Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity.

BACKGROUND: Classic psychedelics, such as psilocybin and LSD, and other serotonin 2A receptor (5-HT2AR) agonists evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been hypothesized to underlie these effects, which is supported by some functional MRI (fMRI) studies. These studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been previously used to identify reliable group-level functional subdivisions of the thalamus from resting-state fMRI (rsfMRI) data. We build on these efforts with a novel data-maximizing ICA-based approach to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity in individual participants. METHODS: Baseline rsfMRI data (n=38) from healthy individuals with a long-term meditation practice was utilized to generate a statistical template of thalamic functional subdivisions. This template was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in follow-up scans from a subset of the same individuals (n=18). We examined correlations with subjective reports of drug effect and compared with a previously reported analytic approach (treating the thalamus as a single functional unit). RESULTS: Several intrathalamic components showed significant psilocybin-induced alterations in spatial organization, with effects of psilocybin largely localized to the mediodorsal and pulvinar nuclei. The magnitude of changes in individual participants correlated with reported subjective effects. These components demonstrated predominant decreases in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance. CONCLUSIONS: We utilized a novel analytic approach to discover psilocybin-induced changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. These changes were not observed using whole-thalamus analyses, suggesting that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.

Models of psychedelic drug action: modulation of cortical-subcortical circuits.

Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.

New Long-Term Opioid Prescription-Filling Behavior Arising in the 15 Months After Orthopaedic Surgery.

BACKGROUND: The opioid crisis is a well-known public health issue. The risk of new long-term opioid prescription-filling behavior has been investigated after certain spinal procedures and total knee and hip arthroplasty. However, this has not been examined after many other common orthopaedic procedures. The purpose of this study was to determine the rates of long-term opioid prescription-filling behavior after common orthopaedic surgical procedures in patients who were not taking opioids preoperatively. METHODS: This study utilized the Virginia All-Payer Claims Database (APCD), an insurance claims database with data from 3.7 to 4 million patients per year. Patients who underwent orthopaedic procedures and who had not filled an opioid prescription in the time period from 2 weeks to 1 year preceding the surgical procedure were selected for evaluation in our study. The percentage of these patients who then filled at least 10 prescriptions or a 120-day supply of opioids in the time period from 90 to 455 days following the surgical procedure was calculated for the 50 most commonly billed orthopaedic surgical procedures. RESULTS: The rate of long-term opioid prescription-filling behavior in patients who were not taking opioids preoperatively for the 50 most common orthopaedic procedures was 5.3% (95% confidence interval, 5.1% to 5.5%). The highest rates were observed after spinal procedures. The lowest rates were seen after anterior cruciate ligament (ACL) reconstruction. Revision surgical procedures were found to have a significantly higher rate than primary procedures (p < 0.05). The rate was also related to increasing case complexity. CONCLUSIONS: New long-term opioid prescription-filling behavior is common after orthopaedic surgical procedures in patients who were not taking opioids preoperatively. Risk factors include spine surgery, revision surgery, and cases with increased complexity. Orthopaedic surgeons need to be aware of this risk. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Effect of Prescription Size on Opioid Use and Patient Satisfaction After Minor Hand Surgery: A Randomized Clinical Trial.

OBJECTIVE: To determine the influence of initial prescription size on opioid consumption after minor hand surgeries. Secondary outcomes include efficacy of pain control, patient satisfaction, and refill requests. BACKGROUND: Retrospective studies have shown that opioid prescriptions for acute pain after surgical procedures are often excessive in size, which encourages misuse. This is the first prospective randomized trial on the influence of initial prescription size on opioid consumption in the setting of acute postsurgical pain. METHODS: In a prospective randomized trial at a single-academic institution, patients were provided an initial prescription of either 10 or 30 hydrocodone/acetaminophen (5/325 mg) pills after surgery. Two hundred opioid-naive patients, aged 19 to 69, undergoing elective outpatient minor hand surgeries were enrolled over 9 months, with a follow-up period of 10 to 14 days. RESULTS: One hundred seventy-four patients were included in this analysis. Patients initially prescribed 30 pills (n = 79), when compared with patients initially prescribed 10 pills (n = 95), used significantly more opioid (P = <0.001, mean 11.9 vs 6.4 pills), had significantly more leftover medication (P = <0.001, mean 20.0 vs 5.2 pills), and were over 3 times more likely to still be taking opioid at follow-up (15% vs 4%). There was no significant difference in refills requested, or in patient satisfaction with postoperative pain control. CONCLUSIONS: Providing large opioid prescriptions for the management of acute pain after minor upper extremity surgeries increases overall opioid use when compared with smaller initial prescriptions. The size of initial opioid prescription is a modifiable variable that should be considered both in patient care and research design.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) use and transitions to injection drug use among street-involved youth.

