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SUPPLEMENTAL INFORMATION Gender-related neuroanatomical differences in alcohol dependence: findings from the ENIGMA Addiction Working GroupMaria Gloria Rossetti a,b, Praveetha Patalay c, Scott Mackey d, Nicholas B. Allen e, Albert Batalla f, Marcella Bellani a, Yann Ying Chye g, Janna Cousijn h, Anna E. Goudriaan i, Robert Hester j, Kent Hutchison k, Chiang-Shan R. Li l, Rocio Martin-Santos m, Reza Momenan n, Rajita Sinha o, Lianne Schmaal p,q, Zsuzsika Sjoerds r, Nadia Solowij s, Chao Suo g, Ruth J. van Holst i, Dick Veltman t, Murat Yücel g, Paul M. Thompson u, Patricia Conrod v, Hugh Garavan d, Paolo Brambilla b,w, Valentina Lorenzetti xa Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italyb Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italyc Centre for Longitudinal Studies and MRC Unit for Lifelong Health and Ageing, IOE and Population Health Sciences, UCL, United Kingdomd Department of Psychiatry, University of Vermont, Burlington, VT, USAe Department of Psychology, University of Oregon, Eugene, Oregon, USAf Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlandsg BrainPark, Turner Institute for Brain and Mental Health, School of Psychological Sciences, & Monash Biomedical imaging Facility, Monash University, Melbourne, Australia h Department of Developmental Psychology, University of Amsterdam, Amsterdam, The NetherlandsI Department of Psychiatry, Amsterdam Institute for Addiction Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlandsj School of Psychological Sciences, University of Melbourne, Melbourne, Australiak Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USAl Department of Psychiatry and Psychology, Hospital Clinic, IDIBAPS, CIBERSAM and Institute of Neuroscience, University of Barcelona, Spainm Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USAn Clinical NeuroImaging Research Core, Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USAo Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USAp Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Australiaq Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australiar Institute of Psychology & Leiden Institute for Brain & Cognition, Leiden University, Leiden, Netherlandss School of Psychology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australiat Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlandsu Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USAv Department of Psychiatry, Universite de Montreal, CHU Ste Justine Hospital, Montreal, Canadaw Department of Pathophysiology and Transplantation, University of Milan, Milan, Italyx Neuroscience of Addiciotn and Mental Health Program, Healthy Brain and Mind Research Centre, School of Behavioral and Health Sciences, Australian Catholic University, Fitzroy VIC AustraliaCorresponding author:Valentina Lorenzetti, PhDSchool of Behavioural and Health Sciences, Australian Catholic University, Daniel Mannix Building, Fitzroy, VIC 3065, AustraliaTel: +61 03 9230 8088Email: valentina.lorenzetti@Deviations from the pre-registered study protocol A few changes were made to the study protocol after the Open Science Framework pre-registration ()1. Number of a-priori Regions of Interest (ROIs)The pre-registered study protocol included the following ROIs: hippocampus, amygdala, thalamus, nucleus accumbens, putamen, caudate, globus pallidus, cerebellum (grey matter and white matter) (left and right), corpus callosum (anterior, middle anterior, central, middle posterior, posterior), total grey matter, total white matter and CSF. However, we summed the five subregions of the corpus callosum in a single ROI as previous evidence showed a consistent pattern of volume differences across the callosal subregions of alcohol-dependent individuals versus controls (25). Moreover, we included two bilateral ROIs i.e., medial OFC and lateral OFC; as those were consistently found altered in people with alcohol dependence versus controls (26-27). 