Discriminating cocaine use from other sympathomimetics using wearable electrocardiographic (ECG) sensors.

BACKGROUND: Our group has established the feasibility of using on-body electrocardiographic (ECG) sensors to detect cocaine use in the human laboratory. The purpose of the current study was to test whether ECG sensors and features are capable of discriminating cocaine use from other non-cocaine sympathomimetics. METHODS: Eleven subjects with cocaine use disorder wore the Zephyr BioHarness™ 3 chest band under six experimental (drug and non-drug) conditions, including 1) laboratory, intravenous cocaine self-administration, 2) after a single oral dose of methylphenidate, 3) during aerobic exercise, 4) during tobacco use (N=7 who smoked tobacco), and 5) during routine activities of daily inpatient living (unit activity). Three ECG-derived feature sets served as primary outcome measures, including 1) the RR interval (i.e., heart rate), 2) a group of ECG interval proxies (i.e., PR, QS, QT and QTc intervals), and 3) the full ECG waveform. Discriminatory power between cocaine and non-cocaine conditions for each of the three outcomes measures was expressed as the area under the receiver operating characteristics (AUROC) curve. RESULTS: All three outcomes successfully discriminated cocaine use from unit activity, exercise, tobacco, and methylphenidate conditions with a mean AUROC values ranging from 0.66 to 0.99 and with least squares means values all statistically different/higher than 0.5 among all subjects [F(3, 99) = 3.38, p =0.02] and among those with tobacco use [F(4, 84) = 5.39, p = 0.0007]. CONCLUSIONS: These preliminary results support discriminatory power of wearable ECG sensors for detecting cocaine use.

Genome-wide meta-analysis of alcohol use disorder in East Asians.

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ~30 AUD risk genes in European populations, but many fewer in East Asians. We conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from five cohorts: (1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP) sample; (2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort; (3) AD in a Han Chinese-Cyto (array) cohort; and (4) two AD Thai cohorts. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4464 East Asians (Genetic Epidemiology Research in Adult Health and Aging (GERA)). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS. Two risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, SE = 0.067, p = 2.47 × 10-10) and nominally associated with pack years of smoking (beta = 0.09, SE = 0.05, p = 4.52 × 10-2) and ever vs. never smoking (beta = 0.06, SE = 0.02, p = 1.14 × 10-2). This is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.

Lower prefrontal cortical synaptic vesicle binding in cocaine use disorder: An exploratory 11 C-UCB-J positron emission tomography study in humans.

Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.

Reliability and validity of DSM-IV and DSM-5 methamphetamine use disorder diagnoses using the Chinese Version of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA).

BACKGROUND: The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) was developed to assess substance-use disorders and other psychiatric traits. We translated the SSADDA into Chinese and evaluated its inter-rater reliability and concurrent validity in diagnosing DSM-IV methamphetamine (MA) dependence and DSM-5 MA-use disorder (MUD). METHODS: The sample comprised 231 participants who were interviewed using the Chinese SSADDA and the Mini-International Neuropsychiatric Interview (Chinese MINI) for concurrent validation. Of the 231 participants, 191 were interviewed by two different interviewers two weeks apart. We evaluated the inter-rater reliability and concurrent validity of the diagnoses using percent agreement and Cohen's kappa coefficient (κ). Cohen's linear weighted kappa was used to assess the reliability of DSM-5 MUD severity. RESULTS: It showed good inter-rater reliability and no significant differences among the DSM-5 MUD (κ = 0.71), DSM-IV MA abuse or dependence (κ = 0.72), and the DSM-IV diagnoses of MA dependence (κ = 0.66) and abuse (κ = 0.68) tested separately. The weighted kappa was 0.67 across the three DSM-5 MUD severity levels. The reliability of each individual diagnostic criterion for DSM-5 MUD ranged from fair to excellent (κ = 0.41-0.80), except for "repeated attempts to quit/control use" (κ = 0.38). The concurrent validity based on MINI-derived diagnoses ranged from good to excellent (κ = 0.65-0.78). CONCLUSIONS: This study shows that the Chinese version of SSADDA has good reliability and validity among Chinese MA users.

Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder.

