Chad R. Edwards

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

While the cerebellum contains the highest density of cannabinoid receptor (CB1) in the brain, no studies have assessed the effect of exogenous cannabinoids on cerebellar-dependent learning in humans. The current study, therefore, examined the effect of chronic cannabis use on classical eyeblink conditioning (EBC), a cerebellar-mediated task which has been shown to be disrupted in CB1 knockout mice. Chronic cannabis users (24 h abstinence before study; positive THC urine drug test) free of DSM-IV Axis-I or -II disorders, were evaluated. A delay EBC task was utilized, in which a conditioned stimulus (CS; 400 ms tone) co-terminated with a corneal air puff unconditioned stimulus (US; 50 ms), thus eliciting a conditioned blink response (CR). The cannabis group exhibited markedly fewer, and more poorly timed CRs as compared to drug-naive controls. There were no differences between the groups in either the unconditioned response (UR) or an EEG measure of selective attention to the CS (N100 auditory ERP), indicating that the disruption observed in the cannabis group was specific to CR acquisition. These results suggest that cannabis use is associated with functional deficits in the cerebellar circuitry underlying EBC, a finding which corroborates the recent work in CB1 knockout mice.

Making faces: Creating three-dimensional parameterized models of facial expression

Previous studies of the perceptual processing and dynamics of emotional expression in faces have been limited by the lack of realistic yet controlled stimuli. The present work offers researchers a method for creating such stimuli for exploring these phenomena. We describe the creation of the stimuli and a series of experiments testing the validity of these stimuli with respect to emotional expressions in humans. Participants evaluated synthesized facial images and standardized photographs of six basic emotional expressions for intensity and accuracy of perceived emotion. Comparisons of these measures were qualitatively similar for synthesized and photographed faces. A manipulation of the magnitude of the synthesized expressions yielded a significant effect on the perceived intensity of expression. In a subsequent multidimensional scaling study, no systematic differences were uncovered in the derived configurations of the synthesized expressions and the photographs. These results are discussed in the context of possible future research applications.

Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia

Theoretical models suggest that symptoms of schizophrenia may be due to a dysfunctional modulatory system associated with the cerebellum. Although it has long been known that the cerebellum plays a critical role in associative learning and motor timing, recent evidence suggests that it also plays a role in nonmotor psychological processes. Indeed, cerebellar anomalies in schizophrenia have been linked to cognitive dysfunction and poor long-term outcome. To test the hypothesis that schizophrenia is associated with cerebellar dysfunction, cerebellar-dependent, delay eye-blink conditioning was examined in 62 individuals with schizophrenia and 62 age-matched non-psychiatric comparison subjects. The conditioned stimulus was a 400 ms tone, which co-terminated with a 50 ms unconditioned stimulus air puff. A subset of participants (25 with schizophrenia and 29 controls) also completed the Wechsler Abbreviated Scale of Intelligence. Participants with schizophrenia exhibited lower rates of eye-blink conditioning, including earlier (less adaptively timed) conditioned response latencies. Cognitive functioning was correlated with the rate of conditioned responsing in the non-psychiatric comparison subjects but not among those with schizophrenia, and the magnitude of these correlations significantly differed between groups. These findings are consistent with models of schizophrenia in which disruptions within the cortico-cerebellar-thalamic-cortical (CCTC) brain circuit are postulated to underlie the cognitive fragmentation that characterizes the disorder.

Sensory Gating Impairments in Heavy Cannabis Users Are Associated With Altered Neural Oscillations

Central cannabinoid receptors mediate neural oscillations and are localized to networks implicated in auditory P50 sensory gating, including the hippocampus and neocortex. The current study examined whether neural oscillations evoked by the paired clicks (S1, S2) are associated with abnormal P50 gating reported in cannabis users. Seventeen heavy cannabis users and 16 cannabis naïve controls participated. Analyses included P50 amplitudes, and time-frequency analyses (event-related spectral perturbations, ERSPs; intertrial coherence, ITC). Consistent with prior studies, cannabis users exhibited reduced P50 gating. The ERSP analysis yielded attenuated high frequency activity in the beta range (13-29 Hz) post-S1 and in the gamma range (30-50 Hz) post-S2 in the cannabis group, compared with the control group. Greater levels of cannabis use were positively associated with high P50 ratios and negatively with post-S2 ERSP gamma power. Findings suggest that heavy cannabis use is associated with aberrant beta and gamma activity in the dual-click procedure, which corroborates recent work demonstrating disruption of beta/gamma by cannabinoid receptor (CB1) agonists in a rat analogue of this task and highlights the translational potential of the dual-click procedure [corrected]

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction

OBJECTIVES Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD. METHODS Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls. RESULTS Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses. CONCLUSIONS These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.

Cerebellum volume and eyeblink conditioning in schizophrenia.

