Patrick D. Skosnik - US grants

[unreadable] DESCRIPTION (provided by applicant): It is well known that use of the drug cannabis can induce subjective distortions of perception in several sensory modalities. However, few direct examinations of the neural effects of cannabis use on early sensory processing have been undertaken, particularly utilizing novel electrophysiological techniques. The overall aim of the current proposal is to examine whether current cannabis users demonstrate deficits in neural synchronization as measured by electroencephalographic (EEG) entrainment to periodic auditory and visual stimulation. Subjects will passively observe periodic sensory stimuli (auditory click-trains (10, 20, 30, 40, and 50 Hz) and photic flickers (8, 13, 18, 25, and 38 Hz) while EEGs are recorded. The ability of the resulting steady-state potentials to synchronize to the specific frequencies of stimulation will be assessed via EEG power, signal to noise ratio, and intertrial coherence. In addition, EEG synchronization during perceptual binding will be assessed utilizing an induced gamma paradigm (moving dot stimuli using Random Dot Kinetograms). Several clinical interviews and psychometric questionnaires will also be administered in order to determine possible relationships between EEG brain measures and the perceptual correlates of cannabis use. It is hypothesized that during the entrainment paradigms cannabis users will exhibit decreased EEG power, signal to noise ratio, and intertrial coherence at the frequencies of stimulation across sensory modalities. It is also predicted that during the induced EEG paradigm, cannabis users will exhibit decreased gamma-band (~ 40 Hz) activity during the perception of coherent moving dots. It is hypothesized that these deficits in EEG neural synchronization will correlate with psychometric measures such as schizotypal personality and perceptual aberration, as well as urinary measures of cannabis metabolites. Taken together, this data may serve to elucidate whether the known cognitive dysfunction observed in cannabis use is in part related to disturbances in early sensory information processing and/or neural synchronization.

[unreadable] DESCRIPTION (provided by applicant): Marijuana, or Cannabis sativa, is the most commonly used illicit drug in the United States. Increased levels of use occur during adolescence and young adulthood, which is of concern from a public health perspective, since these are also critical periods of neural development. This fear is further underscored by the fact that cannabis may act as a gateway drug, since its use may predispose individuals to abuse other illicit drugs. While it is well known that the active ingredient in cannabis, -9-tetrahydrocannabinol (THC) causes abnormalities in cognitive functions such as short-term memory and attention, there are a paucity of data examining the effect of cannabis use on the functional state of the cerebellum, a neural timing structure that is replete with cannabinoid receptors. Therefore, the overall aim of the current proposal is to examine whether current cannabis users demonstrate abnormalities in cerebellar-mediated classical eye blink conditioning (EBC) and paced finger tapping. In addition, assessments of the structural correlates of these deficits will be determined using magnetic resonance imaging (MRI). It is hypothesized that during the EBC paradigm cannabis users will demonstrate poorer learning performance (less and more poorly timed conditioned responses) as compared to controls. During the paced finger tapping tasks, it is predicted that cannabis users will exhibit increased tapping variability and increased tapping rates. It is also predicted that chronic cannabis users will exhibit decreased cerebellar volumes due to long-term endocannabinoid compensatory mechanisms, and that these volumetric changes will correlate with EBC and paced finger tapping performance. Finally, it is hypothesized that deficits in EBC, paced finger tapping, and cerebellar volume will correlate with the amount and length of cannabis use, including urinary levels of THC metabolites. Taken together, data from these studies will further our understanding of the cannabinoid system, which will help elucidate the mechanism of action of one of the most commonly used drugs of abuse.Project Narrative [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Cannabis is the most commonly used illicit drug worldwide. There is increasing recognition of a cannabis dependence syndrome that includes both tolerance and withdrawal. Furthermore, the rates of cannabis use have increased during early adolescence, when the developing brain might be especially susceptible to environmental exposures. This public health concern is further fueled by the fact that the potency of cannabis seems to have increased over the past decades. There is also increasing demand for treatments for cannabis use disorders. Therefore, it is important to fully understand the consequences of cannabis dependence in humans on the brain cannabinoid system. Exogenous cannabinoids produce their psychoactive effects via the activation of brain CB1 receptors (CB1R). Repeated exposure to cannabis and CB1R agonists is associated with the development of tolerance and dependence. While this has been shown to be accompanied by CB1R downregulation in animals, it has yet to be demonstrated in humans, in vivo. The discontinuation of chronic, heavy exposure to cannabinoids in both humans and animals, and the administration of CB1R antagonists to cannabinoid dependent animals, is associated with a clear withdrawal syndrome. Finally, with prolonged abstinence there seems to be a reversal of tolerance, which in animals has been shown to be accompanied by normalization of CB1Rs. However, this has yet to be demonstrated in humans, either post mortem or in vivo. The aim of the current proposal is to use the validated CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) to measure CB1R availability in vivo in cannabis-dependent individuals at 1) baseline, 2) following brief (48 hours) confirmed inpatient abstinence (at the peak of cannabis withdrawal and CB1R downregulation), and 3) after prolonged (4 weeks) confirmed outpatient abstinence. It is expected that at baseline, cannabis-dependent subjects (n=8) will have lower CB1R availability than matched controls (n=8), but this difference will no longer be present after 4 weeks of abstinence. Furthermore, cannabis-dependent subjects will have lower CB1R availability during acute cannabis withdrawal relative to their baseline state. Taken together, it is hoped that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on CB1 receptors, and will shed new light on the status and function of CB1 receptors during active cannabis use, and withdrawal. PUBLIC HEALTH RELEVANCE: Little is known about the consequences of heavy cannabis use on the brain cannabinoid system. This grant application proposes to use brain imaging to study the changes in the brain cannabinoid receptor system as a result of heavy cannabis use, 2 days after stopping cannabis use and again after 4 weeks of abstinence from cannabis.