BACKGROUND: Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). METHODS: Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). RESULTS: Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). CONCLUSIONS: We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Dopamine D2/3 receptor availability in cocaine use disorder individuals with obesity as measured by [11C]PHNO PET.

BACKGROUND: Positron emission tomography (PET) work with the dopamine D3 receptor (D3R) preferring ligand [11C]PHNO in obese individuals has demonstrated higher binding and positive correlations with body mass index (BMI) in otherwise healthy individuals. These findings implicated brain reward areas including the substantia nigra/ventral tegmental area (SN/VTA) and pallidum. In cocaine use disorder (CUD), similar SN/VTA binding profiles have been found compared to healthy control subjects. This study investigates whether BMI-[11C]PHNO relationships are similar in individuals with CUD. METHODS: Non-obese CUD subjects (N = 12) were compared to age-matched obese CUD subjects (N = 14). All subjects underwent [11C]PHNO acquisition using a High Resolution Research Tomograph PET scanner. Parametric images were computed using the simplified reference tissue model with cerebellum as the reference region. [11C]PHNO measures of receptor availability were calculated and expressed as non-displaceable binding potential (BPND). RESULTS: In between-group analyses, D2/3R availability in non-obese and obese CUD groups was not significantly different overall. BMI was inversely correlated withBPND in the SN/VTA (r = -0.45, p = 0.02 uncorrected) in all subjects. CONCLUSION: These data suggest that obesity in CUD was not associated with significant differences in D2/3R availability. This in contrast to previous findings in non-CUD individuals that found increased availability of D3Rs in the SN/VTA associated with obesity. These findings could potentially reflect dysregulation of D3R in CUD, impacting how affected individuals respond to natural stimuli such as food.

Multimodal investigation of dopamine D2/D3 receptors, default mode network suppression, and cognitive control in cocaine-use disorder.

Stimulant-use disorders have been associated with lower availability of dopamine type-2 receptors (D2R) and greater availability of type-3 receptors (D3R). Links between D2R levels, cognitive performance, and suppression of the default mode network (DMN) during executive functioning have been observed in healthy and addicted populations; however, there is limited evidence regarding a potential role of elevated D3R in influencing cognitive control processes in groups with and without addictions. Sixteen individuals with cocaine-use disorder (CUD) and 16 healthy comparison (HC) participants completed [11C]-(+)-PHNO PET imaging of D2R and D3R availability and fMRI during a Stroop task of cognitive control. Independent component analysis was performed on fMRI data to assess DMN suppression during Stroop performance. In HC individuals, lower D2R-related binding in the dorsal putamen was associated with improved task performance and greater DMN suppression. By comparison, in individuals with CUD, greater D3R-related binding in the substantia nigra was associated with improved performance and greater DMN suppression. Exploratory moderated-mediation analyses indicated that DMN suppression was associated with Stroop performance indirectly through D2R in HC and D3R in CUD participants, and these indirect effects were different between groups. To our knowledge, this is the first evidence of a dissociative and potentially beneficial role of elevated D3R availability in executive functioning in cocaine-use disorder.

Simplified Quantification of 11C-UCB-J PET Evaluated in a Large Human Cohort.

11C-UCB-J ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) is a PET tracer for synaptic vesicle glycoprotein 2A, which may be a marker of synaptic density. To simplify the scan protocol, SUV ratios (SUVRs) were compared with model-based nondisplaceable binding potential (BPND) to select the optimal time window in healthy and neuropsychiatric subjects. Methods: In total, 141 scans were acquired for 90 min. Arterial blood sampling and metabolite analysis were conducted. SUVR-1 (centrum semiovale reference region) was computed for six 30-min windows and compared with 1-tissue-compartment model BPND Simulations were performed to assess the time dependency of SUVR-1. Results: Greater correlation and less bias were observed for SUVR-1 at later time windows for all subjects. Simulations showed that the agreement between SUVR-1 and BPND is time-dependent. Conclusion: The 60- to 90-min period provided the best match between SUVR-1 and BPND (-1% ± 7%); thus, a short scan is sufficient for accurate quantification of 11C-UCB-J-specific binding.

Genome-wide association study of alcohol dependence in male Han Chinese and cross-ethnic polygenic risk score comparison.

