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Rapid Partial Regeneration of Brain Volume Duringthe First 14 Days of Abstinence from Alcohol Keywords:

Alcoholism;

Gray Matter; Structural MRI; Voxel-Based Morphometry

Abstract

Background

Chronic alcohol abuse leads to severe damage of the nervous system, including a change in cerebral metabolism and brain morphology. Globalvolume reductions of gray matter (GM) and white matter and an increase in cerebrospinal fluid (CSF) occur after severe alcohol consumption, butabstinent alcoholics also demonstrate a brain volume recovery. The aim of this study was to investigate whether volumetric amelioration takes placealready within the first 2 weeks of abstinence.

Methods

All 49 alcohol-dependent patients included in this study were scanned within the first 24 hours of detoxification and after 2 weeks of supervisedabstinence. Amelioration of volumetric brain loss in alcohol-dependent patients has been investigated, and brain volumes have been compared with55 healthy control subjects using whole-brain segmentation and a voxel-based morphometric approach.

Results

On the first day of abstinence, the global CSF volume was larger and the GM volume was smaller in alcohol-dependent patients compared withhealthy controls. The largest clusters with significant volumetric differences were in the cingulate gyrus, precentral and middle frontal gyrus,cerebellum, and insula. Already after 2 weeks of abstinence, a significant albeit partial recovery of GM volume occurred in several brain regions.

Conclusions

Our results show that recovery of GM volume in alcohol-dependent patients starts within a few days after detoxification but varies between brainregions. This suggests that the general ability to recover and the rate as well as onset of the recovery diverges for different brain regions.

Chronic alcohol abuse has negative psychological, sociological, and biomedical effects. Besides well-known physical consequences like livercirrhosis or hypertension, alcoholism also leads to a severe damage of the nervous system, including detrimental effects on cognitive functions (Mannet al., 1999 ), and a change in cerebral metabolism (Cardenas et al., 2011 ) and brain morphology (Buhler and Mann, 2011 ).

Several studies demonstrate a global volume reduction in gray matter (GM) and white matter (WM) and an increase in cerebrospinal fluid (CSF)volume in alcoholics (Chanraud et al., 2009 ; Demirakca et al., 2011 ; Fein et al., 2002 ; Mechtcheriakov et al., 2007 ; Nicolas et al., 2000 ). Volumechanges occur in the entire cerebral cortex with a focus on the frontal, parietal, and cingulate cortex, and in insula, thalamus, hippocampus, andcerebellum. Brain atrophy has been found not only in alcohol-dependent patients (Mechtcheriakov et al., 2007 ; Nicolas et al., 2000 ) but also inrecently detoxified alcoholics (Demirakca et al., 2011 ) and those who were abstinent from alcohol from months to years (Bartsch et al., 2007Chanraud et al., 2009 ; Fein et al., 2009 ). The reported areas of significant volume loss do not completely overlap in those groups. Nonabstinent orrecently detoxified alcoholics, compared with healthy controls, show volumetric differences in the cerebellum (Bartsch et al., 2007 ; Mechtcheriakovet al., 2007 ; Nicolas et al., 2000 ). In alcoholic patients who have been abstinent for several weeks or months, this region showed no significantvolumetric difference compared with social drinkers (Chanraud et al., 2009 ; Demirakca et al., 2011 ; Wobrock et al., 2009 ).

Previous studies on the effects of alcohol on brain volume concentrated on gender-related differences, but the findings were inconsistent. In somestudies, the interaction of diagnosis and gender is driven by greater abnormalities in male patients (Fein et al., 2009 ; Pfefferbaum et al., 2001 ), whilein other studies, greater differences in women cause the interaction (Hommer et al., 2001 ; Mann et al., 2005 ). In addition, in a recent study, nodiagnosis by gender interaction has been found (Demirakca et al., 2011 ). This discussion is additionally complicated by other differences betweenmen and women, for example in brain volume, body weight, and fat proportion, which all together could lead to different blood alcohol levels evenwhen the same amount of alcohol is consumed.

