Dynamic 3D imaging of cerebral blood flow in awake mice using self-supervised-learning-enhanced optical coherence Doppler tomography.

Cerebral blood flow (CBF) is widely used to assess brain function. However, most preclinical CBF studies have been performed under anesthesia, which confounds findings. High spatiotemporal-resolution CBF imaging of awake animals is challenging due to motion artifacts and background noise, particularly for Doppler-based flow imaging. Here, we report ultrahigh-resolution optical coherence Doppler tomography (µODT) for 3D imaging of CBF velocity (CBFv) dynamics in awake mice by developing self-supervised deep-learning for effective image denoising and motion-artifact removal. We compare cortical CBFv in awake vs. anesthetized mice and their dynamic responses in arteriolar, venular and capillary networks to acute cocaine (1 mg/kg, i.v.), a highly addictive drug associated with neurovascular toxicity. Compared with awake, isoflurane (2-2.5%) induces vasodilation and increases CBFv within 2-4 min, whereas dexmedetomidine (0.025 mg/kg, i.p.) does not change vessel diameters nor flow. Acute cocaine decreases CBFv to the same extent in dexmedetomidine and awake states, whereas decreases are larger under isoflurane, suggesting that isoflurane-induced vasodilation might have facilitated detection of cocaine-induced vasoconstriction. Awake mice after chronic cocaine show severe vasoconstriction, CBFv decreases and vascular adaptations with extended diving arteriolar/venular vessels that prioritize blood supply to deeper cortical capillaries. The 3D imaging platform we present provides a powerful tool to study dynamic changes in vessel diameters and morphology alongside CBFv networks in the brain of awake animals that can advance our understanding of the effects of drugs and disease conditions (ischemia, tumors, wound healing).

Brain functional and structural magnetic resonance imaging of obesity and weight loss interventions.

Obesity has tripled over the past 40 years to become a major public health issue, as it is linked with increased mortality and elevated risk for various physical and neuropsychiatric illnesses. Accumulating evidence from neuroimaging studies suggests that obesity negatively affects brain function and structure, especially within fronto-mesolimbic circuitry. Obese individuals show abnormal neural responses to food cues, taste and smell, resting-state activity and functional connectivity, and cognitive tasks including decision-making, inhibitory-control, learning/memory, and attention. In addition, obesity is associated with altered cortical morphometry, a lowered gray/white matter volume, and impaired white matter integrity. Various interventions and treatments including bariatric surgery, the most effective treatment for obesity in clinical practice, as well as dietary, exercise, pharmacological, and neuromodulation interventions such as transcranial direct current stimulation, transcranial magnetic stimulation and neurofeedback have been employed and achieved promising outcomes. These interventions and treatments appear to normalize hyper- and hypoactivations of brain regions involved with reward processing, food-intake control, and cognitive function, and also promote recovery of brain structural abnormalities. This paper provides a comprehensive literature review of the recent neuroimaging advances on the underlying neural mechanisms of both obesity and interventions, in the hope of guiding development of novel and effective treatments.

Measures of Brain Connectivity and Cognition by Sex in US Children.

