Judith Nottage

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ2=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Disruption of Frontal Theta Coherence by Δ9-Tetrahydrocannabinol is Associated with Positive Psychotic Symptoms

The main ingredient in cannabis, Δ9-tetrahydrocannabinol (THC), can elicit acute psychotic reactions in healthy individuals and precipitate relapse in schizophrenic patients. However, the neural mechanism of this is unknown. We tested the hypothesis that THC psychopathology is related to changes in electroencephalography (EEG) power or inter-regional coherence. In a within-subjects design, participants (n=16) were given intravenous THC (1.25 mg) or placebo under double-blind conditions, during EEG recordings. Using fast-Fourier transform, EEG data were analyzed for power and coherence in the delta (1–3.5 Hz), theta (3.5–7 Hz), alpha (8–13 Hz), beta (14–25 Hz), low-gamma (30–40 Hz), and high-gamma (60–70 Hz) bands during engagement in the n-back test of working memory (WM). Compared with placebo, THC evoked positive and negative psychotic symptoms, as measured by the positive and negative syndrome scale (p<0.001) and slowed WM performance (p<0.05). Under THC, theta power was specifically reduced, (p<0.001) regardless of WM load; however, the reduction showed no relationship with psychotic symptoms or WM impairment. Coherence between bi-frontal electrodes in the theta band was also reduced by THC (p<0.05) and these reductions correlated with the change-in positive psychotic symptoms (rho=0.79, p<0.001). Bi-frontal specificity was suggested by the absence of a relationship between psychotic symptoms and fronto-parietal coherence. The results reveal that the pro-psychotic effects of THC might be related to impaired network dynamics with impaired communication between the right and left frontal lobes.

Resting EEG in psychosis and at-risk populations — A possible endophenotype?

Background Finding reliable endophenotypes for psychosis could lead to an improved understanding of aetiology, and provide useful alternative phenotypes for genetic association studies. Resting quantitative electroencephalography (QEEG) activity has been shown to be heritable and reliable over time. However, QEEG research in patients with psychosis has shown inconsistent and even contradictory findings, and studies of at-risk populations are scarce. Hence, this study aimed to investigate whether resting QEEG activity represents a candidate endophenotype for psychosis. Method QEEG activity at rest was compared in four frequency bands (delta, theta, alpha, and beta), between chronic patients with psychosis (N = 48), first episode patients (N = 46), at-risk populations (“at risk mental state”, N = 33; healthy relatives of patients, N = 45), and healthy controls (N = 107). Results Results showed that chronic patients had significantly increased resting QEEG amplitudes in delta and theta frequencies compared to healthy controls. However, first episode patients and at-risk populations did not differ from controls in these frequency bands. There were no group differences in alpha or beta frequency bands. Conclusion Since no abnormalities were found in first episode patients, ARMS, or healthy relatives, resting QEEG activity in the frequency bands examined is unlikely to be related to genetic predisposition to psychosis. Rather than endophenotypes, the low frequency abnormalities observed in chronic patients are probably related to illness progression and/or to the long-term effects of treatments.

Removing Ballistocardiogram Artifact From EEG Using Short- and Long-Term Linear Predictor

In this paper, a novel source extraction method is proposed for removing ballistocardiogram (BCG) artifact from EEG. BCG appears in EEG signals recorded simultaneously with functional magnetic resonance imaging. The proposed method is a semiblind source extraction algorithm based on linear prediction technique. We define a cost function according to a joint short- and long-term prediction strategy to extract the BCG sources. We call this method SLTP-BSE standing for short- and long-term prediction blind source extraction. The objective of this work is to 1) model the temporal structure of the sources using short-term prediction and 2) impose the prior information about the BCG sources using long-term prediction. These two procedures are simultaneously implemented to optimize the system. The performance of the proposed method is evaluated using both synthetic and real EEG data. The obtained results show that the proposed technique is able to remove the BCG artifact while preserving the task-related parts of the signal. The results of SLTP-BSE are compared with those of well-known BCG removal techniques confirming the superiority of the proposed method.

