Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of δ-9-THC

AbstractBackgroundCannabis and its main psychoactive ingredient δ-9-tetrahydrocannibidiol (THC) can induce transient psychotic symptoms in healthy individuals and exacerbate them in those with established psychosis. However, not everyone experience these effects, suggesting that certain individuals are particularly susceptible. The neural basis of this sensitivity to the psychotomimetic effects of THC is unclear.MethodsWe investigated whether individuals who are sensitive to the psychotomimetic effects of THC (TP) under experimental conditions would show differential hippocampal activation compared with those who are not (NP). We studied 36 healthy males under identical conditions under the influence of placebo or THC (10 mg) given orally, on two separate occasions, in a pseudo-randomized, double-blind, repeated measures, within-subject, cross-over design, using psychopathological assessments and functional MRI while they performed a verbal learning task. They were classified into those who experienced transient psychotic symptoms (TP; n = 14) following THC administration and those who did not (NP; n = 22).ResultsUnder placebo conditions, there was significantly greater engagement of the left hippocampus (p < 0.001) in the TP group compared with the NP group during verbal encoding, which survived leave-one-out analysis. The level of hippocampal activation was directly correlated (Spearman's ρ = 0.44, p = 0.008) with the severity of transient psychotic symptoms induced by THC. This difference was not present when we compared two subgroups from the same sample that were defined by sensitivity to anxiogenic effects of THC.ConclusionsThese results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC.

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Theta-gamma cross-frequency transcranial alternating current stimulation over the trough impairs cognitive control

10.31234/osf.io/4y3uh ◽

2020 ◽

Author(s):

Zsolt Turi ◽

Matthias Mittner ◽

Albert Lehr ◽

Hannah Bürger ◽

Andrea Antal ◽

...

Keyword(s):

Cognitive Control ◽

Repeated Measures ◽

Instrumental Learning ◽

Learning Task ◽

Alternating Current ◽

Double Blind ◽

Bayesian Hierarchical ◽

Theta Wave ◽

Gamma Frequency ◽

Transcranial Alternating Current Stimulation

Cognitive control is a hypothetical mental process, which underlies adaptive goal-directed decisions. Previous studies have linked cognitive control to electrophysiological fluctuations in the theta band and theta-gamma cross-frequency coupling (CFC) arising from the cingulate and frontal cortices. Yet, to date the behavioral consequences of different forms of theta-gamma CFC remain elusive. Here, we studied the behavioral effects of the theta-gamma CFC via transcranial alternating current stimulation (tACS) designed to stimulate the frontal and cingulate cortices. Using a double-blind, randomized, repeated measures study design, 24 healthy participants were subjected to three main, active CFC-tACS protocols: Short gamma frequency bursts (80 Hz) were coupled to an ongoing theta cycle (4 Hz) to coincide with either the peaks or the troughs of the theta wave. In a third condition, the amplitude of the gamma oscillation was modulated by the phase of a theta cycle. In the fourth, control protocol, gamma was continuously superimposed over the theta cycle, therefore lacking any phase-specificity in the CFC. During the 20-minute stimulations, the participants performed a Go/NoGo monetary reward- and punishment-based instrumental learning task. A Bayesian hierarchical logistic regression analysis revealed that CFC-tACS over peak had no effects on the behavioral performance, whereas CFC-tACS over trough and, to a lesser extent, amplitude-modulated tACS reduced performance in conflicting trials. Our results suggest that cognitive control depends on the phase-specificity of the theta-gamma CFC.

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12 tDCS modulation of pavlovian bias under intermittent loss of control

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-bnpa.30 ◽

2020 ◽

Vol 91 (8) ◽

pp. e12.3-e13

Author(s):

Terezie Lekscha Sedlinská ◽

Lara Bolte ◽

Eirik Melsæter ◽

Gábor Csifcsák ◽

Matthias Mittner

Keyword(s):

