Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use
Introduction
According to the Substance Abuse and Mental Health Services Administration (2006), one in two adolescents/early adults have tried cannabis at least once in their lifetime. A recent national survey also reported a history of cannabis (i.e., marijuana) use in approximately 45% of twelfth graders in the United States, with five percent reporting current daily use (Terry-McElrath et al., 2005). In addition, recent studies support the hypothesis that adolescent cannabis use is a gateway to illicit drug use in early adulthood (Fergusson et al., 2006).
In addition, there is increasing concern regarding the potential long-term effects of early cannabis use on neurodevelopment, as data from several epidemiological studies have linked early cannabis use (before age 15 years) with the subsequent development of psychiatric disturbances. Several lines of evidence suggest that long-term cannabis use may be more detrimental to the developing brain than for the mature brain in samples of preclinical individuals (Cha et al., 2006, Landfield et al., 1988, Stiglick and Kalant, 1985), adolescent cannabis users (Medina et al., 2007a), and adult cannabis users with previously documented neuropsychological deficits (Ehrenreich et al., 1999, Pope et al., 2003). Furthermore, morphometric studies involving adult marijuana users have documented, albeit inconsistently (Block et al., 2000), alterations in brain tissue composition among members of this cohort (Matochik et al., 2005), particularly among adults with a history of early use (i.e., use prior to age 17 years) (Wilson et al., 2000). Previous studies have also reported early-age cannabis users to be more vulnerable to manifest psychosis in adulthood than adult users (Arseneault et al., 2004, Caspi et al., 2005).
Most recently, a structural brain imaging investigation examining white matter abnormalities among adolescent cannabis users yielded evidence that both marijuana use and white matter volume are each independent predictors of depressive symptomatology (Medina et al., 2007b). It has also been hypothesized that long-term exposure to cannabis may be associated with the downregulation of the CB1 receptors and suppress oligodendrocyte function over time (Molina-Holgado et al., 2002). In support of this hypothesis, long-term cannabinoid exposure has been found to be associated with decreased expression of myelin-related genes (Grigorenko et al., 2002). Together, these data provide support for a hypothesis that recurrent exposure to cannabis during adolescence may adversely affect white matter development.
Diffusion tensor imaging (DTI) is a powerful magnetic resonance imaging (MRI) technique suited to the study of white matter (WM) axonal structure because it can be used to quantify the magnitude and directionality of tissue water mobility in three dimensions. DTI has been utilized for the characterization of developmental changes in WM diffusion properties throughout the first two decades of life (Ashtari et al., 2007a, Barnea-Goraly et al., 2005, Guo et al., 2007, Schmithorst et al., 2002). Results of DTI studies in typically developing children have shown prominent age-related increases in fractional anisotropy (FA) in numerous brain regions, including the left arcuate fasciculus (Ashtari et al., 2007a, Guo et al., 2007, Schmithorst et al., 2002), prefrontal cortex (Barnea-Goraly et al., 2005), internal capsule (Ashtari et al., 2007a, Barnea-Goraly et al., 2005, Guo et al., 2007, Schmithorst et al., 2002), corpus callosum (Ashtari et al., 2007a, Barnea-Goraly et al., 2005), right inferior longitudinal fasciculus (Guo et al., 2007, Schmithorst et al., 2002) and ventral visual stream WM (Barnea-Goraly et al., 2005), as well as areas extending from sensorimotor regions that appear to correspond to the corticothalamic and cortico-spinal tracts (Schmithorst et al., 2002).
To our knowledge, only a handful of studies have utilized DTI to examine the effect of chronic cannabis use on white matter integrity in adults. Gruber and Yurgelun-Todd (2005) used a region of interest (ROI) approach in 9 heavy cannabis users (HCUs), aged 18–47 years, and 9 healthy comparison subjects. The authors used four ROIs and placed them on a single slice covering only the frontal regions and reported no significant differences in FA, but did find a trend level (p = .09) increase of the trace value parameter among HCUs. Similarly, Delisi and colleagues (2006) reported no evidence of WM integrity loss in young adults aged 18–27 years (n = 10) who were frequent cannabis users during adolescence, relative to 10 age- and sex-matched controls, using whole brain voxelwise analysis. Arnone and colleagues (2006) compared 11 HCUs with demographically matched normal controls using a histogram approach and reported a median FA decrease among marijuana users (p = .03). In a more recent study by Arnone and colleagues (2008), the authors reported decreased FA and mean diffusivity in the corpus callusom in a group of adult HCUs. The lack of consistency in findings across these initial studies of adult cannabis users could be a reflection of small sample sizes, sample heterogeneity (e.g., duration and severity of marijuana use, variation in abstinence duration prior to DTI scanning, etc.), and varied methods of image acquisition and analysis.
