PET imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity.

The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [18F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [18F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [18F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.

Collateral Damage: Neurological Correlates of Non-Fatal Overdose in the Era of Fentanyl-Xylazine.

Non-fatal opioid overdoses are associated with significant morbidity. Hypoxic brain injury caused by opioid-induced respiratory depression is a key mechanism of such morbidity. For example, reports describe an amnestic syndrome in opioid users associated with acute injury to the hippocampus, a brain region that is highly susceptible to hypoxic injury. In our recent study we investigated the effects of non-fatal opioid overdose on the hippocampal volume in a well-characterized sample of opioid use disorder (OUD) patients with a history of overdose (OD) compared to those with no prior overdose (NOD). Using structural magnetic resonance imaging (MRI) and voxel-based morphometry, we observed lower hippocampal volume in patients with a history OD than in the NOD group. These findings support an association between non-fatal opioid overdose and hippocampal injury, which we hypothesize contributes to recently reported cases of OUD related amnestic syndrome. Here we review our study findings and the potential pathophysiological mechanisms underlying the acute and delayed hippocampal injury in nonfatal opioid overdose. We also discuss the implications for the risk of overdose and brain injury with the increased prevalence of fentanyl and xylazine contamination of the illicit opioid supply. Lastly, we highlight considerations for clinical management of the underappreciated neurological injury and cognitive dysfunction in OUD patients.

Blink-induced changes in pupil dynamics are consistent and heritable.

Pupil size and blink rates are heritable but the extent to which they interact with one another has not been properly investigated. Though changes in pupil size due to eye blinks have been reported, they are considered a pupillary artifact. In this study we used the HCP 7T fMRI dataset with resting state eye-tracking data obtained in monozygous and dizygous twins to assess their heritability and their interactions. For this purpose, we characterized the pupil dilation (positive peak) and constriction (negative peak) that followed blink events, which we describe as blink-induced pupillary response (BIPR). We show that the BIPR is highly consistent with a positive dilatory peak (D-peak) around 500ms and a negative constricting peak (C-peak) around 1s. These patterns were reproducible within- and between- subjects across two time points and differed by vigilance state (vigilant versus drowsy). By comparing BIPR between monozygous and dizygous twins we show that BIPR have a heritable component with significant additive genetic (A) and environmental (E) factors dominating the structural equation models, particularly in the time-domain for both D- and C-peaks and amplitude domain for the C-peak. (a2 between 42-49%). Blink duration, pupil size and blink rate were also found to be highly heritable (a2 up to 62% for pupil size). Our study documents an association between BIPR and wakefulness and indicates that BIPR should not be treated as a coincidental artefact, but part of a larger oculomotor system that we label here as Oculomotor Adaptive System, OAS, that is genetically determined.

The HEALthy Brain and Child Development Study (HBCD): NIH collaboration to understand the impacts of prenatal and early life experiences on brain development.

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual's genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.

Sleep deprivation effects on brain state dynamics are associated with dopamine D2 receptor availability via network control theory.

BACKGROUND: Sleep deprivation (SD) negatively affects brain function. Most brain imaging studies have investigated the effects of SD on 'static' brain function. SD effects on functional brain dynamics and their relationship with molecular changes remain relatively unexplored. METHODS: We used functional MRI to examine resting brain state dynamics after one night of SD compared to rested wakefulness (RW) and assessed their association with striatal brain dopamine D2 receptor availability (D2R) measured by PET-[11C]raclopride using network control theory. RESULTS: SD reduced dwell time and persistence probabilities with the strongest effects in two brain states, one characterized by high default mode network and low dorsal attention network activity and the other by high frontal parietal network and low somatomotor network activity. Using network control theory, we showed that after SD there was an overall increase in the control energy required for brain state transitions with effects varying for different brain state transitions. Control energy requirement was negatively associated with transition probabilities under SD and RW and accounted for SD-induced changes in transition probabilities. Alteration in the energy landscape was associated with SD-induced changes in striatal D2R distribution. CONCLUSIONS: These findings demonstrate altered occurrence of internally and externally oriented brain states following acute SD and suggest an association with energy requirements for brain state transitions modulated by striatal D2R.

