Volunteers Underwent Positron Emission Tomography Research Articles

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.

The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin's active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3-30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.

In Search of Baseline: Absolute and Relative Measures of Blood Flow and Oxidative Metabolism in Visual Cortex Stimulated at Three Levels of Complexity

Objective: Functional imaging of regional cerebral blood flow (rCBF) or the blood-oxygenation-level dependent (BOLD) signal is based on the premise that changes of flow and energy metabolism are linked to the same incremental excitation of neurons. The baseline conjecture holds that a single default mode of brain function gives rise to coupled changes of blood flow and oxidative metabolism that raise oxygen’s extraction fraction, when activity falls, and lower the extraction fraction when activity rises. To locate the hypothetical baseline in visual cortex in relation to functional demands, we compared increments of (rCBF) and oxidative metabolism (rCMRO2) during stimulation of visual cortex at three different levels of complexity. Materials and Methods: Healthy volunteers underwent positron emission tomography (PET) with [15O] water and [15O] oxygen while they viewed three stimuli in random order; a cross-hair fixation stimulus without color or spatial frequency (FX), an achromatic white disc stimulus with an 8 Hz on-off rate (WD), and a circular yellow-blue chromatic checkerboard with an 8 Hz color-reversing frequency (YB). For the baseline conjecture to hold, the sum of any pair of contrasts must equal the third at any site of significant change, such that the sum of the contrasts [YB-WD] and [WD-FX] must equal the contrast [YB-FX]. Results: The rCMRO2 and rCBF changes averaged 21% and 52% of the whole-brain average, implying excitation by increasing stimulus complexity. The color reversal contrast ([YB-WD]) revealed bilateral sites of significant change of rCMRO2 and a single left hemisphere site of significant rCBF change in the general region of Brodmann’s areas (BA) 17 and 18 of the lingual gyrus. The spatial frequency contrasts ([YB-FX] and [WD-FX]) revealed single sites of significant change of rCMRO2 and rCBF also in the lingual gyrus but close to the midline. For the midline sites, the [YB-FX] and [WD-FX] contrasts were identical and revealed a baseline between the FX and WD/YB stimulus conditions. For the lateral sites, the [YB-WD] stimulus contrast revealed a baseline between the YB and WD stimulus conditions. Conclusion: The intermediate positions of the baselines indicated the existence in BA 17/18 of at least two populations of cells, a lateral group responding to the absence and presence of color reversal in the presence of a spatial frequency, and a midline group responding only to the absence and presence of spatial frequency.

Brain histamine H1 receptor occupancy measured by PET after oral administration of levocetirizine, a non-sedating antihistamine

Objective: Histamine H1 receptor (H1R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H1R occupancy (H1RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [11C]doxepin, a PET tracer that specifically binds to H1Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H1ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.Results: There was no significant difference between the mean brain H1RO after levocetirizine administration (8.1%; 95% CI: −9.8 to 26.0%) and fexofenadine administration (−8.0%; 95% CI: −26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H1RO of the two antihistamines.Conclusion: At therapeutic dose, levocetirizine does not bind significantly to the brain H1Rs and does not induce significant sedation.

Understanding the Central Pharmacokinetics of Spheroidal Oral Drug Absorption System (SODAS) Dexmethylphenidate

Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy through 12 hours. However, there are no studies of central nervous system (CNS) dopamine transporter occupancies. Eighteen healthy volunteers underwent positron emission tomography (PET) imaging with C-11 altropane before and after administration of oral doses of SODAS dexmethylphenidate. Each group of 6 subjects received 1 of 3 doses (20 mg, 30 mg, 40 mg) before PET imaging at 1, 8, 10, 12 (20 mg and 30 mg), or 1, 8, 10, and 14 (40 mg) hours after dosing. Transporter occupancy was calculated by standard methods. The study was conducted from January 2007 through December 2007. For all doses, plasma dexmethylphenidate levels and CNS dopamine transporter occupancies were greatest at 8 hours and decreased over time at 10, 12, and 14 hours. Plasma dexmethylphenidate levels were correlated to dose (P < .003). Mean plasma levels were ≥ 6 ng/mL to at least 8 hours with 20 mg (5.7 ng/mL), 10 hours with 30 mg, and 12 hours (extrapolated) with 40 mg. Dopamine transporter occupancies in the right caudate were 47% at 8 hours with 20 mg, 42% at hour 10 with 30 mg, and 46% (extrapolated) at hour 12 with 40 mg. Dopamine transporter occupancy was significantly correlated with plasma concentration of dexmethylphenidate (P < .001). These results confirm the study hypothesis that central dopamine transporter occupancy parallels peripheral pharmacokinetic findings in orally administered long-acting dexmethylphenidate in later hours after administration. clinicaltrials.gov Identifier: NCT00593138.