A period of continued abstinence leads to brain volume recovery and restoration of cognitive functions (Agartz et al., 2003 ; Bartsch et al., 2007Cardenas et al., 2007 , 2011 ; Demirakca et al., 2011 ; Gazdzinski et al., 2008 , 2010 ; Mann et al., 1999 , 2005 ; Pfefferbaum et al., 1995 ; Wobrock et al.,2009 ). Sobriety can result in recovery of GM and WM volume and a reduction in CSF volume. The brain regions where GM volume increases
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include the cingulate gyrus, insula, cerebellum, hippocampus, parietal lobe, temporal lobe, anterior frontal gyrus, and periventricular and frontaledges. These longitudinal studies investigated the effect of continued abstinence lasting from 1 to 9 months. However, the time point of the firstscanning session with respect to the date of last alcohol consumption has not been the same for all patients, and the difference range comprisedseveral weeks. This may mask volumetric alterations and cover rapid recovery during the first days of detoxification and cont inued withdrawal.

To clarify the possibility of early recovery, we investigated volumetric brain changes within the first 2 weeks of abstinence. As the interval for possible changes seems to be comparatively short, we made certain to conduct scanning sessions in all alcohol-dependent patients within the first24 hours of detoxification and then exactly 2 weeks later.

Materials and Methods

Participants

The studied sample consisted of 49 alcohol-dependent patients (9 women) and 55 healthy controls (13 women). Participants' characteristics aresummarized in Table 1. All patients met DSM-IV and ICD-10 criteria for alcohol dependence and were recruited from the Department of AddictionMedicine at the Central Institute of Mental Health in Mannheim, Germany, where they underwent an inpatient alcohol withdrawal treatment. The

patients consumed their last alcoholic drink on the day of admission or the day before. Two magnetic resonance (MR) scans (scan 1: duringdetoxification on the first day of abstinence; scan 2: 14 days later) were recorded, and abstinence of all patients was confirmed by unheralded alcohol

breath tests within the 2 week interval. On the first day of abstinence, alcohol was still detectable in 35 patients at a level of 0.39 0.40 g/l. In theremaining 14 patients, alcohol levels had reached zero shortly before magnetic resonance imaging (MRI) started. On the day of the first scan, all

patients were free of benzodiazepines, but 12 patients had received clonidine (adrenergic alpha-2 receptor agonist) before the scanning session totreat withdrawal-associated hypertension or tachycardia. Within the 14 days of abstinence prior to the second MR scan, 36 alcohol-dependent

patients were treated with benzodiazepines and 21 patients with clonidine. Correlation analyses revealed no association ( p > 0.1) of the amount ofclonidine or benzodiazepines with any detected brain volume difference or change at any time point. Alike, including administered clonidine or

benzodiazepines quantities as an additional covariate in analysis of variance (ANOVA), did not significantly alter our results. Hence, we found noindication that the medications affected the results.

Table 1. Characteristics of Alcohol-Dependent Patients and Healthy Controls (mean SD)

Alcohol-dependent patients Healthy controls

All Female Male All Female Male

N 49 9 40 55 13 42

Age (years) 47 10.1 48.2 6.9 46.8 10.7 45.3 11.9 43.9 13.3 45.7 11.5

Alcohol consumption in 3 months prior detox in g/dd (drink sa/dd)211 148

15 drinks

181 101

13 drinks

218 157

16 drinks

23 18

2 drinks

15 7

1 drink

25 19

2 drinks

Proportion of cigarette smoker 80% 89% 77% 31% 31% 31%BMI 24.3 4.1 24.8 3.9 24.2 4.2 24.7 3.5 22.4 3.0 25.4 3.3

dd, drinking day; BMI, body mass index.

a

1 drink contains 14 g alcohol.

The comparison group of 55 healthy controls was recruited by newspaper advertisement and was age- and sex-matched to the group of alcohol-dependent patients (see Table 1). A fraction of 20 healthy controls has also been studied twice with a time interval of 14 days between bothmeasurements.

