The goal of this clinical trial is to examine the neural mechanisms underlying transcranial magnetic stimulation (TMS) using concurrent functional magnetic resonance imaging (fMRI) in both healthy controls (HCs) and patients with high negative affect symptoms, such as depression. Approximately half male and half female participants aged 18-65 will be recruited.

The main questions it aims to answer are:

1. Is the acute/transient effect induced by single-pulse TMS related to the long-term modulatory effect induced by repetitive TMS (rTMS)?
2. Do any of these effects predict negative affect symptoms, such as depression?

Participants will:

1. Complete several tests to assess their cognitive abilities and emotional states
2. Undergo several brain scans, including resting-state fMRI, structural MRI, diffusion tensor imaging (DTI), and task fMRI
3. Have two different types of TMS sequences, single-pulse and repetitive pulses, administered to specific brain regions while undergoing fMRI

The purpose of this study is to examine the neural mechanisms underlying transcranial magnetic stimulation (TMS) using concurrent functional magnetic resonance imaging (fMRI). Research is conducted in both healthy controls (HCs) and patients with high negative affect symptoms, such as depression. Participants will undergo two visits, the first lasting about two hours and the second, scheduled within one week of the first, also lasting about two hours. Approximately half male and half female participants aged 18-65 will be recruited. The aims are to examine (1) whether the acute/transient effect induced by single-pulse TMS is related to the long-term modulatory effect induced by rTMS, and (2) whether any of these effects predict negative affect symptoms, such as depression.

In the first visit, participants will complete several tests to assess their cognitive abilities and emotional states, specifically measuring depression levels. These tests will help explore the relationship between their cognitive/emotional states and brain activity during TMS-fMRI. After the tests, participants will undergo several brain scans to determine the best locations for TMS during the second visit and to measure the strength of connections between different brain regions. During the second visit, participants will undergo three parts of TMS-fMRI scanning. The first part involves applying single-pulse TMS to the dorsolateral prefrontal cortex (DLPFC) and a control area (the vertex) while taking fMRI scans. This helps elucidate how TMS affects deep brain regions related to mood disorders. By comparing brain responses to TMS between healthy controls and patients, researchers can gain important knowledge of whether the neural pathways between stimulated region and these subcortical brain regions are disrupted in patients. The second part includes theta-burst stimulation (TBS) of TMS to the DLPFC, which is a stimulation protocol approved by Food and Drug Administration (FDA). Finally, in the third part, single-pulse TMS is administered again after TBS to see if the TBS has changed the brain's response. Comparing the after-TBS single-pulse TMS-evoked brain responses with before-TBS responses would allow the investigators to track whether the TBS could change the disrupted neural pathways in patients. Investigators will also examine how participants' cognitive/emotional test results and brain connectivity relate to the TMS-evoked brain responses and the effects of TBS. Any potential relationships found can provide insight into the underlying mechanisms of how individual differences in cognitive/emotional functioning and brain connectivity profile might influence or be influenced by brain stimulation, which could ultimately inform personalized approaches to neuromodulation therapies.

Inclusion for patients:

• Diagnosis of major depressive disorder
• Age greater than or equal to 18 years
• Age less than or equal to 65 years
• Able to understand and consent for research participation
• English-speaking

Inclusion for healthy controls:

• Report no lifetime psychiatric diagnosis and treatment
• scores on Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Questionnaire (GAD-7) lower than 4
• Age greater than or equal to 18 years
• Age less than or equal to 65 years
• Able to understand and consent for research participation
• English-speaking

Exclusion for all subjects:

• Age less than 18 years
• Age greater than 65 years
• With epilepsy or seizure disorder
• With implanted ferromagnetic equipment in their face or skull near the stimulation target

MRI Exclusion criteria for all subjects:

• Implanted device including pacemaker, coronary stent, defibrillator, or neurostimulation device that is not MRI-compatible
• Metal in body including bullets, shrapnel, metal slivers
• Claustrophobia
• Uncontrolled high blood pressure
• Blood circulation problems
• Opiate medication, antihypertensive medication, or any medication that interferes with blood flow (interferes with fMRI recordings)
• Significant heart disease, such as atrial fibrillation
• Pregnancy in female participants
• Prior exposure to deep brain stimulation, rTMS, or tDCS (transcranial direct current stimulation) therapies
• History of neurological or cardiovascular disorders, brain surgery, radiation treatment, brain hemorrhage or tumor, stroke, or diabetes
• Significant traumatic brain injury (loss of consciousness, post-injury amnesia, significant radiological/neurological findings, penetrating brain injury)
• Refusal to abstain from illicit drug use for duration of the study
• Refusal to abstain from alcohol within 24 hours of scans

If you would like to participate in the study, click this link to fill out the Screening Form: https://redcap.icts.uiowa.edu/redcap/surveys/?s=DEYHWF8TMCHHW4Y7. Kindly note that our research team will contact you directly only if you meet the eligibility criteria for the study. Due to the high volume of responses, we are unable to reply to individual inquiries or provide feedback about eligibility decisions.

The data will be submitted to the NIMH Data Archive every 6 months.