Background: Despite the popularity of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) among young people across North America and Europe, MDMA is rarely explored in studies of young people at high risk of injecting drugs. We conducted a study among street-involved youth who use illicit drugs in Vancouver, Canada, to understand if use of MDMA is associated with initiation of injection drugs. Methods: We followed injection-naïve participants in the At-Risk Youth Study (ARYS), an ongoing prospective cohort of street-involved youth aged 14-26 who use illicit drugs. Bivariate and multivariate extended Cox models with time-updated variables were used to examine the association between MDMA use and initiation of injection drug use between September 2005 and May 2015. Results: Among 483 youth, 306 (63.4%) had a history of MDMA use and 218 (45.1%) had used MDMA in the previous 6 months at baseline. A total of 105 (21.7%) youth initiated injection drug use over the 10-year period, yielding an incidence density of 8.51 (95% confidence interval [CI]: 6.96-10.30) per 100 person-years. MDMA use was not significantly associated with initiating injection drugs at the bivariate (hazard ratio: 0.93, 95% CI: 0.61-1.42) or multivariate (adjusted hazard ratio: 0.88, 95% CI: 0.57-1.35) level, after adjusting for socio-demographic and substance use confounders. Conclusions: Amid ongoing frequent use of MDMA among some young people in North America, we did not observe an elevated risk of injection initiation among those who used MDMA in this cohort of street-involved youth.

Regular MDMA use is associated with decreased risk of drug injection among street-involved youth who use illicit drugs.

OBJECTIVES: Childhood trauma is common among street-involved youth and is associated with injection drug use. Illicit 3,4-Methylenedioxymethamphetamine (MDMA) use is also common among street-involved youth, and data suggest this substance has clinical utility in management of post-traumatic stress disorder (PTSD) and associated harms. Despite this, little is known about co-occurring patterns of MDMA use and injection drug use. METHODS: Data were derived from a prospective cohort of street-involved youth using illicit drugs in Vancouver, Canada. Using multivariable generalized estimating equation logistic regression, we examined the association between MDMA use and the use of injection drugs, adjusting for confounders such as polysubstance use and sociodemographic factors. RESULTS: 4941 surveys from 1208 participants between September 2005 and May 2015 were included. Of these, 829 (68.6%) were male, 815 (67.5%) reported white ethnicity, and median age was 21.7 years. Overall, 599 (49.6%) participants reported MDMA use, 544 (45.0%) reported injection drug use, and 244 (20.2%) reported concurrent MDMA and injection drug use at least once during the study period. In multivariable analyses, regular MDMA use was significantly negatively associated with injection drug use (Adjusted Odds Ratio [AOR] = 0.57, 95% CI: 0.46-0.69). DISCUSSION: After accounting for socio-demographic factors and polysubstance use, periods of reported regular MDMA use were negatively associated with reported injection drug use among this cohort. These findings suggest that, unlike the use of most other non-injection drugs, illicit MDMA use does not appear to promote injection drug use but rather is associated with a reduced likelihood of injection drug use.

Pilot study of volume contracted state and hospital outcome after stroke.

