Jose Cortes-Briones

Δ9-THC Disrupts Gamma (γ)-Band Neural Oscillations in Humans.

Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ9-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ9-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ9-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ9-THC. Δ9-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ9-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders.

It’s All in the Rhythm: The Role of Cannabinoids in Neural Oscillations and Psychosis

Evidence has accumulated over the past several decades suggesting that both exocannabinoids and endocannabinoids play a role in the pathophysiology of schizophrenia. The current article presents evidence suggesting that one of the mechanisms whereby cannabinoids induce psychosis is through the alteration in synchronized neural oscillations. Neural oscillations, particularly in the gamma (30-80 Hz) and theta (4-7 Hz) ranges, are disrupted in schizophrenia and are involved in various areas of perceptual and cognitive function. Regarding cannabinoids, preclinical evidence from slice and local field potential recordings has shown that central cannabinoid receptor (cannabinoid receptor type 1) agonists decrease the power of neural oscillations, particularly in the gamma and theta bands. Further, the administration of cannabinoids during critical stages of neural development has been shown to disrupt the brains ability to generate synchronized neural oscillations in adulthood. In humans, studies examining the effects of chronic cannabis use (utilizing electroencephalography) have shown abnormalities in neural oscillations in a pattern similar to those observed in schizophrenia. Finally, recent studies in humans have also shown disruptions in neural oscillations after the acute administration of delta-9-tetrahydrocannabinol, the primary psychoactive constituent in cannabis. Taken together, these data suggest that both acute and chronic cannabinoids can disrupt the ability of the brain to generate synchronized oscillations at functionally relevant frequencies. Hence, this may represent one of the primary mechanisms whereby cannabinoids induce disruptions in attention, working memory, sensory-motor integration, and many other psychosis-related behavioral effects.

Going up in Smoke? A Review of nAChRs-based Treatment Strategies for Improving Cognition in Schizophrenia

Cognitive impairment is known to be a core deficit in schizophrenia. Existing treatments for schizophrenia have limited efficacy against cognitive impairment. The ubiquitous use of nicotine in this population is thought to reflect an attempt by patients to selfmedicate certain symptoms associated with the illness. Concurrently there is evidence that nicotinic receptors that have lower affinity for nicotine are more important in cognition. Therefore, a number of medications that target nicotinic acetylcholine receptors (nAChRs) have been tested or are in development. In this article we summarize the clinical evidence of nAChRs dysfunction in schizophrenia and review clinical studies testing either nicotine or nicotinic medications for the treatment of cognitive impairment in schizophrenia. Some evidence suggests beneficial effects of nAChRs based treatments for the attentional deficits associated with schizophrenia. Standardized cognitive test batteries have failed to capture consistent improvements from drugs acting at nAChRs. However, more proximal measures of brain function, such as ERPs relevant to information processing impairments in schizophrenia, have shown some benefit. Further work is necessary to conclude that nAChRs based treatments are of clinical utility in the treatment of cognitive deficits of schizophrenia.

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans.

&NA; Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta‐9‐tetrahydrocannabinol (&Dgr;9‐THC), cannabidiol (CBD), &Dgr;9‐THC + CBD, or placebo. Subjects engaged in a dual‐click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP‐55940, CP‐55940+AM‐251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both &Dgr;9‐THC (p < 0.007) and &Dgr;9‐THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. &Dgr;9‐THC (p < 0.048) and &Dgr;9‐THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the &Dgr;9‐THC condition, S1 theta negatively correlated with gating ratios (r = −0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP‐55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM‐251. Further, CP‐55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM‐251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta‐band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition. HighlightsBoth &Dgr;9‐THC & &Dgr;9‐THC + CBD disrupted P50 gating ratio compared to placebo, while CBD alone had no effect.&Dgr;9‐THC & &Dgr;9‐THC + CBD decreased S1 theta power, & in the &Dgr;9‐THC condition, S1 theta negatively correlated with gating ratios.In rats, CP‐55940 disrupted gating in both brain regions, & this was reversed by AM‐251.Further, CP‐55940 decreased evoked theta & gamma power to S1, which was partially blocked by AM‐251.These human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta‐band.

Cannabinoid-glutamate interactions and neural oscillations: implications for psychosis

Preclinical and clinical data suggest that the cannabinoid and glutamatergic systems are implicated in the pathophysiology of schizophrenia (SZ), the prototypical psychotic disorder. This has led to distinct “cannabis” and “ketamine” models of SZ, respectively. However, these two models need not be mutually exclusive. Indeed, in several brain regions implicated in the putative neural circuitry of SZ (e.g., hippocampus, frontal cortex, cerebellum), cannabinoid receptor type 1 (CB1Rs) and glutamate N‐methyl‐D‐aspartate receptors (NMDARs) have direct and indirect interactions. CB1R agonists and NMDAR antagonists act upon gamma‐aminobutyric acid (GABA) interneurons to reduce GABAergic neurotransmission. This would be predicted to result in the unsynchronized activity of pyramidal neurons, disrupting neural network oscillations involved in information processing, thus leading to psychotomimetic effects. Hence, the overarching aim of the current review is to synthesize the known literature on cannabinoids and glutamate in the context of neural oscillations in SZ. First, discussion of SZ and the basic mechanisms of neural oscillations are discussed, including a summary of the role of theta (4–7 Hz) and gamma (30–80 Hz) oscillations in neurocognition. Next, a brief review of the role of the cannabinoid and glutamatergic systems in SZ is outlined, followed by discussion of the known synaptic interactions between these two systems. Finally, the potential role of CB1Rs and NMDARs, both independently and in combination, on neural oscillations in relation to psychotic symptoms is considered. It is hoped that this review will yield a series of testable hypotheses that may be used to further elucidate the pathophysiology of SZ.