Repeated Measures ◽

Learning Task ◽

Loss Of Control ◽

Learning From Experience ◽

Double Blind ◽

Healthy Humans ◽

Cortical Responses ◽

Human Functioning ◽

The Face ◽

Response Feedback

Objectives/AimsLearning from experience and making decisions based on integrated environmental feedback is crucial for human functioning and wellbeing. Difficulties in learning and decision-making have been found in several psychiatric conditions. Pavlovian bias, a tendency to approach reward and remain passive in the face of punishment, can be advantageous in some situations, while in others, it can lead to maladaptive decisions and needs to be overcome by cognitive control. It has been suggested that healthy humans rely more heavily on Pavlovian bias when instrumental control over environmental reinforcers is compromised. In our study, we were focusing on the influence of transcranial direct current stimulation (tDCS) on Pavlovian bias during and after an intermittent loss of control over rewards and losses.MethodsIn our pilot study, 19 adults underwent three blocks of an orthogonalized go-nogo reinforcement learning task. Blocks 1 and 3 had a response-feedback contingency of 70–30%, enabling learning via trial-and-error. In the second block, the outcome was independent of the participants’ responses (50%-50% contingency level). Cortical responses of all participants were recorded via EEG. Multi-electrode tDCS targeting the medial prefrontal cortex was administered in a randomised, double-blind placebo-controlled manner.ResultsWe conducted a repeated-measures ANOVA with ‘session’ (PRE x tDCS x POST), ‘valence’ (Win x Avoid) and ‘PB-congruency’ (Pavlovian bias congruent x incongruent) as within-factors, ‘group’ (Active stimulation x Sham) as the between- factor and ‘accuracy’ as the dependent variable. The interaction of ‘session’ and ‘PB- congruency’ with F(2,16)=2.62, p=0.09 were marginally significant, pointing towards slightly enhanced Pavlovian bias in the second block. However, the interaction of ‘session’, ‘PB-congruency’ and ‘group’ was not significant (F(2,16)=0.46, p=0.63). The evaluation of the feedback-related negativity (FRN) in the EEG revealed gradually increasing amplitudes in reward trials in the sham group, whereas we found a trend towards reduced FRN amplitude in the active group with F(2,13)=2.83, p=0.08.ConclusionsOur preliminary data show that a loss of control over feedbacks might increase the effect of Pavlovian bias on the choices of all participants. Although active tDCS seems to attenuate cortical responses during feedback evaluation, this effect is not accompanied by alterations in choice behaviour. Our data collection is still ongoing. The results from the full sample of 50 participants will be analysed by February 2020.

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Neurofunctional Effects of Cannabis on Response Inhibition

European Psychiatry ◽

10.1016/s0924-9338(09)70441-9 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1 ◽

Cited By ~ 1

Author(s):

S. Borgwardt ◽

P. Allen ◽

S. Bhattacharyya ◽

P. Fusar-Poli ◽

J.A. Crippa ◽

...

Keyword(s):

Response Inhibition ◽

Repeated Measures ◽

Temporal Cortex ◽

Brain Regions ◽

Anterior Cingulate ◽

Psychotic Symptoms ◽

Double Blind ◽

Subject Design ◽

Mediate Response ◽

The Right

Background:This study examined the effect of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task.Methods:Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled repeated measures within-subject design.Results:Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms.Conclusions:These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated function in regions not usually implicated in response inhibition.

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Opposite Neural Effects of the Main Psychoactive Ingredients of Cannabis- Neural Basis for Potential Therapeutic Effects of Cannabidiol

European Psychiatry ◽

10.1016/s0924-9338(09)70924-1 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

S. Bhattacharyya ◽

P. Fusar-Poli ◽

S. Borgwardt ◽

R. Martin-Santos ◽

C. Carroll ◽

...

Keyword(s):

