Psychiatry and Clinical Neurosciences 2009; 63: 563–568
doi:10.1111/j.1440-1819.2009.01989.x
Regular Article
Frontal and cingulate gray matter volume reduction in heroin dependence: Optimized voxel-based morphometry
pcn_1989
563..568
Haihong Liu, MD,1† Yihui Hao, MD,1† Yoshio Kaneko, MD,2 Xuan Ouyang, MD,1 Yan Zhang, MD,1 Lin Xu, PhD,1,3 Zhimin Xue, MD1* and Zhening Liu, MD, PhD1* 1
Mental Health Institute, Second Xiangya Hospital of Central South University, Changsha, Hunan, 3Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology of Chinese Academy of Science, Kuming, Yunnan, China and 2Yale University School of Medicine, New Haven, Connecticut, USA
Aims: Repeated exposure to heroin, a typical opiate, causes neuronal adaptation and may result in anatomical changes in specific brain regions, particularly the frontal and limbic cortices. The volume changes of gray matter (GM) of these brain regions, however, have not been identified in heroin addiction. Methods: Using structural magnetic resonance imaging and an optimized voxel-based morphometry approach, the GM volume difference between 15 Chinese heroin-dependent and 15 healthy subjects was tested.
HE MECHANISM OF drug addiction has been extensively investigated in the field of neuroscience. Accumulated studies indicate that addiction involves multiple brain circuits and the frontal and limbic cortices are specifically identified as key structures belonging to the involved neural networks.1–3 Repeated exposure to opiates, typically the heroin, may cause molecular and cellular adaptation of specific neurons,4,5 which may result in longstanding detectable anatomical changes in the brain.6 There have been relatively few imaging studies, however, of the anatomical changes in heroin addiction.7–12 Three early computed tomography studies showed decreased ventricle/brain ratio,13 enlarged
T
*Correspondence: Zhimin Xue, MD, Zhening Liu, MD, PhD, Mental Health Institute, Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China. Email:
[email protected] Received 22 December 2008; revised 27 March 2009; accepted 15 April 2009. † Both authors contributed equally to this article.
Results: Compared to healthy subjects, the heroindependent subjects had reduced GM volume in the right prefrontal cortex, left supplementary motor cortex and bilateral cingulate cortices. Conclusion: Frontal and cingulate atrophy may be involved in the neuropathology of heroin dependence. Key words: brain imaging, gray matter, heroin, voxelbased morphometry.
cerebrospinal fluid (CSF) spaces,14 and frontal volume loss in opiate addiction.15 A recent study reported a reduction of the thalamus GM volume and its negative correlation with level of alcohol use in opioid dependence.16 Using structural magnetic resonance imaging (MRI), Lyoo et al. found increased white matter (WM) intensities in the frontal lobes.17 and decreased gray matter (GM) density in the bilateral prefrontal cortices, insular cortex, temporal cortex, left fusiform cortex and right uncus in opiatedependent subjects on methadone maintenance therapy (MMT).18 In our previous study using diffusion tensor MRI, we determined that bilateral frontal and left cingulate WM integrity was disrupted in heroin-dependent subjects on MMT.19 Thus, heroin dependence may induce anatomical changes and the frontal and cingulate regions may be involved. The GM volume changes of these brain regions, however, have not been determined in heroin addiction. Optimized voxel-based morphometry (VBM) is a whole-brain unbiased objective approach that can characterize the differences in regional brain volume
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using structural MRI.20 It is more sensitive in detecting subtle changes in brain volume than conventional methods of volumetry.21 Another advantage of optimized VBM is the introduction of study-specified templates, which is created from structural images of the whole studied sample. The objective of using customized templates is to further reduce any potential bias for images normalization and segmentation.20 This strategy is particularly appropriate when the demography of the studied population is significantly different from that of the population used to develop the VBM approach, as is the case in the present study. In the present study, optimized VBM was used to examine the GM volume difference between Chinese heroin-dependent subjects and healthy controls. We expected to observe that heroin dependence is associated with MRI-detectable GM changes, particularly in the frontal and cingulate cortices.
METHODS Participants The heroin-dependent subjects were recruited from the Addiction Recovery Center, Changsha Mental Health Hospital of Changsha City, Hunan Province, China. All heroin-dependent subjects met the following inclusion criteria: (i) 18–45 years of age; (ii) Han Chinese ethnicity; (iii) right handedness; (iv) diagnosis of heroin dependence using the Structured Clinical Interview for DSM-IV;22 (v) self-reported active heroin use for at least 6 months; (vi) positive urine test for heroin on admission; (vii) willingness to begin MMT; and (viii) voluntary registration for treatment and ability to provide consent for the research. Subjects and controls were excluded if they had (i) a history of psychiatric illness other than heroin dependence; (ii) a history of polysubstance abuse (other than nicotine use); (iii) a history of neurological illness or other serious physical illness; (iv) a history of psychiatric disorders in first-degree relatives; or (v) a contraindication for MRI. Healthy subjects were recruited from the community and were matched for age, sex, ethnicity and education years with the heroin-dependent subjects. The study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University, Hunan, China. Written informed consent was obtained from all subjects.
