Alcohol and Drug Abuse Research Center
Center for Depression, Anxiety and Stress Research
McLean Imaging Center
Clinical Unit Based Research
Mailman Research Center
Shervert H. Frazier Research Institute
Clinical Trials
Inventions for License
Research News


McLean Hospital's Staci Gruber explains the impact of early marijuana use on brain development in Dr. Sanjay Gupta's CNN special, "Weed."

Cognitive and Clinical Neuroimaging Core (CCNC): Overview

The Cognitive and Clinical Neuroimaging Core is dedicated to the examination of cognitive and affective correlates of neural systems, which may mediate symptoms in psychiatric disorders and behaviors related to substance abuse. Techniques used in these investigations include measures of neuropsychological performance, clinical and diagnostic rating scales and instruments and various magnetic resonance imaging methods, including functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). The aim of these studies has been to identify brain abnormalities, particularly disruptions of frontally and temporally mediated networks, which may represent risk factors for psychiatric illness or substance abuse, or which may be the site of pathology in these illnesses.  Recent investigations have combined results from neurocognitive testing and brain imaging in healthy subjects, substance abusers, and subjects with psychiatric disorders as a means of clarifying the possible dysfunctional neural network processes associated with these illnesses. Clinical and neurocognitive assessments, as well as functional and spectroscopic imaging pre and post treatment with a variety of pharmacologic agents have also provided a means for understanding the effect of specific naturopathic and more conventional pharmacological agents on brain function.

CCNC In the News:

  1. Changing marijuana laws (01/24/2014)
  2. About Health #275 "Kids and Marijuana" (12/03/2013)
  3. The brain: For adolescents, a scary path to full development (12/04/2013)
  4. World's Federation Against Drugs (11/19/2010)
    McLean study shows greater cognitive deficits in marijuana users who start young
  5. Science Daily (11/17/2010) 
    Human Study Shows Greater Cognitive Deficits in Marijuana Users Who Start Young
  6. (11/16/2010)
    Smoking 3,000 Joints Is Bad for Your Brain, Study Finds
  7. The Boston Globe (11/16/2010)
    Brain-damage risks higher for younger marijuana users, study says
  8. The Denver Post (11/16/2010)
    Pot smoking changes teens' brains, study shows
  9. FoxNews (11/16/2010)
    Early Marijuana Use May Increase Brain Damage
  10. from The Gainesville Sun (11/16/2010)
    Marijuana Smokers Who Start Early Are at Greatest Risk, Study Finds 
  11. Harvard Gazette (11/16/2010)
    Brain-damage risks higher for younger marijuana users, study says
  12.  ABC News (11/15/2010)
    Early and Chronic Marijuana Use May Damage Brain Function, Says Study
  13. Bloomberg Business Week (11/15/2010)
    Teens Smoking Pot Before Age 16 Show Brain Changes
  14. CNN (11/15/2010)
    Teen brain more prone to drug, alcohol damage
  15. eScience (11/15/2010)
    Early marijuana use a bigger problem
  16. Harvard Gazette (11/15/2010)
    Early marijuana use a bigger problem
  17. (11/15/2010)
    Early 'Pot' Use May Harm Brain More: Study
  18. (11/15/2010)
    Early 'Pot' Use May Harm Brain More: Study
  19. Health News (11/15/2010)
    Teenage Marijuana Use May Damage Cognitive Function
  20. The New York Times (11/15/2010)
    Marijuana Smokers Who Start Early Are at Greatest Risk, Study Finds
  21. The Seattle Times (11/15/2010)
    Early use of pot may change the brain
  22. U.S. News & World Report (11/15/2010)
    Early 'Pot' Use May Harm Brain More: Study
    Smoking before age 16 tied to greater executive function problems
  23. WBUR - National Public Radio (NPR) (11/15/2010)
    Early Marijuana Use May Impair Brain Function
  24. USC's News (11/16/2010)
    Marijuana impacts younger users more severly
  25. Harvard Gazette (04/26/2009)
    A mother’s criticism touches nerve in formerly depressed 

