The authors have declared that no competing interests exist.
Conceived and designed the experiments: HG JJF. Performed the experiments: RPB. Analyzed the data: CGC. Contributed reagents/materials/analysis tools: CGC RPB. Wrote the paper: CGC RPB JJF HG.
Extensive evidence indicates that current and recently abstinent cocaine abusers compared to drug-naïve controls have decreased grey matter in regions such as the anterior cingulate, lateral prefrontal and insular cortex. Relatively little is known, however, about the persistence of these deficits in long-term abstinence despite the implications this has for recovery and relapse. Optimized voxel based morphometry was used to assess how local grey matter volume varies with years of drug use and length of abstinence in a cross-sectional study of cocaine users with various durations of abstinence (1–102 weeks) and years of use (0.3–24 years). Lower grey matter volume associated with years of use was observed for several regions including anterior cingulate, inferior frontal gyrus and insular cortex. Conversely, higher grey matter volumes associated with abstinence duration were seen in non-overlapping regions that included the anterior and posterior cingulate, insular, right ventral and left dorsal prefrontal cortex. Grey matter volumes in cocaine dependent individuals crossed those of drug-naïve controls after 35 weeks of abstinence, with greater than normal volumes in users with longer abstinence. The brains of abstinent users are characterized by regional grey matter volumes, which on average, exceed drug-naïve volumes in those users who have maintained abstinence for more than 35 weeks. The asymmetry between the regions showing alterations with extended years of use and prolonged abstinence suggest that recovery involves distinct neurobiological processes rather than being a reversal of disease-related changes. Specifically, the results suggest that regions critical to behavioral control may be important to prolonged, successful, abstinence.
Cocaine is a major worldwide public health issue for which current treatments are unsatisfactory
Voxel based morphometry
Our prior report characterizing long-term abstinence probed the functional neuroanatomy of cognitive control using a GO/NOGO task
A recent study compared grey and white matter densities in abstinent (1–16 weeks) and current CD individuals and healthy control participants and observed that the current users, compared to controls and abstainers, had lower tissue density in frontal, temporal, cerebellar and subcortical regions. The abstinent group had much less pronounced deficits with lower grey matter density in caudate/putamen and bilateral cerebellum compared to controls
The aim of the present study, using a cross-sectional design, was to examine volume differences in cortical grey matter in a sample of former cocaine addicts who varied in length of abstinence and duration of use. We hypothesized that abstinence duration would be associated with a set of GM volume changes in regions critical to executive function, specifically anterior cingulate and lateral prefrontal cortex. We further hypothesized that any GM volume changes that may be attributable to length of use would be distinct from those related to abstinence duration. Comparison to a non-drug using control group allowed us to assess how changes of GM with abstinence duration relate to volumes typical of drug naïve controls. The cross-sectional design employed here suffers by being unable to resolve whether effects related to abstinence duration arose from abstinence or preceded abstinence. However, it is nonetheless valuable in that it can characterize individuals with a demonstrated ability to remain abstinent over various durations. This characterization may be of therapeutic importance in that observed neurobiological differences might serve as targets for therapy. Additionally, they may be useful biomarkers for possible investigation in future longitudinal studies of abstinence.
This study was approved by the Institutional Review Board of the Nathan S. Klein Institute for Psychiatric Research (NKI).
Eighty-six volunteers (9 female; mean age 38.1, range 20–55) (see
Characteristic | Controls | Cocaine Dependent |
Number of participants | 43 | 43 |
Gender M/F | 41/2 | 36/7 |
Age at time of scanning(years) | 38.7±1.6 (20–55) | 37.5±1.2 (22–54) |
Years of education | 14.6±0.3 (12–20) | 12.3±0.3 (7–17) *** |
Abstinence (Weeks) | Not Applicable | 31.25±4.5 (0.7–102) |
Years of use | Not Applicable | 9.1±1.0 (0.3–24) |
Entries are of the form: mean ± SEM (min-max). Gender was compared using the binomial proportion test; all other observations were compared by Welsh T-tests. C = control, CD = cocaine dependent. Significance code: p ≤ 0.001 ‘***’.
All scanning was conducted on a 1.5T Siemens VISION scanner (Erlangen, Germany) at NKI that was equipped with a 30.5-cm i.d. three-axis local gradient coil and an end-capped quadrature birdcage radio-frequency head coil. High-resolution T1-weighted MPRAGE anatomical images were acquired with the following parameters: TE = 4.9 ms, TR = 11.6 ms, flip angle 8°, FOV 300 mm, 1.2 mm isotropic voxels, matrix 256×256, and 172 sagittal slices.
The high-resolution T1-weighted images were subjected to a voxel-based morphometry (VBM) analysis
The resultant grey matter images of the abstinent CD group were then subjected to voxelwise Huber robust regression
The CD participants did not differ from controls in age (Welch t(77.5) = −0.6, p>0.05, or gender (χ2 = 1.98, p = 0.15), but did differ on years of education (Welch t(82.6) = −5.1, p<0.001; see
Four regions (
The solid line is the robust regression line for CD individuals. The dashed line is the mean GM in the same ROI for the control participants.