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Image acquisition Images were acquired on a 1.5-T GE Signa Twinspeed MR scanner (General Electric Medical System, Milwaukee, WI, USA) equipped with a homogenous birdcage head coil. Head motion was minimized with foam pads provided by the manufacturer. High-resolution whole brain volume T1-weighted images were acquired sagittally with a 3-D spoiled gradient echo (SPGR) pulse sequence (repetition time, 12.1 ms; echo time, 4.2 ms; flip angle, 15°; field of view, 240 ¥ 240 mm; acquisition matrix, 256 ¥ 256; thickness, 1.8 mm; gap, 0; no. excitations, 2; 172 slices.
Image analysis Anatomical images analysis was performed with optimized VBM using the VBM2 toolbox (http:// dbm.neuro.uni-jena.de/vbm), one extension of the SPM2 software package (Wellcome Department of Imaging Neuroscience, University College London, London, UK). Default parameters were used in image preprocessing. The optimized VBM consists of two steps: creation of study-specific whole brain template and GM, WM and CSF priors; and data segmentation, registration to and resegmentation in standard space, using the customized template and tissue priors. The VBM2 toolbox used a hidden Markov random field method to remove maximum of non-brain voxels from the data and minimize the noise level in resulting images. Furthermore, a Jacobian determinant was introduced to modulate the resulting GM images so that the voxel’s values indicate the absolute volume of the local GM. The resulting GM volume partition was smoothed with an isotropic Gaussian kernel of 8 mm full-width at half-maximum (FWHM). The GM volume difference was tested with analysis of covariance (ANCOVA) model co-varying for age and global GM volume. Images were masked with an absolute threshold of 0.1. A combined height threshold at P < 0.001 and extent threshold at k > 200 voxels was set to identify the significant clusters between the two groups. In addition, group difference on demography, volume of global GM, WM and CSF, and total incranial volume (TIV, equal to the sum of volume of global GM, WM and CSF) was tested using SPSS11.5 (SPSS, Chicago, IL, USA).
© 2009 The Authors Journal compilation © 2009 Japanese Society of Psychiatry and Neurology
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Table 1. Clusters with reduced GM volume in heroin dependence vs healthy subjects MNI coordinate Cluster size
Cluster-level P
Peak t
X
Y
Z
Location
Brodmann area
329 356 475
0.037 0.031 0.015
5.27 4.64 4.62 4.45
21 -4 3 -1
56 15 7 14
41 61 31 28
Right prefrontal cortex Left supplementary motor cortex Right cingulate cortex Left cingulate cortex
9 6 24 24
GM, gray matter; MNI, Montreal Neurological Institute.
RESULTS Sample description Images from 15 heroin-dependent subjects (10 men) and 15 healthy subjects (10 men) were recruited and well-matched for age (P = 0.978) and education years (P = 0.061). For heroin-dependent subjects, the average age (mean ⫾ SD) was 30.47 ⫾ 6.17 years (range, 24–42 years) and the average years of education were 10.13 ⫾ 1.96 years (range, 6–12 years). For the healthy subjects the average age was 30.53 ⫾ 6.70 years (range, 21–46 years) and the number of years of education was 11.73 ⫾ 2.49 years (range, 8–15 years). There were no significant differences in age (P = 0.98) and education (P = 0.06) between the two groups. The average number of cigarettes smoked each day by the heroin-dependent subjects was 21.33 ⫾ 5.16 (range, 20–40) while the healthy subjects were non-smokers. For the heroin-dependent group, the average duration of heroin use was 74.53 ⫾ 55.53 months (range, 6–204 months). The average dose of heroin used before entering the recovery center was 1.26 ⫾ 1.09 g (range, 0.1–4.0 g). Routes of heroin use included i.v. (nine subjects) and inhalation (six subjects). Subjects received MMT for an average of 3.60 ⫾ 1.35 days (range, 2–6 days) before the subject was scanned. The highest dosage of methadone that each subject received averaged 25.40 ⫾ 5.70 mg (range, 15–30 mg) and the last dosage of methadone on the scanning day averaged 12.93 ⫾ 4.13 mg (range, 5–18 mg).
Optimized voxel-based morphometry Compared to healthy subjects, heroin-dependent subjects demonstrated reduced GM volume in three clusters: Brodmann area 9 (BA9) of the right prefron-
tal cortex (PFC, cluster level P < 0.037), BA6 of the left supplementary motor cortex (SMC, cluster level P < 0.031) and a cluster located bilaterally in BA24 of the cingulate cortex (CC, cluster level P < 0.015; Table 1; Fig. 1). There were no areas with increased GM volume in heroin dependence. No significant group difference was found in the TIV, volume of global GM, WM and CSF, or ratio of GM/TIV, WM/TIV and CSF/TIV.
