Objective:Identifying obsessive-compulsive disorder (OCD) using brain data remains challenging. Resting-state electroencephalography (EEG) offers an affordable and noninvasive approach, but identifying predictive signals in EEG data has met with little success, even with the application of traditional machine learning methods. We explored whether convolutional neural networks (CNNs) applied to EEG time-frequency representations can distinguish individuals with OCD from healthy controls. Method:We collected resting-state EEG data from 20 unmedicated participants (10 with OCD, 10 healthy controls). Four-second EEG segments were transformed into time-frequency representations. We then trained a 2D CNN using a leave-one-subject-out cross-validation framework to perform subject-level classification and compared its performance to a more traditional support vector machine (SVM) approach. Next, using multimodal fusion, we examined whether adding clinical and demographic information improved classification. Results:The CNN classifier achieved high subject-level performance, distinguishing individuals with an accuracy of 85.0% and an area under the curve (AUC) of 0.88. This significantly outperformed the SVM baseline, which performed no better than chance (45.0% accuracy, AUC: 0.47). A subsequent multimodal analysis revealed that clinical and demographic variables did not contribute any additional independent information. Conclusion:CNNs applied to resting-state EEG show promise for identifying OCD, outperforming traditional machine learning methods. These findings highlight the potential of deep learning to uncover complex, diagnostically relevant patterns in neural data. While limited by sample size, this work supports further investigation into multimodal models for psychiatric classification, warranting replication in larger, more diverse samples.

The balance between excitatory and inhibitory (E/I) activity is critical for brain function, and its disruption is implicated in neuropsychiatric disorders. Electrophysiological signals can be decomposed into periodic (oscillatory) and aperiodic components. In the power spectrum, the periodic component appears as narrowband peaks, while the aperiodic component underlies its characteristic 1/fx power-law decay. Computational models predict that shifts in E/I balance alter the exponent x in specific directions. In a randomized, double-blind, placebo-controlled, within-subject study, healthy volunteers received subanesthetic doses of ketamine and thiopental during an EEG oddball task. These drugs have opposite effects on E/I balance but comparable sedative profiles. Ketamine reduced the PSD exponent, while thiopental increased it, consistent with computational predictions. Changes in the exponent were associated with subjective and cognitive effects. These findings suggest that the PSD exponent has potential as a noninvasive EEG biomarker sensitive to transient shifts in cortical E/I balance.

Converging neuroimaging, genetic, and post-mortem evidence show a fundamental role of synaptic deficits in schizophrenia pathogenesis. However, the underlying molecular and cellular mechanisms that drive the onset and progression of synaptic pathology remain to be established. Here, we used synaptic density positron emission tomography (PET) imaging using the [11C]UCB-J radiotracer to reveal a prominent widespread pattern (p FWE < 0.05) of lower synaptic density in individuals with schizophrenia (n=29), compared to a large sample of healthy controls (n=93). We found that the spatial pattern of lower synaptic density in schizophrenia is spatially aligned (r cca = 0.67; p < 0.001) with higher normative distributions of GABAA/BZ, 5HT1B, 5HT2A, and 5HT6, and lower levels of CB1 and 5HT1A. Competing neighborhood deformation network models revealed that regional synaptic pathology strongly correlated with estimates predicted using a model constrained by both interregional structural connectivity and molecular similarity (.42 < r < .61; p FWE < 0.05). These data suggest that synaptic pathology in schizophrenia is jointly constrained by both global axonal connectivity and local molecular vulnerability. Simulation-based network diffusion models were used to identify regions that may represent the initial sources of pathology, nominating left prefrontal areas (p FWE < 0.05) as potential foci from which synaptic pathology initiates and propagates to molecularly similar areas. Overall, our findings provide in vivo evidence for widespread deficit in synaptic density in schizophrenia that is jointly constrained by axonal connectivity and molecular similarity between regions, and that synaptic deficits spread from initial source regions to axonally connected and molecularly similar territories.

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using 11C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a 11C-UCB-J PET scan. Binding potential, BPND, was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower 11C-UCB-J BPND compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes.

Converging genetic and post-mortem evidence suggests the loss of synapses is fundamental to schizophrenia pathogenesis. The radioligand [11C]UCB-J now allows in vivo examination of synaptic density via positron emission tomography (PET), revealing widespread lower density in schizophrenia. However, the mechanisms explaining the spatial pattern of these alterations remain elusive. Here, we investigate whether the brain's axonal fibres act as conduits for synaptic density loss in schizophrenia, as observed in other neurological syndromes.