Alcohol-related behaviors are moderately heritable and have ethnic-specific characteristics. At present, genetic studies for alcohol dependence (AD) in Chinese populations are underrepresented. We are the first to conduct a genome-wide association study (GWAS) for AD using 533 male alcoholics and 2848 controls of Han Chinese ethnicity and replicate our findings in 146 male alcoholics and 200 male controls. We then assessed genetic effects on AD characteristics (drinking volume/age onset/Michigan Alcoholism Screening Test (MAST)/Barratt Impulsiveness Scale (BIS-11)), and compared the polygenic risk of AD in Han Chinese with other populations (Thai, European American and African American). We found and validated two significant loci, one located in 4q23, with lead SNP rs2075633*ADH1B (Pdiscovery = 6.64 × 10-16) and functional SNP rs1229984*ADH1B (Pdiscovery = 3.93 × 10-13); and the other located in 12q24.12-12q24.13, with lead SNP rs11066001*BRAP (Pdiscovery = 1.63 × 10-9) and functional SNP rs671*ALDH2 (Pdiscovery = 3.44 × 10-9). ADH1B rs1229984 was associated with MAST, BIS_total score and average drinking volume. Polygenic risk scores from the Thai AD and European American AD GWAS were significantly associated with AD in Han Chinese, which were entirely due to the top two loci, however there was no significant prediction from African Americans. This is the first case-control AD GWAS in Han Chinese. Our findings demonstrate that these variants, which were highly linked with ALDH2 rs671 and ADH1B rs1229984, were significant modulators for AD in our Han Chinese cohort. A larger replication cohort is still needed to validate our findings.

Genomewide Association Study of Alcohol Dependence and Related Traits in a Thai Population.

BACKGROUND: Alcohol use (both quantity and dependence) is moderately heritable, and genomewide association studies (GWAS) have identified risk genes in European, African, and Asian populations. The most reproducibly identified risk genes affect alcohol metabolism. Well-known functional variants at the gene encoding alcohol dehydrogenase B and other alcohol dehydrogenases affect risk in European and African ancestry populations. Similarly, variants mapped to these same genes and a well-known null variant that maps to the gene that encodes aldehyde dehydrogenase 2 (ALDH2) also affect risk in various Asian populations. In this study, we completed the first GWAS for 3 traits related to alcohol use in a Thai population recruited initially for studies of methamphetamine dependence. METHODS: All subjects were evaluated with the Thai version of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). A total of 1,045 subjects were available for analysis. Three traits were analyzed: flushing, maximum number of alcoholic beverages consumed in any lifetime 24-hour period ("MAXDRINKS"), and DSM-IV alcohol dependence criterion count. We also conducted a pleiotropy analysis with major depression, the only other psychiatric trait where summary statistics from a large-scale Asian-population GWAS are available. RESULTS: All 3 traits showed genomewide significant association with variants near ALDH2, with significance ranging from 2.01 × 10-14 (for flushing; lead single nucleotide polymorphism (SNP) PTPN11* rs143894582) to pmeta  = 5.80 × 10-10 (for alcohol dependence criterion count; lead SNP rs149212747). These lead SNPs flank rs671 and span a region of over a megabase, illustrating the need for prior biological information in identifying the actual effect SNP, rs671. We also identified significant pleiotropy between major depression and flushing. CONCLUSIONS: These results are consistent with prior findings in Asian populations and add new information regarding alcohol use-depression pleiotropy.

Gray-matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions.