Importance: The neurobiological underpinnings underlying sex differences in cognition during adolescence are largely unknown. Objective: To examine sex differences in brain circuitry and their association with cognitive performance in US children. Design, Setting, and Participants: This cross-sectional study analyzed behavioral and imaging data from 9- to 11-year-old children from the Adolescent Brain Cognitive Development (ABCD) study between August 2017 and November 2018. The ABCD study is an open-science, multisite study following up more than 11 800 youths into early adulthood for 10 years with annual laboratory-based assessments and biennial magnetic resonance imaging (MRI). The selection of ABCD study children for the current analysis was based on the availability of functional and structural MRI data sets in ABCD Brain Imaging Data Structure Community Collection format. Five hundred and sixty participants who had excessive level of head motion (>50% of time points with framewise displacement >0.5 mm) during resting-state functional MRI were excluded from the analyses. Data were analyzed between January and August 2022. Main Outcomes and Measures: The main outcomes were the sex differences in (A) global functional connectivity density at rest and (B) mean water diffusivity (MD) and (C) the correlation of these metrics with total cognitive scores. Results: A total of 8961 children (4604 boys and 4357 girls; mean [SD] age, 9.92 [0.62] years) were included in this analysis. Girls had higher functional connectivity density in default mode network hubs than boys, predominantly in the posterior cingulate cortex (Cohen d = -0.36), and lower MD and transverse diffusivity, predominantly in the superior corticostriatal white matter bundle (Cohen d = 0.3). Age-corrected fluid and total composite scores were higher for girls than for boys (Cohen d = -0.08 [fluid] and -0.04 [total]; P = 2.7 × 10-5). Although total mean (SD) brain volume (1260 [104] mL in boys and 1160 [95] mL in girls; t = 50; Cohen d = 1.0; df = 8738) and the proportion of white matter (d = 0.4) were larger for boys than for girls, the proportion of gray matter was larger for girls than for boys (d = -0.3; P = 2.2 × 10-16). Conclusions and Relevance: The findings of this cross-sectional study on sex differences in brain connectivity and cognition are relevant to the future creation of brain developmental trajectory charts to monitor for deviations associated with impairments in cognition or behavior, including those due to psychiatric or neurological disorders. They could also serve as a framework for studies investigating the differential contribution of biological vs social or cultural factors in the neurodevelopmental trajectories of girls and boys.

Seasonality of brain function: role in psychiatric disorders.

Seasonality patterns are reported in various psychiatric disorders. The current paper summarizes findings on brain adaptations associated with seasonal changes, factors that contribute to individual differences and their implications for psychiatric disorders. Changes in circadian rhythms are likely to prominently mediate these seasonal effects since light strongly entrains the internal clock modifying brain function. Inability of circadian rhythms to accommodate to seasonal changes might increase the risk for mood and behavior problems as well as worse clinical outcomes in psychiatric disorders. Understanding the mechanisms that account for inter-individual variations in seasonality is relevant to the development of individualized prevention and treatment for psychiatric disorders. Despite promising findings, seasonal effects are still understudied and only controlled as a covariate in most brain research. Rigorous neuroimaging studies with thoughtful experimental designs, powered sample sizes and high temporal resolution alongside deep characterization of the environment are needed to better understand the seasonal adaptions of the human brain as a function of age, sex, and geographic latitude and to investigate the mechanisms underlying the alterations in seasonal adaptation in psychiatric disorders.

Heroin- and fentanyl-induced respiratory depression in a rat plethysmography model: potency, tolerance, and sex differences.

The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized the magnitude and duration of respiratory depression, the leading cause of death in opioid overdose cases, induced by heroin or fentanyl and the development of tolerance in male and female rats. We used whole-body plethysmography to first establish dose-response curves by recording breathing for 60 min post-intravenous opioid injection. We then tested the development of respiratory tolerance to acute heroin or fentanyl over several weeks and to chronic fentanyl with acute fentanyl or heroin challenge. Heroin and fentanyl each provoked dose-dependent respiratory depression. Heroin caused prolonged (45-60 min) respiratory depression in female and male rats, characterized by decreased frequency, tidal volume, and minute ventilation, and increased inspiratory time and apneic pause. Fentanyl produced similar changes with a shorter duration (10-15 min). High-dose heroin or fentanyl produced robust respiratory depression that was slightly more severe in females and, when given intermittently (acute doses 2-3 weeks apart), did not lead to tolerance. In contrast, chronic fentanyl delivered with an osmotic minipump resulted in tolerance to acute fentanyl and heroin, characterized by a shorter duration of respiratory depression. This effect persisted during withdrawal in males only. Our model and experimental design will allow for investigation of the neurobiology of opioid-induced respiratory depression and for testing potential therapeutics to reverse respiratory depression or stimulate breathing. Significance Statement Fentanyl was more potent and had shorter duration in producing respiratory depression than heroin in both sexes, while female rats were more sensitive than males to heroin-induced respiratory depression. Tolerance/cross tolerance develops in chronic fentanyl administration but is minimized with long inter-administration intervals.

Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans.

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.