2. Sample SizeThe final sample included 660 rather than 683 people with alcohol dependence as a deeper data quality check was made after the preregistration and 23 additional alcohol-dependent subjects were excluded due to psychiatric comorbidities.3. AnalysisModel 2 aimed at exploring whether monthly standard drinks predicted ROIs volume, separately in men and women with alcohol dependence. However, two additional models, not reported in the preregistration , were run within the alcohol dependent group to have a comprehensive picture of the association between gender, monthly standard drinks and brain volumes. The first model explored the impact of factors including gender and standard drinks on brain volumes; the second included a gender-by-monthly standard drinks interaction term and aimed at exploring whether drinking amount was more strongly related to the volume of men or women. The latter was suggested by reviewers during peer review process.Table S1. Assessment instruments by imaging site Site 1 Site 2 Site 3Site 4Site 5Site 6Site 7Site 8Site 9Site 10N442186129352625240291838PIHutchison ADDIN EN.CITE <EndNote><Cite><Author>Thayer</Author><Year>2016</Year><RecNum>172</RecNum><DisplayText>[1]</DisplayText><record><rec-number>172</rec-number><foreign-keys><key app="EN" db-id="vr0fa5fxb052axerd06xxreisf0az5tvzafp" timestamp="1585232403">172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thayer, Rachel E</author><author>Hagerty, Sarah L</author><author>Sabbineni, Amithrupa</author><author>Claus, Eric D</author><author>Hutchison, Kent E</author><author>Weiland, Barbara J</author></authors></contributors><titles><title>Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry</title><secondary-title>Human brain mapping</secondary-title></titles><periodical><full-title>Human brain mapping</full-title></periodical><pages>2276-2292</pages><volume>37</volume><number>6</number><dates><year>2016</year></dates><isbn>1065-9471</isbn><urls></urls></record></Cite></EndNote>(1 )Hutchison ADDIN EN.CITE <EndNote><Cite><Author>Claus</Author><Year>2011</Year><RecNum>173</RecNum><DisplayText>[2]</DisplayText><record><rec-number>173</rec-number><foreign-keys><key app="EN" db-id="vr0fa5fxb052axerd06xxreisf0az5tvzafp" timestamp="1585235163">173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Claus, Eric D.</author><author>Ewing, Sarah W. Feldstein</author><author>Filbey, Francesca M.</author><author>Sabbineni, Amithrupa</author><author>Hutchison, Kent E.</author></authors></contributors><titles><title>Identifying neurobiological phenotypes associated with alcohol use disorder severity</title><secondary-title>Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology</secondary-title><alt-title>Neuropsychopharmacology</alt-title></titles><alt-periodical><full-title>Neuropsychopharmacology</full-title></alt-periodical><pages>2086-2096</pages><volume>36</volume><number>10</number><edition>2011/06/15</edition><keywords><keyword>Adult</keyword><keyword>Alcoholism/*genetics/*metabolism/psychology</keyword><keyword>Brain Chemistry/drug effects/genetics</keyword><keyword>Ethanol/*administration & dosage</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Phenotype</keyword><keyword>Risk</keyword><keyword>*Severity of Illness Index</keyword><keyword>Surveys and Questionnaires</keyword><keyword>Young Adult</keyword></keywords><dates><year>2011</year></dates><publisher>Nature Publishing Group</publisher><isbn>1740-634X
