Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study.

IntroductionChildhood maltreatment, a well-known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.MethodsWe conducted a pilot study of the relationship between childhood maltreatment (evaluated with the Childhood Trauma Questionnaire; Bernstein and Fink 1998) and resting-state functional connectivity of the amygdala (bilateral region of interest) with functional magnetic resonance imaging in 15 abstinent, methamphetamine-dependent research participants. Within regions that showed connectivity with the amygdala as a function of maltreatment, we also evaluated whether amygdala connectivity was associated positively with negative affect and negatively with healthy emotional processing.ResultsThe results indicated that childhood maltreatment was positively associated with resting-state connectivity between the amygdala and right hippocampus, right parahippocampal gyrus, right inferior temporal gyrus, right orbitofrontal cortex, cerebellum, and brainstem. Furthermore, connectivity between the amygdala and hippocampus was positively related to measures of depression, trait anxiety, and emotion dysregulation, and negatively related to self-compassion and dispositional mindfulness.ConclusionsThese findings suggest that childhood maltreatment may contribute to increased limbic connectivity and maladaptive emotional processing in methamphetamine-dependent adults, and that healthy emotion regulation strategies may serve as a therapeutic target to ameliorate the associated behavioral phenotype. Childhood maltreatment warrants further investigation as a potentially important etiological factor in the neurobiology and treatment of substance use disorders

Functional Connectivity of the Raphe Nuclei: Link to Tobacco Withdrawal in Smokers.

BackgroundAlthough nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies.MethodsFunctional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers.ResultsConnectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal.ConclusionsRelief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking

Is all risk bad? Young adult cigarette smokers fail to take adaptive risk in a laboratory decision-making test

RationaleCigarette smoking has been linked to real-world risky behavior, but this association has been based largely on retrospective self-reports. Limitations of self-report data can be avoided by using laboratory, performance-based measures, such as the Balloon Analogue Risk Task (BART; Lejuez et al., J Exp Psychol Appl 8:75-84, 2002). Initial studies have suggested that smokers display greater risk-taking on this task than nonsmokers, but these studies did not account for drug abuse and psychiatric comorbidities, which are commonplace among smokers.ObjectivesWe sought to examine the performance of smokers and nonsmokers on the BART after excluding drug abuse and psychiatric comorbidities.MethodsWe conducted a study of late adolescent/young adult (age 18 to 21) smokers (n = 26) and nonsmokers (n = 38) performing the BART and excluded individuals with positive drug or alcohol toxicology screens, substance abuse or dependence diagnoses, and/or current psychiatric conditions.ResultsContrary to previous findings, smokers did not display greater risk-taking on the BART than nonsmokers. In fact, when performance was examined trial-by-trial, the nonsmokers displayed progressively greater pumping relative to smokers over time (p < .001), earning them a nonsignificantly greater amount of money than the smokers. Controlling for smoking status, additional analyses revealed that pumping on the BART was positively associated with years of education, nonverbal IQ, and employment.ConclusionsThe results suggest that in young adults, smoking may be associated with a failure to take risks in situations where risk-taking is adaptive

Inter and intra-hemispheric structural imaging markers predict depression relapse after electroconvulsive therapy: a multisite study.

Relapse of depression following treatment is high. Biomarkers predictive of an individual's relapse risk could provide earlier opportunities for prevention. Since electroconvulsive therapy (ECT) elicits robust and rapidly acting antidepressant effects, but has a >50% relapse rate, ECT presents a valuable model for determining predictors of relapse-risk. Although previous studies have associated ECT-induced changes in brain morphometry with clinical response, longer-term outcomes have not been addressed. Using structural imaging data from 42 ECT-responsive patients obtained prior to and directly following an ECT treatment index series at two independent sites (UCLA: n = 17, age = 45.41±12.34 years; UNM: n = 25; age = 65.00±8.44), here we test relapse prediction within 6-months post-ECT. Random forests were used to predict subsequent relapse using singular and ratios of intra and inter-hemispheric structural imaging measures and clinical variables from pre-, post-, and pre-to-post ECT. Relapse risk was determined as a function of feature variation. Relapse was well-predicted both within site and when cohorts were pooled where top-performing models yielded balanced accuracies of 71-78%. Top predictors included cingulate isthmus asymmetry, pallidal asymmetry, the ratio of the paracentral to precentral cortical thickness and the ratio of lateral occipital to pericalcarine cortical thickness. Pooling cohorts and predicting relapse from post-treatment measures provided the best classification performances. However, classifiers trained on each age-disparate cohort were less informative for prediction in the held-out cohort. Post-treatment structural neuroimaging measures and the ratios of connected regions commonly implicated in depression pathophysiology are informative of relapse risk. Structural imaging measures may have utility for devising more personalized preventative medicine approaches

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

Introduction: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. Methods: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. Results: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). Conclusions: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. Trial registration ClinicalTrials.gov Identifier: NCT00099710

Volume of the human hippocampus and clinical response following electroconvulsive therapy

BACKGROUND: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT-induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome. METHODS: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice. RESULTS: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 +/- 2.2%, d = 1.5; right unilateral, 1.6 +/- 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 +/- 1.7%, d = 1.8; right unilateral, 2.7 +/- 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Asberg Depression Rating Scale change -1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069). CONCLUSIONS: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome