Suicidal behavior is a major mental health problem commonly characterized by self-harm and persistent thoughts of wanting to die. Death by suicide is a tragic event that occurs at higher rates committed by those with psychiatric disorders, particularly opioid abuse. Opioid abuse is likely due to factors that affect the mesolimbic and cortico-striatal system in the brain, including alteration of dopamine release and loss of cognitive control. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum is associated with compulsive reward-seeking behavior despite negative effects (e.g., punishment). Abnormalities in the OFC may contribute to dysfunctions in emotional pain processing and decision-making, potentially associated with suicide. Our central hypothesis is that suicidal patients among opioid users will have increased functional connectivity in a circuit, including the OFC, dorsal striatum, and habenula, when compared to non-suicidal patients among opioid users. Moreover, suicidal patients among opioid users receiving non-invasive brain stimulation to the OFC will have reduced the functional connectivity.
With the proposed research, we will use previously collected resting-state fMRI data from the McNair Initiative in Neuroscience Discovery-Menninger and Baylor College of Medicine (MIND-MB. N = 841) to characterize the functional connectivity between the OFC, dorsal striatum, and habenula in suicidal patients among opioid users (AIM 1). We will have opioid users from the MIND-MB data who have an ASSIST score of 4 or more (Risk level: from moderate to high) in the opioid category. Opioid users will be deemed suicidal if they have suicide-related behaviors (attempts) or active suicidal ideation using the Columbia Suicide Severity Rating Scale (C-SSRS). Additionally, to investigate the potential therapeutic efficacy of non-invasive brain stimulation (Transcranial Magnetic Stimulation, TMS) to the OFC for reducing suicidal behaviors and opioid craving, suicidal patients among opioid users will be recruited from the inpatient psychiatric hospital, and will receive a 5-sessions of low frequency repetitive TMS (rTMS) to the OFC in order to induce sustainable functional connectivity decreases between the OFC, dorsal striatum, and habenula (AIM 2). The gold standard to characterize the functional connectivity is to pair brain stimulation with neuroimaging. TMS is a non-invasive, FDA-approved brain stimulation for depression, which is also being pursued as a treatment for opioid use disorder and suicidal ideation. TMS can be paired with fMRI in concurrent TMS-fMRI experiments, which enable the characterization of functional and distributed networks through the causal manipulation of human brain activity. This novel method will assess the functional connectivity between the OFC, dorsal striatum, and habenula in suicidal patients among opioid users to evaluate the efficacy of rTMS in the treatment of suicidal behaviors and opioid craving. We will collect concurrent TMS-fMRI data plus resting state fMRI data before and after rTMS applications to characterize OFC connectivity changes. The results from this proposal will yield a significant step forward in developing the neural-circuit based strategies as treatments for suicidal patients among opioid users. This study will be extended to a large number of suicidal patients for a translational R01 submission.