Structure | Hemisphere | BA | Volume | Center of Mass | Crossover | ||
(µL) | X | Y | Z | Point | |||
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Precentral Gyrus | L | 4 | 896 | −36 | −16 | 62 | 14.1 |
Nodule (Cerebellum) | R | 888 | 4 | −42 | −38 | 6.2 | |
Medial Frontal Gyrus | L | 11 | 392 | −2 | 32 | −14 | 19.5 |
Precentral Gyrus | R | 6 | 368 | 13 | −26 | 73 | 18.6 |
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Cerebellar Tonsil | R | 1976 | 39 | −56 | −53 | 4.6 | |
Portions of STG, IFG, AI | R | 22/13 | 1360 | 49 | 11 | −5 | 2.8 |
Portions of STG, IFG | L | 22/13 | 1088 | −50 | 13 | −7 | 3.7 |
Subcallosal Gyrus | R | 34 | 624 | 12 | 1 | −17 | 8.3 |
Anterior Cingulate | R | 24 | 448 | 4 | 30 | 14 | 6.7 |
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Insula | L | 13 | 1512 | −37 | 9 | 11 | 29.9 |
Cuneus | L | 31 | 1480 | −26 | −79 | 23 | 26.4 |
Superior Frontal Gyrus | L | 8 | 680 | −16 | 46 | 42 | 42.3 |
Culmen | L | 648 | −14 | −48 | −12 | 32.8 | |
Precuneus | R | 19 | 592 | 31 | −78 | 22 | 38.0 |
Cingulate Gyrus | L | 32 | 520 | −10 | 25 | 31 | 44.9 |
Superior Frontal Gyrus | R | 10 | 512 | 24 | 54 | 5 | 37.1 |
Cingulate Gyrus | R | 31 | 384 | 14 | −32 | 41 | 33.3 |
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Cuneus | R | 19 | 520 | 12 | −81 | 36 | 27.6 |
Precuneus | L | 7 | 488 | −4 | −62 | 57 | 26.6 |
Culmen of Vermis | L | 368 | −2 | −64 | 3 | 18.5 |
Center-of-mass coordinates are in the MNI152 (LPI) standard and structure labels are from the Talairach & Tournoux atlas. RL: Right-Left, AP: Anterior-Posterior, IS: Inferior-Superior. STG: Superior Temporal Gyrus, IFG: Inferior Frontal Gyrus, AI: Anterior Insula. BA: Brodmann Area. Crossover point refers to the location on the x-axis (years of use or weeks of abstinence) where the regression (solid) line for the CD users intersects with the mean of the control participants (dashed line). Term refers to the term of interest in the regression model (years of use or weeks of abstinence) from which the clusters were derived. Polarity refers to the sign (positive or negative) of the regression coefficients from which the cluster was generated.
A number of regions (
The solid line is the robust regression line for CD individuals. The dashed line is the mean GM in the same ROI for the control participants.
As abstinence duration correlated with years of education, we conducted cluster-level correlations between GM volumes and weeks of abstinence with both age and years of education included as nuisance regressors. The effects reported above remained significant for all regions.
We conducted a series of Welch T-tests to determine if the GM volumes of users who were abstinent longer than the cross-over point were significantly greater than the volumes of the controls. These tests were performed separately for each ROI with the cross-over points of each ROI identified from the linear regressions. All of these tests were significantly different (all p<0.05).
We tested whether the areas shown to have altered volumes associated with years of use were also observed to change with abstinence. We performed correlations for abstinence effects in those areas that showed years of use effects (and
The present results are some of the first to examine grey matter volumes related to the length of cocaine use and abstinence in a population of former cocaine addicts. We observed several regions displaying decreased GM with increasing years of use. Although these results are necessarily correlational, they suggest a cumulative effect of cocaine use wherein the longer the period of substance use the lower the grey matter volume
If addiction can be characterized as a loss of self-directed volitional control
Impulsivity has been identified as a risk factor for the development of substance use disorders wherein individuals displaying higher levels of impulsivity are prone to both experimentation with and misuse of illicit drugs
Left and right inferior frontal gyrus and right anterior cingulate have been identified as key loci underlying response inhibition
The present results are tempered by some limitations. A fuller characterization of the subjects would be of value in order to assess the psychological consequences of the observed structural changes. In addition, the CD group reported here included individuals who were dependent on alcohol and heroin. While polydrug use of this sort is representative of the CD population, it raises the possibility that the effects reported here could be influenced by these other drug dependencies. Future studies might aim to resolve this ambiguity by recruiting a purely cocaine dependent cohort or a larger sample of polydrug abusers which would facilitate analyses to explore independent and interactive drug use effects. Additionally, future studies should aim to determine whether the number of attempts at abstinence has any bearing on GM change. Finally, consistent with most human clinical studies, it is not possible to address the etiology of the changes reported here. That is, we cannot say with certainty that they arose as a consequence of cocaine consumption or predated it. Notwithstanding this ambiguity, the present results demonstrate a dissociation between the effects of prolonged addiction and extended abstinence. The dissociation between regions showing alterations in grey matter with increased years of use and those altering with increased abstinence suggests that recovery is not simply a reversal of the process of disease. Rather it suggests an asymmetry between the two wherein cortical regions critical to behavioral control may serve as a biomarker of successful abstinence. Furthermore, these systems may be apt for targeting during treatment, such as with mindfulness-based approaches
Data analysis was supported by access to the IITAC high-performance computing cluster, funded by the Higher Education Authority, The National Development Plan and the Trinity Centre for High Performance Computing.