Investigation of the Effects of Repetitive Transcranial Magnetic Stimulation on Cognition in Depression
Condition: Major Depressive Disorder; Treatment Resistant Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
Study type: Observational [Patient Registry]

Summary: 
      According to the World Health Organization, MDD is attributed as the leading cause of
      disability worldwide, leaving 300 million individuals affected. Despite the efficacy of
      pharmacotherapy, a subset of MDD patients, classified as TRD, exhibit suboptimal response and
      thus require alternative treatment options such as rTMS. Emotional-laden "hot"and Neutral
      "cold" cognitions are shown to be dysfunctional in depression. Potential pro-cognitive
      effects remain inconclusive. In this study the investigators seek to investigate whether
      visual scanning patterns of emotionally laden images may be a biological marker and predictor
      of rTMS antidepressant efficacy. If so, then changes in visual scanning patterns are expected
      to precede clinical symptom improvement. Furthermore, changes in visual scanning patterns
      (which characterizes the state of hot cognition) are compared simultaneously to changes in
      cold cognition in order to elucidate the neural mechanisms underlying rTMS-induced changes in
      cognition. It is hypothesized that participants who are responders to rTMS will exhibit a
      decrease in the amount of time spent looking at dysphoric images will precede clinically
      detectable changes in mood as measured by a reduction in the scores on the 17-item Hamilton
      Depression Rating Scale (HDRS-17). The hypothesis for this study corresponds to the
      alleviation of the dysfunction within the hot cognitive system as a result of rTMS and a
      potential compensatory effect of cold cognition as a natural reaction of resetting the
      allocation of cognitive resources.
    

Detailed description: 
      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.

      It has also been suggested that the number of unsuccessful antidepressant treatment trials
      indicating resistance and non-responsiveness in treatment resistant depressed individuals is
      associated with elevated plasma concentration of inflammatory markers of TNF-⍺ and IL-6
      compared to responsive depressed individuals who had undergone one adequate antidepressant
      trial successfully and those with no previous history of antidepressant treatment. As a
      biological marker of rTMS antidepressant efficacy, bloodwork will be obtained a total of 4
      times throughout the course of the study in order to monitor for genotype of serotonin
      transporter polymorphism (5-HTTLPR), brain-derived neurotrophic factor (BDNF) and potential
      alterations in present levels of the inflammatory markers of TNF-⍺ and IL-6 involved in the
      pathophysiological inflammation profile of depression.

      ● Psychiatric scales The severity of depressive symptoms in subjects will be assessed using
      the physician-rated HDRS-17 and self-report QIDS-SR16 psychiatric scales.

      Analysis Following the end of the last visit at Week 6, patients will be grouped by response
      status: responder, and non-responder. Responder is defined as a patient with a change of 50%
      or greater on the HDRS-17 measure from baseline (V2) to the last visit (V8).

      For each stage of testing, following the start of treatment (i.e. V2 to V8), differences from
      baseline (V2) of average visual fixation time, average fixation frequency, HDRS-17 and
      QIDS-SR16 scores will be calculated. The primary outcome measure, i.e., the difference from
      baseline of the average fixation time measured on different visits (V2 to V8), will be
      analyzed using linear mixed effect model with fixed effects and a random subject effect. The
      investigators will initially fit a mixed model with fixed effects of time and group and their
      interaction, and random intercepts and slopes. Similar models will be built for the secondary
      outcome variables comprising of average difference from baseline of fixation frequency,
      HDRS-17 and QIDS-SR16 scores.

      The investigators will use the group main effect and the group-time interaction to test the
      hypothesis that changes in differences from baseline of fixation time differ between
      responders and non-responders. The investigators expect the differences from baseline of
      average fixation time will become more negative (decrease) in the responder group but will
      remain unchanged in the non-responder group. It is also expected that this reduction in the
      differences from baseline of average fixation time will precede any significant changes in
      depressive symptom scores on measures of HDRS-17 or QIDS-SR16.

      Similarly, changes in the secondary outcome measures (difference from baseline of average
      fixation frequency, HDRS-17 and QIDS-SR16 scores) during the study course will also be
      analyzed in order to demonstrate an expected difference between responders and
      non-responders. The investigators expect the difference from baseline of fixation frequency
      will increase and that HDRS-17 and QIDS-SR16 will reduce by the conclusion of this study in
      the responder but not in the non-responder group. The investigators predict, however that any
      change in the HDRS-17 or QIDS-SR16 scores will succeed visual scanning parameters (i.e.,
      difference from baseline of average fixation time or average fixation frequency) and only be
      observed at later time points.
    

Intervention name(s): repetitive transcranial magnetic stimulation
Intervention type(s): Device
Intervention description(s): Repetitive transcranial magnetic stimulation (rTMS) is prescribed as first-line treatment for TRD patients (4). rTMS is safe, tolerable and non-invasive neurostimulation procedure where powerful magnetic pulses are transmitted through the skull into the underlying cortical cortex with the aim of electrical current induction within the neural tissue. This study administers a standard dose of rTMS treatment to the TRD patient sample consisting of high frequency deep TMS (HF-dTMS) stimulation over left dorsolateral prefrontal cortex (L-DLPFC), at the frequency of 18Hz, at 120% value of the individual's motor threshold, in 5 daily sessions per week, taking place each weekday, over the course of 6 weeks. The technology of dTMS, which will be used in this study, is an adaptation of the therapeutic intervention of rTMS with the advancement of possessing higher efficacy in targeting deeper brain regions of interest.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Potential TRD participants in this study will be individuals referred by their family
        doctor or community psychiatrist for diagnostic clarification and/or the provision of
        treatment options for their mood symptoms. Additionally, individuals who respond to the
        study advertisement and based on the telephone screening performed by the study physicians,
        are deemed to meet the study's inclusion and exclusion criteria will be the provision of
        treatment options for their mood symptoms as well as the opportunity to participate in this
        study. Healthy Control participants will be age-,sex- and education- matched to the TRD
        participants and will be representative of the community sample, consisting of healthy
        individuals with no psychiatric illness.
      
Biospecimen description: 
      Whole blood specimen will be retained from all participants at 4 time points in the study
      (Week 0 (baseline), Week 2, Week 6 (last visit) and Week 10 (follow-up)). Bloodwork is
      obtained in order to monitor for genotype of serotonin transporter polymorphism (5-HTTLPR) ,
      BDNF and potential alterations in the present levels of inflammatory markers of TNF-⍺ and
      IL-6 involved in the pathophysiological inflammation profile of depression.
    
Keywords: Repetitive Transcranial Magnetic Stimulation; Hot Cognition; Cold Cognition; Attentional Imaging; Eye tracking; Cognitive impairment; Cognition