Publications by authors named "Cleo L Crunelle"

54 Publications

Cognitive impairment following clinical or recreational use of gamma-hydroxybutyric acid (GHB). A systematic review.

Curr Neuropharmacol 2021 Jun 9. Epub 2021 Jun 9.

Department of Psychiatry, Amsterdam University Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, Netherlands.

Background: GHB (gamma-hydroxybutyric acid; sodium oxybate) is a general anaesthetic that is clinically used for the treatment of narcolepsy, cataplexy, alcohol withdrawal and alcohol relapse prevention. In addition, GHB is recreationally used. Most clinical and recreational users regard GHB as an innocent drug devoid of adverse effects, despite its high dependence potential and possible neurotoxic effects. At high doses, GHB may lead to a comatose state. This paper systematically reviews possible cognitive impairments due to clinical and recreational GHB use.

Methods: PubMed and PsychINFO were searched for literature data about the acute and residual cognitive deficits following GHB use. This review is conducted using the PRISMA protocol.

Results: A total of 43 reports covering human and animal data on GHB-induced cognitive impairments were eligible and reviewed. This systematic review found no indication for cognitive impairments after clinical GHB use. However, it supports the view that moderate GHB use may result in acute short-term cognitive impairments, whereas regular high-dose GHB use and/or multiple GHB-induced comas are probably neurotoxic resulting in long-term residual cognitive impairments.

Conclusion: These results emphasize the need for awareness among clinicians and recreational users to minimize negative health consequences of recreational GHB use, particularly when high doses are used, and GHB-induced comas occur.
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http://dx.doi.org/10.2174/1570159X19666210610094352DOI Listing
June 2021

The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder.

Neurosci Biobehav Rev 2021 Sep 4;128:789-818. Epub 2021 Feb 4.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Wuerzburg, Germany. Electronic address:

Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.

Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.

Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.

Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
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http://dx.doi.org/10.1016/j.neubiorev.2021.01.022DOI Listing
September 2021

[Recommendations for the screening, diagnosis and treatment of patients with comorbid attention deficit hyperactivity- and substance use disorder].

Psychiatr Hung 2020 ;35(4):435-447

Semmelweis Egyetem, Egeszsegtudomanyi Kar, Addiktologiai Tanszek, Budapest, Hungary, E-mail:

Among patients with substance use disorders (SUD), adult attention deficit hyperactivity disorder (ADHD) is one of the most frequently co-occuring disorder. Those SUD patients with comorbid ADHD show earlier onset of substance use, more severe SUD and poor treatment outcomes. Therefore, early recognition of ADHD is highly rele - vant within this patient population. The results of available screening instruments may lay the foundation of timely ADHD diagnosis. Considering the integrated treatment of patients with a dual ADHD+SUD diagnosis, the applica tion of combined pharmaco- and psychotherapy is recommended. Based on the evidence-and consensus-based suggestions, prescription of long-acting methylphenidate, extended-release amphetamines and atomoxetine with up-titration might be the best choice in the treatment of patients who are either unresponsive to standard dose or characterized by therapy resistance. The main purpose of this manuscript is to establish a standing-ground for the effective screening, diagnosis and treatment of ADHD+SUD patients.
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December 2020

Diagnostic Accuracy of Biomarkers of Alcohol Use in Patients With Liver Disease: A Systematic Review.

Alcohol Clin Exp Res 2021 01 25;45(1):25-37. Epub 2020 Dec 25.

Department of Gastroenterology and Hepatology, (FN, JV), University Hospitals KU Leuven, Leuven, Belgium.

Background And Aims: Alcohol-related liver disease is the most frequent cause of cirrhosis and a major indication for liver transplantation. Several alcohol use biomarkers have been developed in recent years and are already in use in several centers. However, in patients with liver disease their diagnostic performance might be influenced by altered biomarker formation by hepatic damage, altered excretion by kidney dysfunction and diuretics use, and altered deposition in hair and nails. We systematically reviewed studies on the diagnostic accuracy of biomarkers of alcohol use in patients with liver disease and performed a detailed study quality assessment.

Methods: A structured search in PubMed/Medline/Embase databases was performed for relevant studies, published until April 28, 2019. The risk of bias and applicability concerns was assessed according to the adapted quality assessment of diagnostic accuracy studies-2 (QUADAS-2) checklist.

Results: Twelve out of 6,449 studies met inclusion criteria. Urinary ethyl glucuronide and urinary ethyl sulfate showed high sensitivity (70 to 89 and 73 to 82%, respectively) and specificity (93 to 99 and 86 to 89%, respectively) for assessing any amount of alcohol use in the past days. Serum carbohydrate-deficient transferrin showed low sensitivity but higher specificity (40 to 79 and 57 to 99%, respectively) to detect excessive alcohol use in the past weeks. Whole blood phosphatidylethanol showed high sensitivity and specificity (73 to 100 and 90 to 96%, respectively) to detect any amount of alcohol use in the previous weeks. Scalp hair ethyl glucuronide showed high sensitivity (85 to 100%) and specificity (97 to 100%) for detecting chronic excessive alcohol use in the past 3 to 6 months. Main limitations of the current evidence are the lack of an absolute gold standard to assess alcohol use, heterogeneous study populations, and the paucity of studies.

Conclusions: Urinary and scalp hair ethyl glucuronide are currently the most validated alcohol use biomarkers in patients with liver disease with good diagnostic accuracies. Phosphatidylethanol is a highly promising alcohol use biomarker, but so far less validated in liver patients. Alcohol use biomarkers can complement each other regarding diagnostic time window. More validation studies on alcohol use biomarkers in patients with liver disease are needed.
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http://dx.doi.org/10.1111/acer.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898850PMC
January 2021

Self-Reported Alcohol, Tobacco, and Cannabis Use during COVID-19 Lockdown Measures: Results from a Web-Based Survey.

