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

Abstract

The main ingredient in cannabis, Δ(9)-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.

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

“…While it is not possible to directly compare the results of our study with this previous study because of obvious methodological differences, including the measurement of acute (using pharmacological challenge) vs non-acute effect of exposure, different cannabis usage patterns in study participants and different task parameters, it nevertheless identifies the fronto-striatal connection as a substrate for both the acute and non-acute effects of cannabinoids, perhaps reflecting the high distribution of cannabinoid CB1 receptors (CB1R) in these regions (Pertwee, 2008). Results presented here are also consistent with previous reports of effect of delta-9-THC on the coherence and synchrony of electrical signals in the frontal cortex (Morrison et al, 2011;Stone et al, 2012). Although opposite effects of delta-9-THC and CBD on brain activation have been described in previous studies (Bhattacharyya et al, , 2012c their influence on functional connectivity has only been addressed in one study so far.…”

Dysfunctional Prefrontal Cortical Network Activity and Interactions following Cannabinoid Receptor Activation

“…Furthermore, intravenous ⌬ 9 -THC administration in healthy volunteers can induce positive (psychotic) symptoms of schizophrenia potentially linked to aberrant intracortical network coordination (Koethe et al, 2009;Morrison et al, 2011) and cannabinoid dysfunction may therefore relate to, and be used to model, broader aspects of the disease, not just cognitive dysfunction. NMDA receptor antagonists are also noted for their psychotomimetic properties, and induce cognitive impairments and distinct changes in neuronal oscillations reminiscent of schizophrenia (Fletcher and Honey, 2006;Lazarewicz et al, 2010;Gilmour et al, 2011).…”

“…Cannabinoid receptor agonists are known to reduce the power of network oscillations in the hippocampus and neocortex (Buonamici et al, 1982;Morrison et al, 2011), and recently, Robbe and colleagues showed that disrupted theta coordination of principal cell firing in the rat hippocampus correlated with spatial working memory impairments induced by systemic cannabinoid receptor agonists (Robbe et al, 2006;Robbe and Buzsáki, 2009). They concluded that proper theta timescale coordination of neuronal spiking in the hippocampus is critical for spatial working memory, even though spatial information content of place cell firing was not affected.…”

1301 – Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings

“…Despite the fact that many individuals tend to discontinue cannabis use after their initial experimentation with the drug [1] and the percentage of individuals who develop dependence is lower than that associated with alcohol (15%) or tobacco (32%) use, around 9% of cannabis users develop dependence in the long term [3,4]. Cannabis use has been associated with a range of acute and chronic mental health problems, such as anxiety, depression, neurocognitive alterations and deficits as well as increased risk of psychotic symptoms and disorders, the severity of these effects being dependent on frequency of use, age of onset and genetic vulnerability [5][6][7][8][9][10][11][12][13][14][15]. These effects are probably related to effects on the endocannabinoid system, which can modulate the neuronal activity of other neurotransmitter systems, such as dopamine, through its action on the most abundant cannabinoid receptor in brain, the cannabinoid receptor 1 (CB1) [16,17].…”