Exclusion criteria for all participants were any substance dependence except nicotine (and alcoholism in the patient group), any psychotropicmedication in the last 3 months, positive urine drug screen, history of brain injury, other psychiatric or neurologic brain disease, any lifetimediagnosis of a psychotic disorder, hepatic encephalopathy, liver cirrhosis, severe medical illness (e.g., severe diabetes, HIV, polyneuropathy, etc.),and MRI-related exclusion criteria (e.g., metal implants). The study was approved by the ethics committee of the medical faculty Mannheim ofHeidelberg University, and an informed written consent was obtained from all participants.

MRI Data Acquisition and Image Processing

The MRI images were acquired on a 3T Siemens Tim Trio system (Erlangen, Germany) using a T1-weighted MPRAGE sequence with a whole-braincoverage (192 slices, 1 mm slice thickness, 256 mm field of view, 1 mm 3 resolution).
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The imaging data have been processed using the voxel-based morphometry toolbox (VBM8, http://dbm.neuro.uni-jena.de/vbm/ ) implemented in theSPM8 package (http://www.fil.ion.ucl.ac.uk/spm/software/spm8/ ). All images were corrected for bias effects, normalized to the Montreal

Neurological Institute (MNI) template using both linear and nonlinear transformation, and classified into GM, WM, CSF, and nonbrain tissue withinthe same generative model (Ashburner and Friston, 2005 ; Luders et al., 2009 ). For normalization, the option of low-dimensional spatialnormalization (as implemented in VBM8) was chosen. For a more thorough removal of the remaining nonbrain tissues, we used the optionThorough Cleanup. The GM and WM images were modulated by multiplication with the Jacobian determinant to account for volume changesresulting from affine and nonlinear transformations during normalization (Good et al., 2001 ). Finally, modulated GM and WM images have beensmoothed with an 8 mm 3 FWHM Gaussian kernel. We checked the output images at each step of processing; the sample homogeneity was controlledusing the VBM8 toolbox. The preprocessed data have been further analyzed using SPM8 (see Statistical Analysis ).

Global Fractional Compartment Volumes

Global GM, WM, and CSF volumes have been calculated by integrating the respective values over all voxels of the segmented images in nativespace (i.e., in spatial correspondence to the original data). The sum of these 3 fractions was used as an estimate for the to tal intracranial volume (TIV;TIV = GM + WM + CSF) (Klauschen et al., 2009 ; Lders et al., 2002 ; Smith et al., 2007 ). To account for the known gender differences in brain size(larger overall GM, WM, and CSF volumes in men than in women) (Filipek et al., 1994 ; Lders et al., 2002 ), we normalized the fractional volumesfor each participant to the individual TIV. These ratios, for example, GM to TIV, have been used for further comparisons using IBM SPSS StatisticsRelease 20.0.0 PASW 18 (Chicago, IL).

Regional Fractional Compartment Volumes

In addition to the global volume changes, we were interested in the volumetric changes in certain regions of interest (ROIs), for which volumereduction has been shown in alcohol-dependent patients and a significant volume recovery because of abstinence was reported. These brain regionsincluded insula, cingulate gyrus, cerebellum (including vermis), anterior frontal gyrus, hippocampus, and parietal and temporal lobe (Bartsch et al.,

2007 ; Cardenas et al., 2007 ; Chanraud et al., 2009 ; Demirakca et al., 2011 ; Gazdzinski et al., 2008 ; Mechtcheriakov et al., 2007 ; Pfefferbaum et al.,1995 ).

Individual GM images of the ROIs were calculated by using the image calculation function in SPM8. For each ROI, a mask of the specified regionwas created using the WFU PIC Atlas (Maldjian et al., 2003 ), and ROI voxels of the modulated MRI images were cut out. The GM volume in eachROI was estimated by integrating the GM voxel values over all voxels within the ROI (Klauschen et al., 2009 ; Lders et al., 2002 ; Smith et al.,2007 ). To account for brain size effects, the values were normalized individually to the TIV and data were further analyzed using SPSS (PASW 18).

Statistical Analysis

The global and regional brain volume estimates, normalized to the individual TIV, were then related to the mean of the corresponding gendersubgroup of healthy controls. This approach allows visualization of interactions accounting for gender effects in global and regional volumeestimates.