FTO variant is associated with changes in BMI, ghrelin, and brain function following bariatric surgery.

BACKGROUNDA polymorphism in the fat mass and obesity-associated gene (FTO) is linked to enhanced neural sensitivity to food cues and attenuated ghrelin suppression. Risk allele carriers regain more weight than noncarriers after bariatric surgery. It remains unclear how FTO variation affects brain function and ghrelin following surgery.METHODSResting-state functional magnetic resonance imaging and cue-reactivity functional magnetic resonance imaging with high-/low-caloric food cues were performed before surgery and at 1, 6, and 12 months after surgery to examine brain function in 16 carriers with 1 copy of the rs9939609 A allele (AT) and 26 noncarriers (TT). Behavioral assessments up to 5 years after surgery were also conducted.RESULTSThe AT group relative to the TT group had smaller BMI loss at 12-60 months after surgery and lower resting-state activity in posterior cingulate cortex following laparoscopic sleeve gastrectomy (group-by-time interaction effects). Meanwhile, the AT group relative to the TT group showed greater food cue responses in dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and insula (group effects). There were negative associations of weight loss with ghrelin and greater activation in DLPFC, DMPFC and insula in the AT but not the TT group.CONCLUSIONThese findings indicate that FTO variation is associated with the evolution of ghrelin signaling and brain function after bariatric surgery, which might hinder weight loss.TRIAL REGISTRATIONChinese Clinical Trial Registry Center, ChiCTR-OOB-15006346.FUNDINGThis work was supported by the National Natural Science Foundation of China (grant nos. 82172023, 82202252, 82302292); National Key R&D Program of China (no. 2022YFC3500603); Natural Science Basic Research Program of Shaanxi (grant nos. 2022JC-44, 2022JQ-622, 2023-JC-QN-0922, 2023-ZDLSF-07); Fundamental Research Funds for the Central Universities (grant nos. ZYTS23188, XJSJ23190, XJS221201, QTZX23093); and the Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse (grant no. Y1AA3009).

Childhood obesity's effect on cognition and brain connectivity worsens with low family income.

Childhood obesity and its adverse health consequences have risen worldwide, with low socioeconomic status increasing the risk in high-income countries like the United States. Understanding the interplay between childhood obesity, cognition, socioeconomic factors, and the brain is crucial for prevention and treatment. Using data from the Adolescent Brain Cognitive Development (ABCD) study, we investigated how body mass index (BMI) relates to brain structural and functional connectivity metrics. Children with obesity or who are overweight (n = 2,356) were more likely to live in poverty and exhibited lower cognitive performance compared with children with a healthy weight (n = 4,754). Higher BMI was associated with multiple brain measures that were strongest for lower longitudinal diffusivity in corpus callosum; increased activity in cerebellum, insula, and somatomotor cortex; and decreased functional connectivity in multimodal brain areas, with effects more pronounced among children from low-income families. Notably, nearly 80% of the association of low income and 70% of the association of impaired cognition on BMI were mediated by higher brain activity in somatomotor areas. Increased resting activity in somatomotor areas and decreased structural and functional connectivity likely contribute to the higher risk of being overweight or having obesity among children from low-income families. Supporting low-income families and implementing educational interventions to improve cognition may promote healthy brain function and reduce the risk of obesity.

Association of Semaglutide With Tobacco Use Disorder in Patients With Type 2 Diabetes : Target Trial Emulation Using Real-World Data.