In the current, preliminary study, we have employed a DTI technique with fifteen gradient directions and isotropic slices using a whole brain voxelwise analysis and diffusion tractography to examine potential relationships between white matter tissue organization (microstructure) and adolescent heavy cannabis use. In addition, we carried out analyses for all diffusion indices, including fractional anisotropy and radial, axial, and mean diffusivity, to study differences in brain structure between adolescent HCUs and healthy comparison subjects without a history of cannabis use. Based on our previous study of normative brain development (Ashtari et al., 2007a) and earlier investigations outlining the areas of brain maturation during adolescence, as well as brain areas where the endogenous cannabinoid system has been documented to influence the development of brain white matter, we hypothesized that subjects with a history of HCU would have diminished FA and increased mean and radial diffusivity in the following brain regions undergoing developmental change during adolescence, as documented by Ashtari and colleagues (2007a): the arcuate fasciculus, internal capsule/thalamic radiation, corpus callosum (documented at a more relaxed threshold in Ashtari et al. (2007a)) and regions of the prefrontal cortex.
Section snippets
Subjects
Fourteen male adolescents and young adults (mean age = 19.3; SD = .8) with a history of heavy cannabis use throughout adolescence, and who were currently enrolled in a residential drug-treatment rehabilitation center to reduce cannabis consumption, were recruited. All individuals were court-ordered after being repeatedly prosecuted for crimes related to possession, sale, or purchase of marijuana. No patient had been court-ordered for other crimes, such as violent offenses. All individuals had been
Sample characteristics
Sample characteristics are summarized in Table 1. HCUs with mean age of 19.3 years (range: 18.0–21.2 years) reported a mean age of first cannabis use of 13.1 years (range: 9.0–15.0 years) and were drug-free for a median duration of 6.7 months (range: 3–11 months) prior to MRI scan. In the 1-year prior to the current period of abstinence, HCUs reported using an average of 5.8 joints per day. Five HCUs met DSM-IV criteria for past alcohol abuse; the remaining nine reported no more than regular
Discussion
In the current preliminary invetigation, voxelwise analysis and tractography were used to compare the WM fiber tract integrity of adolescents/young adults with HCU throughout adolescence to demographically matched healthy comparison subjects. In the first set of analyses, VANCOVA at an FDR corrected statistical threshold (p < .01, 100 extent threshold) revealed four clusters of decreased FA among HCUs relative to healthy comparison subjects, including: bilateral posterior internal
Conclusion
In summary, the current study may differ from previous DTI reports in terms of patient sample characteristics with respect to severity and duration of use, and length of abstinence. We also differed in terms of our image processing approaches with some of previous DTI reports that elected an ROI approach as opposed to a whole brain voxelwise analysis. Furthermore, in order to better understand brain water diffusion behavior in cannabis users, we employed other diffusion parameters (i.e., axial
Role of funding source
Funding for this study was provided by NIMH Grant MH – 070612; the NIMH (Dr. Ashtari), 1RO1-MH073150-01A2 (Dr. Kumra) and 7K23MH64556-06 (Dr. Kumra). NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Conflict of interest statement
None declared.
Acknowledgement
The authors greatly appreciate the aid and cooperation of the residents and staff of Aurora Concepts during the course of this study, as well as the participation of the healthy control subjects. Special acknowledgements in particular to the following individuals for their help in making this project a successful one: Mr. David Roofeh, Dr. Joseph Rhinewine, Ms. Hana Kester, Mr. Britt Anderson, Ms. Emily Thaden, and Dr. Serge Sevy.
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