Eur Addict Res 2020 22;26(6):309-315. Epub 2020 Sep 22.

Department of Psychiatry, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.

Background: The outbreak of coronavirus disease 19 (COVID-19) has led to measures of social distancing and quarantine worldwide. This stressful period may lead to psychological problems, including increases in substance use.

Objective: To investigate changes in alcohol, tobacco, and cannabis consumption before and during COVID-19 lockdown and motives for these changes in substance use.

Method: A web-based survey was filled out by an unselected population during the social distancing measures of the COVID-19 pandemic in Belgium that assessed changes in alcohol, tobacco, and cannabis consumption in the period before and during the COVID-19 lockdown and also asked about reasons for change.

Results: A total of 3,632 respondents (mean age 42.1 ± 14.6 years; 70% female) filled out the survey. Overall, respondents reported consuming more alcohol (d = 0.21) and smoking more cigarettes (d = 0.13) than before the COVID-19 pandemic (both p < 0.001), while no significant changes in the consumption of cannabis were noted. The odds of consuming more alcohol during the lockdown were associated with younger age (OR = 0.981, p < 0.001), more children at home (OR = 1.220, p < 0.001), non-healthcare workers (p < 0.001), and being technically unemployed related to COVID-19 (p = 0.037). The odds of smoking more cigarettes during the lockdown were associated with younger age (OR = 0.988, p = 0.027), current living situation (p < 0.001), lower education (p = 0.015), and working situation related to COVID-19 (p = 0.018). Boredom, lack of social contacts, loss of daily structure, reward after a hard-working day, loneliness, and conviviality were the main reasons for consuming more of the various substances.

Conclusions: During the lockdown, individuals consumed slightly more alcohol and smoked marginally more cigarettes compared to the period before the lockdown. Further research focussing on follow-up of individuals at risk may be useful to provide appropriate care in post-COVID times.
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http://dx.doi.org/10.1159/000510822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573904PMC
November 2020

International Consensus Statement for the Screening, Diagnosis, and Treatment of Adolescents with Concurrent Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder.

Eur Addict Res 2020 7;26(4-5):223-232. Epub 2020 Jul 7.

Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany.

Background: Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment and is associated with poor treatment outcomes. Research on the effect of treatment of childhood ADHD on the prevention of adolescent SUD is inconclusive, and studies on the diagnosis and treatment of adolescents with ADHD and SUD are scarce. Thus, the available evidence is generally not sufficient to justify robust treatment recommendations.

Objective: The aim of the study was to obtain a consensus statement based on a combination of scientific data and clinical experience.

Method: A modified Delphi study to reach consensus based upon the combination of scientific data and clinical experience with a multidisciplinary group of 55 experts from 17 countries. The experts were asked to rate a set of statements on the effect of treatment of childhood ADHD on adolescent SUD and on the screening, diagnosis, and treatment of adolescents with comorbid ADHD and SUD.

Results: After 3 iterative rounds of rating and adapting 37 statements, consensus was reached on 36 of these statements representing 6 domains: general (n = 4), risk of developing SUD (n = 3), screening and diagnosis (n = 7), psychosocial treatment (n = 5), pharmacological treatment (n = 11), and complementary treatments (n = 7). Routine screening is recommended for ADHD in adolescent patients in substance abuse treatment and for SUD in adolescent patients with ADHD in mental healthcare settings. Long-acting stimulants are recommended as the first-line treatment of ADHD in adolescents with concurrent ADHD and SUD, and pharmacotherapy should preferably be embedded in psychosocial treatment. The only remaining no-consensus statement concerned the requirement of abstinence before starting pharmacological treatment in adolescents with ADHD and concurrent SUD. In contrast to the majority, some experts required full abstinence before starting any pharmacological treatment, some were against the use of stimulants in the treatment of these patients (independent of abstinence), while some were against the alternative use of bupropion.

Conclusion: This international consensus statement can be used by clinicians and patients together in a shared decision-making process to select the best interventions and to reach optimal outcomes in adolescent patients with concurrent ADHD and SUD.
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http://dx.doi.org/10.1159/000508385DOI Listing
May 2021

Validity of the ADHD module of the Mini International Neuropsychiatric Interview PLUS for screening of adult ADHD in treatment seeking substance use disorder patients: ADHD screening with MINI-Plus.

Rev Psiquiatr Salud Ment (Engl Ed) 2020 Jun 16. Epub 2020 Jun 16.

Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

Objective: This study aims to assess the validity of the ADHD module of the Mini-International Neuropsychiatric Interview (MINI-Plus) in patients with substance use disorders (SUD), using the Conners' Adult ADHD Diagnostic Interview for DSM-IV (CAADID) as the external criterion.

Method: A cross sectional international multi-center study in 10 countries was conducted in treatment seeking SUD patients. A sample of 1263 patients with both MINI-Plus and CAADID was analyzed to determine the psychometric properties of the MINI-Plus.

Results: According to the CAADID, 179 patients (14.2%) met criteria for adult ADHD, whereas according to the MINI-Plus 227 patients (18.0%) were identified as having adult ADHD. Sensitivity of the MINI-Plus ADHD module was 74%, specificity was 91%, positive predictive value was 60% and negative predictive value was 96%. Kappa was 0.60.

