Andrea L. Malizia

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brains key connector hubs, enabling a state of unconstrained cognition.

First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635

The selective 5-HT1A receptor radioligand, [11C]WAY-100635 ([11C]N-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2- pyridyl)cyclohexanecarboxamide), has been injected intravenously into healthy male volunteers and studied by PET (positron emission tomography). The results provide the first delineation of 5-HT1A receptors in living human brain and demonstrate the potential to use [11C]WAY-100635 for the study of central 5-HT1A receptors in patients with psychiatric and neurological disorders and for the investigation of the pharmacology of drugs acting on the central nervous system.

What do brain imaging studies tell us about anxiety disorders

In-vivo neuroimaging allows the investigation of brain circuits involved in the experience of anxiety and of receptor changes associated with anxiety disorders. This review focuses on studies by research groups who have compared brain activation maps in different forms of anxiety and on binding studies of the benzodiazepine-GABAA receptor. Activation studies have revealed the involvement of many brain areas depending on the condition and the paradigm. However, the orbitofrontal cortex/anterior insula and the anterior cingulate are implicated in all the studies and may represent the nodal point between somatic and cognitive symptoms of any form of anxiety. Most studies of binding at the benzodiazepine-GABAA receptor are not interpretable because of substantial methodological problems, however, regional and/or global reductions are the most consistent finding in panic disorder.

The neurobiology of social phobia.

Abstract Although Social Phobia has been recognised for centuries in comparison with other anxiety disorders, relatively little work has been done to understand its neural basis. The present review attempts to redress this balance by giving an overview of the current state of knowledge in this disorder. By putting together data from the treatment responses to specific agents, the effects of chemical challenges which have been used in other anxiety disorders and by reviewing data on central and peripheral neurotransmitter and endochrine abnormalities, it is possible to begin to generate some potentially testable therories of aetiology and mechanisms. Finally, we review the potential use of neuroimaging techniques to better detail the brain circuits and possibly neurotransmitters involved in social phobia, showing some of our preliminary work using 15O water blood flow PET activation studies to determine the brain circuits in which metabolism is changed during the experience of social anxiety.

Naloxone displacement at opioid receptor sites measured in vivo in the human brain

We report the use of a sensitive non-tomographic positron detecting system to measure the dose-response curve of naloxone in human brain. [11C]Diprenorphine was administered to normal volunteers in tracer amounts and, 30 min later, various bolus doses of naloxone were given (1.5-160 microg/kg) intravenously and change in [11C]diprenorphine binding monitored over the next 30 min. We found that this method produced results consistent with existing data. It was observed that approximately 13 microg/kg of naloxone ( approximately 1 mg in an 80 kg man) was required to produce an estimated 50% receptor occupation. This is consistent with the clinical dose of naloxone used to reverse opiate overdose (0.4 mg-1.2 mg).

The frontal lobes and neurosurgery for psychiatric disorders

The frontal lobe has been the main target for surgical treatment of mental illness over the last 60 years. Initially the surgery was crude and performed on patients with many different psychiatric disorders. Contemporary surgery utilizes stereotactic lesions which interrupt fronto-thalamic and/or fronto-cingulate fibres. The findings of clinical, neurochemical, neuroimaging, neuropsychological and physiological research in this area are summarized. Current advances in clinical neuroscience methods should be used in patients with these lesions to elucidate the neural substrate of post-operative changes and optimize clinical practice.

Venlafaxine occupation at the noradrenaline reuptake site: in-vivo determination in healthy volunteers

Venlafaxine, a serotonin and noradrenaline reuptake inhibitor, is an effective antidepressant at doses of 75 mg p.o. daily and above. Preclinical and healthy volunteer studies have demonstrated that venlafaxine is more potent at the serotonin than at the noradrenaline reuptake site, with noradrenergic blocking effects being observed at doses >75 mg p.o. in man. We used the Multiple Organs Coincidences Counter and [11C] meta hydroxy ephedrine (MHED) to test whether significant occupation of cardiac sympathetic neurones was achieved in man in vivo after the acute administration of venlafaxine 75 mg p.o. in nine healthy volunteers. MHED is a tracer which binds at the noradrenaline reuptake site. This study demonstrates that the [11C]MHED signal is significantly reduced after the administration of venlafaxine 75 mg p.o. thus showing that noradrenaline reuptake blockade is observable at this dose. This effect is predominantly seen in volunteers who received > 1 mg/kg venlafaxine.

Analysis of dynamic radioligand displacement or ''activation'' studies

We present a simple way of assessing dynamic or time-dependent changes in displacement during single-subject radioligand positron emission tomography (PET) activation studies. The approach is designed to facilitate dynamic activation studies using selective radioligands. These studies are, in principle, capable of characterising functional neurochemistry by analogy with the study of functional neuroanatomy using rCBF activation studies. The proposed approach combines time-dependent compartmental models of tracer kinetics and the general linear model used in statistical parametric mapping. This provides for a comprehensive, voxel-based and data-led assessment of regionally specific effects. The statistical model proposed in this paper is predicated on a single-compartment model extended to allow for time-dependent changes in kinetics. We have addressed the sensitivity and specificity of the analysis, as it would be used operationally, by applying the analysis to 11C-Flumazenil dynamic displacement studies. The activation used in this demonstration study was a pharmacological (i.v. midazolam) challenge, 30 min after administration of the tracer. We were able to demonstrate, and make statistical inferences about, regional increases in k2 (or decreases in the volume of distribution) in prefrontal and other cortical areas.

Benzodiazepine receptors and positron emission tomography : ten years of experience. A new beginning ?

neuroscience to describe brain metabolic changes which accompany mental processing and pathology. In psychopharmacology most of the published human literature has explored two areas: dopamine D-2 receptors and benzodiazepine sites on the GABAA complex. The discovery of a benzodiazepine-sensitive allosteric modulatory site on the GABAA receptor ionophore complex (Mohler and Okada, 1977) and the continuing conceptual evolution of its molecular (Delorey and Olsen, 1992; Schofield

A new human (psycho)pharmacology tool : the multiple organs coincidences counter (MOCC)

We describe a novel instrument which is capable of measuring the uptake of radioligand in human organs in vivo with the administration of very small doses of positron-emitting radioligands. This technique readily detects the displacement or reduced uptake of radioligand when a competitive agonist or antagonist is administered. This system provides no tomographic information, but the small radioactive doses involved mean that investigations can be repeated at regular intervals and that female volunteers can also participate. We administered [11 C]flumazenil, [11C]diprenorphine, [11C]meta -hydroxyephedrine (MHED) and [11C]RTI 55 to healthy male volunteers and performed control, pre-loading and displacement experiments. These demonstrate the feasibility of using this technique to investigate benzodiazepine and opiate receptor occupancy, as well as occupancy at dopamine, noradrenaline and serotonin (5-HT) re-uptake sites. This method is likely to be useful in pharmacokinetic/pharmacodynamic experiments, in drug development and discovery and in the development of novel imaging radioligands.