Development of MRI Techniques for Drug-Abuse Applications

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1. Cox regression based modeling of functional connectivity and treatment outcome for relapse prediction and disease subtyping in substance use disorder Functional magnetic resonance imaging (fMRI) has become one of the most widely used noninvasive neuroimaging technique in research of cognitive neurosciences and of neural mechanisms of neuropsychiatric/neurological diseases. A primary goal of fMRI-based neuroimaging studies is to identify biomarkers for brain-behavior relationship and ultimately perform individualized treatment outcome prognosis. However, the concern of inadequate validation and the nature of small sample sizes are associated with fMRI-based neuroimaging studies, both of which hinder the translation from scientific findings to clinical practice. Therefore, the current paper presents a modeling approach to predict time-dependent prognosis with fMRI-based brain metrics and follow-up data. This prediction modeling is a combination of seed-based functional connectivity and voxel-wise Cox regression analysis with built-in nested cross-validation, which has been demonstrated to be able to provide robust and unbiased model performance estimates. Demonstrated with a cohort of treatment-seeking cocaine users from psychosocial treatment programs with 6-month follow-up, our proposed modeling method is capable of identifying brain regions and related functional circuits that are predictive of certain follow-up behavior, which could provide mechanistic understanding of neuropsychiatric/neurological disease and clearly shows neuromodulation implications and can be used for individualized prognosis and treatment protocol design (Zhai et al., Frontiers Neuroscience, 2021). 2. Dose-dependent relationship between social drinking and brain aging Low-level alcohol consumption is commonly perceived as being inconsequential or even beneficial for overall health, with some reports suggesting that it may protect against dementia or cardiovascular risks. However, these potential benefits do not preclude the concurrent possibility of negative health outcomes related to alcohol consumption. To examine whether casual, non-heavy drinking is associated with premature brain aging, we utilized the Brain-Age Regression Analysis and Computational Utility Software package to predict brain age in a community sample of adults n = 240, mean age 35.1 (10.7) years, 48% male, 49% African American. Accelerated brain aging was operationalized as the difference between predicted and chronological age ("brain age gap"). Multiple regression analysis revealed a significant association between previous 90-day alcohol consumption and brain age gap ( = 0.014, p = 0.023). We replicated these results in an independent cohort n = 231 adults, mean age 34.3 (11.1) years, 55% male, 28% African American: = 0.014, p = 0.002. Our results suggest that even low-level alcohol consumption is associated with premature brain aging. The clinical significance of these findings remains to be investigated (Angebrandt et al., Neurobiology of Aging). 3. Repetitive transcranial magnetic stimulation may reduce craving, depression and enhance cognitive performance in patients with opioid use disorder Opioid use disorder (OUD), often comorbid with depressive symptoms, causes substantial health and social burdens. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that used to treat depression. Recent studies showed potential therapeutic effects in rTMS for addictive disorder, but with limited studies in OUD. Therefore, we conducted an add-on double-blinded, sham-controlled rTMS study in OUD patients undergoing methadone maintenance therapy (MMT) to evaluate the treatment effect for heroin use. OUD patients were enrolled from MMT clinics. The active or sham rTMS treatment was applied to the left dorsolateral prefrontal cortex (DLPFC) (15 Hz frequency, 4 seconds per train, inter-train interval of 26 seconds, 40 trains per session, total 11 sessions in 4 weeks). The craving scales of Visual analog scale (VAS), Hamilton Depression Rating Scale (HDRS), Opiate Treatment Index (OTI), urinary morphine tests and cognitive functions were followed up for 12 weeks. Twenty-one OUD patients were enrolled, eleven were on active rTMS and eight were on sham rTMS. There was no significant difference in their baseline characteristics between the two groups. After 12 weeks, VAS and HDRS were significantly decreased in the active rTMS group (P=0.009 and <0.001). Trail Making Test Parts (TMT)-A and -B were also improved in the active rTMS group (P=0.01 and 0.02). Some factors at baseline, including HDRS scores and baseline TMT-B, were correlated to rTMS treatment outcomes. However, the active rTMS group did not show significantly greater improvements than the sham group in OTI or urine morphine test results. Our initial evidence suggested add-on rTMS in MMT may reduce the severity of craving, ameliorate depressive symptoms and improve some cognitive functions in OUD patients. However, further enlargement of sample size is required to evaluate the treatment response of rTMS in heroin use frequency and amount (Tsai et al., American Journal of Drug and Alcohol Abuse, 2021). 4. Low-frequency repetitive transcranial magnetic stimulation to the right dorsolateral prefrontal cortex The positive treatment outcomes of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) when applied over the right dorsolateral prefrontal cortex (DLPFC) in treatment-refractory depression has been verified. However, the mechanism of action behind these results have not been well explored. In this work we used simultaneous functional magnetic resonance imaging (fMRI) during TMS to explore the effect of LF rTMS on brain activity when applied to the right RDLPFC1 (MNI: 50, 30, 36) and left DLPFC sites LDLPFC1 (MNI: -50, 30, 36), LDLPFC2 (MNI: -41, 16, 54). Seventeen healthy adult volunteers participated in this study. To identify brain areas affected by rTMS, an independent component analysis and a general linear model were used. Our results showed an important laterality effect when contrasting rTMS over the left and right sites. Specifically, LF rTMS increased brain activity at the stratum, thalamus and areas of the default mode network when applied to the right, but not to the contralateral left DLPFC. In contrast, no site differences were observed when evaluating the effect of LF rTMS over the two left sites. These findings demonstrate that LF rTMS to the right DLPFC was able to stimulate the cortico-striato-thalamo-cortical pathway, which is dysregulated in patients with major depressive disorder; therefore, justifying the successful outcomes found thus far for LF rTMS in the treatment of depression (under review).