Conclusion: The MINI-Plus has acceptable criterion validity for the screening of adult ADHD in treatment seeking SUD patients.

Scientific Significance: On the basis of the results, The MINI-Plus may be used for the screening of ADHD in SUD patients.
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http://dx.doi.org/10.1016/j.rpsm.2020.04.013DOI Listing
June 2020

Reduced CETP glycosylation and activity in patients with homozygous B4GALT1 mutations.

J Inherit Metab Dis 2020 05 29;43(3):611-617. Epub 2019 Dec 29.

Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco-isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1-CDG patients and compared them with 11 age- and gender-matched, healthy controls. B4GALT1-CDG patients have significantly lowered non-high density lipoprotein cholesterol (HDL-c) and total cholesterol to HDL-c ratio compared with controls and larger HDL particles. Plasma CETP was hypoglycosylated and less active in B4GALT1-CDG patients compared to matched controls. Our study provides insight into the role of protein glycosylation in human lipoprotein homeostasis. The hypogalactosylated, hypo-active CETP found in patients with B4GALT1-CDG indicates a role of protein galactosylation in regulating plasma HDL and LDL. Patients with B4GALT1-CDG have large HDL particles probably due to hypogalactosylated, hypo-active CETP.
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http://dx.doi.org/10.1002/jimd.12200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318693PMC
May 2020

Cognitive outcome after surgical clipping versus endovascular coiling in patients with subarachnoid hemorrhage due to ruptured anterior communicating artery aneurysm.

Acta Neurol Belg 2020 Feb 19;120(1):123-132. Epub 2019 Nov 19.

Collaborative Antwerp Psychiatric Research Institute (CAPRI), Antwerp University, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Ruptured anterior communicating artery aneurysms are commonly associated with deficits in memory and executive functions. However, little studies are available on the effect of surgical clipping (SC) and endovascular coiling (EC) on cognitive functioning. This study evaluates cognitive functioning in 35 patients with subarachnoid hemorrhage after ruptured anterior communicating artery aneurysm (ACoA) compared to 20 healthy controls (HC) and assesses the effect of SC (n = 19) compared to EC (n = 16) on cognitive performances. All participants were investigated with an extensive neuropsychological test battery assessing attention, memory and visuospatial and executive functions. The strength of this study is an in-depth investigation of several cognitive domains together and several memory functions together within the auditory-verbal and visuospatial memory domain for unrelated and related information. The ACoA group was significantly more deficient in attention, auditory-verbal and visuospatial memory and executive functions compared to HCs. No significant differences were found between both groups concerning visuospatial functions. Within the patient group, the SC group, as compared to the EC group, showed a significantly worse performance for auditory-verbal and visuospatial memory. No significant differences could be detected between both groups with regard to attention and visuospatial and executive functions. In conclusion, this study provides evidence for the advantage of EC in ACoA patients over SC in terms of cognitive outcome.
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http://dx.doi.org/10.1007/s13760-019-01245-wDOI Listing
February 2020

Prevalence of metabolic syndrome and its associated risk factors in an African-Caribbean population with severe mental illness.

Psychiatry Res 2019 11 7;281:112558. Epub 2019 Sep 7.

Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.

This cross-sectional study aims to determine the prevalence of metabolic syndrome (MetS) in patients with severe mental illness (SMI) on a Caribbean island, Curaçao, using the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Among 350 patients (240 men and 110 women) with a mean age of 51.9 years (S.D.=13.5) MetS prevalence was 37.4%, significantly higher in female patients (63.6%) compared to male patients (25.4%). Increased waist circumference was present in 51.1%, low HDL in 50.6%, hypertension in 49.4%, hyperglycemia in 28.6% and 25.7% had hypertriglyceridemia. Except for hypertriglyceridemia, all criteria were more prevalent in female patients. Binary logistic regression analysis indicated that female gender, outpatient treatment setting and the absence of substance use disorder were all significant predictors for MetS. Compared to data from the general population obtained by the 2013 National Health Survey Curaçao, this study showed significantly higher prevalence of diabetes and hypertension in patients with SMI. Moreover, female patients had the highest prevalence of diabetes (28.2%), obesity (50.0%) and increased waist circumference (88.2%). This study demonstrates that African-Caribbean patients with SMI are at high-risk for MetS, especially female patients. Our data suggest to focus on modifiable lifestyle risk factors, as promoting physical activity and healthy dietary habits.
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http://dx.doi.org/10.1016/j.psychres.2019.112558DOI Listing
November 2019

Prevalence of metabolic syndrome and its associated risk factors in an African-Caribbean population with severe mental illness.

Psychiatry Res 2019 11 7;281:112558. Epub 2019 Sep 7.

Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.

This cross-sectional study aims to determine the prevalence of metabolic syndrome (MetS) in patients with severe mental illness (SMI) on a Caribbean island, Curaçao, using the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Among 350 patients (240 men and 110 women) with a mean age of 51.9 years (S.D.=13.5) MetS prevalence was 37.4%, significantly higher in female patients (63.6%) compared to male patients (25.4%). Increased waist circumference was present in 51.1%, low HDL in 50.6%, hypertension in 49.4%, hyperglycemia in 28.6% and 25.7% had hypertriglyceridemia. Except for hypertriglyceridemia, all criteria were more prevalent in female patients. Binary logistic regression analysis indicated that female gender, outpatient treatment setting and the absence of substance use disorder were all significant predictors for MetS. Compared to data from the general population obtained by the 2013 National Health Survey Curaçao, this study showed significantly higher prevalence of diabetes and hypertension in patients with SMI. Moreover, female patients had the highest prevalence of diabetes (28.2%), obesity (50.0%) and increased waist circumference (88.2%). This study demonstrates that African-Caribbean patients with SMI are at high-risk for MetS, especially female patients. Our data suggest to focus on modifiable lifestyle risk factors, as promoting physical activity and healthy dietary habits.
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http://dx.doi.org/10.1016/j.psychres.2019.112558DOI Listing
November 2019

Mini Review: Socio-Cultural Influences on the Link Between ADHD and SUD.

