The effect of a mindfulness-based stress intervention on neurobiological and symptom measures in adolescents with early life stress: a randomized feasibility study.

BACKGROUND: Early life stress (ELS) has been linked to poor mental and physical health outcomes in adolescence and adulthood. Mindfulness reduces symptoms of depression and anxiety and improves cognitive and social outcomes in both youth and adults. However, little is known whether mindfulness can mitigate against the adverse neurobiological and psychological effects of ELS. This study aimed to examine the feasibility of conducting a group mindfulness intervention in adolescents with ELS and provide preliminary indication of potential effects on stress-related biomarkers and mental health symptoms. METHODS: Forty adolescents were randomized to receive either eight sessions of Mindfulness-Based Stress Reduction for Teens in group format (MBSR-T; n = 21) or Treatment as Usual Control group (CTRL; n = 17). Outcomes were assessed at baseline and follow-up and included measures associated with neurobiological functioning (immune and endocrine biomarkers) and self-reported mental health (depressive) symptoms. Linear mixed effects models were used to assess the effects of group and time on these outcome measures. RESULTS: Sixteen of the 21 adolescents completed the intervention, attending an average of 6.5 sessions. The model examining cortisol responses to stress induction revealed medium effects trending toward significance (Cohen's d = .56) for anticipatory cortisol levels in the MBSR-T relative to CTRL groups. No significant effects were found in models examining C-reactive protein or interleukin 6 inflammatory markers. The model examining depressive symptoms revealed a medium effect for symptom reduction (Cohen's d = .69) in the MBSR-T relative to CTRL groups. CONCLUSIONS: This study demonstrated feasibility of conducting a group-based MBSR-T intervention for adolescents with ELS. There was some evidence for efficacy on a symptom level with potential subtle changes on a biological level. Future larger studies are needed to determine the efficacy of group-based mindfulness interventions in this population. TRIAL REGISTRATION: Identifier # NCT03633903 , registered 16/08/2018.

A pragmatic clinical trial examining the impact of a resilience program on college student mental health.

BACKGROUND: One in three college students experience significant depression or anxiety interfering with daily functioning. Resilience programs that can be administered to all students offer an opportunity for addressing this public health problem. The current study objective was to assess the benefit of a brief, universal resilience program for first-year college students. METHOD: First-year students at a private, midwestern university participated. This trial used a pragmatic design, delivering the intervention within university-identified orientation courses and was not randomized. The four-session resilience program included goal-building, mindfulness, and resilience skills. The comparison was orientation-as-usual. Primary outcomes included PROMIS® Depression and Anxiety and Connor-Davidson Resilience Scale. Secondary and exploratory outcomes included the Perceived Stress Scale, Emotion Regulation, and Cognitive Behavioral Therapy (CBT) Skills Questionnaires, and Freiburg Mindfulness Inventory. Time by treatment interactions at post-training and semester-end were examined using linear mixed models. RESULTS: Analysis included 252 students, 126 who completed resilience programming and a matched comparison sample. Resilience programming did not relate to improvements in depression at post-training (CI: -2.53 to 1.02; p = .404, d =-0.08), but did at semester-end (95% CI: -4.27 to -0.72; p = .006, d = -0.25) and improvements in perceived stress were observed at post-training (CI: -3.31 to -0.44; p = .011, d = -0.24) and semester-end (CI: -3.30 to -0.41; p = .013, d = -0.24). Emotion regulation, mindfulness, and CBT skills increased, with CBT skills mediating clinical improvements. CONCLUSIONS: Universal implementation of a brief, resilience intervention may be effective for improving college student mental health.

Evaluation of [(18)F]-(-)-norchlorofluorohomoepibatidine ([(18)F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates.

INTRODUCTION: The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α4ß2 receptor radiotracer [(18)F]-(-)-NCFHEB ([(18)F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo. METHODS: [(18)F]-(-)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N-Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC. RESULTS: [(18)F]-(-)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3 ± 16.1 GBq/µmol (n = 6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98-100% of [(18)F]-(-)-NCFHEB specific binding, and the non-displaceable distribution volume (VND) was estimated at 5.9 ± 1.0 mL/cm(3) (n = 2), or 6.6 ± 1.1 mL/cm(3) after normalization by the plasma free fraction fP. Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [(18)F]-(-)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus = 4.1 ± 1.5, frontal cortex = 1.2 ± 0.2, putamen = 0.96 ± 0.45, and cerebellum = 0.10 ± 0.29). CONCLUSION: An efficient microfluidic synthetic method was developed for preparation of [(18)F]-(-)-NCFHEB. PET examination in rhesus monkeys showed that [(18)F]-(-)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α4ß2 receptors. Estimated non-displaceable binding potential (BPND) values in brain regions were better than those of [(18)F]2-FA and comparable to [(18)F]AZAN. These results confirm previous findings and support further examination of [(18)F]-(-)-NCFHEB in humans.