BACKGROUND: An increasing body of research suggests that acute stroke patients who are dehydrated may have worsened functional outcomes. We sought to explore the relationship between a volume contracted state (VCS) at the time of ischemic stroke and hospital outcomes as compared with euvolemic patients. METHODS: We enrolled a consecutive series of ischemic stroke patients from a single academic stroke center within 12 hours from stroke onset. VCS was defined via surrogate markers (blood urea nitrogen/creatinine ratio >15 and urine specific gravity >1.010). The primary outcome was change in NIH Stroke Scale (NIHSS) score from admission to discharge. Multivariable analyses included adjustment for demographics and infarct size. RESULTS: Over an 11-month study period, 168 patients were eligible for inclusion. Of the126 with complete laboratory and MRI data, 44% were in a VCS at the time of admission. Demographics were similar in both the VCS and euvolemic groups, as were baseline NIHSS scores (6.7 vs 7.3; p = 0.63) and infarct volumes (12 vs 16 mL; p = 0.48). However, 42% of patients in a VCS demonstrated early clinical worsening, compared with 17% of the euvolemic group (p = 0.02). A VCS remained a significant predictor of worsening NIHSS in adjusted models (odds ratio 4.34; 95% confidence interval 1.75-10.76). CONCLUSIONS: Acute stroke patients in a VCS demonstrate worse short-term outcomes compared to euvolemic patients, independent of infarct size. Results suggest an opportunity to explore current hydration practices.

Use of on-site detoxification services co-located with a supervised injection facility.

OBJECTIVES: Supervised injection facilities (SIFs) are increasingly being implemented worldwide in response to the harms associated with injection drug use. Although SIFs have been shown to promote engagement of people who use injection drugs (PWID) with external health services, little is known about the potential of co-locating on-site detoxification services with SIFs. The aim of this study was to characterize use of detoxification services co-located at Insite, North America's first SIF, among PWID in Vancouver, Canada. METHODS: Data were derived from two prospective cohorts of PWID in Vancouver, Canada between November 2010 and December 2012. Using multivariable generalized estimating equation logistic regression, we identified factors independently associated with reporting use of detoxification services at the SIF. RESULTS: Among 1316 PWID, 147 (11.2%) reported enrolling in detoxification services co-located with the SIF at least once during the two year study period. In multivariable analyses, after adjustment for other potential cofounders, factors independently and positively associated with use of this service included residence<5 blocks from the SIF (Adjusted Odds Ratio [AOR]=1.70), enrollment in methadone maintenance therapy (AOR=1.90), public injection (AOR=1.53), binge injection (AOR=1.93), recent overdose (AOR=1.90) and frequent SIF use (AOR=8.15) (all p<0.05). DISCUSSION: Use of on-site detoxification services offered at the SIF was common among PWID and associated with frequent SIF use and various markers of vulnerability and drug-related risk. These findings highlight the potential role of SIFs as a point of access to detoxification services for high-risk PWID. Future studies should examine if co-location leads to higher uptake of addiction services in comparison to services that create geographic or other obstacles.

Motor overflow in children with attention-deficit/hyperactivity disorder is associated with decreased extent of neural activation in the motor cortex.

Motor overflow is a developmental phenomenon that typically disappears by late childhood. Abnormal persistence of motor overflow is often present in children with attention-deficit/hyperactivity disorder (ADHD). This study employed functional magnetic resonance imaging (fMRI) during a finger-sequencing task to examine whether excessive motor overflow in children with ADHD is associated with decreased extent of motor circuit activation. Thirty-four right-handed children (18 typically developing controls, 16 ADHD) completed fMRI while performing a finger-sequencing task. Motor overflow was evaluated during a finger-sequencing task and a motor examination (the PANESS) performed outside the scanner. Diagnostic differences in behavioral measures of overflow and extent of activation in the contralateral and ipsilateral motor network ROIs were examined, along with correlations between overflow and extent of activation. Children with ADHD demonstrated greater overflow and lesser extent of activation in left primary motor cortex (BA4) and bilateral premotor cortex (BA6) and supplementary motor area (SMA) during right-hand finger-sequencing compared to controls. Decreased extent of primary motor and premotor activation correlated with increased hand-related overflow movements in children with ADHD but not controls. These findings suggest that overflow movements in children with ADHD may reflect decreased recruitment of neural circuitry involved in active inhibition of homologous motor circuitry unnecessary to task execution.