Most of the evidence for structural brain damage in human substance abusers derives from recently developed applications of magnetic resonance imaging (MRI), which can be used for quantitative morphometrics and for assessment of structural change over time. Many of the relevant studies have involved automated or semi-automated segmentation of the brain into gray and white matter components, for restricted or separate analyses. Techniques that have been used include a wide range from labor-intensive methods, such as manual slice-by-slice tracing and volume drawing of individual structures, as well as more computationally intensive approaches that include pattern matching as well as voxel-based, tensor-based and cortical thickness mapping57
. This review also includes studies that assess white matter signal hyperintensities and diffusion tensor imaging (DTI) indices, since these measures help us understand the state of white matter microstructure in methamphetamine abusing individuals.
The strongest evidence for stimulant-associated differences, and possible stimulant-mediated neurotoxicity, has come from studies that relate to the use of methamphetamine (see , in which reports are presented in the approximate order of publication). We will first review studies of methamphetamine abusers and then discuss studies that assess MDMA abusers.
Imaging evidence for structural abnormalities in amphetamine abusers
The first controlled study to measure brain volumes in amphetamine users compared 9 methamphetamine–dependent young men (27.9 [SD=3.9years]) with 10 cocaine-dependent men and 16 men who did not use drugs58
. It involved semiautomated, histogram-driven measurements of frontal and temporal lobes on 1.5 Tesla (1.5T) T2-weighted MRI scans. Methamphetamine-dependent subjects had used the drug for more than 2 years (mean = 6.7 +/- 3.9 years), although the length of time between most recent consumption and imaging was not available. Smaller volumes of the temporal lobe, but not of the frontal lobe, were found in both methamphetamine and cocaine users, in comparisons with control men. The stimulant using groups did not differ from each other overall. However, only the cocaine group demonstrated an age-related decline in temporal lobe volume. In both groups, reductions in temporal lobe volume were localized primarily to gray matter. Smaller gray matter volume was invariably accompanied by larger white matter volume, consistent with the prolongation of complete myelination into adulthood59
. The trend for increased white matter volume was especially prominent in the methamphetamine group, providing a reduced group difference for total volume. The authors speculated that age-related loss of cortical gray matter in stimulant abusers might be associated with reduced capacity to experience euphoriant effects of psychostimulants such as cocaine60
, the only group to show age-related atrophic reductions. They suggested that this phenomenon might explain the well-established age-related reduction in psychostimulant addiction. However, no interpretation was made for finding stronger temporal than frontal effects. In addition, volumes of only parts of the frontal and temporal lobes were quantified.
In 2004, high-resolution surface-based computational image analysis of structural MRI (performed at 3 T) was used to map regional abnormalities in the cortex, hippocampus, white matter, and ventricles of 22 chronic methamphetamine abusers (mean use = 10.5 years) who used methamphetamine on most of the 30 days prior to entering the study, as compared with 21 age-matched control subjects who did not use amphetamines61
. The methamphetamine abusers had less gray matter, averaging 11.3% below levels found in comparison subjects in the cingulate, limbic, and paralimbic cortices. The abusers displayed 7% white-matter hypertrophy and 7.8% smaller hippocampal volumes. Remarkable MRI-assessed gray matter deficits in regions of the anterior and posterior cingulate cortex of the right hemisphere overlapped regions of abnormal glucose metabolism in another sample of methamphetamine abusers that contained some of the same subjects46
(see ). During a vigilance task, these subjects exhibited high glucose metabolism in posterior cingulate and low glucose metabolism in anterior cingulate. Hippocampal volumes, which displayed deficits in the methamphetamine abuse group, were correlated with performance on a word-recall test. The overall results were consistent with the conclusion that chronic methamphetamine abuse may produce or be associated with a selective pattern of cerebral deterioration, with prominent effects in the medial temporal lobe and limbic cortices. These data are consistent with earlier suggestions of temporal lobe deficits58
and hippocampal deficits that were postulated to contribute to impaired memory performance in methamphetamine abusers. The authors speculated that neuronal deficits and or toxicities might lead to the white-matter hypertrophy noted in both studies through developmental differences, neuroadaptation, neuropil reduction, cell death, adaptive glial proliferation or altered myelination61
Figure 1 Gray matter differences and abnormalities in glucose metabolism on the medial surface of the brain (see 46,61). Group difference map (A) shows mean percentage differences in gray matter volumes in the methamphetamine (MA) group compared with the control (more ...)
