Laurence Reed

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.

Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine- induced psychopathology

Preclinical studies suggest that ketamine-induced psychopathology is mediated, in part, by increased glutamate release, hypothesized to occur via inhibition of GABAergic interneurons. Using proton magnetic resonance spectroscopy (1H-MRS), we tested this hypothesis in healthy humans. Ketamine increased anterior cingulate cortex glutamate levels, which correlated with the degree of positive psychotic symptoms. Ketamine did not affect subcortical gamma-aminobutyric acid (GABA) levels.

Attenuation of Insulin-Evoked Responses in Brain Networks Controlling Appetite and Reward in Insulin Resistance The Cerebral Basis for Impaired Control of Food Intake in Metabolic Syndrome?

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [18F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 ± 5.2 and 23.2 ± 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P < 0.001), relative to global brain. Insulin’s effect was less in ventral striatum and prefrontal cortex in the insulin-resistant subjects (mean ± SD for right ventral striatum 3.2 ± 3.9 vs. 7.7 ± 1.7, P = 0.017). We conclude that brain insulin resistance exists in peripheral insulin resistance, especially in regions subserving appetite and reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

Nicotine Dependence Is Characterized by Disordered Reward Processing in a Network Driving Motivation

BACKGROUND Drug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward. METHODS We applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers. RESULTS Occasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward. CONCLUSIONS This imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction.

FDG-PET findings in the Wernicke-Korsakoff syndrome.

This study reports FDG-PET findings in Wernicke-Korsakoff patients. Twelve patients suffering amnesia arising from the Korsakoff syndrome were compared with 10 control subjects without alcohol-related disability. Subjects received [18F]-fluorodeoxyglucose (FDG-PET) imaging as well as neuropsychological assessment and high-resolution MR imaging with volumetric analysis. Volumetric MRI analysis had revealed thalamic and mamillary body atrophy in the patient group as well as frontal lobe atrophy with relative sparing of medial temporal lobe structures. Differences in regional metabolism were identified using complementary region of interest (ROI) and statistical parametric mapping (SPM) approaches employing either absolute methods or a reference region approach to increase statistical power. In general, we found relative hypermetabolism in white matter and hypometabolism in subcortical grey matter in Korsakoff patients. When FDG uptake ratios were examined with occipital lobe metabolism as covariate reference region, Korsakoff patients showed widespread bilateral white matter hypermetabolism on both SPM and ROI analysis. When white matter metabolism was the reference covariate; Korsakoff patients showed relative hypometabolism in the diencephalic grey matter, consistent with their known underlying neuropathology, and medial temporal and retrosplenial hypometabolism, interpreted as secondary metabolic effects within the diencephalic-limbic memory circuits. There was also evidence of a variable degree of more general frontotemporal neocortical hypometabolism on some, but not all, analyses.

GABAB Receptors in Addiction and Its Treatment

The GABA(B) receptor plays an important role in the control of neurotransmitter release, and experiments using preclinical models have shown that modulation of this receptor can have profound effects on the reward process. This ability to affect the reward process has led to clinical investigations into the possibility that this could be a viable target in the treatment of addiction. Presented here is an overview of a number of studies testing this hypothesis in different drug dependencies. The studies reviewed have used the GABA(B) receptor agonist baclofen, which is currently the only GABA(B) agonist for use in humans. In addition, studies using the non-specific GABA(B) receptor agonists vigabatrin and tiagabine have been included. In some of the studies these were found to have efficacy in the initiation and maintenance of abstinence, as an anti-craving treatment and alleviation of withdrawal syndromes, while in other studies showing limited effects. However, there is enough evidence to suggest that modulators of the GABA(B) receptor have potential as adjunct treatments to aid in the initiation of abstinence, maintenance of abstinence, and prevention of cue-related relapse in some addictions. This potential is at present poorly understood or studied and warrants further investigation.

