Ignite Creation Date:
2024-05-06 @ 5:14 PM
Last Modification Date:
2024-10-26 @ 2:24 PM
Study NCT ID:
NCT05236010
Status:
RECRUITING
Last Update Posted:
2024-07-12
First Post:
2022-02-01
Brief Title:
Control Network Neuromodulation to Enhance Cognitive Training in Complex Traumatic Brain Injury
Sponsor:
University of New Mexico
Organization:
University of New Mexico
Study Overview
Official Title:
Control Network Neuromodulation to Enhance Cognitive Training in Complex Traumatic Brain Injury
Status:
RECRUITING
Status Verified Date:
2024-07
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:
CONNECT-TBI
Brief Summary:
The CONNECT-TBI Trial aims to develop safe effective treatments for complex mTBI that improve cognitive functioning Based on the compelling preliminary data generated by our study team the objective of this study is to conduct a randomized double-blinded sham-controlled Phase II clinical trial of APT-3 combined with rTMS HD-tDCS or sham to treat cognitive control deficits in Veterans with complex mTBI and PPCS At the Baseline Visit participants will undergo demographic neuropsychological behavioral and quality of life testing They will also undergo structural MRI to permit modeling of their brain restingtask-related fMRI to identify the CCN and pseudocontinuous arterial spin labeling pCASL and diffusion tensor imaging DTI to assess for other pathologies They will then be randomized to 16 sessions of APT-3 with concurrent rTMS HD-tDCS or sham stimulation delivered to the unique functional left dorsolateral prefrontal cortex DLPFC a primary node of the CCN Lastly they will repeat all baseline tests and report on 3- and 6-month recovery levels to establish longevity and stability of subjective benefit Given that this individualization protocol has never been attempted for cognitive rehabilitation in military mTBI we expect this trial will generate useful effect sizes for HD-tDCS and rTMS to be used for powering the next step a Phase III multi-center trial
Detailed Description:
Concussions from blast and non-blast mechanisms can lead to prolonged post concussive symptoms PPCS with debilitating consequences for return to service functional independence and quality of life Unfortunately algorithmic rehabilitation modalities are of limited generalizability and have small effect sizes potentially because of limited target engagement while medications are modestly efficacious but carry significant risks eg addiction
Cognitive symptoms after mTBI are common and debilitating Contrary to conventional wisdom mTBI are often not mild in regard to disability with up to 22 of patients reporting functional impairment at one year following injury In particular executive functions such as working memory set shifting and response inhibition appear to be more sensitive to TBI damage and have a greater impact on overall functioning Despite advances in our understanding of PPCS no single treatment yet targets putative TBI mechanisms Medications such as methylphenidate while modestly helpful carry adverse consequences such as disinhibition and cardiovascular effects and little evidence currently exists to recommend any other class of medication Cognitive rehabilitation is only mildly helpful Since the 2009 meeting of the Defense Centers for Excellence of Psychological Health and Traumatic Brain Injury little consensus has been reached regarding the utility or optimum means of delivery for therapist-based rehabilitation of cognitive deficits Importantly several limitations in the evidence base have impeded progress toward a standardized approach to post-TBI cognitive symptoms including 1 varied rehabilitation interventions used ie therapist-based computer-based 2 varied outcome measures studied and 3 lack of generalization of benefits to global functioning The most recent trials of cognitive rehabilitation interventions in military populations have attempted to compare these different rehabilitation approaches While these studies demonstrate that cognitive rehabilitation interventions can improve subjective symptoms and quality of life after mTBI it is not clear how this benefit is achieved nor if it is actually targeting a mTBI related mechanism
Neuromodulation can accelerate cognitive recovery Multiple studies have described use of tDCS in TBI for cognitive performance nearly all targeting the left DLPFC node of the CCN with variable improvements noted from a variety of different stimulation protocols Of note a recent meta-analysis of tDCS for working memory in neuropsychiatric populations showed that anodal tDCS produces significant improvement in online during stimulation working memory accuracy standardized mean difference 077
rTMS also shows promise for treating mTBI rTMS is a powerful neuromodulation technique that induces robust neuroplasticity effectively treats disease and is better characterized in terms of its mechanism of action Recently several small naturalistic and controlled studies have been reported indicating that both excitatory and inhibitory rTMS are safe in the mTBI population and can improve post concussive headaches chronic pain tinnitus and depression A recent negative trial of non-specific rTMS for cognition in severe TBI highlights the important need for more precise methods of patient selection treatment selection and target engagement
Study procedures involve a baseline testing visit 16 treatment visits and a post-treatment testing visit Participants will also be contacted at 3 months and 6 months post treatment for follow-up
Baseline Testing Visit Study assessments for collecting demographic information history and TBI data symptom severity information and neuropsychological testing will be completed at the baseline testing visit Testing will be performed by trained study personnel under direct supervision of the study Co-Investigators
Baseline Visit MRI scanning Subjects will undergo a 60-minute MRI using a 3T Siemens Prisma scanner at both the Albuquerque MRN and Minneapolis CMRR sites High-resolution T1- and T2-weighted images 1 x 1 x 1 mm resolution DTI pCASL resting state fMRI and task-related fMRI will be collected All anatomical data will be reviewed by a board-certified neuroradiologist blinded to group identification All positive findings will be coded for presence location severity and pathology of each abnormality consistent with the imaging CDEs Participants will undergo structural and functional MRI scanning at rest and during a multisensory working memory task The MMWM is a continuous performance test in which subjects respond to simultaneous sequences of visual squares on a grid and auditory spoken numbers stimuli by pressing a button if stimuli in either or both sensory modalities match a previous stimulus 1-back or 2-back