Lower ß2*-nicotinic acetylcholine receptor availability in smokers with schizophrenia.

OBJECTIVE: There is a strong association between cigarette smoking and schizophrenia. Nicotine's actions in the brain are mediated through nicotinic acetylcholine receptors. Those containing α(4) and ß(2) subunits are the most abundant ones in the brain, have the highest affinity for nicotine, and are critical in mediating nicotine's reinforcing properties. Healthy tobacco smokers have significantly higher levels of ß(2)*-nicotinic acetylcholine receptors than do nonsmokers. However, in postmortem studies, smokers with schizophrenia do not show these higher levels. The purpose of this study was to measure ß(2)*-nicotinic acetylcholine receptors in vivo and to relate levels to concurrent behavioral measures of smoking and schizophrenia. METHOD: By using single-photon emission computed tomography with the ß(2)*-nicotinic acetylcholine receptor agonist radiotracer [(123)I]5-IA-85380, the availability of receptors was measured in smokers with schizophrenia (11 men) and matched comparison smokers after 1 week of confirmed smoking abstinence. RESULTS: Smokers with schizophrenia showed significantly lower (21%-26%) ß(2)*-nicotinic acetylcholine receptor availability relative to comparison smokers in the frontal cortex, parietal cortex, and thalamus (in descending order). There was a specific and robust negative correlation between regional ß(2)*-nicotinic acetylcholine receptor availability and negative symptoms. CONCLUSIONS: These are the first in vivo findings of lower ß(2)*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. The relationship between ß(2)*-nicotinic acetylcholine receptor availability and negative symptoms may explain the high rates of smoking in schizophrenia and the relationship between smoking and negative symptoms. Findings support the development of medications targeting the ß(2)*-nicotinic acetylcholine receptor system for the treatment of negative symptoms.

Neuroimaging insights into the role of cortical GABA systems and the influence of nicotine on the recovery from alcohol dependence.

This paper reviews evidence suggesting that nicotine and tobacco smoke profoundly modulate the effects of alcohol on γ-aminobutyric acid (GABA) neuronal function, specifically at the GABA(A)-benzodiazepine receptor (GABA(A)-BZR). The focus of this paper is on recent neuroimaging evidence in preclinical models as well as clinical experiments. First, we review findings implicating the role of alcohol at the GABA(A)-BZR and discuss the changes in GABA(A)-BZR availability during acute and prolonged alcohol withdrawal. Second, we discuss preclinical evidence that suggests nicotine affects GABA neuronal function indirectly by a primary action at neuronal nicotinic acetylcholine receptors. Third, we show how this evidence converges in studies that examine GABA levels and GABA(A)-BZRs in alcohol-dependent smokers and nonsmokers, suggesting that tobacco smoking attenuates the chemical changes that occur during alcohol withdrawal. Based on a comprehensive review of literature, we hypothesize that tobacco smoking minimizes the changes in GABA levels that typically occur during the acute cycles of drinking in alcohol-dependent individuals. Thus, during alcohol withdrawal, the continued tobacco smoking decreases the severity of the withdrawal-related changes in GABA chemistry. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.

A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer's Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Abeta1-40 peptide of several of these compounds were in the low-nanomolar range . The lowest K(i) of 9.3nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its (123)I-radiolabeled form ([(123)I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood-brain barrier (BBB) to any significant extent.

[123I]5-IA-85380 SPECT imaging of beta2-nicotinic acetylcholine receptor availability in the aging human brain.

Human postmortem studies have reported decreases with age in high-affinity nicotine binding in brain. We have been investigating in vivo the availability of the beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) in healthy nonsmokers (18-85 years of age) using [(123)I]5-IA-85380 SPECT imaging. Age and regional beta(2)-nAChR availability (V(T)(,)) have been observed to be inversely correlated in all brain regions analyzed, with decline ranging from 21% (cerebellum) to 36% (thalamus), or by up to 5% per decade of life. Preliminary results have confirmed postmortem reports of age-related decline in high-affinity nicotine binding with age and may elucidate the role of beta(2)-nAChRs in the cognitive decline associated with aging.