Summaries of Selected Ongoing Projects:

Early Marijuana Use Impacts Executive Function and Use Patterns Overall
Marijuana (MJ) remains the most widely abused illicit substance in the United States, and in recent years, a decline in perceived risk of MJ use has been accompanied by a simultaneous increase in rates of use among adolescents. In the current study, we hypothesized that chronic MJ smokers would perform tasks of executive function more poorly than control subjects, and that individuals who started smoking MJ regularly prior to age 16 (early onset) would have more difficulty than those who started after age 16 (late onset). Thirty-four chronic, heavy MJ smokers separated into early and late onset groups and 28 non-MJ smoking controls completed a battery of neurocognitive measures. As hypothesized, MJ smokers performed more poorly than controls on several measures of executive function including the Wisconsin Card Sorting Test (WCST), Stroop Color Word Test, and the Trail Making Test. MJ smokers as a group performed the WCST, a “gold standard” measure of executive function and set shifting abilities, more poorly than controls.  Moreover, early onset smokers performed significantly worse than later onset smokers, achieving fewer categories and making more perseverative errors. During the Stroop Color Word Test, a task used to measure the ability to inhibit inappropriate responses and resist interference, MJ smokers made more commission errors and achieved lower percent accuracy relative to control subjects. Additionally, early onset smokers displaying impaired performance, reflected in lower task accuracy and significantly higher commission errors relative to late onset smokers. In addition to impairments on these tasks, we found that early onset smokers smoked twice as often per week and nearly three times as many grams of MJ per week relative to the late onset smokers.  Findings suggest that earlier MJ onset is related to poorer executive function and increased frequency and magnitude of MJ use relative to later MJ onset. Exposure to marijuana during a period of neurodevelopmental vulnerability, such as adolescence, may result in altered brain development and enduring neuropsychological changes.

Altered Brain Activation during an Inhibitory Task in Early Onset Marijuana Smokers 
Difficulties in the ability to successfully inhibit impulsive behaviors have been reported in marijuana (MJ) smokers, yet few studies have made direct comparisons between early (prior to age 16) and late (age 16 or later) onset MJ smokers, specifically during behavioral inhibition tasks. We recently utilized the Multisource Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) in order to examine potential differences in non-MJ smoking controls (HCs) and early vs late onset chronic, heavy MJ smokers. During the task, subjects were presented with sets of three numbers (1, 2, 3, or 0), with one (target) always different from the other two (distractor) numbers. Subjects were instructed to report the identity of the number that differed from the distractors using a button box.  Results showed that MJ smokers and HCs displayed differences in activation patterns during the MSIT, although there were no behavioral performance differences between the two groups. While HCs exhibited a very focal pattern of activation, MJ smokers demonstrated a much more diffuse pattern. The comparison between MJ subgroups revealed that early onset smokers activated a more focal region of ACC during the task, and in fact appeared more similar to the single sample analysis of healthy controls relative to the late onset smokers, who demonstrated a pattern more similar to MJ smokers overall. Furthermore, analyses approaching statistical significance showed that while early onset smokers had faster reaction times, they made nearly twice as many errors of commission relative to the later onset smokers, which is indicative of a failure to inhibit inappropriate responses. Taken together, these data may reflect both a neural compensation for early exposure to MJ during a vulnerable neurodevelopmental period and a behavioral inability to execute cognitive control. Further investigation is warranted, as early exposure to MJ may result in reorganization of critical brain regions.

