1. Resting Cerebral Blood Volume Fluctuations: Resting-state brain activity has been investigated extensively using BOLD contrast. However, BOLD signal represents the combined effects of multiple physiological processes and its spatial localization is less accurate than that of cerebral blood flow and volume (CBF and CBV). Whole-brain gradient and spin echo (GRASE) based vascular space occupancy (VASO) imaging was used to detect the resting-state brain activity using CBV-weighted signal. Specifically, using ICA, intrinsic brain networks, including default mode, salience, executive control, visual, auditory, and sensorimotor networks were revealed robustly by the VASO technique. Compared to BOLD, VASO images have reduced susceptibility-induced signal loss in frontal and temporal regions, suggesting that 3D-GRASE VASO imaging, with its improved spatial specificity and less sensitivity to susceptibility artifacts, may have advantages in rs-fMRI studies. 2. Neuroplasticity in a rodent model of cocaine addiction: Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine SA. As natural rewards similarly activate the mesolimbic reward system, we also included a sucrose SA group. A third group of nave, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with fMRI following an IV cocaine injection challenge. A strong positive fMRI response was seen in the sedentary control group in such cortico-limbic regions as mPFC and ACC. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine but not for the sucrose SA group. This region-specific group difference may reflect the development of neuroadaptive mechanisms specifically related to the emergence of cocaine addiction-like behavior. 3. Cocaine vs natural reward-associated contextual cue responses: Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. Two groups of rats were trained to associate odor cues with the availability of IV cocaine or oral sucrose followed by prolonged abstinence. Odor cues previously associated with or without (S+/S−) reinforcer (cocaine/sucrose) availability were presented during functional MRI scans. Results demonstrate that a learning effect distinguishing S+ from S−was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA. A main effect of group, distinguishing cocaine from sucrose, was seen in the mPFC (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S−). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions. 4. TE-Dependent spatial and spectral specificity of functional connectivity: Previous studies suggest that spontaneous fluctuations in the rs-fMRI signal may reflect fluctuations in transverse relaxation time (T(2)(*)) rather than spin density (S(0)). However, such S(0) and T(2)(*) features havent been well characterized. In the spatial domain, we found broad, local correlations at short echo times (TE ≤14 ms) due to dominant S(0) contribution, whereas long-range connections mediated by T(2)(*) became explicit at TEs longer than 22 ms. In the frequency domain, compared with the flat spectrum of S(0), spectral power of the T(2)(*)-weighted signal elevated significantly with increasing TE, particularly between 0.008-0.023 Hz and 0.037-0.043 Hz. We propose two indices to measure spectral signal change and spectral contrast-to-noise ratio, for quantifying the RS-fMRI signal. These indices demonstrated TE dependency of connectivity-related fluctuation strength, resembling functional contrasts in activation-based fMRI. 5. Intrinsic resting state activity predicts working memory brain activation and behavioral performance: Although resting-state brain activity has been shown to correspond with task-evoked brain activation, the relationship between intrinsic and evoked brain activity is not fully characterized. Using amplitude of low-frequency fluctuation (ALFF) as an index of intrinsic resting-state activity, we found that ALFF in the middle frontal gyrus and inferior/superior parietal lobules was positively correlated with WM task-evoked activation, while ALFF in the mPFC, PCC, superior frontal gyrus, superior temporal gyrus, and fusiform gyrus was negatively correlated with WM task-evoked deactivation. Further, the relationship between the intrinsic resting-state activity and task-evoked activation in lateral/superior frontal gyri, inferior/superior parietal lobules, superior temporal gyrus, and midline regions was stronger at higher WM task loads. In addition, both resting-state activity and the task-evoked activation in the superior parietal lobule/precuneus were significantly correlated with WM task behavioral performance, explaining similar portions of intersubject performance variance. These data suggest intrinsic resting-state activity facilitates or is permissive of specific brain circuit engagement to perform a cognitive task, and that resting activity can predict subsequent task-evoked brain responses and behavioral performance. 6. Withdrawal from long-term methamphetamine self-administration (SA) normalizes neurometabolites in rhesus monkeys: 1 H magnetic resonance spectroscopy has demonstrated alterations in several neurometabolites in methamphetamine (METH)-dependent individuals in brain regions implicated in addiction. Yet, it is unclear whether these neurochemicals return to homeostatic levels after abstinence, a difficult question to address due to high recidivism and poor study retention in human subjects. We thus utilized a non-human primate model of addiction to explore the effects of long-term drug exposure and withdrawal on brain neurochemistry. Ten rhesus macaques on an active METH SA protocol (avg use 4.6  0.8 years, avg daily intake 0.4 -1.2 mg/kg) and 10 age- and sex-matched drug-naive controls (CONT) were used. Concentrations of several neurochemicals were evaluated at several time points following withdrawal from drug availability (10 monkeys at 1 week, 1 and 3 months, and 6 monkeys at 6 and 12 months;CONT examined at one time point). At 1 week following METH withdrawal, we found increases in myo-inositol in anterior cingulate cortex in the METH group relative to CONT. These alterations showed a linear pattern of decreased levels ('normalization') by 1yr of abstinence. We also found decreases in glutamine and Glx (mainly glutamate and glutamine) in the caudate-putamen of the same animals at early withdrawal showing a similar linear pattern of increasing concentration by 1yr. These results show, despite protracted, long-term use, neurochemical changes seen following long-term drug administration do not persist following prolonged abstinence, suggesting therapeutic effects of long-term withdrawal from drug use.

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Yang, Shaolin; Belcher, Annabelle M; Chefer, Svetlana et al. (2015) Withdrawal from long-term methamphetamine self-administration 'normalizes' neurometabolites in rhesus monkeys: a (1) H MR spectroscopy study. Addict Biol 20:69-79
Lu, Hanbing; Zou, Qihong; Chefer, Svetlana et al. (2014) Abstinence from cocaine and sucrose self-administration reveals altered mesocorticolimbic circuit connectivity by resting state MRI. Brain Connect 4:499-510
Liu, Hua-Shan; Chefer, Svetlana; Lu, Hanbing et al. (2013) Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues. Proc Natl Acad Sci U S A 110:4093-8