Trends and Characteristics of Buprenorphine-Involved Overdose Deaths Prior to and During the COVID-19 Pandemic.

Importance: Buprenorphine remains underused in treating opioid use disorder, despite its effectiveness. During the onset of the COVID-19 pandemic, the US government implemented prescribing flexibilities to support continued access. Objective: To determine whether buprenorphine-involved overdose deaths changed after implementing these policy changes and highlight characteristics and circumstances of these deaths. Design, Setting, and Participants: This cross-sectional study used data from the State Unintentional Drug Overdose Reporting System (SUDORS) to assess overdose deaths in 46 states and the District of Columbia occurring July 2019 to June 2021. Data were analyzed from March 7, 2022, to June 30, 2022. Main Outcomes and Measures: Buprenorphine-involved and other opioid-involved overdose deaths were examined. Monthly opioid-involved overdose deaths and the percentage involving buprenorphine were computed to assess trends. Proportions and exact 95% CIs of drug coinvolvement, demographics, and circumstances were calculated by group. Results: During July 2019 to June 2021, 32 jurisdictions reported 89 111 total overdose deaths and 74 474 opioid-involved overdose deaths, including 1955 buprenorphine-involved overdose deaths, accounting for 2.2% of all drug overdose deaths and 2.6% of opioid-involved overdose deaths. Median (IQR) age was similar for buprenorphine-involved overdose deaths (41 [34-55] years) and other opioid-involved overdose deaths (40 [31-52] years). A higher proportion of buprenorphine-involved overdose decedents, compared with other opioid-involved decedents, were female (36.1% [95% CI, 34.2%-38.2%] vs 29.1% [95% CI, 28.8%-29.4%]), non-Hispanic White (86.1% [95% CI, 84.6%-87.6%] vs 69.4% [95% CI, 69.1%-69.7%]), and residing in rural areas (20.8% [95% CI, 19.1%-22.5%] vs 11.4% [95% CI, 11.2%-11.7%]). Although monthly opioid-involved overdose deaths increased, the proportion involving buprenorphine fluctuated but did not increase during July 2019 to June 2021. Nearly all (92.7% [95% CI, 91.5%-93.7%]) buprenorphine-involved overdose deaths involved at least 1 other drug; higher proportions involved other prescription medications compared with other opioid-involved overdose deaths (eg, anticonvulsants: 18.6% [95% CI, 17.0%-20.3%] vs 5.4% [95% CI, 5.2%-5.5%]) and a lower proportion involved illicitly manufactured fentanyls (50.2% [95% CI, 48.1%-52.3%] vs 85.3% [95% CI, 85.1%-85.5%]). Buprenorphine decedents were more likely to be receiving mental health treatment than other opioid-involved overdose decedents (31.4% [95% CI, 29.3%-33.5%] vs 13.3% [95% CI, 13.1%-13.6%]). Conclusions and Relevance: The findings of this cross-sectional study suggest that actions to facilitate access to buprenorphine-based treatment for opioid use disorder during the COVID-19 pandemic were not associated with an increased proportion of overdose deaths involving buprenorphine. Efforts are needed to expand more equitable and culturally competent access to and provision of buprenorphine-based treatment.

Tobacco, Alcohol, Cannabis, and Other Drug Use in the US Before and During the Early Phase of the COVID-19 Pandemic.