Citicoline and Impulsivity in Marijuana Smokers: Preliminary Results
Currently available as an over-the-counter dietary supplement, citicoline is a nucleotide that plays an important role in cellular metabolism, and has been used therapeutically for stroke, traumatic brain injury, and cognitive dysfunction in the elderly.¬† Citicoline has also been shown to enhance cognitive function in a range of individuals, and previous investigations have reported that treatment with citicoline also increases frontal brain metabolism and reduces craving for illicit substances.¬† Impulsive behavior is often associated with substance abuse, with impulsivity often reported as a risk factor for initiation and maintenance of substance abuse. Given this relationship, we examined the impact of citicoline treatment on reported impulsivity levels in marijuana smokers, and hypothesized that citicoline treatment may reduce impulsivity in this population.¬† This study involved an 8-week placebo-controlled, double-blind clinical trial of citicoline in chronic, heavy, marijuana-smoking individuals.¬† As part of a preliminary analysis, we assessed data from a total of fifteen subjects; 8 in one treatment group (group A) and 7 in the other (group B).¬† Subjects were randomized to receive either 2 grams of citicoline or placebo daily, and were evaluated at multiple time points during the 8-week trial.¬† All subjects completed clinical rating scales at baseline and throughout the 8-week treatment period, which included the Barratt Impulsiveness Scale (BIS).¬† The BIS is a robust 30-item, self-report scale that provides reliable measures of impulsivity on three subscales: attention, motor and non-planning, as well as a total impulsivity score.¬† Results indicated no significant between-group differences on any of the BIS scores at baseline.¬† However, from baseline to treatment week 8, group A demonstrated an overall decrease on each subscale of the BIS including: attention (t(7)=2.225, p=.03), motor (NS), non-planning (t(7)=1.522, p=.09), and total impulsivity (t(7)=1.982, p=.04).¬† Group B showed a significant decrease on the attention subscale of the BIS (t(7)=2.121, p=.04), but demonstrated increases on all other factors of the BIS, although these did not reach statistical significance.¬† Between-group statistical analyses indicated that the overall changes between pre-treatment and week 8 BIS levels were different between the two groups for non-planning (t(13)=1.898, p=.04) and total BIS scores (t(13)=1.542, p=.07).¬† In summary, results suggest that group A exhibited a significant decrease in BIS scores from baseline to the end of the 8-week treatment period, and that this decrease in impulsivity was significantly different from group B.¬† “Breaking the blind” revealed that Group A received active citicoline, while Group B received placebo. Taken together, these data suggest that citicoline reduces impulsivity in chronic, heavy marijuana smokers, which may have treatment implications for other clinical populations with reported difficulty with inhibitory function.

Gone to Pot? Early marijuana use and impulsivity predict neurocognitive impairment and alterations
in brain structure
Despite reports of the negative impact of chronic marijuana (MJ) use, perceived risk of MJ use continues to decline, spurring an increase in MJ use in emerging adults. The current study aimed to assess the impact of early MJ use and impulsivity on neurocognitive performance and white matter microstructure, and to determine if early MJ onset and impulsivity scores could predict performance and structural brain alterations. Forty-six chronic MJ smokers and 31 non-MJ smoking controls completed diffusion tensor imaging (DTI) at 3T and measures of executive function and impulsivity, including the Trail Making Test, Stroop Color Word Test and the Barratt Impulsiveness Scale (BIS). Overall, MJ smokers performed significantly worse on measures executive function, and had lower levels of fractional anisotropy (FA) in the left and right genu relative to controls. Regression analyses revealed that earlier age of MJ onset predicted poorer cognitive performance and altered white matter: earlier MJ onset predicted longer completion times on Trails A (ß= .304, p=.05) and increased errors on Trails B (ß=-.302, p=.05), as well as lower FA in the left and right genu (ß= .344, p=.09; ß= .358, p=.08). Notably, earlier MJ onset also predicted higher frequency (ß=-.346, p=.01) and magnitude of MJ use (ß=- .375, p=.01). MJ smokers also had significantly higher levels of impulsivity on the BIS, which predicted increased errors on Trails B (ß=.353, p=.03), longer derived Trails interference (B-A) time (ß=.401, p=.01), and lower performance accuracy on the Stroop interference condition (ß=.274, p=.09). BIS scores also predicted lower FA in the right genu (ß=-.393, p=.05) in MJ smokers, but not control subjects. These findings underscore the importance of identification and prevention of early MJ use, as MJ exposure during a period of developmental vulnerability appears to result in neurophysiologic changes, greater MJ use, and is related to higher impulsivity, which may have long-term implications.