DESCRIPTION (provided by applicant): Marijuana, or Cannabis sativa, is the most commonly used illicit drug in the United States. Increased levels of use occur during adolescence and young adulthood, which is of concern from a public health perspective, since these are also critical periods of neural development. What is particularly disturbing is the fact that there are over 6000 first-time cannabis users added per day, 62.2 percent of which are under the age of eighteen. This fear is further underscored by the fact that cannabis may act as a gateway drug, since its use may predispose individuals to abuse other illicit drugs. Further, the potency of cannabis (concentration of delta-9- tetrahydrocannabinol (¿9-THC)), is now exceeding 10 percent in the U.S. (compared to 4 percent in 1983), which could have unforeseen consequences for normal brain function. Given the vast number of individuals who consume cannabis on a regular basis, a thorough understanding of the neural mechanisms associated with its behavioral and physiological effects are of considerable relevance. The cerebellum arguably contains the highest density of CB1 receptors in the brain. While it is well known that ¿9-THC causes abnormalities in cognitive functions such as short-term memory and attention, there are a paucity of data examining the effect of exogenous cannabinoids on associative learning, particularly as it relates to cerebellar versus forebrain-dependent classical eyeblink conditioning (EBC). Earlier work from our group has shown that in humans, chronic cannabis use alters conditioned response (CR) acquisition and timing in cerebellar-dependent delay EBC, but not in the forebrain-dependent trace EBC task. However, it remains unclear whether the deficits observed in chronic cannabis users are due to the residual effects of ¿9- THC, some other cannabinoid present in cannabis, CB1 downregulation, or premorbid differences in drug- seeking individuals. Therefore, the overall aim of the current application is to investigate whether acute, i.v. ¿9- THC administration mediates cerebellum- versus forebrain-dependent associative learning in humans as assessed with delay and trace EBC, respectively. The hypothesized outcome, based on known CB1 actions in the cerebellum, is that ¿9-THC (as compared to placebo) will induce impairments in cerebellar dependent delay EBC in a dose-dependent manner (decreased percent CRs and altered CR latency). It is also expected that ¿9-THC will have little or no effect on forebrain-dependent trace EBC. Taken together, it is hoped that data from these studies will further our understanding of the cannabinoid system, particularly in the context of associative learning, which will help elucidate the mechanism of action of one of the most commonly used drugs of abuse. PUBLIC HEALTH RELEVANCE: The public health relevance of this application can be summarized as follows: 1) Cannabis exposure likely produces neural changes in the endogenous cannabinoid system, and the effect of such changes on information processing within the brain is unclear. 2) Understanding how the active ingredient in cannabis (Delta-9-THC) interacts with the neural substrates underlying information processing will improve care and prevention of cannabis abuse/dependence. 3) The proposed study has a high potential for future translational research, as the eyeblink conditioning task is widely employed in animal studies, and the neural circuitry mediating this task is well conserved across species (i.e. result from the current studies will be testable in future animal models of cannabinoid function).

DESCRIPTION (provided by applicant): Marijuana, or Cannabis sativa, is the most commonly used illicit drug worldwide, and rates of its abuse have increased during the past twenty-five years. In fact, in the United States, individuals with disorders related to cannabis exposure are two times higher than for any other illicit drug. Increased levels of use primarily occur during adolescence and young adulthood, which is of concern from a public health perspective since these are also critical periods of neural development. This fear is further underscored by the fact that cannabis may act as a gateway drug, since its use may predispose individuals to abuse other illicit drugs. In addition, the potency of cannabis (concentration of delta-9-tetrahydrocannabinol (? 9-THC)), is now exceeding 10% in the U.S. (compared to 4% in 1983), which could have unforeseen consequences for normal brain function. Given the vast number of individuals who consume cannabis on a regular basis, a thorough understanding of its long-term effects on neural function is vitally important. Cannabis and associated phytocannabinoids exert their effects through the activation of central cannabinoid receptors (CB1R). It is now well-established that repeated exposure to cannabis results in the development of tolerance, dependence, and a withdrawal syndrome upon cessation of use. Long-term cannabinoid exposure also induces a decrease in the number of CB1Rs. However, the functional implications of these changes remain unclear. The resting-state default mode network and task-positive control network may be dependent on an intact endocannabinoid system, which could be compromised by heavy cannabis use. Therefore, the purpose the proposed study is to examine the effects of chronic cannabis use, acute withdrawal, and sustained abstinence on default mode and control brain networks. Functional magnetic resonance imaging (fMRI) will be used to evaluate the default mode network and control network in cannabis-dependent individuals at baseline (smoking as usual), following brief (48 hour) confirmed abstinence (when cannabis withdrawal is most likely to occur), and after prolonged (4 weeks) confirmed abstinence. A sample of healthy control individuals will also be assessed. It is anticipated that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on brain function, and will shed new light on the status and function of neural networks during active cannabis use, withdrawal, and prolonged abstinence.