Alterations in neural structure have been reported in both cocaine-use disorder and gambling disorder, separately, suggesting similarities across addiction diagnoses. Individual variation in neural structure has also been associated with impulsivity, a dimensional construct implicated in addictions. This study combines categorical (diagnosis-based) and dimensional (transdiagnostic) approaches to identify neural structural alterations linked to addiction subtypes and trait impulsivity, respectively, across individuals with gambling disorder (n = 35), individuals with cocaine-use disorder (n = 37) and healthy comparison individuals (n = 37). High-resolution T1-weighted data were analyzed using modulated voxel-based morphometry (VBM). Statistical analyses were conducted using whole-brain general-linear models, corrected for family-wise error (pFWE < .05). Categorical analyses indicated a main effect of diagnostic group on prefrontal (dorsal anterior cingulate and ventromedial prefrontal cortex) gray matter volumes (GMVs), involving decreased GMVs among cocaine-use disorder participants only. Dimensional analyses indicated a negative association between trait impulsivity and cortical (insula) and subcortical (amygdala and hippocampus) GMVs across all participants. Conjunction analysis indicated little anatomical overlap between regions identified as differentiating diagnostic groups and regions covarying with impulsivity. These data provide first evidence of neural structural differences between gambling disorder and an illicit substance-use disorder. They further indicate dissociable effects of diagnostic groupings and trait impulsivity on neural structure among individuals with behavioral and drug addictions. Study findings highlight the importance of considering both categorical and dimensional (e.g. Research Domain Criteria; RDoC) analysis approaches within the context of addictions research.

Shared microstructural features of behavioral and substance addictions revealed in areas of crossing fibers.

BACKGROUND: Similarities between behavioral and substance addictions exist. However, direct neurobiological comparison between addictive disorders is rare. Determination of disorder-specificity (or lack thereof) of alterations within white-matter microstructures will advance understanding of the pathophysiology of addictions. METHODS: We compared white-matter microstructural features between individuals with gambling disorder (GD; n=38), cocaine-use disorder (CUD; n=38) and healthy comparison (HC; n=38) participants, as assessed using diffusion-weighted magnetic resonance imaging (dMRI). To provide a more precise estimate of diffusion within regions of complex architecture (e.g., cortico-limbic tracts), analyses were conducted using a crossing-fiber model incorporating local-orientation modeling (tbss_x). Anisotropy estimates for primary and secondary fiber orientations were compared using ANOVAs corrected for multiple comparisons across space using threshold-free cluster enhancement (pFWE<.05). RESULTS: A main effect of group on anisotropy of secondary fiber orientations within the left internal capsule, corona radiata, forceps major and posterior thalamic radiation, involving reduced anisotropy among GD and CUD participants in comparison to HC participants. No differences in anisotropy measures were found between GD and CUD individuals. CONCLUSIONS: This is the first study to compare diffusion indices directly between behavioral and substance addictions and the largest dMRI study of GD. Our findings indicate similar white-matter microstructural alterations across addictions that cannot be attributed solely to exposure to drugs or alcohol and thus may be a vulnerability mechanism for addictive disorders.

Regional and source-based patterns of [11C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D2 and D3 receptor availability in cocaine-use disorder.

Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BPND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPND in the D2R-rich dorsal striatum and greater BPND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPND that were correlated with regional estimates of D2R-related and D3R-related proportions of BPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

Sex Differences in Methamphetamine Use and Dependence in a Thai Treatment Center.