The tissue partition maps from the VBM image processing were used in analysis of covariance (ANCOVA) and regression analysis (based on ageneral linear model SPM8) to calculate voxel-wise differences between healthy controls and alcohol-dependent patients. Age, gender (except for theevaluation of gender and diagnosis interaction), and TIV served as covariates. Furthermore, we investigated a possible influence of smoking behavioron the brain volume, by applying 2-sample t -tests for smokers and nonsmokers (with SPM8) for alcohol-dependent patients and healthy controls,respectively (see Table 1).

The correlation between drinking severity (assessed by the Form 90 interview; Tonigan et al., 1997 ) and GM volume within the ROIs was assessed by calculating partial correlation coefficients using SPSS (PASW 18). Age was used as a nuisance variable.

The significance level for the VBM analysis has been set to p < 0.05; whole-brain family wise error (FWE) corrected. For all other statistical testing,the significance level was defined to p = 0.05.

Results

Volumetric Differences Between Controls and Alcohol-Dependent Patients on the First Day of Abstinence

Whole-Brain Volume

Group comparisons of the fractional cerebral compartment volumes revealed significant differences between patients and healthy controls. CSF/TIV( p < 0.001) and GM/TIV ( p < 0.001), but not WM/TIV ( p > 0.4) differences gained significant results. A gender effect was detected only for theGM/TIV ratio: it was significantly higher in women compared with men ( p = 0.002). Analyzed for both genders separately, the CSF/TIV ratio was22% higher ( p = 0.001) in alcohol-dependent women and 20% higher in male patients ( p < 0.001), compared with the respective gender-matchedhealthy control group. Furthermore, we observed a smaller GM/TIV ratio in alcohol-dependent men and women (both 7%; p < 0.001 in men,

p = 0.002 in women), while the WM/TIV ratios did not differ significantly from healthy control values ( p > 0.2). No gender by diagnosis interactionwas found (Table 2 and Fig. 1). Smoking status had a significant influence on brain volume, with the nonsmoking subgroup exhibiting smaller
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GM/TIV ( p = 0.006) and WM/TIV ( p = 0.049) ratios and larger CSF/TIV ratio ( p < 0.001) compared with the smoking subgroup in alcohol-dependent patients. In healthy controls, only the WM/TIV ratio was significantly higher ( p = 0.037) in the nonsmoking subgroup.

Figure 1. Percent differences of global gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) and regional GM volumes of alcohol-dependent patients relative to healthy controls (=100%) for each gender, respectively. TIV, total intracranial volume.

Table 2. Relative and Regional Brain Volumes: Results of a 2 2 Factorial Analysis of Variance with the Factors Sex and Diagnosis (mean SD)

Global volumesMale Female p -Value

HC (42) (in%) Pat (40) (in%) HC (13) (in%) Pat (9) (in%) Gender Diagnosis Gender Diagnosis

1. HC, healthy controls; Pat, alcohol-dependent patients; CSF, cerebrospinal fluid; TIV, total intracranial volume; GM, gray matter; WM,white matter.

Age (years) 45.7 11.5 46.8 10.7 43.9 13.3 48.2 6.9 0.960 0.321 0.553

CSF/TIV 17.1 2.0 20.5 3.7 16.0 1.9 19.5 2.1 0.106

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Figure 2. ( A) VBM analysis of gray matter volume loss in alcohol-dependent patients compared with healthy controls for the first scan at the first dayof abstinence (yellow) and 14 days later (orange) and ( B) the results of a paired t -test (increased gray matter: Scan 2 > Scan 1) for alcohol-dependent

patients (green). Family wise error corrected, p < 0.05. In A and B, the first image of each pair displays the same slice, and the white bar indicates the position of the second image in each pair.

Table 3. Peak Voxel of Gray Matter Volume Loss in Alcohol-Dependent Patients Compared with Healthy Controls (Age, Gender and TIV asCovariates), p < 0.05 FWE Corrected, Cluster Size 30 Voxels

MNI label p (FWE) T Z x y z Cluster size1. MNI, Montreal Neurological Institute; FWE, family wise error; TIV, total intracranial volume.