BACKGROUND: Reports of reduced desire to smoke in patients treated with semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) medication for type 2 diabetes mellitus (T2DM) and obesity, have raised interest about its potential benefit for tobacco use disorders (TUDs). OBJECTIVE: To examine the association of semaglutide with TUD-related health care measures in patients with comorbid T2DM and TUD. DESIGN: Emulation target trial based on a nationwide population-based database of patient electronic health records. SETTING: United States, 1 December 2017 to 31 March 2023. PARTICIPANTS: Seven target trials were emulated among eligible patients with comorbid T2DM and TUD by comparing the new use of semaglutide versus 7 other antidiabetes medications (insulins, metformin, dipeptidyl-peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and other GLP-1RAs). MEASUREMENTS: The TUD-related health care measures (medical encounter for diagnosis of TUD, smoking cessation medication prescriptions, and smoking cessation counseling) that occurred within a 12-month follow-up were examined using Cox proportional hazards and Kaplan-Meier survival analyses. RESULTS: The study compared 222 942 new users of antidiabetes medications including 5967 of semaglutide. Semaglutide was associated with a significantly lower risk for medical encounters for TUD diagnosis compared with other antidiabetes medications, and was strongest compared with insulins (hazard ratio [HR], 0.68 [95% CI, 0.63 to 0.74]) and weakest but statistically significant compared with other GLP-1RAs (HR, 0.88 [CI, 0.81 to 0.96]). Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed in patients with and without a diagnosis of obesity. For most of the group comparisons, the differences occurred within 30 days of prescription initiation. LIMITATION: Documentation bias, residual confounding, missing data on current smoking behavior, body mass index, and medication adherence. CONCLUSION: Semaglutide was associated with lower risks for TUD-related health care measures in patients with comorbid T2DM and TUD compared with other antidiabetes medications including other GLP-1Ras, primarily within 30 days of prescription. These findings suggest the need for clinical trials to evaluate semaglutide's potential for TUD treatment. PRIMARY FUNDING SOURCE: National Institutes of Health.

Cannabis and Cannabinoid Signaling: Research Gaps and Opportunities.

Cannabis and its products have been used for centuries for both medicinal and recreational purposes. The recent widespread legalization of cannabis has vastly expanded its use in the United States across all demographics except for adolescents. Meanwhile decades of research have advanced our knowledge of cannabis pharmacology and particularly of the endocannabinoid system with which the components of cannabis interact. This research has revealed multiple targets and approaches for manipulating the system for therapeutic use and to ameliorate cannabis toxicity or cannabis use disorder. Research has also led to new questions that underscore the potential risks of its widespread use, particularly the enduring consequences of exposure during critical windows of brain development or for consumption of large daily doses of cannabis with high content D9 tetrahydrocannabinol (THC). Here we highlight current neuroscience research on cannabis that has shed light on therapeutic opportunities and potential adverse consequences of misuse and point to gaps in knowledge that can guide future research. Significance Statement Cannabis use has escalated with its increased availability. Here we highlight the challenges of cannabis research and the gaps in our knowledge of cannabis pharmacology and of the endocannabinoid system that it targets. Future research that addresses these gaps is needed so that the endocannabinoid system can be leveraged for safe and effective use.

Investigation of [11C]carfentanil for mu opioid receptor quantification in the rat brain.

[11C]Carfentanil ([11C]CFN) is the only selective carbon-11 labeled radiotracer currently available for positron emission tomography (PET) imaging of mu opioid receptors (MORs). Though used extensively in clinical research, [11C]CFN has not been thoroughly characterized as a tool for preclinical PET imaging. As we were occasionally observing severe vital sign instability in rat [11C]CFN studies, we set out to investigate physiological effects of CFN mass and to explore its influence on MOR quantification. In anesthetized rats (n = 15), significant dose-dependent PCO2 increases and heart rate decreases were observed at a conventional tracer dose range (IV, > 100 ng/kg). Next, we conducted baseline and retest [11C]CFN PET scans over a wide range of molar activities. Baseline [11C]CFN PET studies (n = 27) found that nondisplaceable binding potential (BPND) in the thalamus was positively correlated to CFN injected mass, demonstrating increase of MOR availability at higher injected CFN mass. Consistently, when CFN injected mass was constrained < 40 ng/kg (~ 10% MOR occupancy in rats), baseline MOR availability was significantly decreased. For test-retest variability (TRTV), better reproducibility was achieved by controlling CFN injected mass to limit the difference between scans. Taken together, we report significant cardiorespiratory depression and a paradoxical influence on baseline MOR availability at conventional tracer doses in rats. Our findings might reflect changes in cerebral blood flow, changes in receptor affinity, or receptor internalization, and merits further mechanistic investigation. In conclusion, rat [11C]CFN PET requires stringent quality assurance of radiotracer synthesis and mass injected to avoid pharmacological effects and limit potential influences on MOR quantification and reproducibility.