Importance: Information about national substance use trends among youths and adults after mid-March 2020 is limited due to constraints on surveillance during the COVID-19 pandemic. Objective: To evaluate whether substance use prevalence in the early part of the pandemic (2020) differed from the prepandemic periods of 2018 to 2019 and 2016 to 2018. Design, Setting, and Participants: This cross-sectional study was a repeated analysis of 2016 to 2020 data from a nationally representative sample of youths and adults in the Population Assessment of Tobacco and Health (PATH) Study. Participants were representative of the US civilian noninstitutionalized population. Household residents age 13 years or older were interviewed in person from 2016 to 2019 and via telephone in 2020. Exposures: Age, calendar year. Main Outcomes and Measures: Past 30-day self-reported use of any tobacco, any alcohol, binge drinking, cannabis, and any other illegal or misused prescription drugs. Results: The overall nationally representative 2020 sample included 7129 youths (ages 13-17 years), 3628 young adults (ages 18-20 years), and 8874 adults (ages ≥21 years). Comparing 2018 to 2019 with 2020 among youths, prevalence of all substances used declined (eg, cannabis use declined in those aged 16-17 years from 14.9% to 7.6%; absolute difference, -7.3 percentage points [95% CI -8.8 to -5.8 percentage points]). Among young adults, prevalence of all substances other than any alcohol decreased significantly (eg, tobacco use declined from 37.8% to 22.8%; absolute difference, -15.1 percentage points [95% CI -16.8 to -13.3 percentage points]). In adults ages 21 to 24 years, any tobacco use declined from 39.0% to 30.9% (absolute difference, -8.2 percentage points [95% CI, -10.6 to -5.7 percentage points]), and alcohol use increased from 60.2% to 65.2% (absolute difference, 5.0 percentage points [95% CI, 2.3 to 7.7 percentage points]). Among adults aged 25 years or older, any tobacco use declined from 39.0% to 30.9% (absolute difference, -8.2 percentage points [95% CI, -10.6 to -5.7 percentage points]), cannabis use increased from 11.3% to 12.4% (absolute difference, 1.2 percentage points [95% CI, 0.3 to 2.0 percentage points]), and other substance use declined from 5.8% to 3.7% (absolute difference, -2.1 percentage points [95% CI, -2.9 to -1.4 percentage points]). Conclusions and Relevance: In this cross-sectional study, substance use decreased between 2019 and 2020 among those aged 13 to 20 years; consistent declines were not seen in older persons other than tobacco use reductions, and cannabis use increased among adults ages 25 years and older. While social changes during the COVID-19 pandemic could have affected substance use, findings should be interpreted with caution due to differences in data collection methods in 2016 to 2019 and 2020.

Activation of brain arousal networks coincident with eye blinks during resting state.

Eye-blinking has been implicated in arousal and attention. Here we test the hypothesis that blinking-moments represent arousal surges associated with activation of the ascending arousal network (AAN) and its thalamic projections. For this purpose, we explored the temporal relationship between eye-blinks and fMRI BOLD activity in AAN and thalamic nuclei, as well as whole brain cluster corrected activations during eyes-open, resting-state fMRI scanning. We show that BOLD activations in the AAN nuclei peaked prior to the eye blinks and in thalamic nuclei peaked prior to and during the blink, consistent with the role of eye blinking in arousal surges. Additionally, we showed visual cortex peak activation prior to the eye blinks, providing further evidence of the visual cortex's role in arousal, and document cerebellar peak activation post eye blinks, which might reflect downstream engagement from arousal surges.

Trends and Characteristics of Buprenorphine-Involved Overdose Deaths Prior to and During the COVID-19 Pandemic.