A single study assessed effects of prenatal methamphetamine exposure on brain structure and cognitive performance62
. Volumes for whole brains, cerebellum, thalamus and midbrain were similar to those of controls. However, thirteen children (mean age 6.9 years, 4 male) who were exposed to methamphetamine in utero
displayed bilaterally smaller volumes of putamen (17.7%), globus pallidus (28.5%), hippocampus (19.5%), and caudate (13%), as compared to non-exposed children. Moreover, subcortical volumes in hippocampus, putamen and globus pallidus were correlated with deficits in sustained attention and delayed verbal memory, suggesting that methamphetamine exposure during gestation might be neurotoxic to these parts of the developing brain and/or that the predisposition to methamphetamine abuse inherited from the parents might also provide brain substrates for attention and mnemonic deficits.
In contrast to the smaller striatal structures in methamphetamine-exposed children, 50 adults (24 male) who were abstinent from chronic (duration > 2 years) methamphetamine use for an average of four months had larger volumes of the putamen (10%), and the globus pallidus (8%) than healthy comparison subjects (see , reproduced from63
). Female methamphetamine users also had 9.7% larger volumes of the mid-posterior corpus callosum compared to control subjects. Because those methamphetamine abusers with smaller striata had greater lifetime methamphetamine use and more impaired cognitive performance on verbal fluency and speeded motor tasks, the authors proposed that enlargement of the striatum may reflect a compensatory response to methamphetamine toxicity. They propose that the adaptation fails to maintain both function and structural integrity of the striatum after prolonged abuse. Enlargement of the striatum could be produced through inflammation and reactive gliosis, possibly abetted by glia-mediated neurotrophic effects to increase striatal sprouting, as has been shown in response to dopaminergic lesions in experimental animals64
. The larger volume of the mid-posterior corpus callosum in methamphetamine-abusing women may be related to the increased glucose metabolism and perfusion that has been shown to be maximal in the parietal lobes of abstinent methamphetamine abusers47,48,65
, since the parietal fibers cross in this portion of the corpus callosum.
Figure 2 Left: Axial MRI slices showing measured brain regions. CA - caudate, PU - putamen, GP - globus pallidus, TH - thalamus, CB - cerebellum, CV - cerebellar vermis, MB - midbrain. Right: Bar graphs showing larger volumes of lentiform nuclei (putamen and globus (more ...)
Structural abnormalities in the corpus callosum were also observed in methamphetamine abusers who were abstinent for a longer period of time (mean = 21 months)66
. Automated shape analysis indicated greater curvature of the genu and smaller width in both the posterior midbody and isthmus of the corpus callosum of 27 methamphetamine abusers (24 male) relative to comparison subjects. Moreover, both the genu and posterior midbody abnormalities were correlated with lifetime dose of methamphetamine. There were no group differences in total volume of the corpus callosum or of the subregional areas defined by Witelson67
. Since 89% of the sample was composed of men, this observation does not directly conflict with the earlier reports of larger posterior callosal volume in female methamphetamine abusers 63
. The authors suggested that the anterior and posterior shape differences in the interhemispheric white matter tracts may be related to the functional abnormalities that had been observed in frontal and parietal cortices of methamphetamine abusers.
Abnormally large volumes of the striata of former methamphetamine abusers was confirmed in a study that compared healthy individuals to subjects who were HIV+, chronic methamphetamine abusers (abstinent for an average of three months), or both68
. HIV+ status without methamphetamine abuse was associated with smaller volumes than healthy control subjects in cortical and subcortical structures, including the hippocampus. In contrast, methamphetamine dependence in HIV− individuals was associated with larger volumes than control subjects within the caudate nucleus, lenticular nucleus and nucleus accumbens. Volumetric differences in the nucleus accumbens were larger for younger individuals. Because the age at which subjects were studied was highly correlated with the age of the first methamphetamine abuse, it is unclear which factor was most important. Since greater plasticity is associated with younger as compared to older adults, either finding is consistent with interpreting enlargement of the striatum as an adaptive response to amphetamine-mediated toxicity, or even as a predisposing factor to amphetamine abuse.
Although measures of neurocognitive impairment were not generally correlated with subcortical volumes, in the HIV+ methamphetamine abusers, smaller hippocampal volume was associated with more cognitive impairment68
. This relationship suggests that if the lower hippocampal volumes associated with being HIV+ were caused by the HIV virus, that the functional consequences of hippocampal reduction might be exacerbated by methamphetamine abuse. Cortical volume was lower in HIV+ individuals who did not use methamphetamine, but tended to be larger in HIV- methamphetamine abusers, attaining significance in the parietal lobe. Moreover, the opposite cortical abnormalities in methamphetamine abusers and HIV+ individuals were both associated with neurocognitive impairment. This makes it less likely that the larger parietal volume in methamphetamine abusers represents an adaptive compensatory response to amphetamine-mediated toxicity, as suggested for the striatal volume increase.
