Fiona Pepper

Semantic Priming after Ketamine Acutely in Healthy Volunteers and Following Chronic Self-Administration in Substance Users

BACKGROUND Ketamine is used acutely as a model of schizophrenia. It has been suggested that chronic ketamine may also mimic aspects of this disorder, in particular impaired cognitive function. As semantic processing deficits are considered central to cognitive impairments in schizophrenia, this study aimed to characterize semantic impairments following both acute and chronic ketamine. METHODS We examined the acute effects of two doses of ketamine (Experiment 1) using a double-blind, placebo-controlled, independent group design with 48 volunteers. Ketamines chronic effects (Experiment 2) were explored in 16 ketamine users and 16 poly-drug controls. A semantic priming task with a frequency (high and low) and stimulus onset asynchrony (SOA: short-200 msec, long-750 msec) manipulation was used. RESULTS In Experiment 1, acute ketamine produced inverse priming at the long SOA. In Experiment 2, ketamine users showed inverse priming for low-frequency words at the long SOA compared to poly-drug controls. CONCLUSIONS The inverse priming effect at the long SOA induced by acute ketamine was indicative of controlled processing impairments. In ketamine users, there was also an indication of controlled processing impairments. Decreased priming for low-frequency words suggested that long-term ketamine abuse results in damage to the semantic store.

Glutamate, N-acetyl aspartate and psychotic symptoms in chronic ketamine users

RationaleKetamine, a non-competitive NMDA receptor antagonist, induces acute effects resembling the positive, negative and cognitive symptoms of schizophrenia. Chronic use has been suggested to lead to persistent schizophrenia-like neurobiological changes.ObjectivesThis study aims to test the hypothesis that chronic ketamine users have changes in brain neurochemistry and increased subthreshold psychotic symptoms compared to matched poly-drug users.MethodsFifteen ketamine users and 13 poly-drug users were included in the study. Psychopathology was assessed using the Comprehensive Assessment of At-Risk Mental State. Creatine-scaled glutamate (Glu/Cr), glutamate + glutamine (Glu + Gln/Cr) and N-acetyl aspartate (NAA/Cr) were measured in three brain regions—anterior cingulate, left thalamus and left medial temporal cortex using proton magnetic resonance spectroscopy.ResultsChronic ketamine users had higher levels of subthreshold psychotic symptoms (p < 0.005, Cohen’s d = 1.48) and lower thalamic NAA/Cr (p < 0.01, d = 1.17) compared to non-users. There were no differences in medial temporal cortex or anterior cingulate NAA/Cr or in Glu/Cr or Glu + Gln/Cr in any brain region between the two groups. In chronic ketamine users, CAARMS severity of abnormal perceptions was directly correlated with anterior cingulate Glu/Cr (p < 0.05, r = 0.61—uncorrected), but NAA/Cr was not related to any measures of psychopathology.ConclusionsThe finding of lower thalamic NAA/Cr in chronic ketamine users may be secondary to the effects of ketamine use compared to other drugs of abuse and resembles previous reports in individuals at genetic or clinical risk of schizophrenia.

Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

Associative blocking to reward-predicting cues is attenuated in ketamine users but can be modulated by images associated with drug use.

RationaleBlocking is an associative learning process that is attenuated in schizophrenia, can be modulated by cue salience and is accompanied by changes in selective attention. Repeated exposure to ketamine can model aspects of schizophrenia, and frequent users selectively attend to images of the drug.ObjectivesThis study aimed to establish whether (1) ketamine users show attenuated blocking to reward-predicting cues and (2) drug cues can modulate blocking and cause overshadowing of neutral cues that are equally predictive of reward in these individuals.MethodsKetamine users (n = 18) and polydrug controls (n = 16) were assessed on the Drug Cue Reward Prediction Error Task, which indexes blocking and overshadowing to neutral and drug-related cues following Pavlovian reward conditioning. Schizotypy, depression, drug history and ketamine dependence were also assessed.ResultsCompared to controls, ketamine users showed elevated delusional, schizotypal and depressive symptoms, and a reduction in blocking as evidenced by higher accuracy to blocked cues. Drug-related cues were resistant to blocking and seen as more important for earning money by ketamine users compared to controls. Both groups showed overshadowing of neutral cues by drug cues, and ketamine users gave both of these cues higher importance ratings than controls.ConclusionsThese findings provide the first evidence that (1) glutamatergic perturbation is linked to a reduction in blocking and (2) blocking can be modulated by the presence of drug-related cues. The ability of drug cues to bias selective learning about ‘alternative rewards’ has implications for contingency management based addiction treatments.