BACKGROUND AND OBJECTIVE: Males and females who use methamphetamine (MA) differ in sociodemographics, MA diagnoses, comorbidities, and brain activity. The objective of this study was to investigate sex differences in the characteristics of MA use and dependence in patients at a Thai substance treatment center. METHODS: Demographic, MA use, and diagnostic data for 782 MA users were obtained by using the Semi-Structured Assessment for Drug Dependence and Alcoholism-Thai version. Categorical comparisons of males (n = 413, 53%) and females (n = 369, 47%) were made by chi-square test. Factors significantly differentiating men and women with respect to MA-dependence were identified by logistic regression analysis controlling for demographic, diagnostic, and MA use variables. RESULTS: Males admitted to residential drug treatment for MA use had an earlier age of onset for both MA use (17.7 ±â€Š4.1 vs 19.7 ±â€Š6.2 years; t = -5.3, P < 0.001) and dependence (20.4 ±â€Š5.2 vs 22.2 ±â€Š6.4 years; t = -3.6, P < 0.001). Females were more likely than males to be MA-dependent (79% vs 60%; χ1 = 33.7, P < 0.001), and to experience MA withdrawal (65.3% vs 48.9%; χ1 = 21.4, P < 0.001), withdrawal-related hypersomnia (77.2% vs 64.8%; χ1 = 14.5, P < 0.001), fatigue (77.5% vs 70.3%; χ1 = 5.2, P = 0.02), and psychomotor retardation (64.5% vs 57.0%; χ1 = 4.5, P = 0.03). Similarly, females had heavier (eg, largest daily amount [χ1 = 12.4, P < 0.001), more frequent (χ1 = 5.1, P = 0.02]) and greater lifetime episodes of MA use (χ1 = 24.1, P < 0.001) than males. After controlling for such variables by logistic regression, being female remained a significant factor influencing the occurrence of MA-dependence (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.8-4.1, P < 0.001). Shared associated factors (or comorbidities) for MA-dependence in both sexes included nicotine dependence (in males: OR 4.1, 95% CI 2.4-7.0, P < 0.001; and in females: OR 2.4, 95% CI 1.3-4.4, P = 0.007), greater lifetime episodes of MA use (in males: OR 3.5, 95% CI 1.9-6.4, P < 0.001; and in females: OR 5.9, 95% CI 3.1-11.4, P < 0.001), and more frequent use (in males: OR 5.1, 95% CI 2.8-9.1, P < 0.001; and in females: OR 3.6, 95% CI 1.9-6.9, P < 0.001). Comorbid antisocial personality disorder predicted MA-dependence in males only (OR 3.7, 95% CI 1.6-8.6, P = 0.002). CONCLUSIONS: The current study highlights both common (eg, nicotine dependence and severity of MA use) and sex-specific differences (eg, MA use/dependence characteristics and comorbidities), including sex itself, with respect to MA-dependence in a Thai treatment cohort.

The Connecticut Mental Health Center: Celebrating 50 Years of a Successful Partnership Between the State and Yale University.

September 28, 2016, marked the 50th anniversary of the Connecticut Mental Health Center, a state-owned and state-operated joint venture between the state and Yale University built and sustained with federal, state, and university funds. Collaboration across these entities has produced a wide array of clinical, educational, and research initiatives, a few of which are described in this column. The missions of clinical care, research, and education remain the foundation for an organization that serves 5,000 individuals each year who are poor and who experience serious mental illnesses and substance use disorders.

Cocaine dependence and thalamic functional connectivity: a multivariate pattern analysis.

Cocaine dependence is associated with deficits in cognitive control. Previous studies demonstrated that chronic cocaine use affects the activity and functional connectivity of the thalamus, a subcortical structure critical for cognitive functioning. However, the thalamus contains nuclei heterogeneous in functions, and it is not known how thalamic subregions contribute to cognitive dysfunctions in cocaine dependence. To address this issue, we used multivariate pattern analysis (MVPA) to examine how functional connectivity of the thalamus distinguishes 100 cocaine-dependent participants (CD) from 100 demographically matched healthy control individuals (HC). We characterized six task-related networks with independent component analysis of fMRI data of a stop signal task and employed MVPA to distinguish CD from HC on the basis of voxel-wise thalamic connectivity to the six independent components. In an unbiased model of distinct training and testing data, the analysis correctly classified 72% of subjects with leave-one-out cross-validation (p < 0.001), superior to comparison brain regions with similar voxel counts (p < 0.004, two-sample t test). Thalamic voxels that form the basis of classification aggregate in distinct subclusters, suggesting that connectivities of thalamic subnuclei distinguish CD from HC. Further, linear regressions provided suggestive evidence for a correlation of the thalamic connectivities with clinical variables and performance measures on the stop signal task. Together, these findings support thalamic circuit dysfunction in cognitive control as an important neural marker of cocaine dependence.

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO.