Although accumulating evidence suggests that cerebellar abnormalities may be linked to the symptoms and course of schizophrenia, few studies have related structural and functional indices of cerebellar integrity. The present study examined the relationship between the volume of specific subregions of the cerebellum and cerebellar function, as measured by eyeblink conditioning (EBC). Nine individuals with schizophrenia and six healthy comparison participants completed structural magnetic resonance imaging of the brain and a delay EBC procedure. Volumetric measurements were taken for the whole brain, whole cerebellum, cerebellar anterior lobules I-V and posterior lobules VI-VII. The schizophrenia group had smaller cerebellar anterior lobes and exhibited impaired EBC relative to the comparison group. In the comparison group, larger anterior volume correlated with earlier conditioned response onset latencies and increased amplitudes of the unconditioned blink response during paired trials (i.e., when the conditioned and unconditioned stimuli co-occurred). The findings that smaller anterior cerebellar volumes and EBC impairments were associated with schizophrenia are consistent with non-human studies showing that anterior cerebellar abnormalities are associated with deficits in delay EBC. The lack of a significant correlation between indices of EBC and cerebellar volume within the schizophrenia group suggests an aberrant relationship between cerebellar structure and function.

The Effect of Chronic Cannabinoids on Broadband EEG Neural Oscillations in Humans

Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10–50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis naïve controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis.

The interacting role of media violence exposure and aggressive-disruptive behavior in adolescent brain activation during an emotional Stroop task

Only recently have investigations of the relationship between media violence exposure (MVE) and aggressive behavior focused on brain functioning. In this study, we examined the relationship between brain activation and history of media violence exposure in adolescents, using functional magnetic resonance imaging (fMRI). Samples of adolescents with no psychiatric diagnosis or with disruptive behavior disorder (DBD) with aggression were compared to investigate whether the association of MVE history and brain activation is moderated by aggressive behavior/personality. Twenty-two adolescents with a history of aggressive behavior and diagnosis of either conduct disorder or oppositional-defiant disorder (DBD sample) and 22 controls completed an emotional Stroop task during fMRI. Primary imaging results indicated that controls with a history of low MVE demonstrated greater activity in the right inferior frontal gyrus and rostral anterior cingulate during the violent word condition. In contrast, in adolescents with DBD, those with high MVE exhibited decreased activation in the right amygdala, compared with those with low MVE. These findings are consistent with research demonstrating the importance of fronto-limbic structures for processing emotional stimuli, and with research suggesting that media violence may affect individuals in different ways depending on the presence of aggressive traits.

Assessment of forebrain-dependent trace eyeblink conditioning in chronic cannabis users.

While CB1 knockout mice exhibit striking impairments on a cerebellar-dependent task called delay eyeblink conditioning (dEBC), these animals demonstrate intact forebrain-dependent trace EBC (tEBC). Although heavy human cannabis users also show impaired delay EBC, their performance on tEBC is currently unknown. Therefore, 13 heavy cannabis users and 13 cannabis naive controls completed a tEBC procedure. The cannabis group exhibited similar rates of conditioned responding compared to controls in the acquisition and extinction phase. Consistent with reports of overt attentional abnormalities, the cannabis group exhibited decreased N100 ERP amplitudes to the tone CS that were unrelated to mean levels of conditioning across blocks during the acquisition phase. The lack of a significant effect of heavy cannabis use on tEBC reported here, combined with the previous report of impaired dEBC in such users, mirrors the findings observed in CB1 knockout mice, and suggests that the cannabinoid system differentially mediates forebrain- and cerebellar-dependent learning processes in both humans and animals.

Examining the effects of former cannabis use on cerebellum-dependent eyeblink conditioning in humans

RationalePrevious work in humans has shown that chronic cannabis users exhibit disruptions in classical eyeblink conditioning (EBC), a form of associative learning that is known to be dependent on the cerebellum. Based upon previous work in animals, it was hypothesized that these learning deficits were related to cannabinoid receptor (CB1R) downregulation. However, it remains unclear whether there is a recovery of cerebellum-dependent learning after the cessation of cannabis use.MethodsTherefore, former cannabis users (n=10), current cannabis users (n=10), and cannabis-naïve controls (n=10), all free of DSM-IV Axis-I or -II disorders, were evaluated. A standard delay EBC procedure was utilized in which paired presentations of a conditioned stimulus (CS; e.g., tone) and a co-terminating unconditioned stimulus (US; e.g., ocular airpuff) were administered, thus eliciting a conditioned eyeblink response (CR). The primary dependent measures were percentage of CRs and CR latency across conditioning blocks.ResultsSimilar to prior studies, current cannabis users exhibited marked impairments in both the acquisition and timing of CRs compared to controls. Although former cannabis users showed intact CR acquisition compared to controls, they exhibited significantly impaired (shorter) CR latencies. In both cannabis groups, UR amplitude did not differ from controls, indicating normal US processing.ConclusionsThese data suggest that a recovery of function has occurred for the learning of the CS–US association, while the accurate timing of the CR shows lasting impairments. Taken together, these results suggest that heavy cannabis use can disrupt timing-related synaptic plasticity within the cerebellum, even after the cessation of cannabis use.