Front Public Health 2019 26;7:173. Epub 2019 Jun 26.

Department of Psychiatry, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium.

Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development and persistence of substance use disorders (SUD). The prevalence of ADHD in patients with SUD varies across countries and cultures. So far, cross-cultural variance in ADHD prevalence rates among SUD patients was mainly ascribed to methodological differences between studies, leaving the role of societal and cultural practices in the ADHD-SUD link hardly acknowledged. The aim of the present mini review is to address this gap in the literature by providing evidence for the effect of socio-cultural practices on the ADHD-SUD link and suggesting directions for future research. To achieve this goal, we map the influence of socio-cultural factors on the ADHD-SUD link along three lines of research. The first line is concerned with the role of socio-cultural factors in the recognition, diagnosis and treatment of childhood ADHD. The second line of research is concerned with socio-cultural influences on substance use (e.g., religion, ethnic identity, acculturation, and socio-economic status). Finally, we describe potential socio-cultural factors which may operate as mechanisms for reducing or increasing access to substance abuse treatment (e.g., ethnic disparities in health care utilization). Identifying socio-cultural influences on the ADHD-SUD link may provide further insight into the bidirectional association between ADHD and SUD in different contexts and encourage future research in the field.
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http://dx.doi.org/10.3389/fpubh.2019.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606733PMC
June 2019

Diagnosis and treatment of patients with comorbid substance use disorder and adult attention-deficit and hyperactivity disorder: a review of recent publications.

Curr Opin Psychiatry 2019 07;32(4):300-306

Amsterdam Institute of Addiction Research (AIAR), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Purpose Of Review: Attention-deficit and hyperactivity disorder (ADHD) often presents with comorbid substance use disorders (SUD). Due to similarities in key symptoms of both disorders and suboptimal efficacy of the available treatments, clinicians are faced with difficulties in the diagnosis and treatment of these patients with both disorders. This review addresses recent publications between 2017 and 2019 on the etiology, prevalence, diagnosis and treatment of co-occurring ADHD and SUD.

Recent Findings: ADHD is diagnosed in 15-20% of SUD patients, mostly as ADHD with combined (hyperactive/inattentive) presentation. Even during active substance use, screening with the Adult ADHD Self-Report Scale (ASRS) is useful to address whether further diagnostic evaluation is needed. After SUD treatment, the diagnosis of ADHD generally remains stable, but ADHD subtype presentations are not. Some evidence supports pharmacological treatment with long-acting stimulants in higher than usual dosages. Studies on psychological treatment remain scarce, but there are some promising findings on integrated cognitive behaviour therapy.

Summary: Diagnosis and treatment of patients with comorbid ADHD and SUD remain challenging. As ADHD presentations can change during active treatment, an active follow-up is warranted to provide treatment to the individuals' personal strengths and weaknesses.
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http://dx.doi.org/10.1097/YCO.0000000000000513DOI Listing
July 2019

How to Interpret Hair EtG Concentrations in Individuals with High Body Mass Index? Brief Commentary on: Influence of Body Mass Index on Hair Ethyl Glucuronide Concentrations.

Alcohol Alcohol 2019 Mar;54(2):188-189

Toxicological Center, Antwerp University, Antwerp, Belgium.

Body mass index (BMI) is a variable that complicates the interpretation of the alcohol metabolite ethyl glucuronide (EtG) in hair. However, direction on how EtG should currently be interpreted within individuals consuming moderate and excessive daily amounts of alcohol related to their BMI is lacking. In light of interpretation of EtG in individuals with high BMI, we present post hoc analysis of earlier data regarding the effect of BMI on hair EtG concentrations.
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http://dx.doi.org/10.1093/alcalc/agz006DOI Listing
March 2019

Gammahydroxybutyrate in hair of non-GHB and repeated GHB users: A new and optimized method.

Forensic Sci Int 2018 Oct 30;291:193-198. Epub 2018 Aug 30.

Laboratoire National de Santé, Service de Toxicologie, Dudelange, Luxembourg.

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid used recreationally as a drug of abuse due its strong suppressive effect on the central nervous system. The detection window of GHB in blood and urine is very narrow (t1/2=30min) but can be substantially prolonged using alternative matrices such as hair. We here present a newly developed and limited validated method with a solid phase extraction (SPE) using GC-MS/MS to determine concentrations of GHB in hair samples. The soft extraction technique (water and 90min ultrasonic bath) preserves GHB with a high yield and clean extracts. In addition, endogenous GHB can be detected in hair of non-GHB users. However, little is known about GHB concentrations in hair of abstinent, frequent and chronic GHB users. Therefore, we present data from hair samples of healthy volunteers to evaluate the proposed endogenous GHB ranges, and from GHB-dependent patients to address GHB concentrations in hair with GHB intake. In 20 non-GHB users, a mean endogenous concentration of 1.1±0.6ng/mg hair (range of 0.3-2ng/mg) was found. In GHB-dependent patients, concentrations between 6.3-239.6ng/mg hair were found, with no correlation between concentrations in hair and dose of GHB intake. In summary, we present a new and limited validated method, adequately sensitive for the detection of GHB in hair, as well as first-time measurements of GHB concentrations in dependent patients in order to better understand the relationship between the frequency of use/dose and concentrations observed in hair samples.
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http://dx.doi.org/10.1016/j.forsciint.2018.08.025DOI Listing
October 2018

Assessment of ethyl sulphate in hair as a marker for alcohol consumption using liquid chromatography-tandem mass spectrometry.