Communication breakdown: delta-9 tetrahydrocannabinol effects on pre-speech neural coherence

Synchronised neural oscillations preceding speech generation are reduced in patients with schizophrenia, this deficit being implicated in symptom formation. We measured synchronisation of neural oscillations preceding vocalisation in the presence of delta-9 tetrahydrocannabinol (THC) and found they were significantly disrupted. Furthermore, the degree of disruption was related to THC-induced symptoms, suggesting THC may modulate a similar neural substrate to schizophrenia.

State-of-the-Art Analysis of High-Frequency (Gamma Range) Electroencephalography in Humans

Gamma oscillations (>30 Hz) in the brain are involved in attention, perception and memory. They are altered in various pathological states, as well as by neuropharmaceuticals, so that they are of interest in drug and clinical investigations. However, when the human electroencephalogram is recorded on the scalp, this neural high-frequency signal is buried under a range of other electrical signals such that, without careful handling, recordings of the high-frequency electroencephalogram cannot be considered reliable. The artefacts of concern originate from: power line noise, saccade-associated contraction of the extra-ocular muscles, activity of muscles in the scalp, face and neck, screen refresh artefacts and activity of the muscles associated with blinking. Recent progress in dealing with these artefacts is described, including either noise cancellation or phased noise template subtraction for power line noise, regression or independent component analysis for correcting extra-ocular muscle activity and mathematical modelling for reducing scalp, face and neck muscle activity. If the artefacts are properly addressed, the neural gamma signal can be uncovered.

Delta-9-tetrahydrocannabinol disruption of time perception and of self-timed actions.