Why So Impulsive?  White Matter Alterations and Impulsivity in Chronic Marijuana Smokers
Difficulty monitoring and inhibiting impulsive behaviors has been reported in marijuana (MJ) smokers, and neuroimaging studies, which examined frontal systems in chronic MJ smokers, have reported alterations during inhibitory tasks.  Diffusion tensor imaging (DTI) provides a quantitative estimate of white matter integrity at the microstructural level. We applied DTI, clinical ratings and impulsivity measures to explore the hypotheses that chronic, heavy MJ smokers would demonstrate alterations in white matter microstructure and a different association between white matter measures and impulsivity relative to non-smoking control subjects (NS). Fractional anisotropy (FA), a measure of directional coherence, and trace, a measure of overall diffusivity were calculated using manual voxel-based methods for six locations including bilateral frontal regions in 15 chronic MJ smokers and 15 NS. Subjects completed clinical rating scales, including the Barratt Impulsivity Scale (BIS). Analyses revealed significant reductions in left frontal FA in MJ smokers relative to NS and significantly higher levels of trace in the right genu. MJ smokers also had significantly higher BIS total and motor subscale scores relative to NS, which were positively correlated with left frontal FA values. Finally, age of onset of MJ use was positively correlated with frontal FA values and inversely related to trace. These data represent the first report of significant alterations in frontal white matter tracts associated with measures of impulsivity in chronic MJ smokers.  Early MJ use may result in reduced FA and increased diffusivity, which may predict increased impulsivity, and ultimately contribute to the initiation of MJ use or the inability to discontinue use.

Age of Onset of Marijuana Use is Related to White Matter and Behavioral Impulsivity
We recently completed analyses of white matter from a new group of chronic, heavy MJ smokers and control subjects which utilized more advanced tract based spatial statistics (TBSS) techniques which increase the sensitivity and the interpretability of the results compared with voxel-based approaches. As in our previous analysis, we found significantly reduced FA in both the left and right genu of the corpus callosum for the MJ smokers relative to the control subjects. In addition, within the same regions, mean diffusivity was significantly higher in MJ smokers relative to controls. Correlation analyses revealed a significant relationship between the age of MJ onset and FA in both the left and right genu  for early but not late onset smokers.  Further, scores on the Barratt Impulsivity Scale (BIS) were inversely correlated with FA in both regions for the early onset smokers, suggesting a specific relationship between FA and behavioral impulsivity. Overall, MJ smokers have lower FA relative to controls, but perhaps more importantly, the earlier the age of MJ onset, the lower the FA level. Similarly, lower FA is related to higher levels of impulsivity.  Taken together, these findings are consistent with previous DTI studies and reinforce the idea that early onset MJ use impacts white matter development (earlier onset = lower FA, higher diffusivity) and is associated with behavioral impulsivity, a combination likely to have devastating effects on the developing brain.