Importance: Buprenorphine remains underused in treating opioid use disorder, despite its effectiveness. During the onset of the COVID-19 pandemic, the US government implemented prescribing flexibilities to support continued access. Objective: To determine whether buprenorphine-involved overdose deaths changed after implementing these policy changes and highlight characteristics and circumstances of these deaths. Design, Setting, and Participants: This cross-sectional study used data from the State Unintentional Drug Overdose Reporting System (SUDORS) to assess overdose deaths in 46 states and the District of Columbia occurring July 2019 to June 2021. Data were analyzed from March 7, 2022, to June 30, 2022. Main Outcomes and Measures: Buprenorphine-involved and other opioid-involved overdose deaths were examined. Monthly opioid-involved overdose deaths and the percentage involving buprenorphine were computed to assess trends. Proportions and exact 95% CIs of drug coinvolvement, demographics, and circumstances were calculated by group. Results: During July 2019 to June 2021, 32 jurisdictions reported 89 111 total overdose deaths and 74 474 opioid-involved overdose deaths, including 1955 buprenorphine-involved overdose deaths, accounting for 2.2% of all drug overdose deaths and 2.6% of opioid-involved overdose deaths. Median (IQR) age was similar for buprenorphine-involved overdose deaths (41 [34-55] years) and other opioid-involved overdose deaths (40 [31-52] years). A higher proportion of buprenorphine-involved overdose decedents, compared with other opioid-involved decedents, were female (36.1% [95% CI, 34.2%-38.2%] vs 29.1% [95% CI, 28.8%-29.4%]), non-Hispanic White (86.1% [95% CI, 84.6%-87.6%] vs 69.4% [95% CI, 69.1%-69.7%]), and residing in rural areas (20.8% [95% CI, 19.1%-22.5%] vs 11.4% [95% CI, 11.2%-11.7%]). Although monthly opioid-involved overdose deaths increased, the proportion involving buprenorphine fluctuated but did not increase during July 2019 to June 2021. Nearly all (92.7% [95% CI, 91.5%-93.7%]) buprenorphine-involved overdose deaths involved at least 1 other drug; higher proportions involved other prescription medications compared with other opioid-involved overdose deaths (eg, anticonvulsants: 18.6% [95% CI, 17.0%-20.3%] vs 5.4% [95% CI, 5.2%-5.5%]) and a lower proportion involved illicitly manufactured fentanyls (50.2% [95% CI, 48.1%-52.3%] vs 85.3% [95% CI, 85.1%-85.5%]). Buprenorphine decedents were more likely to be receiving mental health treatment than other opioid-involved overdose decedents (31.4% [95% CI, 29.3%-33.5%] vs 13.3% [95% CI, 13.1%-13.6%]). Conclusions and Relevance: The findings of this cross-sectional study suggest that actions to facilitate access to buprenorphine-based treatment for opioid use disorder during the COVID-19 pandemic were not associated with an increased proportion of overdose deaths involving buprenorphine. Efforts are needed to expand more equitable and culturally competent access to and provision of buprenorphine-based treatment.

Overdose mortality rates for opioids or stimulants are higher in males than females, controlling for rates of drug misuse: State-level data.

Importance: Drug overdoses from opioids like fentanyl and heroin and stimulant drugs such as methamphetamine and cocaine are a major cause of mortality in the United States, with potential sex differences across the lifespan. Objective: To determine overdose mortality for specific drug categories across the lifespan of males and females, using a nationally representative state-level sample. Design: State-level analyses of nationally representative epidemiological data on overdose mortality for specific drug categories, across 10-year age bins (age range: 15-74). Setting: Population-based study of Multiple Cause of Death 2020-2021 data from the Centers of Disease Control and Prevention (CDC WONDER platform). Participants: Decedents in the United States in 2020-2021. Main outcome measures: The main outcome measure was sex-specific rates of overdose death (per 100,000) for: synthetic opioids excluding methadone (ICD-10 code: T40.4; predominantly fentanyl), heroin (T40.1), psychostimulants with potential for misuse, excluding cocaine (T43.6, predominantly methamphetamine; labeled "psychostimulants" hereafter), and cocaine (T40.5). Multiple regression analyses were used to control for ethnic-cultural background, household net worth, and sex-specific rate of misuse of the relevant substances (from the National Survey on Drug Use and Health, 2018-2019). Results: For each of the drug categories assessed, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate for the separate drug categories was relatively stable across jurisdictions: synthetic opioids (2.5 [95%CI, 2.4-2.7]), heroin, (2.9 [95%CI, 2.7-3.1], psychostimulants (2.4 [95%CI, 2.3-2.5]), and cocaine (2.8 [95%CI, 2.6-2.9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment for state-level ethnic-cultural and economic variables, and for sex-specific misuse of each drug type (especially for bins in the 25-64 age range). For synthetic opioids, the sex difference survived adjustment across the lifespan (i.e., 10-year age bins ranging from 15-74), including adolescence, adulthood and late adulthood. Conclusions and Relevance: The robustly greater overdose mortality in males versus females for synthetic opioids (predominantly fentanyl), heroin, and stimulant drugs including methamphetamine and cocaine indicate that males who misuse these drugs are significantly more vulnerable to overdose deaths. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose. Key Points: Question: What are the current national trends in overdose mortality from opioids (synthetic opioids such as fentanyl, and heroin) and stimulant drugs (psychostimulants such as methamphetamine and cocaine) for males and females, over the lifespan (overall range 15-74 years)?Findings: State-level analyses of data from CDC for 2020-2021 indicate that after controlling for rates of drug misuse, males had significantly greater (2-3 fold) overdose mortality rates than females for synthetic opioids, heroin, psychostimulants and cocaine. These findings were generally consistent across the lifespan, studied as 10-year age bins (especially in the 25-64 age range).Meaning: These data indicate that males who misuse opioids and stimulant drugs are considerably more vulnerable to overdose mortality, compared to females. This finding calls for research on the underlying biological, behavioral, and social factors.