Treatment for Opioid Use Disorder: Population Estimates - United States, 2022.

In 2022, 81,806 opioid-involved overdose deaths were reported in the United States, more than in any previous year. Medications for opioid use disorder (OUD), particularly buprenorphine and methadone, substantially reduce overdose-related and overall mortality. However, only a small proportion of persons with OUD receive these medications. Data from the 2022 National Survey on Drug Use and Health were applied to a cascade of care framework to estimate and characterize U.S. adult populations who need OUD treatment, receive any OUD treatment, and receive medications for OUD. In 2022, 3.7% of U.S. adults aged ≥18 years needed OUD treatment. Among these, only 25.1% received medications for OUD. Most adults who needed OUD treatment either did not perceive that they needed it (42.7%) or received OUD treatment without medications for OUD (30.0%). Compared with non-Hispanic Black or African American and Hispanic or Latino adults, higher percentages of non-Hispanic White adults received any OUD treatment. Higher percentages of men and adults aged 35-49 years received medications for OUD than did women and younger or older adults. Expanded communication about the effectiveness of medications for OUD is needed. Increased efforts to engage persons with OUD in treatment that includes medications are essential. Clinicians and other treatment providers should offer or arrange evidence-based treatment, including medications, for patients with OUD. Pharmacists and payors can work to make these medications available without delays.

Major Gaps in the Cascade of Care for Opioid Use Disorder: Implications for Clinical Practice.

This Viewpoint examines a recent report that used data from the 2022 National Survey on Drug Use and Health to estimate the opioid cascade of care, a framework to characterize the adult US populations who needed and received opioid use disorder (OUD) treatment, as well as discusses ways in which clinicians can close gaps in care.

Imaging neuroinflammation in individuals with substance use disorders.

Increasing evidence suggests a role of neuroinflammation in substance use disorders (SUDs). This Review presents findings from neuroimaging studies assessing brain markers of inflammation in vivo in individuals with SUDs. Most studies investigated the translocator protein 18 kDa (TSPO) using PET; neuroimmune markers myo-inositol, choline-containing compounds, and N-acetyl aspartate using magnetic resonance spectroscopy; and fractional anisotropy using MRI. Study findings have contributed to a greater understanding of neuroimmune function in the pathophysiology of SUDs, including its temporal dynamics (i.e., acute versus chronic substance use) and new targets for SUD treatment.

The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats.

RATIONALE: Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders. OBJECTIVE: In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history. METHODS: We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle. RESULTS: Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions. CONCLUSIONS: These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

Estimated Number of Children Who Lost a Parent to Drug Overdose in the US From 2011 to 2021.

