This study aims to investigate changes in functional connectivity over a four week treatment course with intermittent theta burst stimulation (iTBS) in patients with major depressive disorder (MDD). To this end, seven weekly resting-state fMRI (rs-fMRI) scans at 7 tesla (7T) will precede, accompany and follow the iTBS treatment course. By obtaining several samples of the modulatory effects of iTBS on functional connectivity networks and simultaneous measurements of the depressive symptoms it will be possible to assess the time course of changes in connectivity across different networks, and to assess the overall relationship between the network modulation and the antidepressant effects of the treatment over time.

The immense disease burden of major depressive disorder (MDD) and unsatisfactory response rates to pharmacological and psychological interventions highlight the need for further development of treatment alternatives. The development of these alternatives relies on an understanding of the pathophysiology of depression, which has, despite considerable efforts, remained largely elusive. Findings have converged on the proposition that depression cannot be attributed to a singular factor and is better understood as a dysfunctional interaction of multiple parameters. At the neural level, depression is described as a dysfunction of several cortical and sub-cortical networks associated with affective salience, cognitive control and self-reverential thoughts. Encouragingly, several studies have shown that pathological alterations in one of these networks, the Default Mode network, may normalize following several weeks of treatment using repetitive transcranial magnetic stimulation (rTMS), an accepted treatment for major depression.

The present study aims to elucidate the time course of this modulatory effect on the different networks showing pathological connectivity profiles. Specifically, our aim is to obtain several measurements of functional connectivity and concomitant measures of the symptoms of depression prior to, throughout, and following the 4 week treatment course of iTBS, a faster but equally effective non-invasive brain stimulation technique compared to rTMS. Due to the fact that weekly changes in network connectivity are expected to be relatively small, the stronger BOLD Signal at 7T and the fact that peak temporal correlation coefficients calculated between network nodes have been shown to be significantly higher at 7T than 3T (e.g.) in the Default Mode network should greatly aid in detecting these differences. At each of the 7 measurement time points, fluctuations of BOLD signal will be recorded during a rs-fMRI scan lasting about 15 minutes. Our approach will allow to characterize the temporal profiles of the antidepressant effects of iTBS, thereby furthering our understanding of the mechanism by which iTBS contributes to the normalization of pathological neural connectivity and the reduction of depression symptoms. This proposed longitudinal functional imaging of therapeutic changes is highly relevant to the field of clinical neuroscience and should further advance our understanding of the pathophysiology of depression.

Inclusion Criteria:

• Participant is able to provide consent.
• Diagnosis of Major Depressive Disorder according to DSM-V criteria.
• The duration of the current episode is at least four weeks and no more than five years.
• During the current episode, at least one antidepressant (adequate duration and dosage) was not effective OR at least two antidepressants were intolerable due to side effects.

Exclusion Criteria:

• The participant does not fulfill requirements for iTBS treatment according to safety guidelines.
• Cardiac or neurological surgery, active implants, metal parts within the body, claustrophobia.
• Pregnancy or breast-feeding.
• Psychiatric illness, e.g. substance abuse, psychosis, bipolar disorder, anorexia, obsessive compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder, personality disorder.
• Antipsychotic medication not approved for the treatment of depression.
• Acute suicidality.
• Conditions related to increased intracranial pressure.
• Brain injury or stroke.
• History of epilepsy in patient or in first-degree relative.
• Cerebral aneurysm.
• Neurological illness (e.g. dementia (score of less than 25 in Mini Mental State Exam), Parkinson's disease, chorea huntington, multiple sclerosis).
• Course of electroconvulsive therapy (ECT) within the last three months

Outpatients at the psychiatric hospital of the University Hospital Bonn. The patients diagnosis of major depressive disorder will be verified via the structured clinical interview for DSM-5. iTBS protocols in line with international standards administered by a trained professional.

Additionally, a healthy control sample is included in the study.