Altered white matter microstructure in adolescent substance users

Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, we used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. We evaluated 36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505). MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.

[1]  T. Yokoyama,et al.  Oligodendrocyte myelin glycoprotein (OMgp) in rat hippocampus is depleted by chronic ethanol consumption , 2006, Neuroscience Letters.

[2]  C. Spielberger,et al.  Manual for the State-Trait Anxiety Inventory , 1970 .

[3]  M. J. Meloy,et al.  Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders. , 2004, Alcoholism, clinical and experimental research.

[4]  S. Tapert,et al.  Neuropsychological correlates of adolescent substance abuse: Four-year outcomes , 1999, Journal of the International Neuropsychological Society.

[5]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[6]  M. Cohen-Zion,et al.  Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry. , 2007, Neurotoxicology and teratology.

[7]  Matcheri S Keshavan,et al.  Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders. , 2005, Alcoholism, clinical and experimental research.

[8]  Vaibhav A. Diwadkar,et al.  Cannabis use and brain structural alterations in first episode schizophrenia — A region of interest, voxel based morphometric study , 2008, Schizophrenia Research.

[9]  L. Kozlowski,et al.  The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. , 1991, British journal of addiction.

[10]  G. Cabral,et al.  The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. , 1999, The Journal of pharmacology and experimental therapeutics.

[11]  Derek K. Jones,et al.  “Squashing peanuts and smashing pumpkins”: How noise distorts diffusion‐weighted MR data , 2004, Magnetic resonance in medicine.

[12]  J. Giedd.  Structural Magnetic Resonance Imaging of the Adolescent Brain , 2004, Annals of the New York Academy of Sciences.

[13]  Thomas E. Nichols,et al.  Acquisition and voxelwise analysis of multi-subject diffusion data with Tract-Based Spatial Statistics , 2007, Nature Protocols.

[14]  M. Raichle,et al.  Tracking neuronal fiber pathways in the living human brain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Vince D. Calhoun,et al.  Functional neural networks underlying response inhibition in adolescents and adults , 2007, Behavioural Brain Research.

[16]  A. Pfefferbaum,et al.  Disruption of Brain White Matter Microstructure by Excessive Intracellular and Extracellular Fluid in Alcoholism: Evidence from Diffusion Tensor Imaging , 2005, Neuropsychopharmacology.

[17]  Alan C. Evans,et al.  Brain development during childhood and adolescence: a longitudinal MRI study , 1999, Nature Neuroscience.

[18]  E. Sacanella,et al.  Atrophy of the corpus callosum in chronic alcoholism , 1997, Journal of the Neurological Sciences.

[19]  Gregory G. Brown,et al.  fMRI response to spatial working memory in adolescents with comorbid marijuana and alcohol use disorders. , 2005, Drug and alcohol dependence.

[20]  D. Pandya,et al.  Segmentation of subcomponents within the superior longitudinal fascicle in humans: a quantitative, in vivo, DT-MRI study. , 2005, Cerebral cortex.

[21]  J. Rice,et al.  Comparison of direct interview and family history diagnoses of alcohol dependence. , 1995, Alcoholism, clinical and experimental research.

[22]  S. Tapert,et al.  Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects. , 2008, Alcoholism, clinical and experimental research.

[23]  Khader M. Hasan,et al.  White matter development during late adolescence in healthy males: A cross-sectional diffusion tensor imaging study , 2007, NeuroImage.

[24]  S. Kumra,et al.  Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use. , 2009, Journal of psychiatric research.

[25]  Mark Jenkinson,et al.  Fast, automated, N‐dimensional phase‐unwrapping algorithm , 2003, Magnetic resonance in medicine.

[26]  Arthika Bappal,et al.  A preliminary DTI study showing no brain structural change associated with adolescent cannabis use , 2006, Harm reduction journal.

[27]  Philip D. Harvey,et al.  White matter changes in schizophrenia: evidence for myelin-related dysfunction. , 2003, Archives of general psychiatry.