Marijuana and Mood: A Role in Bipolar Disorder
Bipolar disorder (BPD) remains a leading cause of disability across the world, and individuals with co-occurring BPD and substance abuse often experience poor treatment response, relapse of mood symptoms and psychosocial difficulties. While precise reasons for comorbidity remain unclear, some studies of bipolar patients report that substance use is directly related to at least one symptom, and that the majority of patients report symptom improvement as a result of substance use. As twenty to fifty percent of patients with BPD report using MJ, we examined the impact of MJ use on mood symptoms in MJ-smoking bipolar patients (MJBP) and pure MJ smokers (MJ) in order to test the hypothesis that bipolar patients would experience improved mood after smoking MJ. To assess mood changes multiple times per day and before and after smoking MJ, subjects were given Palm Pilot devices uploaded with an application containing electronic versions of several clinical rating scales, including the Profile of Mood States (POMS), Hamilton Anxiety Scale (HAM-A), Montgomery-Asberg Depression Rating Scale (MADRS), and the Young Mania Rating Scale (YMRS).  In addition, subjects recorded episodes of smoking, including amount, frequency and mode of MJ use. A difference score was calculated from pre-MJ scales as compared to post-MJ scales, completed within 4 hours of smoking MJ. T-tests for within and between-group differences on the change scores were computed.  Significant improvement in mood symptoms was noted in the MJBP group after smoking MJ for the POMS, HAM-A and MADRS scales, while the MJ group appeared to have a slight worsening of symptoms. Notably, total mood disturbance (TMD), a composite measure of the POMS, was significantly reduced from 23.13 to 12.22 in the MJBP group but increased from -6.19 to -2.45 in the pure MJ group. These pilot data suggest that MJBP subjects experience a significant improvement in mood symptoms after smoking MJ while pure MJ smokers exhibit a slight worsening of clinical state. Consistent with previous reports of BPD patients using drugs to improve mood-related symptoms, these data underscore the likelihood that MJ may act as a mood stabilizer for some patients with BPD, and highlight the importance of examining cannabinoid-based therapies.

Altered affective processing in bipolar disorder: an fMRI study
Previous studies have reported that patients with bipolar disorder (BPD) exhibit altered emotional processing and regulation. However, results remain largely inconsistent across studies.  The aim of the current study was to further examine affective processing in patients with bipolar disorder.Twenty-three patients diagnosed with BPD (Type I) and 18 healthy matched controls completed a backward-masked affect paradigm while undergoing functional magnetic resonance imaging. Participants also completed a computerized, overt task of facial emotional discrimination after scanning. Results demonstrated altered affective processing of happy and fearful stimuli in bipolar participants in the amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) relative to controls.  BPD participants also displayed significant deficits in identifying fearful facial affect.This study has a moderate sample size, and the patients with BPD were significantly older than the healthy control participants; this did not appear to impact results, and although statistically significant, it is not likely biologically significant. These findings may have implications for patients with BPD, as altered affective processing could result in deficits in reading social cues.

Uncinate fasciculus is associated with cognitive function and impulsivity in bipolar disorder: An enhanced tractography analysis
Traditional tractography methods have revealed alterations in patients with bipolar disorder (BD), however, they rely on averaging white matter (WM) along an entire fiber tract. It would be advantageous to be able to determine where along WM tracts differences occur. The aim of this study was to study the structural integrity of the uncinate fasciculus (UF) and its relation to cognition in patients with BD using an enhanced tractography method via length parameterizing. Based on previous work, we hypothesized that patients with BD would have deficits in WM integrity in this region as well as impairments in executive function and impulsivity. Forty adults (17 healthy controls (HC), 23 with BD) underwent diffusion tensor imaging at 3T and cognitive assessment. Measures of executive function and impulsivity included the Trail Making test (Trails B) and Barratt Impulsiveness Scale (BIS11). The UF tract was segmented into different subregions (frontal and temporal) using a novel length parameterizing method and fractional anisotropy (FA) was examined between groups. FA was reduced in BD group compared to HCs and this difference was localized primarily to the frontal section of the tract rather than the temporal (p=0.004 for the frontal vs p=0.067 for the temporal). Patients with BD showed greater impairment on measures of executive functioning (p=0.010) and impulsivity (p=0.002) compared to HCs. FA in the frontal UF tract was negatively correlated with Trails B (r=0.424, p=0.031) and positively correlated with BIS11 (r=0.364, p=0.057) in the BD group. These correlations were not demonstrated in the HCs. These findings suggest reduced FA in the frontal UF tract is associated with poorer executive function and higher impulsivity in BD. The length parameterized tractography technique is promising, and may provide a more sensitive approach to evaluating the integrity of WM tracts with additional localization details.