5-HT1A receptor binding in euthymic bipolar patients using positron emission tomography with [carbonyl-11C]WAY-100635

BackgroundThis study was undertaken to examine whether brain 5-HT1A receptor binding is reduced in euthymic bipolar patients. MethodsEight medicated euthymic bipolar patients and 8 healthy volunteers underwent positron emission tomography scanning using the selective 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635. ResultsNo significant difference in global postsynaptic parametric binding potential (BPND) was found between euthymic bipolar patients (mean±SD, 4.24±0.76) and healthy volunteers (mean±SD, 4.34±0.86). Ninety five percent Confidence Intervals for the difference in group mean global postsynaptic BPND were –0.77 to 0.97. Analysis of regional BPND did not reveal regional differences between patients and healthy controls. LimitationsThe number of subjects studied was limited and all subjects were on medication. ConclusionsIn contrast to previous findings of reduced 5-HT1A receptor binding in untreated unipolar and bipolar depressed patients [Sargent, P.A., Kjaer, K.H., Bench, C.J., Rabiner, E.A., Messa, C., Meyer, J., Gunn, R.N., Grasby, P.M., Cowen, P.J., 2000. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch. Gen. Psychiatry 57, 174–180]; [Drevets, W.C., Frank, E., Price, J.C., Kupfer, D.J., Holt, D., Greer, P.J., Huang, Y., Gautier, C., Mathis, C., 1999. PET imaging of serotonin1A receptor binding in depression. Biol. Psychiatry 46, 1375–1387] and in recovered unipolar depressed patients [Bhagwagar, Z., Rabiner, E.A., Sargent, P.A., Grasby, P.M., Cowen, P.J., 2004. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol. Psychiatry 9, 386–92], this study found no difference in 5-HT1A receptor BPND between medicated euthymic bipolar patients and healthy controls. Normal 5-HT1A receptor BPND in these patients may be a result of drug treatment or could indicate that reduced 5-HT1A receptor binding is specific to the depressed state in bipolar patients.

Relationship Between Neuroticism Personality Trait and Serotonin Transporter Binding

Personality trait is thought to be one of the important factors for vulnerability to depression. The relation between serotonin transporter (5-HTT) polymorphism and anxiety-related personality has been investigated in genetic research. In this study, we investigated the relation between in vivo regional 5-HTT binding in the brain and personality inventory measures in normal male volunteers. Thirty-one healthy male volunteers underwent positron emission tomography scans with (11)C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile ([(11)C]DASB) to measure 5-HTT and completed revised NEO Personality Inventory. Correlation of [(11)C]DASB binding potentials (BP) with personality inventory measures was calculated using region-of-interest analysis and statistical parametric mapping based on the BP images. Neuroticism was positively correlated with 5-HTT binding in the thalamus (p = .004). No significant correlation was observed in any other brain region. Within the neuroticism dimension, the facet of depression was positively correlated with 5-HTT binding in the thalamus (p = .001). Subjects with higher thalamic 5-HTT binding are more likely to express higher levels of neuroticism and depressive feeling. Serotonin transporter binding in the thalamus might be a marker of vulnerability to depression.

Isoflurane Alters the Amount of Dopamine Transporter Expressed on the Plasma Membrane in Humans