Most prior work with positron emission tomography (PET) dopamine subtype 2/3 receptor (D2/3R) non-selective antagonist tracers suggests that obese (OB) individuals exhibit lower D2/3Rs when compared with normal weight (NW) individuals. A D3-preferring D2/3R agonist tracer, [11C](+)PHNO, has demonstrated that body mass index (BMI) was positively associated with D2/3R availability within striatal reward regions. To date, OB individuals have not been studied with [11C](+)PHNO. We assessed D2/3R availability in striatal and extrastriatal reward regions in 14 OB and 14 age- and gender-matched NW individuals with [11C](+)PHNO PET utilizing a high-resolution research tomograph. Additionally, in regions where group D2/3R differences were observed, secondary analyses of 42 individuals that constituted an overweight cohort was done to study the linear association between BMI and D2/3R availability in those respective regions. A group-by-brain region interaction effect (F7, 182=2.08, p=0.047) was observed. Post hoc analyses revealed that OB individuals exhibited higher tracer binding in D3-rich regions: the substantia nigra/ventral tegmental area (SN/VTA) (+20%; p=0.02), ventral striatum (VST) (+14%; p<0.01), and pallidum (+11%; p=0.02). BMI was also positively associated with D2/3R availability in the SN/VTA (r=0.34, p=0.03), VST (r=0.36, p=0.02), and pallidum (r=0.30, p=0.05) across all subjects. These data suggest that individuals who are obese have higher D2/3R availability in brain reward regions densely populated with D3Rs, potentially identifying a novel pharmacologic target for the treatment of obesity.

Age-related changes in binding of the D2/3 receptor radioligand [(11)C](+)PHNO in healthy volunteers.

OBJECTIVE: Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [(11)C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. METHODS: Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [(11)C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. RESULTS: Regional [(11)C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=-0.56, corrected p=0.0008) and putamen (r=-0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. CONCLUSION: In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [(11)C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

Modafinil and sleep architecture in an inpatient-outpatient treatment study of cocaine dependence.

OBJECTIVE: To determine whether the increase in slow-wave sleep associated with modafinil treatment in chronic cocaine users mediates improved clinical outcomes. METHOD: 57 cocaine dependent participants were randomized to receive modafinil 400mg or placebo daily during a period of inpatient treatment followed by six weeks of outpatient treatment. Participants underwent polysomnographic sleep recording during inpatient treatment prior to and after starting modafinil. Outpatient treatment consisted of weekly cognitive behavioral therapy. Contingency management was used to promote participation in treatment and research demands, including thrice weekly visits during the outpatient phase for urine toxicology screens and other assessments. The primary clinical outcome was the percent of urine toxicology screens that were negative for cocaine. RESULTS: Modafinil treatment was associated with a higher mean percentage (52% vs. 26%) of cocaine-free urine screens (p=0.02) and an increase in N3 sleep time (p=0.002). The change in N3 sleep time mediated the higher rate of cocaine-free urine screens. Modafinil treatment was also associated with more consecutive days abstinent during outpatient treatment, greater survival of abstinence, higher daily rates of abstinence, and less sleep degradation typically associated with abstinence from chronic cocaine use. CONCLUSIONS: Morning-dosed modafinil improves slow-wave sleep in abstinent cocaine users in the inpatient setting, and this effect is a statistical mediator of improved clinical outcomes associated with continued modafinil treatment. The high rates of abstinence achieved in this trial suggest that promoting healthy sleep physiology in an inpatient setting may be important in the effective treatment of cocaine dependence.

Brain Activity During Cocaine Craving and Gambling Urges: An fMRI Study.

Although craving states are important to both cocaine dependence (CD) and pathological gambling (PG), few studies have directly investigated neurobiological similarities and differences in craving between these disorders. We used functional magnetic resonance imaging (fMRI) to assess brain activity in 103 participants (30 CD, 28 PG, and 45 controls) while they watched videos depicting cocaine, gambling, and sad scenarios to investigate the neural correlates of craving. We observed a three-way urge type × video type × diagnostic group interaction in self-reported craving, with CD participants reporting strong cocaine cravings to cocaine videos, and PG participants reporting strong gambling urges to gambling videos. Neuroimaging data revealed a diagnostic group × video interaction in anterior cingulate cortex/ventromedial prefrontal cortex (mPFC), activating predominantly to cocaine videos in CD participants, and a more dorsal mPFC region that was most strongly activated for cocaine videos in CD participants, gambling videos in PG participants, and sad videos in control participants. Gender × diagnosis × video interactions identified dorsal mPFC and a region in posterior insula/caudate in which female but not male PG participants showed increased responses to gambling videos. Findings illustrate both similarities and differences in the neural correlates of drug cravings and gambling urges in CD and PG. Future studies should investigate diagnostic- and gender-specific therapies targeting the neural systems implicated in craving/urge states in addictions.