Patrick D. Skosnik

Modulation of attentional inhibition by norepinephrine and cortisol after psychological stress

Two of the most salient physiological responses to stress are increased norepinephrine (NE) and cortisol (CORT) activities. However, it is unclear how these neurochemical events affect cognition, especially attention. We examined the effects of mild psychological stress on selective attention, as assessed by the negative priming (NP) paradigm. Salivary measures of the stress hormone CORT and alpha-amylase (a correlate of NE) were assayed to probe the relationship between the stress response and attentional inhibition. Healthy subjects (N = 20) engaged in the attention task, which was then followed by 15 min of a stressful video game before a return to the attentional task. Baseline saliva samples were obtained before the experiment began, 1 min after the video-game stressor, and 20 min post-stress. Subjects showed a significant reduction in NP and a decrease in reaction time (RT) after the video game. Moreover, alpha-amylase levels increased significantly after the stressor, indicating the role of NE in the acute stress response. While CORT levels remained unchanged after stress, CORT correlated significantly with both NP scores and RT after the stressor. These results imply that mild psychological stress can significantly alter attentional processes. Given the increase in alpha-amylase and the correlation between attention and CORT after stress, it seems likely that attentional processes are under tight control by brain systems which mediate the fight-or-flight response.

Cannabis use is associated with schizotypy and attentional disinhibition

While most neurochemical research into the pathogenesis of schizophrenia (SZ) has focused on the dopaminergic, glutamatergic, and serotonergic systems, the exact nature and cause of this disorder have proven intractable. Given the recent discovery and elucidation of the endogenous cannabinioid system, a re-examination of the cannabis-induced exacerbation hypothesis of SZ is warranted. The purpose of the present study was to assess whether current cannabis users exhibit personality correlates and neurocognitive deficits similar to those observed in SZ patients. 15 current cannabis users, 15 drug-free controls, and 10 past cannabis users were assessed on tasks which assess attentional inhibition, spatial working memory, olfactory identification, and schizotypal personality. Current cannabis users demonstrated deficits in attentional inhibition, decreased reaction time, and significantly higher scores on the schizotypal personality questionnaire (SPQ) compared with the non-using and past cannabis using groups. No group differences were found on the working memory or olfactory identification tasks. These results suggest that cannabis use can mimic attentional deficits seen in acute schizophrenia and is associated with schizotypal personality, thus setting the stage for a possible cannabinoid model of SZ.

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.

The effect of selective attention on the gamma-band auditory steady-state response

Studies have demonstrated that selective attention can modulate the steady-state evoked potential to repetitive visual and tactile stimulation. However, examinations of the effect of attention on the auditory steady-state response (ASSR) have proven equivocal. The current experiment therefore utilized EEG to examine the effect of attention on the ASSR in healthy humans (n=15). Auditory click trains in the beta (20 Hz) and gamma (40 Hz) ranges were randomly presented binaurally in an oddball discrimination paradigm (each frequency served as the oddball (target) in each of two blocks). A Fast Fourier Transform was used to assess the effect of attention on the ASSR (signal power), and phase consistency across trials was assessed using the phase-locking factor (PLF). As expected, both 20 and 40 Hz targets elicited a robust P300 response, with maximal amplitudes over parietal regions. For the ASSR, it was found that EEG signal power was larger to 40 Hz targets compared to 40 Hz frequent stimuli across all frontocentral electrodes. No differences in signal power were observed during 20 Hz stimulation. Finally, increased PLF values were observed for 40 Hz targets compared to frequent trials. These results provide evidence that selective attention can enhance signal power and phase-locking of the ASSR, particularly to auditory stimulation in the gamma range.

Affect processing and positive syndrome schizotypy in cannabis users

While cannabis is associated with positive syndrome schizophrenia (SZ), it is unclear whether cannabinoids are also related to negative symptoms such as affective blunting. We examined whether cannabis use is associated with schizotypy and utilized event-related potentials (ERPs) to assess affect processing. Cannabis users demonstrated increased P300 amplitudes for unpleasant trait words, and demonstrated higher positive syndrome schizotypy which correlated with levels of cannabis use. The cannabis group also exhibited lower negative syndrome schizotypy. The lack of blunted responses during the affect ERP and decreased negative subscale schizotypy scores provide evidence that the endocannabinoid theory of schizophrenia may be primarily relevant in relation to positive syndrome SZ.

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]

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.

Relationship between steady-state and induced gamma activity to motion

When a moving stimulus is presented at a specific temporal frequency, both steady-state responses and induced &ggr; activity may be elicited in the electroencephalogram. The electroencephalogram was recorded when study participants viewed random dot kinematograms under three conditions: coherent motion, incoherent motion and stationary. Dot position was changed at a rate of 9.3 Hz in the coherent and incoherent conditions. Induced power at 40 Hz was increased during coherent motion compared with the other conditions. In contrast, the steady-state response at 9.3 Hz showed a trend for increased power during the incoherent condition. These results suggest that steady-state responses to moving stimuli reflect sensory activation, while the induced &ggr; activity indexes perceptual processes.

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.