PROJECT SUMMARY AND ABSTRACT Background: Cannabis is the most commonly used illicit drug worldwide. The potency of cannabis has increased and so has the use of highly potent synthetic cannabinoids (`Spice'). Furthermore, the ?medical? and recreational use of cannabis is increasingly being legalized across the U.S. Therefore, it is important to understand the consequences of chronic cannabinoid exposure on the brain, including the consequences of these changes on neural function, and importantly if/how these evolve when cannabis use stops. Cannabinoid receptor (CB1R) availability can be measured in vivo using Positron Emission Tomography (PET). Neural oscillations, an index of information processing, are sensitive to the effects of CB1R activation and can be measured using electroencephalography (EEG). Hypotheses: Cannabis dependent subjects (CDs) will show lower CB1R availability at baseline relative to controls. CB1R availability will begin to normalize after 48 hours of abstinence (but not to HC levels) and will return to control levels after 4 weeks of abstinence. CDs will exhibit decreased ?- and ?-band neural oscillations compared to HCs at baseline, which will be most disrupted after 48 hours of abstinence and will return to control levels after 4 weeks of abstinence. Across the 3 time points, measures of ?- and ?-band oscillations will correlate with CB1R availability. Finally, CB1R availability, ?- and ?-band power, and coherence will correlate with performance on the cognitive tasks. Methods: The proposed study will utilize 1) CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) and 2) EEG to evaluate the temporal course of CB1R availability and neural oscillations, respectively, in cannabis-dependent individuals (n=25) at baseline (smoking cannabis as usual), following brief (48 hour) monitored inpatient abstinence (when cannabis withdrawal is most likely to occur), and after prolonged (4 weeks) monitored abstinence. Neurocognitive outcomes (e.g., verbal learning) which are known to be impaired by chronic cannabis exposure will also be assessed in order to relate the receptor and electrophysiological findings to domains germane to ?real world? functioning. A sample of healthy control individuals (n=12) will also be assessed at the same time points. This design will allow both within-subject and between-subject analyses across three time points.Taken together, it is hoped that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on CB1Rs, and will shed new light on the status and function of CB1Rs during active cannabis use, and withdrawal.

ABSTRACT Depression affects around ten percent of people in the United States. Two-thirds of these patients do not respond to traditional antidepressants and are diagnosed with treatment-resistant depression (TRD). Also, conventional antidepressants take approximately three to four weeks to show effects. Ketamine, a drug that has been traditionally used as an anesthetic agent, represents a promising hope. At doses lower than those utilized for anesthesia, ketamine has been found to improve depressive symptoms in more than half of the patients diagnosed with TRD. Recently, an isomer of ketamine, esketamine, has been approved by the FDA for the treatment of TRD. Repeated dosing of ketamine and esketamine augment their antidepressant effect, prolonging the therapeutic benefit from a few days to up to a few weeks and increasing response and remission rates. Animal models of depression have shown that a single dose of ketamine works by increasing neuroplasticity, the ability of the brain to change and adapt. However, how repeated ketamine treatments augment the antidepressant effect is not known. Understanding the underlying mechanism of augmented therapeutic effect in humans would make it possible to a) prolong ketamine?s antidepressant effect beyond a few weeks, b) increase response and remission rates, and c) develop novel molecules with better response and remission rates. Therefore, we are proposing to combine two techniques to understand the brain changes associated with the augmented improvements in patients. The first technique is electroencephalography (EEG), which monitors the electrical activity of the neocortex, the part of the brain involved in memory, decision making, and mood, features that are affected in depression. Using an EEG task that measures neuroplasticity, we will probe the neocortex to identify changes in neuroplasticity associated with the sustained antidepressant effects in patients diagnosed with TRD treated with repeated ketamine dosing. They will undergo the EEG task before they begin their treatment, after their first treatment, and then again after they finish all their treatments. The second technique is computer modeling of the neocortex using a computer model that has been developed to understand the brain mechanisms generating EEG, called the Human Neocortical Neurosolver (HNN). We will use HNN to make mechanistic interpretations of the neocortical mechanisms underlying the EEG changes associated with the sustained antidepressant effect. This will identify the neocortical changes responsible for the sustained therapeutic response, which may allow for better treatment targeting.