Repeated Measures ◽

Psychotic Disorders ◽

Therapeutic Potential ◽

Memory Task ◽

Neural Substrates ◽

Psychotic Symptoms ◽

Therapeutic Effects ◽

Neural Basis ◽

Repeated Measures Design ◽

Opposing Effects

There is considerable interest in the therapeutic potential of Cannabidiol (CBD), the second most abundant component of Cannabis. While delta-9-THC, the main psychoactive ingredient of cannabis, impairs memory and induces anxiety and psychotic symptoms acutely and increases the risk of psychotic disorders in regular cannabis users, CBD does not impair memory, may have anxiolytic and possibly antipsychotic effects. Hence, we compared directly the acute neural effects of these two active ingredients of cannabis, by combining pharmacological challenge with fMRI. Using a double-blind, repeated measures design and oral challenge with 10mg of delta-9-THC, 600mg of CBD or placebo in 15 healthy volunteers, we examined whether delta-9-THC and CBD have opposing effects on the neural substrates of verbal memory and fear processing and whether they also have opposing effects on the neural substrates of anxiety and psychotic symptoms induced by delta-9-THC. Delta-9-THC induced anxiety and psychotic symptoms acutely while there was a trend for a reduction in anxiety but no change in psychotic symptoms with CBD. During the memory task, delta-9-THC attenuated and CBD increased activation in the striatum bilaterally. Effect of delta-9-THC on striatal activation was inversely correlated with the psychotic symptoms induced by it concomitantly. During the processing of fearful faces, delta-9-THC increased and CBD attenuated activation in the amygdala and these effects correlated with their anxiogenic and anxiolytic effects respectively. These opposing effects of CBD on the key neural substrates for psychotic symptoms and anxiety induced by delta-9-THC may suggest its possible therapeutic role in countering these conditions.

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tDCS-Induced Memory Reconsolidation Effects and Its Associations With Structural and Functional MRI Substrates in Subjective Cognitive Decline

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.695232 ◽

2021 ◽

Vol 13 ◽

Author(s):

Lídia Vaqué-Alcázar ◽

Lídia Mulet-Pons ◽

Kilian Abellaneda-Pérez ◽

Cristina Solé-Padullés ◽

María Cabello-Toscano ◽

...

Keyword(s):

At Risk ◽

Cognitive Decline ◽

Functional Mri ◽

Memory Performance ◽

Verbal Learning ◽

Learning Task ◽

Memory Reconsolidation ◽

Subjective Cognitive Decline ◽

Experimental Session ◽

Double Blind

Previous evidence suggests that transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex (l-DLPFC) can enhance episodic memory in subjects with subjective cognitive decline (SCD), known to be at risk of dementia. Our main goal was to replicate such findings in an independent sample and elucidate if baseline magnetic resonance imaging (MRI) characteristics predicted putative memory improvement. Thirty-eight participants with SCD (aged: 60–65 years) were randomly assigned to receive active (N = 19) or sham (N = 19) tDCS in a double-blind design. They underwent a verbal learning task with 15 words (DAY-1), and 24 h later (DAY-2) stimulation was applied for 15 min at 1.5 mA targeting the l-DLPFC after offering a contextual reminder. Delayed recall and recognition were measured 1 day after the stimulation session (DAY-3), and at 1-month follow-up (DAY-30). Before the experimental session, structural and functional MRI were acquired. We identified a group∗time interaction in recognition memory, being the active tDCS group able to maintain stable memory performance between DAY-3 and DAY-30. MRI results revealed that individuals with superior tDCS-induced effects on memory reconsolidation exhibited higher left temporal lobe thickness and greater intrinsic FC within the default-mode network. Present findings confirm that tDCS, through the modulation of memory reconsolidation, is capable of enhancing performance in people with self-perceived cognitive complaints. Results suggest that SCD subjects with more preserved structural and functional integrity might benefit from these interventions, promoting maintenance of cognitive function in a population at risk to develop dementia.

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Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study

Journal of Psychopharmacology ◽

10.1177/0269881120922967 ◽

2020 ◽

Vol 34 (8) ◽

pp. 839-847 ◽

Cited By ~ 1

Author(s):

Kate Merritt ◽

Ana Catalan ◽

Samuel Cowley ◽

Arsime Demjaha ◽

Matthew Taylor ◽

...