Bae and associates69
assessed the prevalence, severity and location of T2-weighted MRI white matter signal hyperintensities (WMH) in 33 methamphetamine abusers who were abstinent for an average of 18 months. WMH represent patchy or diffuse changes associated with structural abnormalities that included dilated perivascular spaces, demyelination, astrocytic gliosis and arteriosclerosis70
. Such findings have also been found more frequently in both cocaine abusers and opiate abusers relative to control subjects71-73
. Methamphetamine abusers had greater prevalence of WMH (33%) than control subjects (3%), and greater severity of both periventricular and deep WMH, primarily in the frontal lobes. Unlike cocaine addicts71
, methamphetamine abusers showed no difference in the insular region. The severity of deep WMH was correlated both with higher lifetime dose and the average daily dose of methamphetamine during abuse, but was not related to the duration of abstinence. Male methamphetamine abusers had more prevalent WMH than female abusers. While male methamphetamine abusers also had greater severity of WMH than healthy males (odds ratio = 18.9), female methamphetamine abusers did not have significantly greater severity of WMH than healthy females (odds ratio = 1.2).
One study used both semi-automated segmentation and a stereological method to assess MRI volume abnormalities in 16 males currently abusing drugs through intravenous administration. The majority (9) abused methamphetamine along with other drugs74
. Intravenous drugs had been abused for between seven and twelve years. The specificity of structural abnormalities for amphetamine abuse is unclear because all intravenous drug users, but none of the control group, ingested cannabis. In addition, most drug abusers self-administered cocaine and heroin as well as methamphetamine by intravenous routes. Although these potential confounding factors complicate interpretation, the two volume assessment methods did produce highly correlated estimates (r=0.65, p<0.001). Both methods found that substance abusers had a significantly lower proportion of white matter in the frontal lobe than control subjects. In contrast, there were no group differences in the proportion of whole brain white or gray matter, frontal gray matter, or lateral ventricular volume.
Although an abnormally low proportion of frontal white matter was reported by analyses using both methods, this result is inconsistent with other studies that measured cortical gray and white matter volumes (). These contrasting reports document either no difference in white matter volumes, increased white matter volumes, or decreased gray matter volumes. The abnormally low proportion of frontal white matter may be associated with features specific to this study, such as the methods used to determine the proportion of white matter, or the confounding effects of other addictive substances. Abnormally small white matter volumes have been associated with alcohol abuse75
. Cocaine abuse has been associated with impaired myelination76,77
. While no subjects reported histories of or current alcohol abuse, 88% of the drug-abusing sample reported intravenous use of cocaine, as compared to the 56% who reported methamphetamine abuse. Therefore, differences from the control group are at least as likely to be related to use of cocaine as to use of methamphetamine.
Voxel-based morphometry (VBM) is a whole-brain method for assessing volume differences between tissue segmented brain images which has been developed and popularized within the Statistical Parametric Mapping (SPM) software package78,79
. VBM was used to compare gray matter and white matter between healthy control subjects and former methamphetamine users who were abstinent for either less than six months (n=11) or more (n=18) than six months80
. Lower “gray matter density” was reported in the right middle frontal gyrus (BA 10) of methamphetamine abusers, as compared to control subjects. Methamphetamine abusers also scored lower on a neurospsychological test of executive functioning, the Wisconsin Card Sort Test (WCST). Total WCST errors of methamphetamine abusers, but not control subjects, were correlated with the right middle frontal gray matter density within the area that provided the largest group difference. Both the gray matter and WCST scores were closer to control values in methamphetamine abusers who reported long-term abstinence, relative to those who reported only short-term abstinence. There were no significant white- matter abnormalities. Results could not be separately assessed for women.
A recent report of structural brain abnormalities in methamphetamine abusers came from authors who used diffusion tensor imaging (DTI) to assess white matter integrity81
. DTI measures changes in microstructural white matter organization by providing measures of functional anisotropy (FA) and diffusivity of water flow. These measures are sensitive to disorganization and damage to axons and their myelin sheaths82-83
. Decreased white-matter integrity was inferred from abnormally low FA in bilateral frontal white matter voxels at the anterior commissure-posterior commissure (AC-PC) plane and in right hemisphere prefrontal white matter 5 mm above the AC-PC plane in 32 abstinent (>1 month) methamphetamine abusers, as compared to 30 healthy comparison subjects. Frontal executive functions, as assessed by WCST total errors, were also impaired in methamphetamine abusers. WCST errors correlated with FA values in right prefrontal white matter 5 mm above the AC-PC plane. Separate gender analyses revealed that both the FA and WCST abnormalities associated with methamphetamine abuse were significant only in the male, but not in the female subjects, suggesting the possibility for a protective factor in female methamphetamine abusers. Whether such differences represent a predisposition to addiction or are secondary to stimulant toxicity needs to be clarified through prospective study designs.