Isoflurane increases extracellular dopamine concentration and causes trafficking of the dopamine transporter (DAT) in transfected cells. Also, the binding potentials of highly specific positron-emitting DAT ligands are altered by isoflurane in rhesus monkeys. The purpose of this study was to determine the dose-response curve for isoflurane altering the binding potential of one of these ligands ([F-18]FECNT) in humans. Twenty human volunteers underwent positron emission tomography using [F-18]FECNT. All subjects were scanned while awake and then again after assignment to one of four groups (n = 5 each): awake-control, propofol-control, or light or deep isoflurane anesthesia as defined by Bispectral Index monitoring. Bispectral Index values in the light anesthesia group were 40 +/- 7 (end-tidal isoflurane, 1.02 +/- 0.08) versus 27 +/- 10 (end-tidal isoflurane, 1.6 +/- 0.3) in the deep anesthesia group. The within-subject percent change in putamen binding potential between the awake and second scans was determined for each subject, averaged within groups, and compared across groups. The [F-18]FECNT binding potential exhibited a biphasic shape as a function of anesthetic dose. The binding potential for the second scan in the awake-control and propofol-control groups was significantly less than the initial scan; for the light anesthesia group, the binding potential was significantly increased during anesthesia, and no change was detected between the two scans in the deeper anesthesia group. Isoflurane causes a dose-dependent change in the [F-18]FECNT binding potential for DAT consistent with isoflurane causing trafficking of the DAT between the plasma membrane and the cell interior. Concentrations of isoflurane below minimum alveolar concentration causes DAT to be trafficked to the plasma membrane from the cell interior, but no net trafficking occurs at higher concentrations. The data are most easily explained if isoflurane alters the amount of functionally expressed DAT through an indirect pathway. This phenomena should be more fully explored to help make the next generation of anesthetics more mechanistically specific and to reduce undesired side effects.

Neutral substrates for postural balance in humans

In order to investigate the neural substrates in the intact human brain, healthy volunteers underwent positron emission tomography (PET) with [ 15O]H 2O while they were adopting several postures: lying, sitting passively (reclining) and standing in different manners. Compared with the supine posture, statistical parametric mapping (SPM) showed that bipedal standing with eyes open activated the cerebellar anterior lobe and the visual cortex, and standing on one foot activated the anterior vermis, ipsilateral to the weight-bearing side. Bipedal standing further activated the vermis in comparison with the sitting posture, indicating that passive sitting might have been insufficient to evoke significant neuronal activation in the postural control system in healthy subjects. Standing in tandem was accompanied by activation within the visual association cortex, anterior and posterior vermis as well as the midbrain. Standing with eyes closed activated the prefrontal cortex (Brodmann area (BA): 8/9). These results confirmed that the cerebellar vermis efferent system plays an important role in human postural control and suggested that the visual association cortex may subserve regulating postural balance while standing.

Oxygen consumption of cerebral cortex fails to increase during continued vibrotactile stimulation.

The coupling of oxidative metabolism to the blood flow of the sensory motor hand area is uncertain. The authors tested the hypothesis that continued vibrotactile stimulation ultimately must lead to increased oxygen consumption consumption. Twenty-two healthy right-handed young volunteers underwent positron emission tomography (PET) with the [(15)O]water bolus injection method to measure water clearance (K1H2O an index of blood flow (CBF), and with the [(15)O]oxygen bolus inhalation method to measure CMR(O2). The CMR(O2) was measured 30 seconds and 20 minutes after onset of intermittent (1 second on, 1 second off) vibrotactile stimulation (110 Hz) and compared with baseline measurements without stimulation. The K1H2O and CMR(O2) changes (delta K1H2O and delta CMR(O2)) were determined using intersubject averaging, together with magnetic resonance imaging based stereotaxic registration technique. The K1H2O increase was 21 +/- 4% and 12 +/- 4% at 30 seconds and 20 minutes after onset of stimulation, respectively. No significant increase of CMR(O2) was found until 30 minutes after the onset of stimulation. The authors conclude that blood flow and oxidative metabolism undergo uncoupling during sustained phasic stimulation of the sensory hand area. Therefore, neuronal activity stimulated in this manner does not rely on significantly increased oxidative phosphorylation.

Functional activation of right temporal and occipital cortex in processing tonal melodies

Cerebral blood flow changes were measured to examine the cortical basis for perceptual analysis of musical information. Twelve normal right-handed volunteers underwent positron emission tomography (PET) scanning using the bolus water technique while listening to two types of stimuli: (1) unfamiliar tonal melodies, and (2) sequences of noise bursts, acoustically matched to the melodies for duration, intensity, and onset/offset characteristics. Subtracting the latter from the former PET image provides information regarding melodic processing beyond that associated with nonspecific auditory stimulation. Anatomical localization was provided by superimposing the average PET subtraction image on the average magnetic resonance image for the subjects tested. Results indicated significant increases in blood flow while listening to melodies in the right associative auditory cortex, suggesting that specialized neural systems in the right temporal lobe participate in higher-order perceptual analysis. In addition, regions of significant activity were observed in the right occipital lobe, within areas classically described as associative visual cortex. This result may implicate these regions in hitherto unexplored aspects of auditory processings, or may possibly reflect engagement of visuospatial processing mechanisms in perception of melodies.