J.F. William Deakin

Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco–Magnetic Resonance Imaging Study

CONTEXT Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. OBJECTIVES To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. DESIGN Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level-dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. SETTING Wellcome Trust Clinical Research Facility, Manchester, England. PARTICIPANTS Thirty-three healthy, right-handed men were recruited by advertisements. INTERVENTIONS In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. MAIN OUTCOME MEASURES Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores. RESULTS Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. CONCLUSIONS These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

The Effect of Citalopram Pretreatment on Neuronal Responses to Neuropsychological Tasks in Normal Volunteers: An fMRI Study

Changes in serotonin neurotransmission have also been implicated in the etiology and treatment of impulse control disorders, depression, and anxiety. We have investigated the effect of enhancing serotonin function on fundamental brain processes that we have proposed are abnormal in these disorders. In all, 12 male volunteers received citalopram (7.5 mg intravenously) and placebo pretreatment in a single-blind crossover design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces. Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss (ie relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric disorders but argue for a process-specific, rather than general effect. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human psychiatric disorders.

Affective cognition and its disruption in mood disorders.

In this review, we consider affective cognition, responses to emotional stimuli occurring in the context of cognitive evaluation. In particular, we discuss emotion categorization, biasing of memory and attention, as well as social/moral emotion. We discuss limited neuropsychological evidence suggesting that affective cognition depends critically on the amygdala, ventromedial frontal cortex, and the connections between them. We then consider neuroimaging studies of affective cognition in healthy volunteers, which have led to the development of more sophisticated neural models of these processes. Disturbances of affective cognition are a core and specific feature of mood disorders, and we discuss the evidence supporting this claim, both from behavioral and neuroimaging perspectives. Serotonin is considered to be a key neurotransmitter involved in depression, and there is a considerable body of research exploring whether serotonin may mediate disturbances of affective cognition. The final section presents an overview of this literature and considers implications for understanding the pathophysiology of mood disorder as well as developing and evaluating new treatment strategies.

Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT1A receptors in ventral prefrontal cortex in schizophrenia

We previously reported increased glutamatergic innervation in orbital frontal cortex in schizophrenia. In view of the evidence that one serotonin (5-HT) receptor, the 5-HT(1A) subtype, is associated with cortical glutamatergic neurons, we have used quantitative receptor autoradiography to measure the specific binding of the 5-HT(1A) receptor ligand [3H]8-OH-DPAT (2 nM) in sections of orbital frontal cortex taken from 18 control and 12 schizophrenic postmortem brains. Schizophrenic patients, as compared with controls, had increased 5-HT(1A) receptor binding in the three orbital frontal regions examined. These effects were pronounced in the male subgroup, and were most apparent in the outer cortical laminae. These data are consistent with the hypothesis that schizophrenia is associated with an abnormal glutamatergic afferent innervation of orbital frontal cortex.

Instrumental responding for rewards is associated with enhanced neuronal response in subcortical reward systems

The response of human reward systems to different reinforcers, including food, drugs and money, has been investigated in a number of recent functional neuroimaging studies. They have varied, however, in terms of whether or not a behavioural response was required to obtain rewards. The aim of the present study was to determine whether neuronal responses to financial reward are significantly modulated by the requirement to make a behavioural response. Twelve subjects were scanned using functional magnetic resonance imaging (fMRI) while performing a simple target detection task. Certain targets acted as cues predicting financial reinforcement; some additionally required that a movement be executed, while others did not. There were also targets that required a movement but were not predictive of reward. We observed, as expected, responses within motor and reward systems associated with main effects of movement and reward, respectively. Critically, the reward responses were significantly modulated by the requirement to make an intervening behavioural response. Blood oxygenation level-dependent (BOLD) responses in the amygdala and striatum were significantly enhanced when a movement was required, while reward-related response in the orbitofrontal cortex was independent of movement. These results suggest important dissociations within human reward systems, reflecting different properties of rewards. The striatum and amygdala may mediate the function of rewards in eliciting goal-directed behaviour, while the orbitofrontal cortex mediates incentive value.

CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms

Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n=1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5′ end of the CNR1 gene significantly interacts with the 3′ end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene × environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression––and probably also for co-morbid psychiatric conditions such as substance use disorders––through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.

The CREB1-BDNF-NTRK2 Pathway in Depression: Multiple Gene-Cognition-Environment Interactions.

BACKGROUND The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression. METHODS A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design. RESULTS In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206. CONCLUSIONS Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.

Citalopram modulation of neuronal responses to aversive face emotions : a functional MRI study

This study investigated the serotonergic modulation of face emotion processing using blood oxygen level-dependent (BOLD) functional MRI. In a placebo-controlled, balanced order design, intravenous citalopram (7.5 mg) was given to 12 male volunteers 60 min before a covert face emotion recognition task. Angry, disgusted and fearful faces produced BOLD signal responses, which were broadly consistent with previous findings. Citalopram enhanced the BOLD signal response in the left posterior insula (together with nonprespecified pulvinar and visual cortex) but attenuated activation in the left amygdala to disgusted faces and right amygdala activation to fearful faces. No citalopram modulation of BOLD responses to angry faces were found. These results suggest that serotonin modulates low-level amygdala activation to aversive stimuli.

Increased amygdala responses to sad but not fearful faces in major depression: relation to mood state and pharmacological treatment

OBJECTIVE Increased amygdala response to negative emotions seen in functional MRI (fMRI) has been proposed as a biomarker for negative emotion processing bias underlying depressive symptoms and vulnerability to depressive relapse that are normalized by antidepressant drug treatment. The purpose of this study was to determine whether abnormal amygdala responses to face emotions in depression are related to specific emotions or change in response to antidepressant treatment and whether they are present as a stable trait in medication-free patients in remission. METHOD Sixty-two medication-free unipolar depressed patients (38 were currently depressed, and 24 were in remission) and 54 healthy comparison subjects underwent an indirect face-emotion processing task during fMRI. Thirty-two currently depressed patients were treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring citalopram plasma concentrations. RESULTS Patients with current depression had increased bilateral amygdala responses specific to sad faces relative to healthy comparison subjects and nonmedicated patients in stable remission. Treatment with citalopram abolished the abnormal amygdala responses to sad faces in currently depressed patients but did not alter responses to fearful faces. CONCLUSIONS Aberrant amygdala activation in response to sad facial emotions is specific to the depressed state and is a potential biomarker for a negative affective bias during a depressive episode.

Regionally selective deficits in uptake sites for glutamate and gamma-aminobutyric acid in the basal ganglia in schizophrenia

In a post-mortem study of schizophrenic and control subjects, the sodium-dependent binding of D-[3H]aspartate and [3H]nipecotic acid were used to investigate uptake sites of glutamate and gamma-aminobutyric acid (GABA), respectively, in subcortical brain regions. Binding to the glutamate uptake site was substantially reduced in both the putamen and lateral pallidum of the schizophrenic subjects. Binding to the GABA uptake site was substantially reduced in the putamen; smaller reductions were apparent in the caudate nucleus and lateral pallidum. The results suggest that glutamatergic and GABAergic mechanisms in the basal ganglia are abnormal in schizophrenia. These abnormalities could be relevant to the development of psychosis but could also relate to the spectrum of mild motor disturbances often described in the disease.