Importance: Parents' overdose death can have a profound short- and long-term impact on their children, yet little is known about the number of children who have lost a parent to drug overdose in the US. Objective: To estimate the number and rate of children who have lost a parent to drug overdose from 2011 to 2021 overall and by parental age, sex, and race and ethnicity. Design, Setting, and Participants: This was a cross-sectional study of US community-dwelling persons using data from the National Survey on Drug Use and Health (2010-2014 and 2015-2019) and the National Vital Statistics System (2011-2021). Data were analyzed from January to June 2023. Exposure: Parental drug overdose death, stratified by age group, sex, and race and ethnicity. Main Outcomes and Measures: Numbers, rates, and average annual percentage change (AAPC) in rates of children losing a parent aged 18 to 64 years to drug overdose, overall and by age, sex, and race and ethnicity. Results: From 2011 to 2021, 649 599 adults aged 18 to 64 years died from a drug overdose (mean [SD] age, 41.7 [12.0] years; 430 050 [66.2%] male and 219 549 [33.8%] female; 62 606 [9.6%] Hispanic, 6899 [1.1%] non-Hispanic American Indian or Alaska Native, 6133 [0.9%] non-Hispanic Asian or Pacific Islander, 82 313 [12.7%] non-Hispanic Black, 485 623 [74.8%] non-Hispanic White, and 6025 [0.9%] non-Hispanic with more than 1 race). Among these decedents, from 2011 to 2021, an estimated 321 566 (95% CI, 276 592-366 662) community-dwelling children lost a parent aged 18 to 64 years to drug overdose. The rate of community-dwelling children who lost a parent to drug overdose per 100 000 children increased from 27.0 per 100 000 in 2011 to 63.1 per 100 000 in 2021. The highest rates were found among children of non-Hispanic American Indian or Alaska Native individuals, who had a rate of 187.1 per 100 000 in 2021, more than double the rate among children of non-Hispanic White individuals (76.5 per 100 000) and non-Hispanic Black individuals (73.2 per 100 000). While rates increased consistently each year for all parental age, sex, and race and ethnicity groups, non-Hispanic Black parents aged 18 to 25 years had the largest AAPC (23.8%; 95% CI, 16.5-31.6). Rates increased for both fathers and mothers; however, more children overall lost fathers (estimated 192 459; 95% CI, 164 081-220 838) than mothers (estimated 129 107; 95% CI, 112 510-145 824). Conclusions and Relevance: An estimated 321 566 children lost a parent to drug overdose in the US from 2011 to 2021, with significant disparities evident across racial and ethnic groups. Given the potential short- and long-term negative impact of parental loss, program and policy planning should ensure that responses to the overdose crisis account for the full burden of drug overdose on families and children, including addressing the economic, social, educational, and health care needs of children who have lost parents to overdose.

Blink-related arousal network surges are shaped by cortical vigilance states.

The vigilance state and the excitability of cortical networks impose wide-range effects on brain dynamics that arousal surges could promptly modify. We previously reported an association between spontaneous eye-blinks and BOLD activation in the brain arousal ascending network (AAN) and in thalamic nuclei based on 3T MR resting state brain images. Here we aimed to replicate our analyses using 7T MR images in a larger cohort of participants collected from the Human Connectome Project (HCP), which also contained simultaneous eye-tracking recordings, and to assess the interaction between the blink-associated arousal surges and the vigilance states. For this purpose, we compared blink associated BOLD activity under a vigilant versus a drowsy state, a classification made based on the pupillary data obtained during the fMRI scans. We conducted two main analyses: i) Cross-correlation analysis between the BOLD signal and blink events (eye blink time-series were convolved with the canonical and also with the temporal derivative of the Hemodynamic Response Function, HRF) within preselected regions of interests (ROIs) (i.e., brainstem AAN, thalamic and cerebellar nuclei) together with an exploratory voxel-wise analyses to assess the whole-brain, and ii) blink-event analysis of the BOLD signals to reveal the signal changes onset to the blinks in the preselected ROIs. Consistent with our prior findings on 3T MRI, we showed significant positive cross correlations between BOLD peaks in brainstem and thalamic nuclei that preceded or were overlapping with blink moments and that sharply decreased post-blink. Whole brain analysis revealed blink-related activation that was strongest in cerebellum, insula, lateral geniculate nucleus (LGN) and visual cortex. Drowsiness impacted HRF BOLD (enhancing it), time-to-peak (delaying it) and post-blink BOLD activity (accentuating decreases). Responses in the drowsy state could be related to the differences in the excitability of cortical, subcortical and cerebellar tissue, such that cerebellar and thalamic regions involved in visual attention processing were more responsive for the vigilant state, but AAN ROIs, as well as cerebellar and thalamic ROIs connected to pre-motor, frontal, temporal and DMN regions were less responsive. Such qualitative and quantitative differences in the blink related BOLD signal changes could reflect delayed cortical processing and the ineffectiveness of arousal surges during states of drowsiness. Future studies that manipulate arousal are needed to corroborate a mechanistic interaction of arousal surges with vigilance states and cortical excitability.