Mapping the brain in younger and older asymptomatic HIV-1 men: Frontal volume changes in the absence of other cortical or diffusion tensor abnormalities

INTRODUCTION Over the past decade the developments made in treating people with human immune deficiency virus (HIV) have greatly improved quality of life and life expectancy. However, the nature of asymptomatic HIV-associated minor neurocognitive disorder (HAND) remains unclear. In this study we explored the occurrence of neuropsychological and neuroimaging changes in medically and psychiatrically stable HIV-1 infected patients on highly active antiretroviral treatment (HAART) from two separate age groups. METHODS Participants included 20 HIV-1 infected younger (aged 20-40) and 20 HIV-1 older patients (aged 50-75). Comparisons were made with 20 age- and education-matched younger and 22 matched older healthy seronegative males. Participants were stable on treatment and asymptomatic at study onset with undetectable HIV-1 viral loads, and free of medical or psychiatric co-morbidity, alcohol or substance misuse. A detailed neuropsychological assessment was used and volumetric-magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) performed to assess grey and white-matter integrity. RESULTS We found significant effects of ageing on memory, grey and white matter measures. Comparison of the HIV-positive and HIV-negative groups did not show significant differences on the neuropsychological tests after Bonferroni correction, and there were no significant age by HIV status interactions. However, we did find reduced grey matter volume on MRI in our HIV-positive participants within the medial and superior frontal gyri. We also found significant ageing effects in fronto-temporal grey and white matter, independent of the effect of HIV. CONCLUSIONS The results from this study suggest that HIV-1 disease by itself does not significantly impair cognitive function when patients are otherwise asymptomatic. Nevertheless, the imaging techniques were sensitive enough to detect subtle grey matter changes not normally evident until much later in the disease. If confirmed in a longitudinal study this frontal grey matter change could represent an important biomarker for trials in HIV disease.

Attenuation of Amydgala and Frontal Cortical Responses to Low Blood Glucose Concentration in Asymptomatic Hypoglycemia in Type 1 Diabetes: A New Player in Hypoglycemia Unawareness?

OBJECTIVE—Loss of ability to recognize hypoglycemia (hypoglycemia unawareness) increases risk of severe hypoglycemia threefold in insulin-treated diabetes. We set out to investigate the cerebral correlates of unawareness in type 1 patients. RESEARCH DESIGN AND METHODS—Regional changes in brain glucose kinetics were measured using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), in 13 men with type 1 diabetes—6 with hypoglycemia awareness and 7 with hypoglycemia unawareness—at euglycemia (5 mmol/l) and hypoglycemia (2.6 mmol/l), in random order. RESULTS—Epinephrine responses to hypoglycemia were reduced in hypoglycemia unawareness (P < 0.0003), as were symptoms. Statistical parametric mapping (SPM) of FDG uptake using SPM2 at a statistical threshold of P < 0.005 showed increased FDG uptake in left amygdala in hypoglycemia awareness, but not in hypoglycemia unawareness (region of interest analysis −0.40 ± 1.03 vs. 3.66 ± 0.42, respectively; P = 0.007), and robust increase in bilateral ventral striatum during hypoglycemia (region of interest analysis hypoglycemia unawareness 3.52 ± 1.02 vs. awareness 6.1 ± 0.53; P = 0.054). Further analysis at the statistical threshold of P < 0.01 showed bilateral attenuated activation of brain stem regions and less deactivation in lateral orbitofrontal cortex in hypoglycemia unawareness. CONCLUSIONS—Ventral striatal, amygdala, brain stem, and orbitofrontal responses to hypoglycemia indicate engagement of appetitive motivational networks, associated with integrated behavioral responses to hypoglycemia. Reduced responses in these networks in hypoglycemia unawareness, particularly failure of amygdala and orbifrontal cortex responses, suggest habituation of higher behavioral responses to hypoglycemia as a basis for unawareness. New approaches may be needed to restore awareness effectively in practice.

Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents.

Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder).

FDG-PET Analysis and Findings in Amnesia Resulting From Hypoxia

The assumptions underlying neuroimaging, and problems in its analysis and interpretation, are commonly underestimated in neuropsychology. The ways in which fluoro-deoxy-glucose (FDG) positron emission tomography (PET) data can be analysed are discussed. PET findings from four patients who had suffered severe amnesia, following episodes of acute hypoxia, are presented. These patients had shown evidence of medial temporal (hippocampal and parahippocampal) atrophy on MRI brain scans. The PET data were analysed in several different ways. The converging findings were that the patients showed bilateral thalamic hypometabolism, and there was also evidence of retrosplenial hypometabolism bilaterally. Cognitively, these patients performed most like other patients with medial temporal lesions, but the results indicate that structural lesions can have distal metabolic effects on structures elsewhere. These findings are interpreted in the light of neuroanatomical observations concerning parallel projections between medial temporal lobe structures and the thalamus, some of which pass via the retrosplenium.