1. Dorsolateral Prefrontal Cortical Circuits Predict Cocaine Relapse: Implications for Neuromodulation Treatment Although the dorsolateral prefrontal cortex (DLPFC) has become the principal site to deliver transcranial magnetic stimulation (TMS) for the therapeutic intervention of such neuropsychiatric disorders as depression and addiction, its underlying neurobiological mechanisms remains unclear. Moreover, due to the heterogeneity of this region, the locus that produces the most efficacious treatment outcome remains poorly defined. We thus tested the ability of functional connectivity (FC) of circuits from seeds covering the entire DLPFC to a) determine if DLPFC based functional circuits could predict cocaine dependence treatment efficacy and b) identify loci providing significant prediction power. A Cox regression model was applied to predict treatment outcome success/relapse following a psychosocial treatment intervention for cocaine dependence. We established the proof-of-principle by choosing a DLPFC seed locus based on a recent TMS pilot study showing efficacy for cocaine relapse and demonstrated that the FC from this seed in our cohort predicted cocaine relapse with an accuracy of 85.0%. We then conducted subsequent exploratory analyses used 132 loci evenly distributed within the entire left DLPFC to identify potential novel sites/circuits that might also predict cocaine relapse. We then identified two of the 132 exploratory loci also significantly predicted relapse with an accuracy of 86.4% and 84.6%. Specific DLPFC-centric protective and risk circuits were also identified from all three loci, which may serve as potential neuromodulation targets to treat drug dependence and provide objective biomarker assessments of treatment adequacy. 2. Simultaneous TMS and MRI on human brains TMS has been used in the treatment of psychiatric disorders, predominately over the DLPFC. Although therapeutic efficacy of TMS has been shown, the effects remain variable across individuals and sizable non-responders are always present, underscoring the importance to understand the underlying neural mechanism of TMS. We recently set up a concurrent TMS and MRI platform, which can be used to investigate acute and chronic effects of TMS modulation on the brain. As an initial step, we are using the platform to assess acute effects of TMS on brain activity captured by fMRI. Simultaneous TMS and fMRI are being used to map the modulatory effects of TMS on the brain when stimulation is applied over three sites on the DLPFC: i) MNI = -50, 30, 36 (L-DLPFC1) that showed reduced cocaine relapse in cocaine users after TMS treatment (Terraneo et al., 2016); ii) the contralateral mirror side MNI = 50, 30, 36 (R-DLPFC1), or iii) MNI=-41, 16, 54 (L-DLPFC2) that represents the 5-cm rule commonly used for depression. A low-frequency (LF) of 0.4 Hz or high-frequency (HF) of 10Hz stimulation at 100% of the motor threshold is used. Brain activation induced by TMS was examined with two fMRI runs, during which TMS was applied in an interleaved on and off block pattern. LF-TMS had one TMS pulse per imaging frame, while the HF-TMS had 5 pulses per imaging frame applied at a 10 Hz rate during the TMS epochs. This study is still at its early stage and we report here preliminary results from 8 healthy participants acquired for both LF and HF over the L-DLPFC1. At a relatively liberal statistical threshold (voxelwise p<0.01), the HF-TMS on L-DLPFC1 elicited activation in the insula, superior temporal gyrus, and cerebellum, while the LF-TMS on the same DLPFC cite elicited activation in the insula, putamen and cerebellum and deactivation in the superior parietal lobe. A comprehensive analysis and interpretation of the data will be performed upon completion of 40-50 participants 3. Regional excitation-inhibition balance predicts default-mode network (DMN) deactivation via functional connectivity. Deactivation of the human DMN is one of the most reliable observations from neuroimaging and has significant implications in development, aging, and various neuropsychiatric disorders. However, the neural mechanism underlying DMN deactivation remains elusive. As the coordination of regional neurochemical substrates and interregional neural interactions are both essential in support of brain functions, a quantitative description of how they impact DMN deactivation may provide new insights into the mechanism. Using an n-back working memory task fMRI and magnetic resonance spectroscopy, we probed the pairwise relationship between task-induced deactivation, interregional functional connectivity and regional excitation-inhibition balance (evaluated by glutamate/GABA ratio) in the posterior cingulate cortex/precuneus (PCC/PCu), a hub of DMN. Task-induced PCC/PCu deactivation correlated with its excitation-inhibition balance and interregional functional connectivity, where participants with lower glutamate/GABA ratio, stronger intra-DMN connections and stronger antagonistic DMN-SN (salience network)/ECN (executive control network) inter-network connections had greater PCC/PCu deactivation. Mediation analyses revealed that the DMN-SN functional interactions partially mediated the relationship between task-induced deactivation and the excitation-inhibition balance at the PCC/PCu. The triple-relationship discovered in the present study has the potential to bridge DMN-deactivation related findings from various neuroimaging modalities and may provide new insights into the neural mechanism of DMN deactivation. Moreover, this finding may have significant implications for neuropsychiatric disorders related to the DMN dysfunction and suggests an integrated application of pharmacological and neuromodulation-based strategies for rescuing DMN deactivation deficits. (Gu et al., NeuroImage, 2019) 4. Alterations of brain structure and function in smokers with monoamine oxidase A variation. The monoamine oxidase A (MAOA) enzyme metabolizes monoamine neurotransmitters such as dopamine, serotonin and norepinephrine, and its genetic polymorphism (rs1137070) influences its activity level and is associated with smoking behaviors. However, the underlying neural mechanisms of the gene environment interactions remain largely unknown. In this study, we aimed to explore the interactive effects of the rs1137070 and cigarette smoking on gray matter volume (GMV) and functional connectivity strength (FCS). A total of 81 smokers and 42 nonsmokers were enrolled in the present study. Voxel-based morphometry analysis showed a significant rs1137070 genotype smoking effect on the GMV of the left orbitofrontal cortex (OFC), such that individuals with risk allele had greater GMV among nonsmokers but not smokers. Meanwhile, rs1137070 variant and nicotine dependence interactively altered the FCS of the right hippocampus, the left inferior parietal lobule (IPL), the left dorsolateral prefrontal cortex and bilateral OFC. In addition, the FCS in the left IPL was correlated with smoking initiation and smoking years in smokers with the risk allele. These findings suggest that MAOA rs1137070 contributes to the susceptibility to nicotine dependence through its influence on brain circuits involved in reward and attention and interacts with smoking in the progression. (Shen et al., Eur J Neurosci, 2018)