Cingulate gyrus

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A paired t -test in alcohol-dependent patients revealed several brain regions with significant GM volume recovery after 2 weeks of abstinence(Fig. 2 B). The largest clusters with significant recovery were found in the cingulate gyrus, temporal gyrus, parietal lobule, cerebellum, and precuneus(Table 5).

Table 4. Global and Regional Gray Matter Volume Changes (mean SD) Measured at the First Day of Abstinence (1. Scan) and After 14 Days ofAbstinence (2. Scan)

Global volumesAlcohol-dependent patients (49) Healthy controls (20)

1. Scan(in%)

2. Scan(in%)

p paired t -test 1. Scan (in%)

2. Scan(in%)

p paired t -test

1.

CSF, cerebrospinal fluid; TIV, total intracranial volume; GM, gray matter; WM, white matter.

CSF/TIV 20.3 3.5 20.1 3.4 0.006 17.0 2.0 17.0 2.0 0.508

GM/TIV 41.9 2.9 42.3 2.8 0.001 45.0 1.9 45.1 2.0 0.317

WM/TIV 37.7 2.0 37.6 2.0 0.130 38.0 1.6 37.9 1.6 0.527

Regional volumes

Insula/TIV 0.96 0.10 0.97 0.11

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et al., 2011 ; Hommer et al., 2001 ), no global WM volume difference was detected. GM/TIV ratios in the investigated ROIs were significantly smallerin the alcohol-dependent patients, and VBM analyses showed that volume loss in these regions spanned over large clusters (except for thehippocampus, where VBM found no voxels with significant differences). Nonetheless, GM volume reduction affects other regions as well, namelythe precentral gyrus, and precuneus. Volume reduction in alcohol-dependent patients in the frontal lobe, parietal lobe, temporal lobe, and thecerebellum was previously reported by Cardenas and colleagues (2007 ). These authors additionally found a reduction in the occipital lobe volume. Inanother study, Demirakca and colleagues (2011 ) observed no volume shrinkage in the cerebellum in alcohol-dependent patients 4 to 37 days after thelast alcohol consumption but GM shrinkage most prominent in the insula and the cingulate gyrus, regions which also showed a significant volumedecrease in our study.

Cigarette smoking is common among alcohol-dependent patients, and hence, it was previously discussed whether changes in brain volume in

alcohol-dependent patients can be solely attributed to alcohol consumption. In contrast to previous studies (Das et al., in press; Gazdzinski et al.,2005 ; Liao et al., in press), we found no evidence of smoking effects on GM volume in our sample; among the healthy controls, the whole-brainGM/TIV ratio showed no significant differences for the smoking and nonsmoking subgroup, and the VBM analyses revealed significant differencesonly in 1 small-sized cluster. On the contrary, the nonsmoking subgroup ( N = 10) from the alcoholic group exhibited larger brain volume loss onglobal and regional level (not in the VBM analyses). On the first day of abstinence, nonsmoking alcohol -dependent patients had smaller GM/TIV andWM/TIV and larger CSF/TIV ratios than the smoking subgroup, while neither age nor alcohol consumption was significantly different between thesubgroups. Brain volume shrinkage prevailed also 14 days later except for the cerebellum, where the difference between the smoking andnonsmoking alcohol-dependent patients has faded. This finding agrees with the significantly higher larger GM/TIV increase in the cerebellum withinthe first 2 weeks of abstinence for nonsmoking alcoholics compared with smoking alcoholics. In agreement with Yeh and colleagues (2007 ), wesuggest that smaller regional brain volumes in the first measurement are related to faster volume gains. Nevertheless, we would be cautious with theinterpretation of results derived from only 10 nonsmoking alcohol-dependent patients, as there is still a chance of obtaining a random result becauseof the small sample size.

