Cognitive Flexibility in Depression and TMS Response

Cognitive flexibility will be evaluated in cases of treatment-resistant depression using a neuropsychological test battery. This battery will be applied only before the TMS treatment.

Wisconsin Card Sorting Test (WCST): The WCST evaluates cognitive flexibility, problem-solving skills, and executive functioning. It measures an individual's ability to adapt to changing rules or conditions and to shift cognitive strategies when faced with new tasks. This test assesses the ability to overcome perseveration (sticking to an incorrect rule) and adapt to the correct rule based on feedback. The WCST uses a deck of 128 cards, each with one of four shapes (circle, triangle, star, or cross), in one of four colors (red, green, yellow, or blue), and with one of four numbers (1, 2, 3, or 4). It is valuable for understanding how patients adapt to new information, shifting circumstances, and challenges, making it a key part of cognitive evaluations in clinical settings.

The Trail Making Test (TMT) is a widely used neuropsychological assessment tool designed to evaluate cognitive functions, including executive functioning, cognitive flexibility, visual attention, and processing speed. The test is divided into two parts: TMT-A and TMT-B, each measuring different cognitive aspects.

Cognitive Aspects Measured by TMT:

Cognitive Flexibility: The ability to switch between tasks (TMT-B) and adjust strategies is a key indicator of executive functioning. Poor performance on TMT-B may suggest deficits in cognitive flexibility.

Attention and Processing Speed: TMT-A measures basic processing speed and attention. Delays or errors in completing the test can indicate difficulties with these cognitive domains.

Executive Functioning: Both parts of the TMT assess aspects of executive functioning, particularly planning, mental flexibility, and working memory.

Verbal fluency (VF) tasks are widely used in neuropsychological assessments to measure cognitive functions such as language production, executive control, and semantic memory. These tasks provide valuable insights into the cognitive abilities of individuals, especially those with psychiatric and neurological conditions. The primary aim of this evaluation is to assess changes in verbal fluency performance in individuals undergoing TMS treatment for depression, specifically treatment-resistant depression. Verbal fluency is commonly assessed through two main types of tasks: Phonemic Fluency: The ability to generate words beginning with a specific letter (e.g., "K" "A," or "S") within a set time limit. Semantic Fluency: The ability to generate words belonging to a specific category (e.g., animals, fruits, etc.) within the same time limit.

The relationship between cognitive flexibility, assessed through neuropsychological tests (WCST, TMT, VF), will be evaluated prior to the TMS procedure. For cases of treatment-resistant depression, a ≥ 50% reduction in the PHQ-9 score is generally considered a clinically significant response to treatment. The PHQ-9 score ranges from a minimum of 0, indicating no depressive symptoms, to a maximum of 27, indicating severe depressive symptoms. The interpretation of PHQ-9 scores is as follows: 0-4 indicates minimal or no depression, 5-9 indicates mild depression, 10-14 indicates moderate depression, 15-19 indicates moderately severe depression, and 20-27 indicates severe depression.

A ≥ 50% reduction in the PHQ-9 score is often considered a clinically significant response to treatment. The PHQ-9 scoring ranges from a minimum score of 0, indicating no depressive symptoms, to a maximum score of 27, indicating severe depressive symptoms. The interpretation of PHQ-9 scores is as follows: 0-4 indicates minimal or no depression, 5-9 indicates mild depression, 10-14 indicates moderate depression, 15-19 indicates moderately severe depression, and 20-27 indicates severe depression.

Patients undergoing TMS treatment will be evaluated using the Clinical Global Impression (CGI) scale, which will be applied both before and after the TMS treatment to assess changes in clinical status. The CGI is a standardized tool consisting of two main components: CGI-Severity (CGI-S), which evaluates the severity of the patient's condition on a 7-point scale (1 = normal, 7 = extremely ill), and CGI-Improvement (CGI-I), which assesses the degree of improvement or worsening compared to baseline on a similar 7-point scale (1 = very much improved, 7 = very much worse). This scale provides clinicians with a practical and reliable method for monitoring the effectiveness of treatment and patient progress over time.

Depressive symptoms will be evaluated using the Patient Health Questionnaire (PHQ-9) both before and after the TMS treatment to assess the effectiveness of the TMS protocol. The PHQ-9 is a widely used self-administered tool consisting of nine questions designed to assess the severity of depression symptoms experienced over the past two weeks. Each question is rated on a scale from 0 to 3, where 0 indicates no symptom and 3 represents the most severe symptom. The total score, which ranges from 0 to 27, provides a quantitative measure of depressive symptom severity. Higher scores on the PHQ-9 indicate more intense depressive symptoms.

For the purpose of evaluating treatment response, a greater than 50% reduction in the PHQ-9 score following the TMS treatment will be considered indicative of a positive response to the therapy. This significant reduction in score reflects a marked improvement in depressive symptoms, signaling the effectiveness of the TMS protocol.

Recording any adverse events or unexpected side effects noted during or after the transcranial magnetic stimulation (TMS) sessions, to evaluate the safety profile of the treatment. There is no standardized method for evaluating the side effects of TMS, a clinician will evaluate the participants for known side effects including changes in hearing, local pain, muscle contractions, headache, non-specific tingling, and discomfort.

Drug interactions during TMS treatment will be assessed using the TMS side effect questionnaire. Medications that lower the seizure threshold, such as bupropion, will be documented prior to the TMS procedure. During the procedure, any side effects, such as headaches and intense application site pain, will be evaluated using the Visual Analog Scale (VAS). The Visual Analog Scale (VAS) consists of a straight line, typically 10 cm long (or sometimes 100 mm), where one end represents no symptoms (e.g., "0" or "no pain") and the other end represents the most severe symptoms imaginable (e.g., "10" or "worst possible pain"). Patients are asked to mark a point on the line that corresponds to the severity of their symptom, and this point is then measured in centimeters or millimeters to provide a numerical score reflecting the intensity of the symptom. The minimum value (0) represents no symptoms at all, such as "no pain" or "no nausea," while the maximum value (10) represents the most intense