[28]  R. Harris,et al.  Gene expression in human alcoholism: microarray analysis of frontal cortex. , 2000, Alcoholism, clinical and experimental research.

[29]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[30]  E. Sacanella,et al.  High ethanol intake and malnutrition in alcoholic cerebellar shrinkage. , 2000, QJM : monthly journal of the Association of Physicians.

[31]  B. Tabachnick,et al.  Using Multivariate Statistics , 1983 .

[32]  P. Jezzard,et al.  Correction for geometric distortion in echo planar images from B0 field variations , 1995, Magnetic resonance in medicine.

[33]  S. Tapert,et al.  Spatial working memory performance and fMRI activation interaction in abstinent adolescent marijuana users. , 2007, Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors.

[34]  Nikos Makris,et al.  Frontal white matter and cingulum diffusion tensor imaging deficits in alcoholism. , 2008, Alcoholism, clinical and experimental research.

[35]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[36]  Edith V. Sullivan,et al.  Dysmorphology and microstructural degradation of the corpus callosum: Interaction of age and alcoholism , 2006, Neurobiology of Aging.

[37]  P. Basser,et al.  Toward a quantitative assessment of diffusion anisotropy , 1996, Magnetic resonance in medicine.

[38]  P. Brachet,et al.  Δ9‐Tetrahydrocannabinol induces apoptosis in C6 glioma cells , 1998 .

[39]  A. Toga,et al.  In vivo evidence for post-adolescent brain maturation in frontal and striatal regions , 1999, Nature Neuroscience.

[40]  J. MacFall,et al.  Diffusion tensor measures of the corpus callosum in adolescents with adolescent onset alcohol use disorders. , 2008, Alcoholism, clinical and experimental research.

[41]  Babak A. Ardekani,et al.  A functional MRI study of visual oddball: evidence for frontoparietal dysfunction in subjects at risk for alcoholism , 2004, NeuroImage.

[42]  F. Rodríguez de Fonseca,et al.  Presence of cannabinoid binding sites in the brain from early postnatal ages. , 1993, Neuroreport.

[43]  B. Tabachnick,et al.  Using multivariate statistics, 5th ed. , 2007 .

[44]  T. Paus.  Mapping brain maturation and cognitive development during adolescence , 2005, Trends in Cognitive Sciences.

[45]  Thomas F. Nugent,et al.  Dynamic mapping of human cortical development during childhood through early adulthood. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D S O'Leary,et al.  Effects of frequent marijuana use on brain tissue volume and composition , 2000, Neuroreport.

[47]  S. Tapert,et al.  Depressive symptoms in adolescents: associations with white matter volume and marijuana use. , 2007, Journal of child psychology and psychiatry, and allied disciplines.

[48]  John A Matochik,et al.  Altered brain tissue composition in heavy marijuana users. , 2005, Drug and alcohol dependence.

[49]  Alan C. Evans,et al.  Structural maturation of neural pathways in children and adolescents: in vivo study. , 1999, Science.

[50]  V. Pickel,et al.  Ultrastructural Localization of the CB1 Cannabinoid Receptor in μ-Opioid Receptor Patches of the Rat Caudate Putamen Nucleus , 2001, The Journal of Neuroscience.

[51]  M. Paulus,et al.  Functional MRI of inhibitory processing in abstinent adolescent marijuana users , 2007, Psychopharmacology.

[52]  Karen I. Bolla,et al.  Abnormal brain activity in prefrontal brain regions in abstinent marijuana users , 2004, NeuroImage.

[53]  S. Tapert,et al.  Psychometric evaluation of the Customary Drinking and Drug Use Record (CDDR): a measure of adolescent alcohol and drug involvement. , 1998, Journal of studies on alcohol.

[54]  R. Hampson,et al.  Assessment of cannabinoid induced gene changes: tolerance and neuroprotection. , 2002, Chemistry and physics of lipids.

[55]  Timothy Edward John Behrens,et al.  Characterization and propagation of uncertainty in diffusion‐weighted MR imaging , 2003, Magnetic resonance in medicine.