Association of COVID-19 with endocarditis in patients with cocaine or opioid use disorders in the US.

The incidence of endocarditis in the US is increasing, driven in part by the rise in intravenous drug use, mostly opioids and stimulant drugs (cocaine and methamphetamine). Recent reports have documented that individuals with COVID-19 are at increased risk for cardiovascular diseases. However, it is unknown whether COVID-19 is associated with increased risk for endocarditis in patients with opioid or stimulant use disorders. This is a retrospective cohort study based on a nationwide database of electronic health records (EHRs) of 109 million patients in the US, including 736,502 patients with a diagnosis of opioid use disorder (OUD) and 379,623 patients with a diagnosis of cocaine use disorder (CocaineUD). Since Metamphetamine use disorder is not coded we could not analyze it. We show that the incidence rate of endocarditis among patients with OUD or CocaineUD significantly increased from 2011 to 2022 with acceleration during 2021-2022. COVID-19 was associated with increased risk of new diagnosis of endocarditis among patients with OUD (HR: 2.23, 95% CI: 1.92-2.60) and with CocaineUD (HR: 2.24, 95% CI: 1.79-2.80). Clinically diagnosed COVID-19 was associated with higher risk of endocarditis than lab-test confirmed COVID-19 without clinical diagnosis. Hospitalization within 2 weeks following COVID-19 infection was associated with increased risk of new diagnosis of endocarditis. The risk for endocarditis did not differ between patients with and without EHR-recorded vaccination. There were significant racial and ethnic differences in the risk for COVID-19 associated endocarditis, lower in blacks than in whites and lower in Hispanics than in non-Hispanics. Among patients with OUD or CocaineUD, the 180-day hospitalization risk following endocarditis was 67.5% in patients with COVID-19, compared to 58.7% in matched patients without COVID-19 (HR: 1.21, 95% CI: 1.07-1.35). The 180-day mortality risk following the new diagnosis of endocarditis was 9.2% in patients with COVID-19, compared to 8.0% in matched patients without COVID-19 (HR: 1.16, 95% CI: 0.83-1.61). This study shows that COVID-19 is associated with significantly increased risk for endocarditis in patients with opioid or cocaine use disorders. These results highlight the need for endocarditis screening and for linkage to infectious disease and addiction treatment in patients with opioid or cocaine use disorders who contracted COVID-19. Future studies are needed to understand how COVID-19 damages the heart and the vascular endothelium among people who misuse opioids or cocaine (presumably also methamphetamines).

Association of COVID-19 with endocarditis in patients with cocaine or opioid use disorders in the US.