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study

Summary Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms. Methods In this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 28 healthy controls underwent 18F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from first-episode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures. Findings Glutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis (R2=0·16, p=0·03, β −1·71 × 10−4, SE 0·76 × 10−4). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0·015). In healthy controls, there was no significant relationship between dopamine and glutamate measures (R2=0·04, p=0·39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity (R2=0·14, p=0·046, β 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations (R2=0·16, p=0·03, β −1·71 × 10−4, SE 7·63 × 10−5). No relationships were seen with negative symptoms (positive symptoms, mean [SD] −18·4 (6·6) negative symptoms, mean [SD] −15·4 [6·1]). Interpretation These observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis. Funding Medical Research Council, Wellcome Trust, Biomedical Research Council, South London and Maudsley NHS Foundation Trust, JMAS Sim Fellowship, Royal College of Physicians (Edinburgh) (SJ).

9.2 BRAIN STRUCTURAL AND NEUROCHEMICAL HETEROGENEITY AND HOMOGENEITY IN PSYCHOTIC DISORDERS: TRANSDIAGNOSTIC PET AND MRI IMAGING FINDINGS IN SCHIZOPHRENIA AND BIPOLAR AFFECTIVE DISORDER

Abstract Background Psychosis is seen in a number of disorders and treated with the same drugs. However, there is considerable variability in response to treatment and clinical course. Understanding the neurobiology underlying psychosis across diagnoses and in treatment response is important to help guide the development of new treatments and biomarkers for treatment response. Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders. Methods Two cohorts of first episode patients, one with a diagnosis of schizophrenia (n=16) and another with a diagnosis of bipolar affective disorder (n=22) received 18F-DOPA PET and [1H]-MR spectroscopy imaging and clinical measures. All patients had experienced a psychotic episode and received clinical follow-up over 18 months to determine diagnostic stability. We then conducted a meta-analysis using a novel meta-analytic approach to quantify variability in measures to investigate structural and neurochemical heterogeneity in schizophrenia and bipolar affective disorder. The entire PubMed, EMBase and PsychInfo databases were searched from inception to identify relevant studies and the natural log of the measures of dispersion and the coefficient of variance. Results Striatal dopamine synthesis capacity (Kicer) was significantly elevated in both bipolar (effect size=1.02; p<0.003) and schizophrenia (effect size=0.9; p<0.05) groups, compared to controls. There was no significant difference in dopamine synthesis capacity between bipolar and schizophrenia groups (p>0.4). Kicer was significantly positively correlated with positive psychotic symptom severity in the transdiagnostic group of people with psychosis (r=0.52, p<0.004), and in the bipolar group after adjusting for manic symptom severity (r=0.6, p<0.01). There were no differences in glutamate levels in the anterior cingulate cortex. In the meta-analyses a total of 128 studies were identified including >4000 patients and >4000 controls. Variability ratio was significantly increased in patients relative to controls in gray matter volumes in temporal lobe (VR=1.1, p=0.004) and thalamus (VR=1.16, p<0.001), and in striatal dopamine receptor density (p<0.05) but unaltered in frontal cortex and significantly reduced in the anterior cingulate cortex (VR=0.9, p=0.02) Discussion Elevated dopamine synthesis capacity is associated with psychosis across diagnostic boundaries and linked to the severity of psychotic symptoms, even after adjusting for manic symptom severity. Striatal dopamine receptor density and structural gray matter volumes in a number of cortical and sub-cortical regions show heterogeneity in psychotic disorders, but frontal cortical regions show unaltered and, in the case of the anterior cingulate cortex, reduced heterogeneity, suggesting alterations are homogenous across patients. Taken together these findings striatal dopamine synthesis and structural changes in frontal cortex are common mechanisms linked to psychosis across disorders.