Keyword(s):

Nitric Oxide ◽

Glyceryl Trinitrate ◽

Verbal Memory ◽

Alternative Hypothesis ◽

Controlled Trial ◽

Verbal Learning ◽

Nitric Oxide Donor ◽

Psychotic Symptoms ◽

First Episode ◽

Double Blind

Background: There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent studies of SNP in patients with psychosis have mixed results, and the drug has to be administered intravenously. Glyceryl trinitrate (GTN) is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. Aims: We explored the safety and potential effects of GTN in unmedicated patients with a first episode of psychosis. Methods: This was a single-centre, randomised, double-blind, placebo-controlled trial from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients received 3 × sprays of GTN or placebo for three consecutive days, and were re-assessed on Days 1, 2, 3 and 7. The primary outcome was cognition (Jumping to Conclusions task), secondary outcomes were symptoms (Positive and Negative Syndrome Scale (PANSS)), verbal memory (Hopkins Verbal Learning task), and mood (Bond–Lader Visual Analogue Scales). Results: Nineteen patients were randomised, and 13 participants were included in the analyses. Compared with placebo, GTN was well tolerated, but was not associated with significant effects on cognition, symptoms, or mood. Bayesian statistics indicate that our results were 2× more likely under the null hypothesis than the alternative hypothesis, providing anecdotal evidence that GTN does not improve psychotic symptoms. Conclusions: We found no indication of an effect of GTN on symptoms of psychosis or cognition.

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Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control

Psychological Medicine ◽

10.1017/s0033291714000920 ◽

2014 ◽

Vol 44 (15) ◽

pp. 3315-3328 ◽

Cited By ~ 28

Author(s):

S. Bhattacharyya ◽

C. Iyegbe ◽

Z. Atakan ◽

R. Martin-Santos ◽

J. A. Crippa ◽

...

Keyword(s):

Protein Kinase ◽

Repeated Measures ◽

Road Traffic ◽

Protein Kinase B ◽

Inferior Frontal Gyrus ◽

Physiological Effect ◽

Individual Variability ◽

Neural Basis ◽

Double Blind ◽

Repeated Measures Design

Background.What determines inter-individual variability to impairments in behavioural control that may underlie road-traffic accidents, and impulsive and violent behaviours occurring under the influence of cannabis, the most widely used illicit drug worldwide?Method.Employing a double-blind, repeated-measures design, we investigated the genetic and neural basis of variable sensitivity to cannabis-induced behavioural dyscontrol in healthy occasional cannabis users. Acute oral challenge with placebo or Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was combined with functional magnetic resonance imaging, while participants performed a response inhibition task that involved inhibiting a pre-potent motor response. They were genotyped for rs1130233 single nucleotide polymorphisms (SNPs) of the protein kinase B (AKT1) gene.Results.Errors of inhibition were significantly (p = 0.008) increased following administration of THC in carriers of the A allele, but not in G allele homozygotes of theAKT1rs1130233 SNP. The A allele carriers also displayed attenuation of left inferior frontal response with THC evident in the sample as a whole, while there was a modest enhancement of inferior frontal activation in the G homozygotes. There was a direct relationship (r = − 0.327,p = 0.045) between the behavioural effect of THC and its physiological effect in the inferior frontal gyrus, whereAKT1genotype modulated the effect of THC.Conclusions.These results require independent replication and show that differing vulnerability to acute psychomotor impairments induced by cannabis depends on variation in a gene that influences dopamine function, and is mediated through modulation of the effect of cannabis on the inferior frontal cortex, that is rich in dopaminergic innervation and critical for psychomotor control.

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T40. GLYCERYL TRINITRATE IN FIRST EPISODE PSYCHOSIS UNMEDICATED WITH ANTIPSYCHOTICS: A RANDOMISED CONTROLLED FEASIBILITY STUDY

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.600 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S246-S247

Author(s):

Kate Merritt ◽

Ana Catalan ◽

Samuel Cowley ◽

Arsime Demjaha ◽

Matthew Taylor ◽

...

Keyword(s):