Drug Test Anal 2018 Oct 19;10(10):1566-1572. Epub 2018 Jun 19.

Toxicological Centre, University of Antwerp, Belgium.

Ethyl glucuronide (EtG) and ethyl sulphate (EtS) are 2 non-oxidative and direct metabolites of ethanol. EtG is known to accumulate in hair and has proved to be a reliable biomarker for detection of chronic alcohol consumption. EtS has been analysed in blood and urine but has never been reported in hair. This article presents the first analytical assay based on liquid chromatography coupled to tandem mass spectrometry for the quantification of EtS in hair. Sample preparation, chromatographic, and mass spectrometric parameters, such as solid-phase extraction, column type, and transitions were optimised. The method was validated according to the guidelines of the European Medicine Agency, fulfilling the requirements for limit of quantification (LOQ), linearity, accuracy, precision, carry-over, matrix effects, and recovery. Linearity ranged from 5 to 500 pg mg and the LOQ was achieved at 5 pg mg . The novel method was successfully applied to hair samples (n = 40) from patients treated for alcohol use disorders. EtS concentrations in hair ranged from 24 to 1776 pg mg , while EtG concentrations in hair ranged from 1 to 1149 pg mg . Hair concentrations of EtS and EtG were compared to assess the relationship between both biomarkers. There was a significant and positive correlation between EtS and EtG in hair, suggesting that EtS can be used as a biomarker for alcohol consumption. Relatively high basal EtS levels were observed in alcohol-abstinent persons, comparable to what has been reported for EtG. The developed analytical procedure offers an alternative method to prove alcohol consumption using hair analysis.
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http://dx.doi.org/10.1002/dta.2410DOI Listing
October 2018

International Consensus Statement on Screening, Diagnosis and Treatment of Substance Use Disorder Patients with Comorbid Attention Deficit/Hyperactivity Disorder.

Eur Addict Res 2018 6;24(1):43-51. Epub 2018 Mar 6.

Department of Psychiatry, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.

Adult attention deficit/hyperactivity disorder (ADHD) often co-occurs with substance use disorders (SUD) and is associated with early onset and more severe development of SUD and with reduced treatment effectiveness. Screening tools allow for a good recognition of possible ADHD in adults with SUD and should be used routinely, followed by an ADHD diagnostic process initiated as soon as possible. Simultaneous and integrated treatment of ADHD and SUD, using a combination of pharmaco- and psychotherapy, is recommended. Long-acting methylphenidate, extended-release amphetamines, and atomoxetine with up-titration to higher dosages may be considered in patients unresponsive to standard doses. This paper includes evidence- and consensus-based recommendations developed to provide guidance in the screening, diagnosis and treatment of patients with ADHD-SUD comorbidity.
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http://dx.doi.org/10.1159/000487767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986068PMC
September 2018

Lower Limbic Metabotropic Glutamate Receptor 5 Availability in Alcohol Dependence.

J Nucl Med 2018 04 18;59(4):682-690. Epub 2018 Jan 18.

Division of Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Animal studies suggest an important role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the pathophysiology of alcohol dependence, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGlu5 availability in alcohol-dependent subjects versus controls using F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (F-FPEB) PET. Dynamic 90-min F-FPEB scans combined with arterial blood sampling were acquired for 16 recently abstinent alcohol-dependent subjects and 32 age-matched controls. Regional mGlu5 availability was quantified by the F-FPEB total distribution volume using both a voxel-by-voxel and a volume-of-interest analysis with partial-volume effect correction. Alcohol consumption within the last 3 mo was assessed by questionnaires and by hair ethyl glucuronide analysis. Craving was assessed using the Desire for Alcohol Questionnaire. mGlu5 availability was lower in mainly limbic regions of alcohol-dependent subjects than in controls ( < 0.05, familywise error-corrected), ranging from 14% in the posterior cingulate cortex to 36% in the caudate nucleus. Lower mGlu5 availability was associated with higher hair ethyl glucuronide levels for most regions and was related to a lower level of craving specifically in the middle frontal gyrus, cingulate cortex, and inferolateral temporal lobe. These findings provide human in vivo evidence that limbic mGlu5 has a role in the pathophysiology of alcohol dependence, possibly involved in a compensatory mechanism helping to reduce craving during abstinence.
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http://dx.doi.org/10.2967/jnumed.117.199422DOI Listing
April 2018

Keratinous matrices for the assessment of drugs of abuse consumption: A correlation study between hair and nails.

Drug Test Anal 2018 Jan 5. Epub 2018 Jan 5.

Toxicological Centre, University of Antwerp, Belgium.