DISCUSSION The present study provides evidence that heroindependent subjects show reductions of GM volume in the right PFC (BA9), left SMC (BA6) and bilateral CC (BA24). The finding supports the anatomical changes of frontal and cingulate regions in heroin
Figure 1. Compared to healthy subjects, heroin-dependent subjects had gray matter volume reduction in the right prefrontal cortex (PFC), left supplementary motor cortex (SMC) and bilateral cingulate cortex (CC).
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dependence. The PFC, SMC and CC (particularly the anterior CC) play important roles in cognitive control,23–25 which is critical to the goal-directed behavior. Cognitive control involves the ability to coordinate thought and action in accordance with internal goals.26,27 The active maintenance of PFC activity indicates the representation of goals, assignment of valence and selection of action to achieve them.24,28 The SMC is active before movements occur and seems to be crucial for linking cognition to action.25 Individuals with anomalies in the PFC, SMC and CC may be impulsive and prefer immediate rewards to delayed, but more beneficial, consequences.3 Thus, drug addiction is characterized by compulsive and persistent drug-taking behavior despite serious negative consequences. Substantial evidence indicates significant lower frontal and cingulate GM volume in subjects dependent on other addictive drugs. Both active and abstinent cocaine-dependent subjects showed reduced frontal GM volume,29,30 and the reduction is negative associated with impairment of executive function.29 Studies have documented that the frontal GM volume reduction is particularly involved in alcohol dependence.31–33 A recent VBM study found extensive lower GM volume in bilateral dorsolateral frontal and cingulate cortices in detoxified male alcoholic subjects with good psychosocial functioning.34 Negative findings, however, were demonstrated in ventromedial PFC in a study using region-of-interest approach on the abstinent alcoholic subjects with decision-making deficit.35 Active methamphetamine abuse shows decreased GM in cingulate and other limbic cortices.36 The finding of lower frontal GM volume is replicated in anatomical studies on subjects dependent on two or more substances.29,37,38 Therefore, frontal and cingulate GM volume reduction is one of the common findings in drug addiction. More extensive and severe anatomical changes may exist in the whole population of heroin dependence, suggested by many case reports.7–12 The effects of heroin on GM volume may be underestimated in the present study. All the heroin-dependent subjects were physically healthy and volunteered for heroin abstinence and MMT. Subjects with active withdrawal symptoms were excluded in order to obtain better cooperation with imaging. It is possible, therefore, that the population of heroin-dependent subjects examined in this study is not representative of the full heroin-dependent population and that examining all
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heroin-dependent subjects would indicate different patterns of GM volume changes. Future imaging studies tracking the natural history of heroin abuse may improve the understanding of biological correlates and their trajectory in heroin dependence. In interpreting the findings of the present study, the prevalence of nicotine use in the heroindependent subjects should be considered. Previous studies have demonstrated that nicotine is associated with increased GM volume in patients with schizophrenia39 and alcoholic subjects during prolonged sobriety.40 Nicotine may reduce the incidence of neurodegenerative illness, such as Parkinson’s disease, via a mechanism of neuroprotection.41 But a VBM study showed that smokers (nicotine-dependent adults) had lower GM density in bilateral PFC and right cerebellum than non-smokers.42 These findings highlight the potential confounding role of nicotine in GM studies. Future MRI studies on heroin dependence will benefited from recruiting healthy smokers or heroin-dependent non-smokers. Other limitations include the relative small sample size (n = 15), large range of heroin abuse duration (6–204 months), and different methods of heroin-taking. Several aspects of the present study are noteworthy. This is the first optimized VBM study to test the GM volume, rather than the density/concentration in heroin dependence. Moreover, the study used the customized whole-brain template and tissue priors to process the anatomical images, which improves the characterization of GM changes in Chinese subjects dependent on heroin. Finally, the findings further support frontal and cingulate abnormalities as one of the common findings in drug addiction,1 thus indicating that a unified mechanism may underlie disparate forms of addiction.3,43 In conclusion, the present anatomical MRI and optimized VBM study found GM volume reduction in right PFC, left SMC and bilateral CC in heroin dependence, supporting the concept of anatomical changes in the brain with repeated exposure to drugs. Frontal and cingulate regions may be particularly affected in addiction.
ACKNOWLEDGMENTS The work was supported by grants from the National Natural Science Foundation of China (30530250 to Lin Xu) and 973 Program (2006CB500800 to Lin Xu and 2007CB512308 to Zhening Liu).
© 2009 The Authors Journal compilation © 2009 Japanese Society of Psychiatry and Neurology
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