[56]  K. Mackie,et al.  Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration , 2003, The Journal of Neuroscience.

[57]  R. Constable,et al.  Functional Correlates of Verbal Memory Deficits Emerging During Nicotine Withdrawal in Abstinent Adolescent Cannabis Users , 2007, Biological Psychiatry.

[58]  I. Grant,et al.  Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study , 2003, Journal of the International Neuropsychological Society.

[59]  Sven Ekholm,et al.  Diffusion-Weighted MR Imaging of the Brain , 2010, American Journal of Neuroradiology.

[60]  L. Hourani,et al.  Results from the 2008 National Survey on Drug Use and Health: National Findings , 2007 .

[61]  J. Borrell,et al.  Cannabinoids Promote Oligodendrocyte Progenitor Survival: Involvement of Cannabinoid Receptors and Phosphatidylinositol-3 Kinase/Akt Signaling , 2002, The Journal of Neuroscience.

[62]  A. Snyder,et al.  Quantitative diffusion-tensor anisotropy brain MR imaging: normative human data and anatomic analysis. , 1999, Radiology.

[63]  L. Frank.  Characterization of anisotropy in high angular resolution diffusion‐weighted MRI , 2002, Magnetic resonance in medicine.

[64]  Daniel Rueckert,et al.  Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data , 2006, NeuroImage.

[65]  P. Basser,et al.  Diffusion tensor MR imaging of the human brain. , 1996, Radiology.

[66]  V. Wedeen,et al.  Reduction of eddy‐current‐induced distortion in diffusion MRI using a twice‐refocused spin echo , 2003, Magnetic resonance in medicine.

[67]  Stefan Skare,et al.  A Model-Based Method for Retrospective Correction of Geometric Distortions in Diffusion-Weighted EPI , 2002, NeuroImage.

[68]  D. Le Bihan,et al.  Diffusion tensor imaging: Concepts and applications , 2001, Journal of magnetic resonance imaging : JMRI.

[69]  E. Granholm,et al.  Substance use and withdrawal: Neuropsychological functioning over 8 years in youth , 2002, Journal of the International Neuropsychological Society.

[70]  H. Pope.  Cannabis, cognition, and residual confounding. , 2002, JAMA.

[71]  T. Wenger,et al.  Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study☆ , 2000, Peptides.

[72]  J. Giedd,et al.  Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging , 2006, Neuroscience & Biobehavioral Reviews.

[73]  Kevin W Chen,et al.  Prevalence and correlates of past-year substance use, abuse, and dependence in a suburban community sample of high-school students. , 2004, Addictive behaviors.

[74]  L. Chang,et al.  Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation. , 2006, Brain : a journal of neurology.

[75]  R. Harris,et al.  Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics , 2002, Journal of neurochemistry.

[76]  V. Menon,et al.  White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. , 2005, Cerebral cortex.

[77]  William Gardner,et al.  Neurobehavioral disinhibition in childhood predicts early age at onset of substance use disorder. , 2003, The American journal of psychiatry.

[78]  N. Rothwell,et al.  Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide‐induced nitric oxide release in astrocyte cultures , 2002, Journal of neuroscience research.

[79]  Christian Beaulieu,et al.  Diffusion tensor imaging of neurodevelopment in children and young adults , 2005, NeuroImage.

[80]  S. Skare,et al.  Noise considerations in the determination of diffusion tensor anisotropy. , 2000, Magnetic resonance imaging.

[81]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[82]  Theo G. M. van Erp,et al.  Diffusion Tensor Imaging of the Superior Longitudinal Fasciculus and Working Memory in Recent-Onset Schizophrenia , 2008, Biological Psychiatry.

[83]  Heidi Johansen-Berg,et al.  Changes in white matter microstructure during adolescence , 2008, NeuroImage.

[84]  Edith V. Sullivan,et al.  Supratentorial Profile of White Matter Microstructural Integrity in Recovering Alcoholic Men and Women , 2006, Biological Psychiatry.