Keratinous matrices - hair and nails - accumulate substances over time and allow retrospective investigation of past consumption. Analysis of these matrices can provide information complementary to blood and urine analysis or can be used as standalone. So far, research has primarily focused on the detection of substances in hair, while studies in nails are scarce. In this study, we assessed concentrations of drugs of abuse and their metabolites in hair, fingernails, and toenails collected from the same individuals to evaluate differences and correlations between matrices. A total of 26 hair, 24 fingernail, and 18 toenail samples were collected. Samples were analysed by a validated liquid chromatography-tandem mass spectrometry method able to simultaneously detect the following compounds: amphetamine (AMP), methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine, morphine (MOR), codeine (COD), 6-monoacetylmorphine (6-MAM), methadone (MTD), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine (COC), benzoylecgonine (BE), and ecgonine methyl ester (EME). Strong positive correlations between hair, fingernails, and toenails were present for COC, BE, EME, AMP and MDMA. MOR, COD, 6-MAM, MTD and EDDP showed positive trends. Concentrations were generally higher in nails compared to hair. Ratios between parent compounds and their metabolites were assessed for 6-MAM/MOR, EDDP/MTD, BE/COC and EME/COC. Preliminary cut-off concentrations for COC, BE, EME and AMP in fingernails and toenails were proposed. In light of these results, nails can be considered as a useful alternative to hair for monitoring of long-term drug consumption. However, care should be taken regarding the variability in the accumulation of compounds between the matrices.
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http://dx.doi.org/10.1002/dta.2356DOI Listing
January 2018

Accelerated HF-rTMS in the elderly depressed: A feasibility study.

Brain Stimul 2018 Jan - Feb;11(1):247-248. Epub 2017 Oct 31.

Department of Psychiatry and Medical Psychology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2017.10.018DOI Listing
October 2017

Ethyl glucuronide in keratinous matrices as biomarker of alcohol use: A correlation study between hair and nails.

Forensic Sci Int 2017 Oct 26;279:187-191. Epub 2017 Aug 26.

Toxicological Center, University of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium. Electronic address:

To quantify alcohol use, objective, specific and sensitive long-term alcohol markers are necessary. Ethyl glucuronide (EtG), a direct metabolite of alcohol, accumulates in keratinous matrices such as hair and nails, and is a specific and sensitive long-term biomarker for the detection of chronic alcohol consumption. So far, research has primarily focused on the detection of EtG in hair, and studies on its measurement in nails are scarce. In this article, we assessed EtG concentrations in hair, finger- and toenails from the same individuals in order to evaluate the direct correlation between the matrices. To this end, a total amount of 45 hair, 41 fingernail, and 13 toenail samples were collected from patients treated for alcohol use disorders at two psychiatric centers in Belgium. Samples were analyzed by gas chromatography-tandem mass spectrometry. Hair EtG concentrations ranged from 123pg/mg for chronic excessive alcohol consumption, 59-123pg/mg for moderate alcohol consumption, and <59pg/mg for alcohol abstinence. In light of these results, nails may be a useful alternative to hair samples for monitoring of long-term alcohol consumption, e.g., in cases where hair is not available. Further studies are needed to establish cut-off values for EtG levels in nails.
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http://dx.doi.org/10.1016/j.forsciint.2017.08.022DOI Listing
October 2017

A straightforward, validated liquid chromatography coupled to tandem mass spectrometry method for the simultaneous detection of nine drugs of abuse and their metabolites in hair and nails.

Anal Chim Acta 2017 Apr 25;960:101-109. Epub 2017 Jan 25.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium; Toxicology and TDM Laboratory, ZNA Stuivenberg Hospital, Lange Beeldekenstraat 267, B2060 Antwerp, Belgium.

Hair and nails allow for a stable accumulation of compounds over time and retrospective investigation of past exposure and/or consumption. Owing to their long window of detection (weeks to months), analysis of these matrices can provide information complementary to blood and urine analysis or can be used in standalone when e.g. elimination from the body has already occurred. Drugs of abuse are often used together and, therefore, multi-analyte methods capable of detecting several substances and their metabolites in a single run are of importance. This paper presents the development and validation of a method based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the simultaneous detection of nine drugs of abuse and their metabolites in hair and nails. We focused on a simple and straightforward sample preparation to reduce costs, and allow application in routine laboratory practice. Chromatographic and mass spectrometric parameters, such as column type, mobile phase, and multiple reaction monitoring transitions were optimized. The method was validated according to the European Medicine Agency guidelines with an assessment of specificity, limit of quantification (LOQ), linearity, accuracy, precision, carry-over, matrix effects, recovery, and process efficiency. Linearity ranged from 25 to 20 000 pg mg hair and from 50 to 20 000 pg mg nails, and the lowest calibration point achieved the requirements for the LOQ (25 pg mg for hair and 50 pg mg for nails). Although it was not the main focus of the article, the reliability of the method was proven through successful participation in a proficiency test, and by investigation of authentic hair and nail samples from self-reported drug users. In the future, the method should allow comparison between the two matrices to acquire an in-depth knowledge of nail analysis and to define cutoff levels for nail analysis, as they exist for hair.
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http://dx.doi.org/10.1016/j.aca.2017.01.022DOI Listing
April 2017

Hair ethyl glucuronide concentrations in teetotalers: Should we re-evaluate the lower cut-off?

Forensic Sci Int 2017 May 14;274:107-108. Epub 2016 Nov 14.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium; Toxicology and TDM Laboratory, ZNA Stuivenberg, Antwerp, Belgium.

Aims: Ethyl glucuronide in hair (hEtG) can be used to assess the retrospective consumption of alcohol. A lower cut-off of 7pg/mg hair in the 0-3cm proximal scalp hair segment has been used for repeated alcohol consumption in the previous three months. While a concentration below this cut-off is stated not to contradict self reported abstinence, it is often used to assess whether an individual has remained abstinent in the period prior to hair sampling. Here, we address hEtG concentrations in alcohol consuming individuals and critically evaluate this cut-off value.

