Study on iTBS Regulating the Reward Circuit Function to Improve Anhedonia in Depression

Anhedonia, defined as the diminished capacity to experience pleasure, is a core symptom of Major Depressive Disorder (MDD). Patients with anhedonia exhibit a pervasive loss of interest or pleasure in all or almost all previously enjoyable activities, which frequently leads to a profound reduction in the desire to engage in rewarding behaviors. Previous studies have reported that anhedonia occurs in 37% to 72% of depressed individuals. Patients with depression accompanied by anhedonia tend to respond poorly to medication and psychotherapy but show relatively better responses to conventional physical treatments such as electroconvulsive therapy (ECT). Research has shown that improving anhedonia significantly enhances social functioning in depressed patients. Therefore, more effective treatments targeting anhedonia are needed. Achieving breakthroughs in therapeutic approaches and understanding their underlying mechanisms will contribute substantially to progress in this field.

Theta-burst stimulation (TBS) utilizes a stimulation pattern that closely mimics the natural firing frequencies of cerebral neurons. Accumulating evidence has demonstrated the clinical efficacy of intermittent TBS (iTBS) in alleviating depressive symptoms. Thus, this study aims to investigate and evaluate whether the proposed iTBS protocol can effectively improve anhedonia symptoms in depressed patients by regulating functional abnormalities.

The stimulation targets in our protocol include (1) dual-target stimulation at the left dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). (2) single-target stimulation at the left DLPFC.

The main questions it aims to answer are:

• Whether iTBS of dual-target stimulation (left DLPFC and OFC) can improve the symptoms of anhedonia and better than single-target stimulation?
• Whether iTBS of the dual targets of left DLPFC and OFC can improve the anhedonia symptom by correcting the abnormal functional connectivity of DLPFC-NAc and OFC-sgACC, regulating the functional abnormalities of NAc and sgACC, and indirectly repairing the overall dysfunction of the reward circuit?

Inclusion criteria

• Aged 18-45 years, and right-handed;
• Diagnosed with major depressive disorder (MDD) by at least two qualified psychiatrists, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), with a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 20 or a 17-item Hamilton Depression Rating Scale (HAMD-17) score ≥ 17;
• Evaluated by a psychiatrist as having prominent anhedonia, and meeting the cutoff criteria on two self-report anhedonia scales, including a Snaith-Hamilton Pleasure Scale, Chinese version (SHAPS-C) score ≥ 20, or a Temporal Experience of Pleasure Scale, Chinese version (TEPS-C) score ≤ 76;
• Medication type and dosage remained unchanged for at least 4 weeks prior to treatment initiation and throughout the study period;
• MADRS item 10 score ≤ 4.

Exclusion criteria

• A history of epilepsy, seizures, stroke, or other serious organic brain diseases;
• Presence of severe infectious diseases, malignant tumors, or other major unstable medical conditions;
• Intellectual disability or developmental delay, presence of psychotic symptoms, or meeting the diagnostic criteria for other psychiatric disorders;
• A history of substance abuse or psychoactive substance use;
• Presence of intracranial implants (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes), or any other metallic objects in or near the head that cannot be safely removed (excluding dental fillings);
• Contraindications to MRI or structural intracranial abnormalities detected on MRI;
• Pregnant or breastfeeding women;
• Receipt of electroconvulsive therapy (ECT) within the past 6 months, or transcranial magnetic stimulation (TMS) within the past 3 months;
• Current daily use of lorazepam > 2 mg (or an equivalent dose), or use of antiepileptic drugs at any dose;
• Presence of strong suicidal ideation, or a MADRS item 10 score > 4.