The incidence of endocarditis in the US is increasing, driven in part by the rise in intravenous drug use, mostly opioids and stimulant drugs (cocaine and methamphetamine). Recent reports have documented that individuals with COVID-19 are at increased risk for cardiovascular diseases. However, it is unknown whether COVID-19 is associated with increased risk for endocarditis in patients with opioid or stimulant use disorders. This is a retrospective cohort study based on a nationwide database of electronic health records (EHRs) of 109 million patients in the US, including 736,502 patients with a diagnosis of opioid use disorder (OUD) and 379,623 patients with a diagnosis of cocaine use disorder (CocaineUD). Since Metamphetamine use disorder is not coded we could not analyze it. We show that the incidence rate of endocarditis among patients with OUD or CocaineUD significantly increased from 2011 to 2022 with acceleration during 2021-2022. COVID-19 was associated with increased risk of new diagnosis of endocarditis among patients with OUD (HR: 2.23, 95% CI: 1.92-2.60) and with CocaineUD (HR: 2.24, 95% CI: 1.79-2.80). Clinically diagnosed COVID-19 was associated with higher risk of endocarditis than lab-test confirmed COVID-19 without clinical diagnosis. Hospitalization within 2 weeks following COVID-19 infection was associated with increased risk of new diagnosis of endocarditis. The risk for endocarditis did not differ between patients with and without EHR-recorded vaccination. There were significant racial and ethnic differences in the risk for COVID-19 associated endocarditis, lower in blacks than in whites and lower in Hispanics than in non-Hispanics. Among patients with OUD or CocaineUD, the 180-day hospitalization risk following endocarditis was 67.5% in patients with COVID-19, compared to 58.7% in matched patients without COVID-19 (HR: 1.21, 95% CI: 1.07-1.35). The 180-day mortality risk following the new diagnosis of endocarditis was 9.2% in patients with COVID-19, compared to 8.0% in matched patients without COVID-19 (HR: 1.16, 95% CI: 0.83-1.61). This study shows that COVID-19 is associated with significantly increased risk for endocarditis in patients with opioid or cocaine use disorders. These results highlight the need for endocarditis screening and for linkage to infectious disease and addiction treatment in patients with opioid or cocaine use disorders who contracted COVID-19. Future studies are needed to understand how COVID-19 damages the heart and the vascular endothelium among people who misuse opioids or cocaine (presumably also methamphetamines).

Associations among body mass index, working memory performance, gray matter volume, and brain activation in healthy children.

To investigate the neural mechanisms underlying the association between poorer working memory performance and higher body mass index (BMI) in children. We employed structural-(sMRI) and functional magnetic resonance imaging (fMRI) with a 2-back working memory task to examine brain abnormalities and their associations with BMI and working memory performance in 232 children with overweight/obesity (OW/OB) and 244 normal weight children (NW) from the Adolescent Brain Cognitive Development dataset. OW/OB had lower working memory accuracy, which was associated with higher BMI. They showed smaller gray matter (GM) volumes in the left superior frontal gyrus (SFG_L), dorsal anterior cingulate cortex, medial orbital frontal cortex, and medial superior frontal gyrus, which were associated with lower working memory accuracy. During the working memory task, OW/OB relative to NW showed weaker activation in the left superior temporal pole, amygdala, insula, and bilateral caudate. In addition, caudate activation mediated the relationship between higher BMI and lower working memory accuracy. Higher BMI is associated with smaller GM volumes and weaker brain activation in regions involved with working memory. Task-related caudate dysfunction may account for lower working memory accuracy in children with higher BMI.

Disruption in seasonality, patient characteristics and disparities of respiratory syncytial virus infection among young children in the US during and before the COVID-19 pandemic: 2010-2022.

Respiratory syncytial virus (RSV) infections and hospitalization have surged sharply among young children. Here we test how the seasonal patterns of RSV infections in 2022 compared with those from other COVID-19 pandemic and pre-pandemic years. For this purpose, we analyzed a nation-wide and real-time database of electronic health records of 56 million patients across 50 states in the US. The monthly incidence rate of first-time RSV infection in young children (<5 years of age) and very young children (<1 year of age) followed a seasonal pattern from 2010 to 2019 with increases during the autumn, peaking in winter, subsiding in spring and summer. This seasonal pattern was significantly disrupted during the COVID-19 pandemic. In 2020, the incidence rate of RSV infections was remarkably low throughout the year. In 2021, the RSV season expanded to 9 months starting in the early summer and peaking in October. In 2022, RSV infections started to rise in May and were significantly higher than in previous years reaching a historically highest incidence rate in November 2022. There were significant racial and ethnic disparities in the peak RSV infection rate during 2010-2021 and the disparities further exacerbated in 2022 with peak incidence rate in black and Hispanic children 2-3 times that in white children. Among RSV-infected children in 2022, 19.2% had prior documented COVID-19 infection, significantly higher than the 9.7% among uninfected children, suggesting that prior COVID-19 could be a risk factor for RSV infection or that there are common risk factors for both viral infections. Our study calls for continuous monitoring of RSV infection in young children alongside its clinical outcomes and for future work to assess potential COVID-19 related risk factors.