Testing differences in the activity of event-related potential sources: Important implications for clinical researchers

http://dx.doi.org/10.1016/j.clinph.2014.04.008 1388-2457/ 2014 International Federation of Clinical Neurophysiology. Source analysis of electroencephalographic (EEG) data is an increasingly popular tool that allows investigators to estimate the location, direction, and strength of the electric currents within the brain. Clinical researchers have increasingly exploited userfriendly Linear Distributed Source Model (LDSM) software packages (such as sLORETA-KEY) to extend classical event-related potential (ERP) experiments. However, methodological biases and inferential errors may have occurred. Spatial solutions tend to be accurately reported, but, use of standard methods to quantify source activity can introduce error into group/condition comparisons of ‘‘ERP generators’’, especially when the experimental effect is hypothesized to alter ERP peak amplitude or latency. Since 2010 alone, this journal has published a number of clinical studies reporting source localization of ERPs in which one cannot exclude one or more of these methodological or inferential issues (outlined in Table 1). We illustrate the potential pitfalls with proposed solutions. In LDSMs-based analyses, either cortical grey matter is divided into a number of voxels or cortical surface is modeled as a mesh with a number of vertices, each of which is assigned a three dimensional vector representing electric activity (EAV), a current density vector in the first case, or an electric dipole in the second. The length (norm) and orientation of an EAV correspond, respectively, to the magnitude and direction of flow of the reconstructed current (Pascual-Marqui, 2002). Grossly, positive scalp potentials would result from currents flowing towards scalp sensors, whereas negative scalp potentials would result from currents flowing away from these sensors. As EEG signals are purported to result from the summed field potentials generated by cortical neurons whose dendritic trees are perpendicular to the cortical surface, EAVs are frequently constrained to be oriented in this direction (Grech et al., 2008). To facilitate statistical comparison and graphical representation, it is common to then reduce each EAV (possessing three values per voxel or vertex) to its norm (|x|, a single positive number). Consequently, information about the direction of flow of current is lost. The norm solution, favored by popular software packages, is therefore not a complete reconstruction of the activity underlying the signals recorded at the scalp; instead, it only yields the magnitude of the activity. Although a perfectly valid measure in itself, source magnitude may be insensitive to some facets of underlying neural processes and cannot be directly related to the scalp ERPs. A temporal window centered on the peak of the scalp ERP is defined. Sources at each time point within this window are reconstructed and averaged across time to yield what is interpreted as the ‘ERP source’.

17.2 EFFICACY OF CANNABIDIOL IN THE TREATMENT OF EARLY PSYCHOSIS.

Abstract Background Cannabidiol is a component of herbal cannabis, studied for a number of potential pharmaceutical indications, more recently, its potential anti-psychotic effects with an extremely favorable side effect profile. Cannabidiol content of cannabis may also attenuate the psychotic and cognitive effects associated with cannabis use. Early psychosis is associated with alterations in the endocannabinoid system and is marked by limited engagement in treatment, reluctance to use traditional antipsychotics, sensitivity to medication side effects and heavy cannabis use. Cannabidiol may thus represent a more acceptable and tolerable antipsychotic medication in this phase of illness with a novel mechanism of action. Methods Data will be presented from an ongoing double blind, placebo controlled, within subject, crossover study examining the effects of Cannabidiol (800mg/day) versus placebo in individuals within the first 7 years of their psychotic illness. Subjects participate in two treatment periods, each four weeks long separated by at least 2 weeks of washout. Results Data will be presented on the effects of Cannabidiol on psychotic symptoms (measured on the Positive and Negative Syndrome Scale), cognitive deficits (MATRICS battery), electrophysiological biomarkers of information processing (Resting EEG and ERPs relevant to psychosis and cannabinoids), metabolic parameters and general functioning. Discussion Cannabidiol is a novel drug that has shown potential efficacy in the treatment of psychotic symptoms. Early psychosis is a critical treatment period during which treatment engagement and adherence is critical and duration of untreated psychosis is associated with long term negative consequences. Cannabidiol may thus represent a more acceptable and tolerable medication to target this vulnerable population.

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans

Background: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans. Aims: Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg). Methods: Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention. Results/outcomes: Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions. Conclusions/interpretation: These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.

Electroencephalography and Cannabis: From Event-Related Potentials to Oscillations

Cannabis continues to be one of the most commonly used drugs worldwide. In parallel with advances in our understanding of the endocannabinoid system, numerous studies have begun to examine the effects of exogenous cannabinoids on human brain function. Electroencephalography (EEG) is one of the few noninvasive techniques that can directly record neural activity in humans. This chapter reviews studies that have utilized EEG in an attempt to examine the chronic and acute effects of cannabinoids on various aspects of neural function. A brief discussion of the nature of EEG is included, followed by sections describing the effects of cannabinoids on event-related potentials and neural oscillations. Last, a brief discussion of potential future directions for studies on the electrophysiological correlates of cannabinoids is included.Abstract Cannabis continues to be one of the most commonly used drugs worldwide. In parallel with advances in our understanding of the endocannabinoid system, numerous studies have begun to examine the effects of exogenous cannabinoids on human brain function. Electroencephalography (EEG) is one of the few noninvasive techniques that can directly record neural activity in humans. This chapter reviews studies that have utilized EEG in an attempt to examine the chronic and acute effects of cannabinoids on various aspects of neural function. A brief discussion of the nature of EEG is included, followed by sections describing the effects of cannabinoids on event-related potentials and neural oscillations. Last, a brief discussion of potential future directions for studies on the electrophysiological correlates of cannabinoids is included.