Nitric Oxide ◽

Clinical Trials ◽

Controlled Trial ◽

Verbal Learning ◽

Nitric Oxide Donor ◽

Psychotic Symptoms ◽

First Episode ◽

Nitric Oxide Donors ◽

Double Blind ◽

Randomised Controlled

Abstract Background There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent early phase studies of SNP in patients with psychosis have had mixed results, and the drug has to be administered intravenously. GTN is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. We explored the safety and effectiveness of GTN in unmedicated patients with a first episode of psychosis. Methods A single-centre, randomized, double-blind, placebo-controlled trial was conducted from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients with a first episode of psychosis were recruited from the South London and Maudsley NHS Trust, London, UK. Nineteen patients were randomised to receive 3 x sprays of GTN or placebo for 3 consecutive days, and re-assessed on Day 7. Thirteen participants were included in the final analyses. At each assessment point, symptom levels were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive performance was evaluated using the Jumping to Conclusions (JTC) and the Hopkins Verbal Learning (HVLT) tasks. Results Compared to placebo, GTN was well tolerated, but it was not associated with significant effects on either psychotic symptoms or cognition. Bayesian statistics indicated with moderate confidence that GTN does not have a therapeutic effect. Discussion This study indicates that nitric oxide donors are not therapeutically beneficial in psychosis. It also highlights the difficulties in recruiting unmedicated patients with psychosis. Future clinical trials would benefit from frameworks built into clinical services, to signpost patients not responding to medication and those discontinuing medication to clinical trials of alternatives.

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O5.2. CBD MODULATION OF HIPPOCAMPAL GLUTAMATE IN PSYCHOSIS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa028.025 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S11-S11

Author(s):

Aisling O’Neill ◽

Luciano Annibale ◽

Grace Blest-Hopley ◽

Robin Wilson ◽

Sagnik Bhattacharyya

Keyword(s):

Drug Administration ◽

Repeated Measures ◽

Placebo Treatment ◽

Psychotic Symptoms ◽

Resonance Spectroscopy ◽

Treatment Change ◽

Double Blind ◽

Antipsychotic Effect ◽

Syndrome Scale ◽

Dopaminergic Neurotransmitter

Abstract Background Emerging evidence supports the antipsychotic effect of cannabidiol (CBD), a non-intoxicating component of cannabis, in people with psychosis. However, how CBD might exert its antipsychotic effect remains unclear. While current antipsychotic medications typically target the dopaminergic neurotransmitter system, preclinical findings suggest that CBD may directly or indirectly affect multiple distinct modes of neural signalling, including both glutamate and dopamine. However, no study has as yet investigated the effect of CBD on brain glutamate levels in patients with psychosis as a potential mechanism underlying its antipsychotic effects. Methods We investigated the effects of a single oral dose of CBD (600mg), compared to a matched placebo, in patients within 5 years of onset of psychosis, using a double-blind, randomized, placebo-controlled, repeated-measures, within-subject cross-over design, with at least a one-week interval between scans to allow washout of CBD. After drug administration, 13 patients (mean age 27.73, 66.7% male) were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was assessed using the Positive and Negative syndrome scale (PANSS) 60mins before drug administration (T1, pre scan), and 270mins after drug administration (T2, post scan). Effects of CBD on left hippocampal glutamate levels, symptoms, and correlations between hippocampal glutamate and symptoms were investigated. Results Compared to placebo, there was a significant increase in left hippocampal glutamate in the psychosis patients under CBD treatment (z= -1.80; p=0.035). Under placebo treatment, change in positive psychotic symptoms (as indexed using the T1 minus T2 PANSS positive symptoms subscale scores) was directly correlated with left hippocampal glutamate levels (rho= 0.69, p=0.004), such that symptoms increased as hippocampal glutamate levels decreased. This significant relationship was not observed under the CBD treatment (rho= 0.102, p=0.72). Discussion This suggests that positive psychotic symptoms may be driven by abnormal hippocampal glutamate concentration, which is sensitive to modulation by CBD. These findings are in keeping with the purported antipsychotic effects of CBD in psychosis, and provide novel insight into the neurochemical interactions underlying these effects.

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Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis

Psychological Medicine ◽

10.1017/s0033291719003519 ◽

2020 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Aisling O'Neill ◽

Robin Wilson ◽

Grace Blest-Hopley ◽

Luciano Annibale ◽

Marco Colizzi ◽

...

Keyword(s):

Functional Connectivity ◽

Repeated Measures ◽

Block Design ◽

Study Drug ◽

Learning Task ◽

Blood Oxygen Level Dependent ◽

Antipsychotic Treatment ◽

Blood Oxygen Level ◽

Double Blind ◽

Associate Learning

Abstract Background Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown. Methods Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest. Results Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients. Conclusions This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

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