Methods: Ten individuals remained abstinent from alcohol for 12 weeks. A lock of hair was cut before the start of the study, and the regrown hairs were cut after twelve weeks of abstinence. Hair EtG concentrations were measured both at baseline and after 12 weeks of abstinence. Study compliance was assessed by urine analysis every 2-3 days by liquid chromatography-tandem mass spectrometry with a lower limit of quantification (LLOQ) of 0.1μg/mL. HEtG concentrations were assessed in the first 3cm hair using gas chromatography-tandem mass spectrometry with an LLOQ of 0.2pg/mg.

Results: At the beginning of the study, participants had hEtG concentrations ranging between
Discussion: In participants consuming no alcohol, all but one had low, but measurable hEtG concentrations (up to 4.5pg/mg hair), which was in the participant with the highest pre-study alcohol consumption. As only regrown hairs were cut, it is not likely that this was due to residual EtG from the pre-study period.

Conclusions: Although the number of specimens was low, this study reports measurable hEtG concentrations following total abstinence, although not exceeding the current 7pg/mg cut-off for hair. A suitable sensitive method (GC-MS/MS) is preferred when assessing alcohol abstinence. We propose that the current cut-off of 7pg/mg should be discussed further, and, in view of the small study sample, evaluated using a larger sample size.
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http://dx.doi.org/10.1016/j.forsciint.2016.11.008DOI Listing
May 2017

Influence of Body Mass Index on Hair Ethyl Glucuronide Concentrations.

Alcohol Alcohol 2017 Jan 20;52(1):19-23. Epub 2016 Oct 20.

Laboratoire National de Santé, Service de Toxicologie, Dudelange, Luxembourg.

Aim: Analysis of ethyl glucuronide (EtG) concentrations in hair is increasingly used to estimate the consumption of alcohol of the prior months. Linear correlations between the amount of alcohol consumed and the concentration of EtG in hair have been reported, and several variables that may influence this correlation have been investigated: e.g. cosmetic hair treatments, gender influences or hair color. Here, we investigate the influence of body mass index (BMI) on this correlation.

Methods: A post hoc analysis on the influence of BMI on the relation between amounts of alcohol consumed and the measured EtG concentrations in hair in 199 participants.

Results: Our data show higher EtG concentrations in participants with high BMI (≥25) compared to participants with low BMI (<25) (P = 0.001) across a wide range of amounts of alcohol consumed.

Conclusions: We conclude that BMI should be taken into account when interpreting hair EtG concentrations.

Short Summary: Ethyl glucuronide concentrations in hair (hEtG) can be used to estimate the consumption of alcohol of the prior months. Body mass index (BMI) influences this relation and BMI should be taken into account when interpreting hEtG concentrations in participants with high BMI (≥25) compared to participants with low BMI (<25).
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http://dx.doi.org/10.1093/alcalc/agw079DOI Listing
January 2017

Persistence and Subtype Stability of ADHD Among Substance Use Disorder Treatment Seekers.

J Atten Disord 2019 Oct 27;23(12):1438-1453. Epub 2016 Feb 27.

24 University of Haifa, Israel.

To examine ADHD symptom persistence and subtype stability among substance use disorder (SUD) treatment seekers. In all, 1,276 adult SUD treatment seekers were assessed for childhood and adult ADHD using Conners' Adult ADHD Diagnostic Interview for (4th ed.; ; CAADID). A total of 290 (22.7%) participants met CAADID criteria for childhood ADHD and comprise the current study sample. Childhood ADHD persisted into adulthood in 72.8% ( = 211) of cases. ADHD persistence was significantly associated with a family history of ADHD, and the presence of conduct disorder and antisocial personality disorder. The combined subtype was the most stable into adulthood (78.6%) and this stability was significantly associated with conduct disorder and past treatment of ADHD. ADHD is highly prevalent and persistent among SUD treatment seekers and is associated with the more severe phenotype that is also less likely to remit. Routine screening and follow-up assessment for ADHD is indicated to enhance treatment management and outcomes.
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http://dx.doi.org/10.1177/1087054716629217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002258PMC
October 2019

Hair ethyl glucuronide and serum carbohydrate deficient transferrin for the assessment of relapse in alcohol-dependent patients.

Clin Biochem 2016 May 3;49(7-8):554-9. Epub 2016 Feb 3.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium; Toxicology and TDM Laboratory, ZNA Stuivenberg Hospital, Antwerp, Belgium.

Objectives: Ethyl glucuronide in hair (hEtG) and serum carbohydrate deficient transferrin (%CDT) are valuable markers for alcohol abuse, but their diagnostic accuracy to monitor abstinence and relapse is unclear. Here, we investigate to what extent repeated measurements of hEtG and %CDT can be used to monitor relapse in alcohol-dependent patients during abstinence treatment.

Design And Methods: HEtG and %CDT were measured in individuals starting treatment for alcohol dependence both at treatment entry and 3months later. Alcohol consumption and relapse episodes were recorded using the Time Line Follow Back and by alcohol breath and urine tests, and correlated with hEtG and %CDT measurements.

Results: Fifteen patients completed the study, of which nine had one or more relapses. Hair EtG and serum %CDT identified whether a relapse occurred in 78% and 57% of cases, respectively. Only hEtG correlated with the amount of alcohol consumed before treatment entry (Pearson r=0.92; p<0.001). The specificity of %CDT to assess abstinence during treatment was 100%. HEtG had a specificity of only 17%; however, in all patients who remained abstinent, hEtG decreased with >85% from initial values. Mean hEtG, but not %CDT, differed significantly between patients who relapsed and patients who remained abstinent (p=0.034).

