T2 relaxation time alterations underlying neurocognitive deficits in alcohol-use disorders (AUD) in an Indian population: A combined conventional ROI and voxel-based relaxometry analysis
Introduction
Chronic alcohol consumption is known to impair performance in a variety of cognitive functions, as assessed by various neuropsychological studies. Attention, working memory, visuospatial abilities, executive functions, learning skills, and verbal fluency have all been shown to be impaired in alcohol-use disorders (AUD) (Ambrose, Bowden, & Whelan, 2001; Demir et al., 2002, Fama et al., 2004, Oscar-Berman and Marinković, 2007, Stavro et al., 2013, Uekermann et al., 2003). Magnetic resonance imaging (MRI) techniques have contributed significantly to our understanding of the effects of heavy alcohol use on structural, biochemical, and functional changes in the human brain, which might underlie these impaired cognitive abilities. Structural imaging has consistently revealed that AUD individuals have reduced gray and white matter volumes, particularly in the frontal lobe, temporal lobe, hippocampus, and cerebellum (Chanraud et al., 2009, Demirakca et al., 2011, Fein et al., 2006, Mechtcheriakov et al., 2007). Proton magnetic resonance spectroscopy (1H MRS) studies in subjects with AUD have also demonstrated lowered concentrations of N-acetyl-l-aspartate (NAA) and increased concentrations of choline-containing compounds (Cho), most notably in the frontal lobe, temporal lobe, occipital lobe, and cerebellum (Bendszus et al., 2001, Gazdzinski et al., 2008, Modi et al., 2011, Parks et al., 2002, Ross and Bluml, 2001). Diffusion tensor imaging (DTI) studies in subjects with AUD have shown decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in the corpus callosum, temporal lobe, cingulum, frontal lobe, hippocampus, occipital lobe, cerebellum, and centrum semiovale, which is suggestive of compromised axonal or myelin integrity (Bagga et al., 2014, Chanraud et al., 2009, Pfefferbaum et al., 2006, Trivedi et al., 2013). fMRI results also revealed changes in brain activation pattern (enhanced or diminished activation) in AUD individuals in response to different fMRI tasks, such as abstract reasoning (Bagga, Singh, et al., 2014), semantic judgment (Bagga et al., 2013), working memory (Pfefferbaum et al., 2001), attention (Campanella et al., 2013), and simple decision making (Gilman, Davis, & Hommer, 2010), suggestive of decreased efficiency of relevant brain networks.
Despite a large body of literature demonstrating functional, metabolic, morphological, and microstructural alterations associated with AUD as discussed above, very few studies specifically sought to examine the alterations in associated hemodynamic or paramagnetic properties (as reflected by T2 relaxation times [T2-RT]) in this population. In a study of central pontine T2-RT measurements in patients with alcoholic Korsakoff's syndrome (KS) and asymptomatic alcoholic patients, prolonged T2-RT was observed in KS patients. In asymptomatic alcoholic patients, T2-RT increased significantly with older age (Sullivan & Pfefferbaum, 2001). In another study by Agartz, Sääf, Wahlund, and Wetterberg (1991), conducted at lower field strength, no differences were found in T2-RT in AUD and control subjects. However, this study also found a correlation between atrophy and T1-RT in AUD subjects.
T2 relaxometry is a non-invasive quantitative MR measure that maps T2-RT and has been established as a reliable tool for assessing brain tissue abnormalities in conditions such as temporal lobe epilepsy (Jackson et al., 1993, Pell et al., 2008, Pell et al., 2004), Alzheimer's disease (Laakso et al., 1996), and various mental health disorders (Neema et al., 2009, Oh et al., 2007). The technique has been found to be useful for identifying early abnormalities that are not obvious on visual assessment of MRI images (Armspach et al., 1991, Barbosa et al., 1994, Grenier et al., 2002, Miller et al., 1989, Neema et al., 2007, Whittall et al., 2002). These studies have suggested that prolonged T2-RT has been attributed to diffuse abnormality, or pathological processes such as edema, demyelination, and gliosis, or to “small lesions” which are undetected by visual inspection of conventional MR images. The relaxometry studies provide a more detailed characterization of tissues, compared with conventional qualitative imaging approaches (Deoni, 2010) and have shown promise in their ability to detect diffuse damage in various brain regions (Neema et al., 2007). The measurement of the T2 time is commonly achieved by the relatively simple acquisition of multiple spin echo images acquired at a range of echo times. The time constant of the exponential signal decay represents the rate of T2 relaxation. Earlier, analysis of T2 relaxometry data had been carried out by manual placement of regions of interest (ROIs) over predefined areas of anatomy. However, the search space is then obviously limited to those areas chosen for ROI placement. Voxel-based relaxometry (VBR) analysis is a relatively new technique that provides an unbiased and even-handed assessment of major differences in T2-RT throughout the brain, identifying regions of highly significant differences that withstand correction for multiple comparisons (Pell et al., 2004).
Based on the above findings, we hypothesize that we will observe T2-RT alterations in brain regions (frontal, temporal, and parietal lobe) that show changes on structural, metabolic, and functional studies, and that the alterations for various cognitive abilities known to be impaired in AUD subjects.
In the present study, T2 relaxometry was carried out using both voxel-based analysis and ROI analysis with the following objectives: (1) identifying regions of T2-RT alterations in AUD subjects as compared to controls, and (2) identifying the correlation of T2-RT with the neuropsychological test scores of brain dysfunction.
To the best of our knowledge, this is the first VBR-based study to assess the alterations in T2-RT associated with AUD.
Section snippets
Subjects
The study included 25 AUD subjects and 25 healthy control subjects. All study participants were men, between 30 and 45 years of age, and all were non-smokers. All the subjects were matched for age, education, and socio-economic status. The AUD subjects were recruited from an army rehabilitation center, and met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for alcohol dependence, and had abstained from drinking alcohol for approximately 2 weeks (median = 17 days). The
Voxel-based analysis
The voxel-based relaxometry followed methods described by Pell et al. (2004). First, the relaxation maps were spatially normalized in Statistical Parametric Mapping (SPM8, Wellcome Department of Cognitive Neurology, London, UK, http://www.fil.ion.ucl.ac.uk/spm) software package implemented in MATLAB R2008a (Version 7.6.0, MathWorks, Sherbon, MA) to the same stereotactic space using the T2 template. Since the T2 maps have relatively poor tissue contrast, this step was carried out via initial
Results
The AUD subjects and control subjects were similar with respect to mean age, years of education, and body mass index (Table 1). Drinking history variables for the AUD subjects are presented in Table 1.
Discussion
Recent studies on subjects with AUD have shown that extent of brain damage and the degree of cognitive impairments observed in subjects with AUD differ across individuals within and across populations. Thus, our study, which was carried out on an Indian population, would help in filling the substantial gap in the research literature on influence of environment on alcohol abuse patterns, and a near absence of studies on adults with AUD in an Indian population.
From a genetic perspective,
Conclusions
In conclusion, this study explored the alterations in T2-RT in AUD subjects in an Indian population. This is the first study that employed VBR to analyze whole-brain T2-RT alterations in this population. The prolonged T2-RT in these brain regions is suggestive of tissue disruption or loss of myelination, which in turn would have resulted in impaired cognitive abilities observed in these subjects.
Acknowledgments
This work was supported by DRDO R&D Project No. INM 311 (4.1) and Council of Scientific and Industrial Research (CSIR), India. None of the authors has any conflict of interest to declare.
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