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ADDIN EN.CITE.DATA (21-24)Study nameETOHOlanzapineIRCNIAAANESDA-ADADPG study Cannabis Prospective Chronic cannabis users (Barcelona)Chronic CannabisChronic Cannabis- MemoryLocationInclusion criteria(Alcohol dependent)Alcohol dependence (DSM-IV; APA, 1994)>/= 5 drinks/ per occasion (men) >/= 4 drinks/ per occasion (women)>/= five times in the past month.Alcohol dependence (DSM-IV; APA, 1994)Alcohol dependence (DSM-IV; APA, 1994)Alcohol dependence (DSM-IV; APA, 1994)Alcohol abuse or dependence, alcohol abstinence >/= 2 weeks----Exclusion criteria (Alcohol dependent and control)Axis I psychiatric disordersSCIDSCID SCIDSCIDMINI plusCIDIMINIPRISM, medical historySCIDSCID, medical historyUrine toxicology (MRI day)Positive screensPositive screensPositive screensPositive screensPositive screensPositive screensPositive screens (alcohol, illicit)Positive screens (alcohol, illicit)Positive screens (alcohol, illicit)Positive screens (alcohol, illicit)Breath test(MRI day)PositivePositivePositivePositivePositive-----General MRI contraindicationOther substances, Current abuse or dependence--Use of psychoactive medication-----OthersSevere alcohol withdrawalSevere alcohol withdrawal IQ < 80- Use of psychoactive medication - age< 18 years, - IQ < 80Left-handedness, femaleLeft-handedness Scanner parameters, MRI scansVoxel size, mm31x1x11x1x11x1x10.9x0.9x1-1.51x1x11x1x11x1x1.21.17x1.17x1.21x1x1.11x1x1.1MR sequenceMPREAGEMPREAGEMPREAGEMPREAGEGradient EchoGradient EchoTurbo Field EchoFast Spoiled Gradient Inversion-RecoverySpoiled Gradient Recalled EchoMPREAGEEcho5-echo multi-echo5-echo multi-echoTR, ms 2350235023504.5-7.8999.611.86.41900TE, ms 1.64, 3.5, 5.36, 7.22 & 9.081.64, 3.5, 5.36, 7.22 & 9.083.34, 12.2-3.13.63.64.64.22.92.15Flip angle 7°7°7°6°8°8°8°15°8°12°Martrix256x256x176256x256x176256x256x176256x256x176256x231x170256x256x170256x256x182256x256x124256x256x180256x256x176Manufacturer, model3.0T Siemens Trio3.0T Siemens Trio3.0T Siemens Trio1.5 T GE magnet3.0T Phillips Intera3.0T Phillips Intera3.0T Phillips Intera1.5 T Signa Excite system3.0T Phillips Intera3.0T Siemens TrioHead coil12-channel radio frequency coil12-channel radio frequency coilsingle‐channel, standard‐quadrature coil12-channel radio frequency coileight-channel radio frequency coileight-channel radio frequency coileight-channel radio frequency coil eight-channel radio frequency coileight-channel radio frequency coil32-channel radio frequency coilTreatment seekingoutpatients (with & without treatment seeking)outpatients (with & without treatment seeking)inpatientsinpatientsoutpatientsoutpatients (treatment seeking) ----Substance use measuresPre-MRI abstinence24 h 24 h 11-17 days (mean:15 days)24 h 24 h ≥ 15 days (mean:18 days)Severity of AUDAUDIT, TLFBAUDITTLFBAUDITAUDITStandard drinks/month, NCigarettes/month, N-AUD =Alcohol use disorder; SCID = Structured Clinical Interview for DSM Disorders (Spitzer et al. 1994; First et al. 2001); MINI = Mini Neuropsychiatry International Interview (Lecrubier et al. 1997; Sheehan et al. 1997; Swift et al. 1998); Inter- national Diagnostic interview (CIDI; Robins et al. 1988); PRISM = Psychiatric Research Interview for Substance and Mental Disorders (, Hasin et al. 1996); AUDIT = Alcohol Use Disorders Identification Test (Saunders et al. 1993); TLFB = Time-line Follow-back (Sobell and Sobell, 1992). StDr= standard drinks; Cig= cigarettes; mo=monthTable S2. Participants’ demographic and substance use characteristics, by imaging site Site 1 Site 2 Site 3Site 4Site 5Site 6Site 7Site 8Site 9Site 10Men/Women229/13899/5687/2990/4436/2535/025/1525/016/217/18Age28.64 (8.13); 