After 14 days of abstinence, brain volume differences in alcohol-dependent patients could be identified in basically the same regions observed on thefirst day of abstinence, except for precuneus and middle temporal gyrus that exhibited significant volumetric differences compared with healthycontrols. In several regions, the differences were reduced as indicated by decreased cluster sizes but still significant. It is important to note that theextent of volume recovery from the first day of abstinence to 14 days afterward depends on the brain region, and hence, the recovery rate seems tovary between regions. For example, recovery in the cerebellum seems to happen faster in comparison with the cingulate gyrus, as indicated by agreater volume gain within the 2-week interval. This is also reflected in the intraindividual GM volume increase within the 2-week interval. Asignificant increase in GM volume was found only in the cingulate gyrus, temporal gyrus, parietal lobule, cerebellum, and precuneus, but not in the

precentral gyrus or frontal gyrus. The brain volume recovery in these 2 latter regions seems either to be slower or starting later in comparison to therecovery in the cerebellum, and might in the long run not be completely reversible (as has been suggested by Fein et al., 2006 ). These differences inrecovery rate or recovery onset of atrophic GM regions become more evident when we compare our results with previous VBM studies investigatingthe effects of different time intervals with respect to withdrawal.

Volumetric shrinkage in the cerebellum, including the vermis, was only found in those VBM studies that were performed in nonabstinent alcoholics(Mechtcheriakov et al., 2007 ; Nicolas et al., 2000 ). Studies that started at a later time point after detoxification (Chanraud et al., 2009 ; Fein et al.,2009 ) reported no volumetric difference in the cerebellum. In addition, a gain in cerebellar brain volume was reported in a longitudinal study wherethe first scan was obtained within the first week after detoxification (Bartsch et al., 2007 ). In the study by Demirakca and colleagues (2011 ) where

the time interval for the first scan spanned 4 to 37 days into abstinence, neither cerebellar shrinkage nor its gain was observed in a second MRscanning session after 3 months. Our results show that already after 2 weeks of abstinence, the cerebellar volume significantly increases comparedwith the first day of abstinence. Volumetric differences in the cerebellum are unlikely to be found if the scan is performed after 2 weeks ofabstinence. In addition, we found a small volumetric recovery in the insula that showed a large volume gain after 3 months of abstinence in the

previous study by Demirakca and colleagues (2011 ). Studies on brains of alcoholics that were abstinent for months to years (Chanraud et al., 2009Fein et al., 2009 ) indicate that some alcohol-induced brain damage might not be reversible at all. Altogether this leads to the conclusion that thegeneral ability for recovery, the recovery rate, and/or its onset varies between different brain regions.

Limitations

The aim of the study was to examine the brain volume differences between healthy controls and alcohol-dependent patients on their first day ofabstinence and to study the recovery within the first 14 days of abstinence. To examine alcohol effects, the participants had to meet several exclusioncriteria (e.g., no substance dependence except nicotine [and alcohol for the patients], no history of brain injury, no lifetime diagnosis of a psychoticdisorder, etc.), and we matched both groups for age and gender to make them as homogenous as possible. However, we could not control for every

possible difference between the groups that might possibly affect brain morphology (e.g., IQ, education, risk factors for Alzheimer disease, etc.).Hence, we cannot conclude that our findings of differences in brain morphology between the healthy controls and the alcohol-dependent patients aresolely attributed to the misuse of alcohol. Nonetheless, to the best of our knowledge, morphologic changes in the order observed have not beendescribed for any of the risk factors or group differences not taken into account here, and the results on the brain volume changes within the 14 daysof abstinence are unaffected by those considerations.

To perform the VBM analyses, we used the SPM8 software package, which allows a whole-brain VBM analysis including the cerebellum. Comparedwith the cortex, the cerebellum has a different structure, and for VBM analysis, this creates a particular challenge in terms of accurate normalization.A specific cerebellum-optimized procedure was established (Diedrichsen, 2006 ). A recent publication shows that common whole-brain VBMmethods tend to underestimate volumetric changes in the cerebellum (Kuhn et al., 2012 ).

Acknowledgments
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This study was funded by the DFG through a center grant (SFB636, project D7) and within the framework of Nationales Genomforschungsnetz(NGFN + No. 01GS08152, see www.ngfn-alkohol.de and Spanagel et al., 2010 ) by the Bundesministerium fr Bildung und Forschung.

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