Background: Evidence suggests that serotonergic psychedelics (e.g. psilocybin), have rapid-acting and long-lasting antidepressant effects after a single dose. However, the mechanism underlying these effects remain unclear. One proposed mechanism is that these drugs promote neuroplasticity. However, this has not been conclusively demonstrated in humans. Aims: We hypothesized that relative to placebo, psilocybin would: (1) increase electroencephalographic (EEG) correlates of neuroplasticity, (2) reduce depression symptoms, and (3) changes in EEG would correlate with improvements in depression. Methods: In this double-blind, placebo-controlled, within-subject study, individuals with major depressive disorder (MDD; n = 19) were administered placebo followed by psilocybin (0.3 mg/kg) in a fixed order (placebo, followed by psilocybin 4 weeks later). EEG indices of neuroplasticity (tetanus-induced long-term potentiation) as assessed via auditory evoked theta (4–8 Hz) power and measures of depression (GRID Hamilton Rating Scale for Depression-17 (GRID-HAM-D-17)) were measured at several time-points after placebo and psilocybin (24 h and 2 weeks after each session). Results: EEG theta power doubled in amplitude 2 weeks after a single psychedelic dose of psilocybin but not after placebo. Further, improvements in depression symptoms 2 weeks after psilocybin were correlated with increases in theta power. Conclusions: The increased theta power observed represents evidence of sustained changes in the brain following psilocybin. Given the correlation with enhancement in depressive symptoms, changes in theta may represent an EEG biomarker of the sustained effects of psilocybin, and may shed light on potential mechanisms of psilocybin’s antidepressant effect. Taken together, these results complement the emerging notion that psilocybin, and perhaps other psychedelics, can produce long-term alterations in neuroplasticity.

Drug- and alcohol-related motor vehicle accidents are a leading cause of morbidity and mortality worldwide. Compared to alcohol, less is known about the effects of cannabis on driving and even less about their combined effects. To characterize the combined and separate effects of ethanol and tetrahydrocannabinol (THC) on perceived ability to drive, subjective effects, and simulated driving. In a within-subject (crossover), randomized, placebo-controlled, double-blind, 2 × 2 design, the effects of oral THC (10 mg [dronabinol] or placebo) and low-dose intravenous ethanol (clamped at BAC 0.04% or placebo) on perceived ability to drive, simulated driving (standard deviation of lateral position [SDLP]), subjective effects (e.g., “high”), and physiological effects (e.g., heart rate) were studied in healthy humans (n = 18). Subjects reported reductions in perceived ability to drive (THC < ethanol < combination) which persisted for ~ 6 h (placebo = ethanol, THC < combination). Ethanol and THC produced synergistic effects on heart rate, significant differences compared to either drug alone on perceived ability to drive and feeling states of intoxication (e.g., high), as well increases in SDLP compared to placebo. Perceived ability to drive is reduced under the influence of THC against the backdrop of blood alcohol levels that are below the legal limit. People should be aware that the effects of oral THC on driving may persist for up to six hours from administration. Findings are relevant to the increasingly common practice of combining alcohol and cannabinoids and the effects on driving.

Sleep is a vital biological process, serving an important role in proper neurodevelopment, energy conservation, brain waste clearance, modulation of immune responses, neurocognition, mood, memory consolidation and performance/vigilance. Many of these processes are altered in psychiatric illnesses. There is mounting evidence that the endocannabinoid system (ECS) plays a key role in the sleep/wake cycle. Acute administration and chronic use of THC and cannabis have been shown to alter sleep in small studies of healthy, young people. Sleep disturbances are also part of cannabis withdrawal syndrome and include increased sleep complaints, decreased SWS and increased REM. Sleep disturbances are a promising target for treatment of cannabis use disorder. Given the link between cannabinoids and psychosis, the role of cannabis-induced sleep alterations in psychosis-prone individuals and schizophrenia patients warrants further study.

Background: THC and CBD are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations.Methods: In this double-blind randomized placebo-controlled counterbalanced Human Laboratory Study, we examined the effects of three different dose ratios of CBD:THC (1:1, 2:1, and 3:1) on "neural noise," an electrophysiological biomarker of psychosis known to be sensitive to cannabinoids as well as subjective and psychotomimetic effects. Healthy volunteers (n=28, 12 women) with at least one prior exposure to cannabis participated in the study.Outcomes: The lowest CBD (2.5 mg):THC (0.035 mg/kg) ratio (1:1) resulted in maximal attenuation of both THC-induced psychotomimetic effects (Positive and Negative Syndrome Scale [PANSS] positive: Anova Type Statistic [ATS]=7.83, p(corrected)=0.015) and neural noise (ATS=8.83, p(corrected)=0.009). Further addition of CBD did not reduce the subjective experience of THC-induced "high" (p>0.05 for all CBD doses).Interpretation: These novel results demonstrate that CBD attenuates specific THC-induced subjective and objective effects relevant to psychosis in a dose/ratio-dependent manner. Given the increasing global trend of cannabis liberalization and application for medical indications, these results assume considerable significance given the potential dose-related interactions of these key phyto-cannabinoids. Trial registration: The trial was registered in clinicaltrials.gov ID: NCT01180374.

Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21–83 years old). Partial volume correction was applied to the PET data. Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9

Background: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature. Methods: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo ( n = 19) followed by psilocybin (0.3 mg/kg) ( n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period. Results: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin ( d′ = 1.02–2.27) than after placebo ( d′ = 0.65–0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects. Conclusions: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.

Disruptions in neural oscillations are believed to be one critical mechanism by which cannabinoids, such as delta-9-tetrahyrdrocannabinol (THC; the primary psychoactive constituent of cannabis), perturbs brain function. Here we briefly review the role of synchronized neural activity, particularly in the gamma (30-80 Hz) and theta (4-7 Hz) frequency range, in sensation, perception, and cognition. This is followed by a review of clinical studies utilizing electroencephalography (EEG) which have demonstrated that both chronic and acute cannabinoid exposure disrupts neural oscillations in humans. We also offer a hypothetical framework through which endocannabinoids modulate neural synchrony at the network level. This also includes speculation on how both chronic and acute cannabinoids disrupt functionally relevant neural oscillations by altering the fine tuning of oscillations and the inhibitory/excitatory balance of neural circuits. Finally, we highlight important clinical implications of such oscillatory disruptions, such as the potential relationship between cannabis use, altered neural synchrony, and disruptions in sensation, perception, and cognition, which are perturbed in disorders such as schizophrenia.

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18–55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.

Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated the sex differences in the acute subjective, psychotomimetic, cognitive, and physiological effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. Healthy male and female individuals, with limited exposure to cannabis, participated in a double blind, placebo-controlled study of intravenous (IV) placebo or THC at two doses (0.015 mg/kg and 0.03 mg/kg). Visual analog scale (VAS) was used to measure subjective effects, Psychotomimetic States Inventory (PSI) and the Clinician-Administered Dissociative Symptoms Scale (CADSS) were used to assess the psychotomimetic effects and perceptual alterations, respectively, and Rey Auditory Verbal Learning Task (RAVLT) was used to evaluate cognitive effects. Outcome variables were represented as the peak change from baseline for each variable, except RAVLT which was used only once per the test day after the subjective effects. A total of 42 individuals participated in this study. There were no significant differences between male and female participants in background characteristics. There was a significant main effect of sex on the VAS scores for THC-induced “High” (F1,38 = 4.27, p < 0.05) and a significant dose × sex interaction (F2,77 = 3.38, p < 0.05) with female participants having greater “High” scores than male participants at the lower THC dose (0.015 mg/kg). No other sex differences were observed in acute subjective, psychotomimetic, cognitive, or physiological effects of THC. There were significant sex differences in subjective effects of feeling “High” at a lower dose of THC. However, there were no other sex-related differences in the subjective, physiological, or cognitive effects of THC.

| 10:30 am | Opening of Meeting | || | 10:45 am | Opening Remarks – Dr. Jeff Daskalakis, CCNP

Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations. In this double-blind randomized placebo-controlled counterbalanced human laboratory experiment, we examined the effects of three different dose ratios of CBD: THC (1:1, 2:1 and 3:1) on ‘neural noise’, an electrophysiological biomarker of psychosis known to be sensitive to cannabinoids as well as subjective and psychotomimetic effects. Interestingly, the lowest CBD:THC ratio (1:1) resulted in maximal attenuation of both THC induced psychotomimetic effects (PANSS positive - ATS = 7.83, df = 1, p corr = 0.015) and neural noise (ATS = 8.83, df = 1, p corr = 0.009) with an inverse-linear dose response relationship. Further, in line with previous studies, addition of CBD did not reduce the subjective experience of THC induced “high” (p > 0.05 for all CBD doses). These novel results demonstrate that CBD attenuates THC induced subjective and objective effects relevant to psychosis- but in a dose/ratio dependent manner. Given the increasing global trend of cannabis liberalization and application for medical indications, these results assume considerable significance given the potential dose related interactions of these key phyto-cannabinoids.