Conclusions: HEtG was more sensitive than serum %CDT to assess relapse in alcohol-dependent patients and was positively correlated with the amounts of alcohol consumed. In contrast, serum %CDT was more specific for assessing abstinence. We highlight the benefit of repeated measurements of hEtG and serum %CDT for monitoring abstinence during treatment.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.11.023DOI Listing
May 2016

Kinetic modeling and long-term test-retest reproducibility of the mGluR5 PET tracer 18F-FPEB in human brain.

Synapse 2016 Apr 8;70(4):153-62. Epub 2016 Feb 8.

Division of Nuclear Medicine, KU Leuven - University of Leuven and University Hospital Leuven, Herestraat 49, Leuven, 3000, Belgium.

(18)F-FPEB is a promising PET tracer for studying the metabotropic glutamate subtype 5 receptor (mGluR5) expression in neuropsychiatric disorders. To assess the potential of (18)F-FPEB for longitudinal mGluR5 evaluation in patient studies, we evaluated the long-term test-retest reproducibility using various kinetic models in the human brain. Nine healthy volunteers underwent consecutive scans separated by a 6-month period. Dynamic PET was combined with arterial sampling and radiometabolite analysis. Total distribution volume (V(T)) and nondisplaceable binding potential (BP(ND)) were derived from a two-tissue compartment model without constraints (2TCM) and with constraining the K(1)/k(2) ratio to the value of either cerebellum (2TCM-CBL) or pons (2TCM-PONS). The effect of fitting different functions to the tracer parent fractions and reducing scan duration were assessed. Regional absolute test-retest variability (aTRV), coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were computed. The 2TCM-CBL showed best fits. The mean 6-month aTRV of V(T) ranged from 8 to 13% (CR < 25%) with ICC > 0.6 for all kinetic models. BPND from 2TCM-CBL with a sigmoid fit for the parent fractions showed the best reproducibility, with aTRV ≤ 7% (CR < 16%) and ICC > 0.9 in most regions. Reducing the scan duration from 90 to 60 min did not affect reproducibility. These results demonstrate for the first time that (18)F-FPEB brain PET has good long-term reproducibility, therefore validating its use to monitor mGluR5 expression in longitudinal clinical studies. We suggest a 2TCM-CBL with fitting a sigmoid function to the parent fractions to be optimal for this tracer.
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http://dx.doi.org/10.1002/syn.21890DOI Listing
April 2016

Ethyl glucuronide concentrations in hair: a controlled alcohol-dosing study in healthy volunteers.

Anal Bioanal Chem 2016 Mar 9;408(8):2019-25. Epub 2015 Nov 9.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium.

Ethyl glucuronide (EtG) is a minor phase II metabolite of alcohol that accumulates in hair. It has been established as a sensitive marker to assess the retrospective consumption of alcohol over recent months using a cut-off of ≥7 pg/mg hair to assess repeated alcohol consumption. The primary aim was to assess whether amounts of alcohol consumed correlated with EtG concentrations in hair. Additionally, we investigated whether the current applied cut-off value of 7 pg/mg hair was adequate to assess the regular consumption of low-to-moderate amounts of alcohol. A prospective controlled alcohol-dosing study in 30 healthy individuals matched on age and gender. Individuals were instructed to drink no alcohol (N = 10), 100 g alcohol per week (N = 10) or 150 g alcohol per week (N = 10) for 12 consecutive weeks, before and after which hair was collected. Throughout the study, compliance to daily alcohol consumption was assessed by analyzing urine EtG three times weekly. Participants in the non-drinking group had median EtG concentrations of 0.5 pg/mg hair (interquartile range (IQR) 1.7 pg/mg; range < 0.21-4.5 pg/mg). Participants consuming 100 and 150 g alcohol per week showed median EtG concentrations of 5.6 pg/mg hair (IQR 4.7 pg/mg; range 2.0-9.8 pg/mg) and 11.3 pg/mg hair (IQR 5.0 pg/mg; range 7.7-38.9 pg/mg), respectively. Hair EtG concentrations between the three study groups differed significantly from one another (p < 0.001). Hair EtG concentrations can be used to differentiate between repeated (low-to-moderate) amounts of alcohol consumed over a long time period. For the assessment of repeated alcohol use, we propose that the current cut-off of 7 pg/mg could be re-evaluated.
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http://dx.doi.org/10.1007/s00216-015-9117-0DOI Listing
March 2016

Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users.

Hum Brain Mapp 2015 Oct 28;36(10):4222-30. Epub 2015 Jul 28.

Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objectives: Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT).

Experimental Design: Amygdala activity and amygdala connectivity during the EFMT were assessed in 51 cocaine using males and 32 non-drug-using healthy males using functional magnetic resonance imaging (fMRI). Within the cocaine use group, we explored whether amygdala activation was associated with age of first use of cocaine and duration of cocaine use to distinguish between amygdala activation alterations as a cause or a consequence of cocaine use.

Principal Observations: We observed hyperactivity of the amygdala, thalamus, and hippocampus and reduced amygdala connectivity with the anterior cingulate gyrus in response to angry and fearful facial expressions in current cocaine users compared to controls. Increased amygdala activation was independently associated with earlier age of first cocaine use and with longer exposure to cocaine.

Conclusions: Our findings suggest that amygdala hyperactivity to biologically salient stimuli may represent a risk factor for an early onset of cocaine use and that prolonged cocaine use may further sensitize amygdala activation. High amygdala activation to emotional face processing in current cocaine users may result from low prefrontal control of the amygdala response to such stimuli.
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http://dx.doi.org/10.1002/hbm.22913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869379PMC
October 2015
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