We tested the hypothesis that THC disrupts self-timed actions in healthy volunteers, and that this eff ect is related to self-rated perceptions of time distortion. We found that THC impaired subjective time perception and reduced the rate of button pressing, although the change in the rate of button pressing was more closely related to impaired concentration and intoxication. We conclude that THC-induced disruption of self-timed actions may arise from a diff erent mechanism to alterations in time perception. Disruption of the ability to judge time is a common eff ect shared by diff erent classes of drugs with disparate mechanisms of action. This impairment manifests as a change in the subjective awareness of the passing of time, with individuals sometimes experiencing phenomena such as time stopping or changing in speed; and as an alteration in the ability to correctly judge time periods and to generate self-timed actions in a consistent manner [4] . Diff erent mechanisms are hypothesised to underlie the estimation and generation of short (1 s or less) time spans (thought to be sub-conscious and dependent upon cerebellar function), and longer periods of time (thought to be governed by thalamo-cortico-striatal circuits) [1] . Here we test the hypothesis that THC disrupts the timing of self-generated actions in healthy volunteers, and that the degree of disruption correlates with self-rated perceptions of time change, attention and concentration. The study was approved by the Joint Institute of Psychiatry and Maudsley Hospital Ethics Committee. All subjects provided written informed consent. 16 healthy volunteers [9 female, mean (SD) age 26 (6) years] were recruited through advertising as part of an ongoing study. All attended for testing twice and were given an intravenous injection of 1.25 mg THC on one occasion and placebo on the other in a counterbalanced randomised double-blind manner. At 20 min after injection, subjects were asked to press a button at a self-timed rate of approximately 1 press per second for 70 presses. At 30 min post-injection they completed a self-rated questionnaire scoring cannabis-induced eff ects on 6 questions related to time perception or intoxication ( “ my perception of time is altered ” ; “ there is an unusual delay between my thinking and speaking ” ; “ I can ’ t focus my attention ” ; “ I can ’ t sustain my concentration ” ; “ I feel sleepy ” and “ I feel drunk ” ) on a scale from 1 – 5. We compared the change in mean press-rate between placebo and THC using a paired t-test. We then investigated whether change in press rate was related to changes in time perception, changes in attention or due to a general eff ect of intoxication by linear regression of percentage change in tap-time on responses to the 6 questions, with model simplifi cation by the backward stepwise method. All statistical tests were conducted using the R statistical programming language [2] . THC led to subjective impairment of time perception (df = 15, t = 3.74, p < 0.005), to the experience of an unusual delay between thinking and speaking (df = 15, t = 3.16, p < 0.01; r = 0.79, p = 0.0003), as well as to subjective impairment in attention (df = 15, t = 4.04, p < 0.005) and concentration (df = 15, t = 4.99, p < 0.0005). It also induced feelings of drowsiness (df = 15, t = 3.22, p < 0.01) and of feeling drunk (df = 15, t = 3.92, p < 0.005). THC induced a signifi cant slowing of mean (SD) tap time from 1.49 (0.49) seconds for placebo to 1.73 (0.7) seconds for THC (df = 15, t = 2.263, p < 0.05). Stepwise linear regression revealed that percent slowing of tap time was related to impaired concentration only (F 1,14 = 6.15, p < 0.05), although post-hoc testing revealed a signifi cant relationship with subjective intoxication (F 1,14 = 5.866, p < 0.05) and a trend relationship with the subjective feeling of a delay between thinking and speech (F 1,14 = 3.73, p < 0.1). There are a number of limitations of this study, most notably the relatively small sample size, and the fact that this analysis (although planned) was performed as part of an ongoing study. The small size increases variability as well as increasing the risk of failing to detect a true positive. Nonetheless, we found a signifi cant eff ect of THC on the subjective experience of time passing, as well as a slowing in self-generated tap time. The latter fi nding is in contrast to a previous study that showed that smoked cannabis increased the rate of counting and tapping in individuals with a history of moderate or heavy cannabis use [4] . It is not clear whether this discrepancy was due to diff erences in subject group (the volunteers in the present study had considerably lower previous exposure to cannabis), dose (accurate determination of total THC dose is not possible with smoked cannabis, and may have varied between subjects) or route of administration (off ers the rate of onset of THC-induced eff ects). Alternatively, the diff erences may have arisen because THC alone was used in the present study, whereas smoked cannabis also contains a number of other active chemicals, most notably cannabidiol [3] . In the present study, change in tap time was related at trend level only to distortions in time perception, having a stronger association with subjective impairments in concentration and to feelings of intoxication, suggesting that alterations in self-timed tapping may arise through a diff erent mechanism from subjective changes in the experience of the passage of time. It is possible to speculate that feelings of intoxication, and impairments in tap timing arose from eff ects of THC on subcortical brain regions, whereas subjective experience of time was related to eff ects on higher brain function. Ongoing work in our laboratory will investigate this possibility.

Gamma Band Oscillations in the Early Phase of Psychosis: A Systematic Review

HighlightsGamma oscillations are synchronised by parvalbumin positive interneurons.Gamma band responses to tasks were reduced in psychosis and at risk populations.Artefacts occurring within the gamma band have not been adequately addressed.Longitudinal studies with larger sample sizes, addressing sources of bias are needed. &NA; Abnormal gamma oscillations, measured by electroencephalography (EEG), have been associated with chronic psychotic disorders, but their prevalence in the early phase of psychosis is less clear. We sought to address this by systematically reviewing the relevant literature. We searched for EEG studies of gamma band oscillations in subjects at high risk for psychosis and in patients with first episode psychosis. The following measures of gamma oscillations were extracted: resting power, evoked power, induced power, connectivity and peak frequency. Forty‐five studies with a total of 3099 participants were included. There were potential sources of bias in the study designs and potential artefacts. Although there were few consistent findings, several studies reported decreased evoked or induced power in both high risk subjects and first episode patients. Studies using larger samples with serial EEG measurements, and designs that minimise artefacts that occur at the gamma frequency may advance work in this area.