Investigation of Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on "Hot" and "Cold" Cognitive Systems In Treatment Resistant Depression (TRD)

Repetitive transcranial magnetic stimulation (rTMS) is prescribed as first-line treatment for patients with Major Depressive Disorder. rTMS is safe, tolerable and non-invasive neurostimulation procedure. rTMS is characterized by an advantage in comparison to traditional pharmacotherapy in the sense that it exerts higher spatial precision in anatomical targeting of the specifically intended brain region compared to medications. The brain region of interest targeted with deep TMS in this study is the left-dorsolateral prefrontal cortex (L-DLPFC) which has been implicated in pathophysiology of depression.

Emotionally-laden functions within the brain are classified as "hot cognition" and contrastingly, affective-neutral areas regulating domains such as concentration, attention, learning and memory and executive function correspond to the characterization of "cold cognition" system. Both ''hot'' (emotion-laden) and ''cold'' (emotion-independent) cognition are known to take a role in the pathophysiology of MDD.

It is known that individuals suffering from depression experience impairments in hot cognition and as a result dedicate excessive focus to negative information, thereby producing negativity bias. A dysfunctional cold cognition system in depression also persists due to hypoactivity and abnormal functional connectivity of its underlying networks. The potential effects of rTMS on hot and cold cognition are currently uncertain. This study seeks to simultaneously evaluate hot and cold cognitive processes in response to deep TMS in order to elucidate the underlying cognitive mechanisms involved. More specifically, the investigators seek to explore the interaction between the two in terms of the time course and magnitude of the improvements in each system in response to TMS, and their relationship to mood improvement.

Methodology The subjects in the TRD group will undergo High Frequency deep TMS (HF-dTMS) stimulation over L-DLPFC, at the frequency of 18Hz, at 120% motor threshold value, for 5 daily sessions per week, over the course of 6 weeks. After the completion of treatment course at the conclusion of the 6 week mark, one post-treatment follow-up visit will take place at 1 month in order to assess any longer-term effects on cognition and depressive symptoms.

• Visual scanning The visual scanning test will consist of the presentation of 81 slides: 32 test slides (consisting of emotional images taken from Karolinska Directed Emotional Faces (KDEF) standardized library of facial expressions as well as a set of images with suicidal valence) and 49 filler slides. Each of the test and filler slides will contain four images at each of the four quadrants of the slide. The subjects' visual scanning behavior of the test slides will be analyzed while the scanning behavior of the filler slides will not be analyzed. Filler slides will change from session to session while the images on the test slides will remain the same. The position as well as the order of presentation of the four images on each test slide will randomly change between sessions. By using a large number of filler slides (different filler slides for each session), a randomized order for the presentation of the test slides and a randomized order for the position of the four images on each test slide, the investigators are aiming to minimize the possibility that patients' scanning behavior will be affected by recall from previous presentations. Each slide will be presented for 11 seconds for a total presentation time of 15 minutes.
• CANTAB measures For measuring the domains of cold cognition, the CANTAB measure which is a series of cognitive tests will be utilized. This battery is comprised of tests in the following cognitive domains: Attention, Executive Function, Memory and Social-Emotional Cognition. For the purposes of this study, the following cognitive tests will be implemented: For the domain of Attention, Motor screening task (MOT) [2 minutes] which evaluates potential sensorimotor or comprehension deficits, and Rapid Visual Information Processing (RVP) [7 minutes] which measures sustained attention are administered. For the domain of Executive Function, One Touch Stockings of Cambridge (OTS) [10 minutes] test that is built upon the foundation of "Tower of Hanoi" test and evaluates working memory and spatial planning subdomains of executive function will be implemented. For the domain of Memory, Verbal Recognition Memory (VRM) [10 minutes] will be used. VRM is a measure of new learning and verbal memory through the ability of collecting verbal information and its retrieval. For the domain of Social-Emotional Cognition, Emotion Recognition Task (ERT) [6-10 minutes] will be utilized which assesses the subject's ability in identification of six basic human emotions in facial expression along that expression's magnitude spectrum. Overall time allocated to conducting the aforementioned CANTAB measures will be approximately 40 minutes. As the subjects are engaging with these tests, the eye-tracking apparatus will be set up in the meantime [15-20 minutes] to enhance efficiency in time management and optimize the use of time. Following the completion of CANTAB tests, the subjects will promptly begin and complete the visual eye-tracking exercise [15 minutes]. Total time allocated to these measures of hot and cold cognition will approximate 1 hour.
• Bloodwork Past research indicates elevated levels of plasma inflammatory markers in depressive patients compared to non-depressed individuals among which markers such as tumor necrosis factor ⍺ (TNF-⍺) and interleukin-6 (IL-6) have been most reliably seen to exhibit heightened concentration levels in plasma. It has also been shown that depressed individuals had a higher likelihood of portraying non-response towards antidepressant medication carry a higher level of inflammatory markers at baseline and follow-up than those who responded to antidepressant therapy.