Suicide is the 10th leading cause of death for Americans of all ages and more people in the United States now die from suicide than die from car accidents. Although death by firearm remains the most common cause of suicide in the United States, an intentional overdose of substance usage such as prescription opioids accounts for over 5,000 suicides per year. In 2017, more than 70,000 drug overdose deaths occurred, making it the leading cause of injury-related death, and well over half (67.8%) involved opioids. The dramatic increase in opioid overdose raises concerns about their contribution to suicidal outcomes (e.g., suicidal behavior, ideation, and attempts). Abuse of prescription opioids is characterized by the persistence of opioid use despite negative consequences. The neurobiology of opioid abuse involves the mesolimbic dopamine systems as the main neural substrate for opioid reward, and altered dopamine release in this system plays a role in opioid abuse. Moreover, the cortico-striatal system, especially the orbitofrontal cortex (OFC), has been associated with the abuse of many substances, including opioids and alcohol. Structural brain alterations in frontal areas, particularly the OFC, may cause executive control dysfunctions of mood which are highly associated with suicidal ideation. Recent preclinical work has shown that higher input from the OFC to the dorsal striatum (dSTR) is associated with compulsive reward-seeking behavior despite negative effects (e.g., punishment). In this study, the investigators propose that OFC/dSTR connectivity may be one neural differentiator that distinguishes between those who become compulsive users after initial opioid use and those that do not. Moreover, suicidal patients among those who become compulsive users may have higher OFC/dSTR connectivity compared to non-suicidal patients.

The OFC is functionally connected to other cortical brain regions (e.g., prefrontal and parietal cortices) but also subcortical areas in the dorsal striatum, a core reward circuitry region. The functional connectivity between the OFC and the dorsal striatum also plays an important role in addiction, particularly opioid abuse, and suicide behaviors. Thus, it is clear that the investigators need a better understanding of the therapeutic mechanisms using non-invasive brain stimulation (e.g., TMS) treatment to the OFC as applied to opioid users. As such, the investigators propose to use a combination of interleaved TMS-fMRI, a novel method to observe and characterize causal manipulations of functional neural circuits, targeting the OFC and resting state functional magnetic resonance imaging (fMRI) to longitudinally study psychiatric symptoms (e.g., opioid craving, suicidal behaviors) changes in opioid users.

Inclusion Criteria Opioid Use Patients:

Each potential subject will be eligible for inclusion in this study only if the specific criteria listed below are met:

• Be male or female aged 18-60 years old
• Participation in H-22611;
• Meets a World Health Organization Alcohol, Smoking and Substance Involvement Screening Test (WHO-ASSIST) score of 4+ in the opioid category;
• Has depressive symptoms according to the Patient Health Questionnaire (PHQ)-9;
• Has active suicidal thoughts according to Suicide Behaviors Questionnaire-Revised (SBQ-R);
• Be able to verbalize understanding of consent form, able to provide written informed consent, and verbalize willingness to complete study procedures;
• Female subjects must be non-nursing and not pregnant at the times of fMRI experiments and rTMS treatment;
• Has no contraindications to MRI (pacemaker, cochlear implants, metal in eyes, other metal implants, etc.); Meets the pre-screening magnetic resonance imaging (MRI) questions provided by the Center for Advanced MR Imaging (CAMRI);
• Has no contraindications to TMS (any types of non-removable metal in their head except the mouth, or within 12 inches of the coil, etc.).

Inclusion Criteria Healthy Controls:

Each potential subject will be eligible for inclusion in this study only if the specific criteria listed below are met:

• Be male or female aged 18-60 years old;
• No history of severe medical or neurological illnesses per history;
• Be able to verbalize understanding of consent form, able to provide written informed consent, and verbalize willingness to complete study procedures;
• Female subjects must be non-nursing and not pregnant at the time of fMRI experiments;
• Has no contraindications to MRI (pacemaker, cochlear implants, metal in eyes, other metal implants, etc.): Meets the pre-screening MRI questions provided by the Center for Advanced MR Imaging (CAMRI);
• Has no contraindications to TMS (any types of non-removable metal in their head except the mouth, or within 12 inches of the TMS coil, etc.).

Exclusion Criteria:

Any potential subject who meets any of the following criteria will be excluded from participating in the study if s/he has

• In the opinion of the clinician and the research team at admission, be expected to fail to complete the study protocol due to not tolerable to receive rTMS;
• Unable to understand the design and requirements of the study;
• Unable to sign informed consent for any reason;
• Has an unstable medical condition, including Acquired immunodeficiency syndrome (AIDS), acute hepatitis, active TB, unstable cardiac disease, unstable diabetes, hepatic or renal insufficiency;
• Female subjects who are pregnant or nursing;
• Contraindications to MRI (pacemaker, cochlear implants, metal in the eye, other metal implants, etc.): Do not meet the pre-screening MRI questions provided by the CAMRI;
• Contraindications to the noninvasive brain stimulation (NIBS) (any types of non- removable metal in their head except the mouth, or within 12 inches of the coil, etc.) Additional exclusion criteria for the TMS experiments are based on the recommendations described by the international consensus panel on brain stimulation;
• Non-English speaking subjects (we do not have the staff and resources to include other languages)

The participant will not be aware of if they are receiving TMS treatment or sham TMS treatment.