Mesolimbic Dopamine Function is Related to Salience Network Connectivity: An Integrative PET and MR Study

Background A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, involve abnormalities in both the mesolimbic dopamine system and the cortical salience network. Both systems play a key role in the detection of behaviorally relevant environmental stimuli. Although anatomical overlap exists, the functional relationship between these systems remains unknown. Preclinical research has suggested that the firing of mesolimbic dopamine neurons may activate nodes of the salience network, but in vivo human research is required given the species-specific nature of this network. Methods We employed positron emission tomography to measure both dopamine release capacity (using the D2/3 receptor ligand 11C-PHNO, n = 23) and dopamine synthesis capacity (using 18F-DOPA, n = 21) within the ventral striatum. Resting-state functional magnetic resonance imaging was also undertaken in the same individuals to investigate salience network functional connectivity. A graph theoretical approach was used to characterize the relationship between dopamine measures and network connectivity. Results Dopamine synthesis capacity was associated with greater salience network connectivity, and this relationship was particularly apparent for brain regions that act as information-processing hubs. In contrast, dopamine release capacity was associated with weaker salience network connectivity. There was no relationship between dopamine measures and visual and sensorimotor networks, indicating specificity of the findings. Conclusions Our findings demonstrate a close relationship between the salience network and mesolimbic dopamine system, and they are relevant to neuropsychiatric illnesses in which aberrant functioning of both systems has been observed.

Dopamine Function in Cigarette Smokers: An |[lsqb]|18F|[rsqb]|-DOPA PET Study

Tobacco addiction is a global public health problem. Addiction to tobacco is thought to involve the effects of nicotine on the dopaminergic system. Only one study has previously investigated dopamine synthesis capacity in cigarette smokers. This study, exclusively in male volunteers, reported increased dopamine synthesis capacity in heavy smokers compared with non-smokers. We sought to determine whether dopamine synthesis capacity was elevated in a larger sample of cigarette smokers that included females. Dopamine synthesis capacity was measured in 15 daily moderate smokers with 15 sex- and age-matched control subjects who had never smoked tobacco. Dopamine synthesis capacity (indexed as the influx rate constant Kicer) was measured with positron emission tomography and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine. There was no significant group difference in dopamine synthesis capacity between smokers and non-smoker controls in the whole striatum (t28=0.64, p=0.53) or any of its functional subdivisions. In smokers, there were no significant relationships between the number of cigarettes smoked per day and dopamine synthesis capacity in the whole striatum (r=−0.23, p=0.41) or any striatal subdivision. These findings indicate that moderate smoking is not associated with altered striatal dopamine synthesis capacity.

Dopamine Function in Cigarette Smokers

Tobacco addiction is a global public health problem. Addiction to tobacco is thought to involve the effects of nicotine on the dopaminergic system. Only one study has previously investigated dopamine synthesis capacity in cigarette smokers. This study, exclusively in male volunteers, reported increased dopamine synthesis capacity in heavy smokers compared with non-smokers. We sought to determine whether dopamine synthesis capacity was elevated in a larger sample of cigarette smokers that included females. Dopamine synthesis capacity was measured in 15 daily moderate smokers with 15 sex- and age-matched control subjects who had never smoked tobacco. Dopamine synthesis capacity (indexed as the influx rate constant Kicer) was measured with positron emission tomography and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine. There was no significant group difference in dopamine synthesis capacity between smokers and non-smoker controls in the whole striatum (t28=0.64, p=0.53) or any of its functional subdivisions. In smokers, there were no significant relationships between the number of cigarettes smoked per day and dopamine synthesis capacity in the whole striatum (r=−0.23, p=0.41) or any striatal subdivision. These findings indicate that moderate smoking is not associated with altered striatal dopamine synthesis capacity.