21-5539.68 (6.8); 22-5630.49 (8.17); 18-5034.23 (9.87); 21-5948.25 (9.14); 24-6838.8 (10.81); 21-5721.85 (2.38); 18-2622.08 (3.43); 18-2935.00 (10.07); 21-5130.34 (11.48); 18-55Education14.56 (2.33); 5-2213.55 (2.05); 8-2015.34 (2.56); 11-2615.41 (2.87); 5-2413.48 (3.55); 6.2314.43 (4.40); 7-2415.03 (2.02); 11-2012.92 (2.36); 8-1815 (3.51); 10-2514.08 (1.72); 11-29Alcohol use, StDr/mo78.81 (66.59); 13-466175.27 (110.23); 0-624125.94 (201.32); 0-840365.94 (226.70); 24-87162.93 (50.80); 0-160411.2 (365.77); 48-93021.28 (26.49); 0-96 13.00 (11.00); 0-4023.39 (22.48); 0-7022.14 (25.45); 1-100Tobacco use, Cig/mo81.68 (161.00); 0-865162.52 (237.97); 0-1200359.61 (277.19); 0-1120284.54 (174.65); 8-600208.03 (302.48); 0-930-44.86 (109.77); 0-45627.00 (114.90); 0-54027.81 (103.52); 0-41529.9 (82.94); 0-455Cig = cigarettes, mo = monthly, StDr = standard drink. Values for age, education, alcohol use and tobacco use are mean (SD), range.Figure S1: Distribution of monthly standard drinks values before (figure A) and after (figure B) the square root transformation Supplemental methods and resultsSensitivity analysis in a subsample matched by alcohol use A sensitivity analysis was run on a subsample where men and women with alcohol dependence were matched by monthly standard drinks (Table S3). First, we matched the amount of monthly standard drinks between alcohol dependent men and women (β= 0.55, p= .945) by means the STATA package “psmatch2” for propensity score matching (25). Second, we replicated the analyses to explore i) the impact of group, gender and group-by-gender on the volume of a-priori ROIs of people with alcohol dependence versus controls (Table 4 and 5) and ii) the association between gender and monthly standard drinks and brain volumes of those ROIs that demonstrated significant group-by-gender effects (alcohol-dependent group only) (Table 7). Table S3. Demographic and substance use characteristics of the sensitivity subsample where men and women with alcohol dependence were matched by monthly standard drinks ControlsAlcohol dependentGroup(Alcohol dependent vs controls)Gender(Men vs Women)Group-by-GenderSite§MenWomenMenWomenβ (95% CI)pβ (95% CI)Pβ (95% CI)pVarGender, N (%)227 (69.63)99 (30.28)298 (56.65)228 (43.35)-------Age?30.44 (10.57); 18-6829.76 (10.15); 18-5832.89 (10.29); 21-6632.78 (10.55); 18-625.30 (2.56-8.06)<.001**0.84 (-1.25, 2.93).4310.14 (-2.40, 2.69).914.41Education15.14 (2.95)15.63 (2.86)14.11 (2.47)14.35 (2.55)-1.1 (-2.51, -0.90)<.001**-0.26 (-0.90, 0.38).427-0.09 (-0.87, 0.69).824.11Alcohol use, StDr/mo28.66 (30.15)17.51 (22.05)111.26 (103.91)107.08 (107.31)135.58 (103.89, 167.26)<.001**11.85 (-11.64, 35.34).323-11.29 (-39.52, 16.92).433.25Tobacco use, Cig/mo25.07 (91.27)42.85 (101.39)155.22 (226.31)141.96 (232.88)244.02 (152.56, 335.49)<.001**-19.46 (-92.62, 53.71).60229.47 (-53.33, 112.26).485.17Note: Cig = cigarettes, mo = monthly, StDr = standard drink, Var = variance. Differences in gender distribution measured with chi2 test (χ2=14.33, p <.001). Values for education, alcohol use and tobacco use are mean (sd); values for age are mean (sd), range. § Site-level variation estimated as an intraclass correlation (ICC). * p <.05 **p <.001Sensitivity analyses in a subsample with tobacco use dataAdditional analyses were run on a subsample with tobacco use (i.e. monthly cigarettes) data, including 465 subjects with alcohol dependence (173 women) and 140 controls (40 women) to check if group, gender, group-by-gender effects observed in the original sample may have been influenced by tobacco use. Specifically, we replicate the analysis twice, with and without monthly cigarettes among the confounders. We found that tobacco use (presence vs absence) did not significantly affect the results (Table S4). Table S4. Group, gender and group-by-gender effects in a subsample of alcohol dependent (n= 465) and control (n= 140) participants with tobacco use dataMixed effect model accounting for age, education, ICVMixed effect model accounting for age, education, ICV, monthly cigarettesGroup (Alcohol dependent vs Control)Gender (Men vs Women)Group-by-GenderSite§Group (Alcohol dependent vs Control)Gender (Men vs Women)Group-by-GenderSite§β (95% CI)pβ (95% CI)pβ (95% CI)pVarβ (95% CI)pβ (95% CI)pβ (95% CI)pVarBrain regionOFC medialL-48.94 (-326.56, 228.67).73018.72 (-204.79, 242.22).870-6.41 (-245.45, 232.64).958.31-17.46829 (-298.65, 263.72).90312.68 (-210.55, 235.91).911-0.07 (-238.83, 238.70)1.00.32R-164.64 (-430.92, 101.63).226-15.027 (-230.15, 200.10).89110.70 (-219.42, 240.82).927.29-135.80 (-405.55, 133.95).324-19.19 (-234.13 195.76).89615.29 (-214.66, 245.25).896.30lateralL-276.29 (-616.18, 63.59).111103.69 (-167.69, 375.07).454-221.89 (-512.04, 68.25).134.36-275.71 (-619.52, 68.09).116103.60 (-167.87, 375.07).454-221.80 (-512.10, 68.50.134.36R-290.23 (-652.74, 72.28).1173.01 (-286.37, 292.40).984-110.69 (-420.08, 198.70).483.36-277.70 (-644.52, 89.12).1380.96 (-288.48, 290.40).995-108.26 (-417.76, 201.24).493.36HippocampusL-117.12 (-324.68, 90.44).269165.64 (-5.91, 337.19).058-164.84 (-348.50, 18.83).079.21-100.96 (-311.25, 109.34).347163.54 (-7.97, 335.04).062-161.99 (-345.65, 21.67).084.21R-178.66 (-384.86, 27.53).089104.42 (-68.04, 276.87).235-73.21 (-257.97, 111.54).437.17-148.76 (-358.07, 60.54).164100.18 (-72.02, 272.38).254-67.86 (-252.36 116.64).471.18AmygdalaL-5.54 (-110.12, 99.05).91798.65 (15.43, 181.86).020*-62.67 (-151.61, 26.27).167.3911.79 (-93.70, 117.28).82796.35 (13.41, 179.29).023*-59.72 (-148.37, 28.93).187.40R-10.77 (-114.88, 93.33).839123.65 (41.27, 206.03).003-105.78 (-193.81, -7.76).019*.442.41 (-102.74, 107.57).964121.76 (39.54, 203.99).004*-103.59 (-191.46, -15.72).021*.45Nucleus accumbensL6.79 (-49.69, 63.28).81432.88 (-11.14, 76.90).143-22.86 (-69.87, 24.15).341.636.88 (-50.21, 63.97).81332.86 (-11.17, 76.90).144-22.84 (-69.88, 24.19).341.63R-12.13 (-66.36, 42.10).66135.30 (-7.21, 77.81).104-26.45 (-71.86, 18.96).254.54-12.43 (-67.25, 42.40).65735.34 (-7.19, 77.87).103-26.50 (-71.93, 18.93).253.54Caudate L24.01 (-176.20, 224.21).814-4.306 (-165.37, 156.76).958-37.81 (-210.03, 134.40).667.3226.41 (-176.18, 229.00).798-4.73 (-165.84, 156.39).954-37.37 (-209.68, 134.94).671.32R23.39 (-195.56, 242.34).8342.843 (-169.76, 175.45).974-40.07 (-224.47, 144.34).670.4725.76 (-195.64, 247.15).8202.45 (-170.21, 175.11).978-39.63 (-224.13, 144.86).674.47PutamenL-89.98 (-439.10, 259.14).613195.87 (-80.93, 472.68).165-4.71 (-300.51, 291.09).975.42-88.55 (-441.62, 264.51).623195.65 (-81.25, 472.54).166-4.45 (-300.40, 291.50).977.42R-39.64 (-352.45, 273.16).804190.10 (-56.61, 436.82).13116.99 (-246.60, 280.58).899.47-53.75 (-369.85 262.35).739192.24 (-54.50, 438.97).12714.51 (-249.15, 278.17).914.47Globus PallidusL-10.83 (-131.47, 109.81).86021.76 (-75.58, 119.09).66190.47 (-13.62, 194.56).088.30-10.97 (-133.02, 111.08).86021.78 (-75.59, 119.15).66190.44 (-13.71, 194.59.089.30R60.73 (-38.31, 159.76).22957.03 (-23.05, 137.12).163-5.01 (-90.66, 80.64).909.2962.49 (-37.76, 162.74).22256.76 (-23.34, 136.87).165-4.73 (-90.42, 80.96).914.29ThalamusL218.48 (-162.48, 599.44).261378.87 (78.041, 679.71).014*-383.20 (-704.63, -61.78).019*.46256.07 (-128.80, 640.94).192373.99 (73.47, 674.51).015*-376.81 (-697.95, -55.67).021*.46R-102.03 (-420.10, 216.03).530260.91 (5.25, 516.56).045*-24.92 (-298.27, 248.43).858.32-97.63 (-419.44, 224.19).552260.30 (4.57, 516.04).046*-24.15 (-297.64 249.34).863.32Corpus Callosum50.56 (-193.26, 294.38).68437.37 (-166.72, 241.45).720-159.37 (-378.10, 59.36).153.1766.76 (-180.04, 313.56).59635.48 (-168.55, 239.51).733-156.18 (-374.93, 62.57).162.17CerebellumGML-1410.34 (-4002.99, 1182.31).2861716.45 (-308.84, 3741.74).097-2358.58 (-4522.02 -195.13).033*.58-1158.10 (-3775.25, 1459.05).3861679.90 (-343.36, 3703.16).104-2313.56 (-4475.12, -152.00).036*.57R-811.52 (-3439.07, 1816.02).5451648.08 (-400.24, 3696.40).115-2066.93 (-4254.81, 120.96).064*.61-634.26 (-3288.50, 2019.98).6401622.31 (-425.43, 3670.05).120-2035.36 (-4222.89, 152.17).068.605WML-378.87 (-1540.95, 783.21).523-1140.76 (-2061.49 -220.03).015*302.18 (-681.89, 1286.26).547.42-219.86 (-1391.56, 951.84).713-1162.92 (-2081.56, -244.29).013*330.708 (-651.31, 1312.73).509.41R-257.33(-1478.83, 964.16).680-851.11 (-1816.89, 114.68).08457.064 (-975.08, 1089.20).914.44-97.60 (-1329.25, 1134.06).877-873.66 (-1837.45, 90.14).07685.58 (-944.63, 1115.79).871.43Total GM-5633.20 (-22025.37 10758.98).50116142.13 (3252.28 29031.99).014*-20805.16 (-34577.68 -7032.64).003*.49-2712.52 (-19237.68 13812.64).74815729.1 (2889.51, 28568.69).016*-20323.75 (-34043.83 -6603.67).004*.51Total WM-1381.80 (-20990.41, 18226.81).89013577.52 (-1723.98, 28879.03).082-17184.51 (-33529.2 -839.81).039*.59-327.04 (-20144.52, 19490.45).97413414.28 (-1885.09, 28713.65).086-17002.44 (-33346.7 -658.18).041*.59CSF29.08 (-73.26, 131.42).578-42.52 (-127.62, 42.58).32759.65 (-31.52, 150.82).200.1931.86 (-71.86, 135.57).547-42.77 (-127.89, 42.36).32560.01 (-31.21, 151.23).197.19β = beta, CI = confidence interval, CSF = Cerebrospinal fluid, GM = grey matter, L = left, OFC = orbitofrontal cortex, R = right, Var = variance, WM = white matter.§ Site-level variation estimated as an intraclass correlation (ICC). * p(uncorrected) < .05References ADDIN EN.REFLIST 1.Thayer RE, Hagerty SL, Sabbineni A, Claus ED, Hutchison KE, Weiland BJ. Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry. Human brain mapping 2016; 37(6): 2276-2292.2.Claus ED, Ewing SWF, Filbey FM, Sabbineni A, Hutchison KE. Identifying neurobiological phenotypes associated with alcohol use disorder severity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2011; 36(10): 2086-2096.3.Sinha R, Sinha R, Li CSR, Sinha R, Li CSR. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug and Alcohol Review 2007; 26(1): 25-31.4.Li C-sR, Luo X, Yan P, Bergquist K, Sinha R. Altered Impulse Control in Alcohol Dependence: Neural Measures of Stop Signal Performance. Alcoholism: Clinical and Experimental Research 2009; 33(4): 740-750.5.Seo D, Jia Z, Lacadie CM, Tsou KA, Bergquist K, Sinha R. Sex differences in neural responses to stress and alcohol context cues. Human brain mapping 2011; 32(11): 1998-2013.6.Senatorov VV, Damadzic R, Mann CL, Schwandt ML, George DT, Hommer DW et al. Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons. Brain 2015; 138(1): 69-79.7.Grodin EN, Lin H, Durkee CA, Hommer DW, Momenan R. Deficits in cortical, diencephalic and midbrain gray matter in alcoholism measured by VBM: Effects of co-morbid substance abuse. NeuroImage: Clinical 2013; 2: 469-476.8.Momenan R, Steckler LE, Saad ZS, van Rafelghem S, Kerich MJ, Hommer DW. Effects of alcohol dependence on cortical thickness as determined by magnetic resonance imaging. Psychiatry Research: Neuroimaging 2012; 204(2-3): 101-111.9.Sjoerds Z, Van Den Brink W, Beekman A, Penninx B, Veltman D. Response inhibition in alcohol-dependent patients and patients with depression/anxiety: a functional magnetic resonance imaging study. Psychological medicine 2014; 44(8): 1713-1725.10.Jansen JM, van Holst RJ, van den Brink W, Veltman DJ, Caan MW, Goudriaan AE. Brain function during cognitive flexibility and white matter integrity in alcohol‐dependent patients, problematic drinkers and healthy controls. Addiction biology 2015; 20(5): 979-989.11.van Holst RJ, Clark L, Veltman DJ, van den Brink W, Goudriaan AE. Enhanced striatal responses during expectancy coding in alcohol dependence. Drug and alcohol dependence 2014; 142: 204-208.12.Cousijn J, Wiers RW, Ridderinkhof KR, van den Brink W, Veltman DJ, Goudriaan AE. Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls. Neuroimage 2012; 59(4): 3845-3851.13.Cousijn J, Goudriaan AE, Ridderinkhof KR, van den Brink W, Veltman DJ, Wiers RW. Neural responses associated with cue‐reactivity in frequent cannabis users. Addiction biology 2013; 18(3): 570-580.14.Blanco‐Hinojo L, Pujol J, Harrison BJ, Macià D, Batalla A, Nogué S et al. Attenuated frontal and sensory inputs to the basal ganglia in cannabis users. Addiction biology 2017; 22(4): 1036-1047.15.Pujol J, Blanco-Hinojo L, Batalla A, López-Solà M, Harrison BJ, Soriano-Mas C et al. Functional connectivity alterations in brain networks relevant to self-awareness in chronic cannabis users. Journal of psychiatric research 2014; 51: 68-78.16.Batalla A, Soriano‐Mas C, López‐Solà M, Torrens M, Crippa JA, Bhattacharyya S et al. Modulation of brain structure by catechol‐O‐methyltransferase Val158Met polymorphism in chronic cannabis users. Addiction biology 2014; 19(4): 722-732.17.Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C et al. Regional brain abnormalities associated with long-term heavy cannabis use. Archives of general psychiatry 2008; 65(6): 694-701.18.Solowij N, Yücel M, Respondek C, Whittle S, Lindsay E, Pantelis C et al. Cerebellar white-matter changes in cannabis users with and without schizophrenia. Psychological medicine 2011; 41(11): 2349-2359.19.Solowij N, Walterfang M, Lubman DI, Whittle S, Lorenzetti V, Styner M et al. Alteration to hippocampal shape in cannabis users with and without schizophrenia. Schizophrenia research 2013; 143(1): 179-184.20.Lorenzetti V, Solowij N, Whittle S, Fornito A, Lubman DI, Pantelis C et al. Gross morphological brain changes with chronic, heavy cannabis use. The British Journal of Psychiatry 2015; 206(1): 77-78.21.Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain 2012; 135(7): 2245-2255.22.Harding IH, Solowij N, Harrison BJ, Takagi M, Lorenzetti V, Lubman DI et al. Functional connectivity in brain networks underlying cognitive control in chronic cannabis users. Neuropsychopharmacology 2012; 37(8): 1923-1933.23.Jakabek D, Yücel M, Lorenzetti V, Solowij N. An MRI study of white matter tract integrity in regular cannabis users: effects of cannabis use and age. Psychopharmacology 2016; 233(19-20): 3627-3637.24.Yücel M, Lorenzetti V, Suo C, Zalesky A, Fornito A, Takagi MJ et al. Hippocampal harms, protection and recovery following regular cannabis use. Translational psychiatry 2016; 6(1): e710-e710.25.Ruiz S M, Oscar‐Berman, M, Sawyer, K S, Valmas M M, Urban T & Harris G J (2013). Drinking history associations with regional white matter volumes in alcoholic men and women.?Alcoholism: Clinical and Experimental Research,?37(1), 110-122.26.Mackey S, Allgaier N, Chaarani B, Spechler P, Orr C, Bunn J et al. Mega-analysis of gray matter volume in substance dependence: general and substance-specific regional effects. Am J Psychiatry. 2019; 176(2): 119-128.27.Zahr NM. Structural and microstructral imaging of the brain in alcohol use disorders. Handb Clin Neurol. , vol. 125. Elsevier2014, pp 275-290.28.Leuven E, and Sianesi B,. PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing (2003). Software, ................
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