Prenatal Caffeine Exposure Is Linked to Elevated Sugar Intake and BMI, Altered Reward Sensitivity, and Aberrant Insular Thickness in Adolescents: An ABCD Investigation.

Prenatal caffeine exposure (PCE) has been positively associated with elevated body mass index (BMI) in children. Why this association occurs is unclear, but it is possible that PCE alters the in utero development of brain structures associated with food preference, leading to more total sugar intake (TSI, grams) later in childhood. To test this hypothesis, we investigated if PCE (daily/weekly/<weekly vs. no exposure) and elevated BMI are associated with increased TSI, neural activation during large reward anticipation (monetary incentive delay task-functional MRI) and structural changes (thickness, mm) in taste processing regions of children (n = 5534; 9-11 years) from the large-scale Adolescent Brain Cognitive Development (ABCD) study. Linear mixed-effect models, after covariate adjustments, identified a positive association (p < 0.05, all |ßs| > 0.01) of excessive PCE (vs. no exposure) with elevated BMI (daily/weekly/daily limit; consistent in boys and girls), increased TSI (daily) and insular thickness (daily/weekly), as well as low middle frontal cortex (MFC) activation (daily). Our sub-analysis revealed an association of daily/weekly PCE (vs. no exposure) with increased gram sugar intake from soft drinks. We also identified a positive relationship of excessive PCE with elevated TSI and increased insular thickness (a key gustatory region), while in a Sobel test, reward sensitivity (reduced brain reactivity to reward anticipation in MFC; tracks reward outcomes) mediated (Test statistic = 2.23; p = 0.02) the PCE-linked BMI changes in adolescents. Our findings suggest that excessive PCE might be detrimental to frontal lobe development and altered reward sensitivity to food, thereby increasing risk for elevated TSI and obesity. Our results support recommendations to limit caffeine intake during pregnancy.

Brain glutamate and sleep efficiency associations following a ketogenic diet intervention in individuals with Alcohol Use Disorder.

Background: We previously showed that ketogenic diet (KD) was effective in curbing alcohol withdrawal and craving in individuals with alcohol use disorder (AUD). We hypothesized that the clinical benefits were due to improvements in sleep. To test this, we performed a secondary analysis on the KD trial data to (1) examine the effects of KD on total sleep time (TST) and sleep quality and (2) investigate the association between KD-induced alterations in cingulate glutamate concentration and changes in TST and sleep quality. Methods: AUD individuals undergoing alcohol detoxification were randomized to receive KD (n=19) or standard American diet (SA; n=14) for three weeks. TST was measured weekly by self-report, GENEActive sleep accelerometer, and X4 Sleep Profiler ambulatory device. Sleep quality was assessed using subjectively ratings of sleep depth and restedness and Sleep Profiler (Sleep Efficiency [%]). Weekly 1H magnetic resonance spectroscopy scans measured cingulate glutamate levels. Results: TST was lower in KD than SA and increased with effect of time. Sleep depth, restedness, and Sleep Efficiency improved with time, but exhibited no effect of diet. In KD and SA combined, week 1 cingulate glutamate levels correlated positively with Sleep Efficiency, but not with TST. Conclusions: Although cingulate glutamate levels correlated positively with Sleep Efficiency in week 1, KD-induced glutamate elevation did not produce significant sleep improvements. Rather, KD was associated with lower TST than SA. Given the well-established associations between sleep and alcohol relapse, longer follow up assessment of KD's impact on sleep in AUD is warranted.

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants.

The functional and pharmacological significance of the dopamine D4 receptor (D4R) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human DRD4 gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a D4R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D4.4R and D4.7R). DRD4 polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding D4.7R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D4R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D4R. We review the evidence conveying a significant and differential role of D4.4R and D4.7R in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic α2A receptor (α2AR)-D4R heteromers and dopamine D2 receptor (D2R)-D4R heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the D4R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.