=0.019, associative striatum: p=0.008, sensorimotor striatum: p=0.004, amygdala: p=0.040, and right hippocampus: p=0.025). Individual differences in the cue-induced craving response predicted the magnitude of [18F]fallypride responses within the striatum (ventral limbic: r=0.581, p=0.048; associative: r=0.589, p=0.044; sensorimotor: r=0.675, p=0.016). To our knowledge this study provides the first evidence of drug cue-induced DA release in the amygdala and hippocampus in humans. The preferential induction of DA release among high-craving responders suggests that these aspects of the limbic reward network might contribute to drug-seeking behavior.

Decreased [18F]MPPF Binding Potential in the Dorsal Raphe Nucleus After a Single Oral Dose of Fluoxetine: A Positron-Emission Tomography Study in Healthy Volunteers

BACKGROUND Brain serotonin-1A (5-HT(1A)) autoreceptors internalize when activated by agonist or by their endogenous ligand, serotonin. This positron-emission tomography (PET) study tested the hypothesis that 5-HT(1A) autoreceptor internalization might be indexed in vivo by a decrease in the specific binding of the 5-HT(1A) radioligand, 4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1 piperazinyl]ethyl-N-2-pyridinyl-benzamide ([(18)F]MPPF), in the dorsal raphe nucleus (DRN) of healthy adult men administered a single oral dose of the selective serotonin reuptake inhibitor, fluoxetine. METHODS [(18)F]MPPF binding potential was measured in the DRN and other brain regions endowed with 5-HT(1A) receptors in eight healthy volunteers, 5 hours after the randomized, double-blind administration of fluoxetine (20 mg) or placebo. RESULTS In every subject, [(18)F]MPPF binding potential was decreased in the DRN only (44% +/- 22 SD), in response to fluoxetine. CONCLUSIONS Imaging the functional state of 5-HT(1A) autoreceptors (i.e., internalization) in the human brain, using [(18)F]MPPF/PET, may represent a promising avenue for investigating the neurobiology of serotonin-related disorders and notably of major depression.

Stress‐induced dopamine release in human medial prefrontal cortex—18F‐Fallypride/PET study in healthy volunteers

Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [18F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BPND) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BPND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. Results: The psychological stressor significantly decreased [18F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress‐induced decrease in [18F]fallypride binding in the dmPFC, the greater the stress‐induced increases in heart rate. Conclusions: The present study provides evidence of stress‐induced dopamine release in the mPFC in humans, in vivo. Synapse 67:821–830, 2013.

Improved work-up procedure for the production of [18F] flumazenil and first results of its use with a high-resolution research tomograph in human stroke

INTRODUCTION The central benzodiazepine receptor (cBZR)-gamma-aminobutyric acid (GABA(A)) receptor complex in the human brain plays an important role in many neurological and psychiatric disorders. (18)F-Labeled flumazenil ([(18)F]FZ) provides a potentially useful tracer to investigate those disorders by means of positron emission tomography (PET). METHODS [(18)F]Flumazenil was synthesized from its nitro-precursor Ro 15-2344 in DMF at high temperatures between 150 degrees C and 160 degrees C. Other solvents like acetonitrile and dimethylsulfoxide were also investigated as reaction media. A new HPLC method for the final purification of [(18)F]FZ was developed to circumvent some difficulties associated with a previously published procedure sometimes led to a contamination of [(18)F]FZ with Ro 15-2344. The final purification of the radiotracer was achieved using a Waters Symmetry Prep C18 HPLC column with elution with 0.05 M sodium acetate (NaOAc) buffer (pH 5)/THF/MeOH (80:10:10). RESULTS [(18)F]FZ could be synthesized in reproducible radiochemical yields (RCYs) of 15-20% (decay corrected to EOB) after 80 min overall synthesis time. The synthesized [(18)F]FZ was applied for the first time in a human PET study in a patient with ischemic right middle cerebral artery stroke using the HRRT high-resolution research scanner (Siemens Medical Solution, Knoxville, TN, USA). CONCLUSIONS [(18)F]FZ is a potentially useful GABA receptor-binding PET ligand. A modified procedure for its preparation in reproducibly high radiochemical yields has been described and the [(18)F]FZ thus produced has been used successfully in a pilot clinical study.

External awareness and GABA—A multimodal imaging study combining fMRI and [18F]flumazenil-PET

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so‐called intrinsic and extrinsic systems, have been well‐defined, the associated biochemical mechanisms still remain unclear. We used a well‐established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [18F]FMZ‐PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders. Hum Brain Mapp 35:173–184, 2014.

Brain Regional α-[11C]Methyl-L-Tryptophan Trapping in Medication-Free Patients With Obsessive-Compulsive Disorder

CONTEXT The hypothesis of a serotonin (5-hydroxytryptamine [5-HT]) dysfunction in obsessive-compulsive disorder (OCD) stems largely from the clinical efficacy of 5-HT reuptake inhibitors. Serotonergic abnormalities in the unmedicated symptomatic state, however, remain to be fully characterized. OBJECTIVE To investigate brain regional 5-HT synthesis, as indexed by positron emission tomography and the α-[(11)C]methyl-L-tryptophan trapping constant (K*), in treatment-free adults meeting criteria for OCD. DESIGN Between-group comparison. SETTING Department of Psychiatry and Montreal Neurological Institute, McGill University, and Department of Psychology, McGill University Health Centre, Quebec, Canada. PARTICIPANTS Twenty-one medication-free patients with OCD (15 men with a mean [SD] age of 33.2 [9.3] years and 6 women with a mean [SD] age of 35.8 [7.1] years) and 21 healthy controls matched for age and sex (15 men with a mean [SD] age of 32.9 [10.1] years and 6 women with a mean [SD] age of 36.5.5 [8.6] years). Main Outcome Measure The α-[(11)C]methyl-L-tryptophan brain trapping constant K*, which was analyzed with Statistical Parametric Mapping (SPM8) and with proportional normalization (extent threshold of 100 voxels with a peak threshold of P ≤ .005). RESULTS Compared with healthy controls, the patients with OCD exhibited significantly greater α-[(11)C]methyl-L-tryptophan trapping in the right hippocampus and left temporal gyrus (Brodmann area 20). In the larger subsample of all men, these same differences were also evident, as well as higher K* values in the caudate nucleus. Individual differences in symptom severity correlated positively with K* values sampled from the caudate and temporal lobe of the patients with OCD, respectively. There were no regions where the patients exhibited abnormally low K* values. Volumetric analyses found no morphometric alterations that would account for the group differences. CONCLUSION The results support previous reports of greater striatal and temporal lobe activity in patients with OCD than in healthy controls and suggest that these disturbances include a serotonergic component. Previously reported glucose metabolic disturbances in OCD involving the orbitofrontal and cingulate cortices, in comparison, might reflect postsynaptic changes in the serotonergic system.