Brain mGlu5 Is Linked to Cognition and Cigarette Smoking but Does Not Differ From Control in Early Abstinence From Chronic Methamphetamine Use.

BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

Structural indices of brain aging in methamphetamine use disorder.

BACKGROUND: Methamphetamine use is surging globally. It has been linked to premature stroke, Parkinsonism, and dementia, suggesting that it may accelerate brain aging. METHODS: We performed a retrospective study to determine if structural indices of brain aging were more prevalent prior to old age (26 - 54 years) in individuals with Methamphetamine Use Disorder (MUD), who were in early abstinence (M ± SD = 22.1 ± 25.6 days) than in healthy control (HC) participants. We compared T1-weighted MRI brain scans in age- and sex-matched groups (n = 89/group) on three structural features of brain aging: the brain volume/cerebrospinal fluid (BV/CSF) index, volume of white matter hypointensities/lesions, and choroid plexus volume. RESULTS: The MUD group had a lower mean BV/CSF index and larger volumes of white matter hypointensities and choroid plexus (p-values < 0.01). Regression analyses showed significant age-by-group effects, indicating different age trajectories of the BV/CSF index and choroid plexus volume, consistent with abnormal global brain atrophy and choroid plexus pathology in the MUD group. Significant age and group main effects reflected a larger volume of white matter hypointensities for older participants across groups and for the MUD group irrespective of age. None of the three measures of brain aging correlated significantly with recent use or duration of recent abstinence from methamphetamine. CONCLUSIONS: Premature brain pathology, which may reflect cerebrovascular damage and dysfunction of the choroid plexus, occurs in people with MUD. Such pathology may affect cognition and thereby efficacy of behavioral treatments for MUD.

Negative affect and craving during abstinence from smoking are both linked to default mode network connectivity.

BACKGROUND: Negative affect and craving during abstinence from cigarettes predict resumption of smoking. Therefore, understanding their neural substrates may guide development of new interventions. Negative affect and craving have traditionally been linked to functions of the brain's threat and reward networks, respectively. However, given the role of default mode network (DMN), particularly the posterior cingulate cortex (PCC), in self-related thought, we examined whether DMN activity underlies both craving and negative affective states in adults who smoke. METHODS: 46 adults who smoke abstained from smoking overnight and underwent resting-state fMRI, after self-reporting their psychological symptoms (negative affect) and craving on the Shiffman-Jarvik Withdrawal Scale and state anxiety (negative affect) on the Spielberger State-Trait Anxiety Inventory. Within-DMN functional connectivity using 3 different anterior PCC seeds was tested for correlations with self-report measures. Additionally, independent component analysis with dual regression was performed to measure associations of self-report with whole-brain connectivity of the DMN component. RESULTS: Craving correlated positively with connectivity of all three anterior PCC seeds with posterior PCC clusters (pcorr<0.04). The measures of negative affective states correlated positively with connectivity of the DMN component to various brain regions, including posterior PCC (pcorr=0.02) and striatum (pcorr<0.008). Craving and state anxiety were correlated with connectivity of an overlapping region of PCC (pcorr=0.003). Unlike the state measures, nicotine dependence and trait anxiety were not associated with PCC connectivity within DMN. CONCLUSIONS: Although negative affect and craving are distinct subjective states, they appear to share a common neural pathway within the DMN, particularly involving the PCC.

Nicotine dependence and insula subregions: functional connectivity and cue-induced activation.

Nicotine dependence is a major predictor of relapse in people with Tobacco Use Disorder (TUD). Accordingly, therapies that reduce nicotine dependence may promote sustained abstinence from smoking. The insular cortex has been identified as a promising target in brain-based therapies for TUD, and has three major sub-regions (ventral anterior, dorsal anterior, and posterior) that serve distinct functional networks. How these subregions and associated networks contribute to nicotine dependence is not well understood, and therefore was the focus of this study. Sixty individuals (28 women; 18-45 years old), who smoked cigarettes daily, rated their level of nicotine dependence (on the Fagerström Test for Nicotine Dependence) and, after abstaining from smoking overnight (~12 h), underwent functional magnetic resonance imaging (fMRI) in a resting state. A subset of these participants (N = 48) also completing a cue-induced craving task during fMRI. Correlations between nicotine dependence and resting-state functional connectivity (RSFC) and cue-induced activation of the major insular sub-regions were evaluated. Nicotine dependence was negatively correlated with connectivity of the left and right dorsal, and left ventral anterior insula with regions within the superior parietal lobule (SPL), including the left precuneus. No relationship between posterior insula connectivity and nicotine dependence was found. Cue-induced activation in the left dorsal anterior insula was positively associated with nicotine dependence and negatively associated with RSFC of the same region with SPL, suggesting that craving-related responsivity in this subregion was greater among participants who were more dependent. These results may inform therapeutic approaches, such as brain stimulation, which may elicit differential clinical outcomes (e.g., dependence, craving) depending on the insular subnetwork that is targeted.