Ignite Creation Date:
2024-05-06 @ 1:15 PM
Last Modification Date:
2024-10-26 @ 1:11 PM
Study NCT ID:
NCT03977038
Status:
COMPLETED
Last Update Posted:
2023-03-15
First Post:
2019-05-23
Brief Title:
Investigation of the Effects of Repetitive Transcranial Magnetic Stimulation on Cognition in Depression
Sponsor:
Sunnybrook Health Sciences Centre
Organization:
Sunnybrook Health Sciences Centre
Study Overview
Official Title:
Investigation of Effects of Repetitive Transcranial Magnetic Stimulation rTMS on Hot and Cold Cognitive Systems In Treatment Resistant Depression TRD
Status:
COMPLETED
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 hotand 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 subjects ability in identification of six basic human emotions in facial expression along that expressions 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 ie 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 ie 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 ie difference from baseline of average fixation time or average fixation frequency and only be observed at later time points
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 subjects ability in identification of six basic human emotions in facial expression along that expressions 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 ie 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 ie 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 ie difference from baseline of average fixation time or average fixation frequency and only be observed at later time points
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None