[85]  Lai Xu,et al.  Joint source based morphometry identifies linked gray and white matter group differences , 2009, NeuroImage.

[86]  S. Tapert,et al.  The influence of marijuana use on neurocognitive functioning in adolescents. , 2008, Current drug abuse reviews.

[87]  Lawrence R. Frank,et al.  Microstructural integrity of the corpus callosum linked with neuropsychological performance in adolescents , 2008, Brain and Cognition.

[88]  E Granholm,et al.  Neurocognitive functioning of adolescents: effects of protracted alcohol use. , 2000, Alcoholism, clinical and experimental research.

[89]  Khader M Hasan,et al.  Development and organization of the human brain tissue compartments across the lifespan using diffusion tensor imaging , 2007, Neuroreport.

[90]  S. Wakana,et al.  Fiber tract-based atlas of human white matter anatomy. , 2004, Radiology.

[91]  M. Yücel,et al.  Regional brain abnormalities associated with long-term heavy cannabis use. , 2008, Archives of general psychiatry.

[92]  Clare E. Mackay,et al.  Corpus callosum damage in heavy marijuana use: Preliminary evidence from diffusion tensor tractography and tract-based spatial statistics , 2008, NeuroImage.

[93]  P Sham,et al.  A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia , 2007, Psychological Medicine.

[94]  David Bonekamp,et al.  Diffusion tensor imaging in children and adolescents: Reproducibility, hemispheric, and age-related differences , 2007, NeuroImage.

[95]  Linda C. Sobell,et al.  Timeline Follow-Back A Technique for Assessing Self-Reported Alcohol Consumption , 1992 .

[96]  L. Chassin,et al.  Trajectories of alcohol and drug use and dependence from adolescence to adulthood: the effects of familial alcoholism and personality. , 2004, Journal of abnormal psychology.

[97]  Gen Kanayama,et al.  Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study , 2004, Psychopharmacology.

[98]  Babak A. Ardekani,et al.  ttention-Deficit/Hyperactivity Disorder: Preliminary Diffusion Tensor Imaging Study , 2005 .

[99]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[100]  P. Casellas,et al.  Stimulation of Cannabinoid Receptor CB1 Induces krox-24 Expression in Human Astrocytoma Cells (*) , 1995, The Journal of Biological Chemistry.

[101]  L. Kirisci,et al.  Relation between cognitive distortions and neurobehavior disinhibition on the development of substance use during adolescence and substance use disorder by young adulthood: a prospective study. , 2004, Drug and alcohol dependence.

[102]  V. Schmithorst,et al.  Cognitive functions correlate with white matter architecture in a normal pediatric population: A diffusion tensor MRI study , 2005, Human brain mapping.

[103]  Daniel Rueckert,et al.  Nonrigid registration using free-form deformations: application to breast MR images , 1999, IEEE Transactions on Medical Imaging.

[104]  Deborah A Yurgelun-Todd,et al.  Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation. , 2005, Brain research. Cognitive brain research.

[105]  M. Horsfield,et al.  Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging , 1999, Magnetic resonance in medicine.

[106]  J. Hewitt,et al.  Item response theory analysis of DSM-IV cannabis abuse and dependence criteria in adolescents. , 2008, Journal of the American Academy of Child and Adolescent Psychiatry.

[107]  August B. Hollingshead,et al.  Two Factor Index of Social Position , 1957 .

[108]  John P. Allen,et al.  Measuring Alcohol Consumption: Psychosocial and Biochemical Methods , 1992 .

[109]  M. Cohen-Zion,et al.  Neuropsychological functioning in adolescent marijuana users: Subtle deficits detectable after a month of abstinence , 2007, Journal of the International Neuropsychological Society.

[110]  M. McGue,et al.  A Developmental Perspective on Alcohol and Youths 16 to 20 Years of Age , 2008, Pediatrics.

[111]  R. Theilmann,et al.  Abstinent adolescent marijuana users show altered fMRI response during spatial working memory , 2008, Psychiatry Research: Neuroimaging.