Neuromodulation Training Sessions 16 total 1 hr each In Albuquerque following completion of the Baseline Visit participants will receive either active HD-tDCS active rTMS or sham stimulation to the left DLPFC for a total of 30 minutes 4 daysweek for 4 consecutive weeks During neuromodulation sessions subjects will describe physical sensations such as tingling or itching using a 10-point anchored Likert scale Administration of HD-tDCS will be stopped immediately if subjects report 8 or above for discomfort or if subjects wish to stop at any time Subjects will have their mood energy pain and arousal levels assessed using visual analog 10-point scales These checks will occur every ten minutes during the stimulation session
HD-tDCS The Star-Stim 8 high-definition transcranial electrical stimulator will be used to administer HD-tDCS Targeting of the left DLPFC will be done by utilizing a standard EEG cap fitted snugly to the subjects head Several 10-20 EEG system positions will be measured and confirmed to ensure that the cap is correctly oriented on the head Round 1 cm2 HD-tDCS electrodes will be utilized to deliver anodal current and receive cathodal current Two anodal electrodes will be placed on the scalp over the functionally determined DLPFC delivering approximately 1 mA of current each in order to reduce overall sensation Six return electrodes will be placed in various positions around the anodes Precise electrode placement for each subject will be determined according to current modeling software that will use each individuals MRI T1 images to construct a 3-dimensional finite element model aiming to maximize current density within the DLPFC while minimizing current density outside of it Current for the treatment condition will be applied at 20 mA for 30 minutes for a total delivered charge of 60 mA-min Current will be ramped up over 1 minute at initiation and ramped down over 1 minute with termination Impedances are monitored in real-time for each channel to ensure that they do not exceed recommended limits eg 200 kilo-ohms
rTMS Participants will receive 16 sessions of TMS to the functional area in the DLPFC identified with fMRI while performing a working memory task A Magventure MagPro Transcranial Magnetic Stimulator Albuquerque NM and a Magstim Rapid 2 Transcranial Magnetic Stimulator Minneapolis MN will be used to administer active and sham rTMS to the left dorsolateral prefrontal cortex in 54 Veterans and Warfighters 36 active 18 sham with mTBI and cognitive postconcussive symptoms At the first session dose titration will be performed After sitting comfortably in the chair the subjects head is held with a moldable pillow and they are given earplugs to protect against coil discharge noise Surface electromyography leads will be applied to clean skin over the right hand over the first dorsal interosseous FDI muscle The motor cortex hotspot for the muscle will be identified with single-pulse TMS delivered to the contralateral hemisphere Resting motor threshold will be determined to be the lowest stimulation intensity necessary to elicit a motor-evoked potential meeting TMS Clinical Society conventional criteria of 50 uV peak-to-peak on 5 out of 10 trials The subjects fMRI data is loaded into the neuronavigation tracking computer to locate the functional hotspot within the DLPFC An infrared camera connected to the targeting computer will track the three-dimensional positions of the subjects head and the TMS coil in real time via affixed tracking markers The TMS coil is then positioned over the left forehead using the co-registered MRI data and identified head landmarks In each session up to 1800 pulses will be delivered according to conventional parameters for excitatory TMS eg 60 trains of 10 triplet pulses frequency 5 Hz train duration 2 seconds intertrain interval 8 seconds Magnetic field strength will be 120 of resting motor threshold Ramp up of magnetic field strength may be utilized in the first session for tolerability Side effects will be monitored and coil angle adjusted to improve tolerability if necessary without compromising placement
Sham The sham group n36 total will be split half n18 will receive sham HD-tDCS and half n18 will receive sham rTMS Participants receiving sham HD-tDCS will receive a current ramp up to the intensity of the real intervention in 30 seconds then the current will ramp down to 01 mA an amount that has been shown not to have any physiologic effect With 1 minute left in the stimulation session the current will ramp up to full strength in 30 seconds then ramp down in 30 seconds This paradigm is used as a control condition rather than the absence of stimulation to equate aspects of the procedure preparation and application of electrodes and to give the participant a degree of physical sensation that is somewhat similar to that of the real stimulation group while remaining well below the level sufficient to affect brain function and behavior To accomplish a double blind the HD-tDCS machine is programmed to randomize sham versus active stimulation and keeps track of the stimulation protocol for later querying Sham rTMS is delivered with a sham coil which delivers no physiologically active magnetic fields to the brain It creates a similar sound as the active rTMS coil and features electrodes that contact the skin and deliver a mild electrical current which resembles the sensations caused by typical rTMS pulses Double blind is maintained through use of randomized program codes assigned to each subject and which dictate the choice of coil for the participant
Cognitive Training Tasks For all groups participants will be administered the APT-3 training battery for 30 minutes at each session during treatment and sham Each sessions material will be determined by the study staff in advance according to a predetermined syllabus and the participant will proceed through the material as efficiently as they can If rTMS is given the training will take place after rTMS is completed If HD-tDCS is given the training will take place concurrently while the stimulation is occurring
Post-treatment Visit After the 16 neuromodulation training sessions are completed the testing and assessments from the Baseline Visit is repeated for the Post-treatment Visit including neuropsychological testing symptom assessment and MRI Demographic information will not be repeated
Long term follow-up 30 min each At 3 months and 6 months after receiving neuromodulation and cognitive training subjects will be contacted via telephone and administered symptom burden and quality of life assessment tools
Cognitive symptoms after mTBI are common and debilitating Contrary to conventional wisdom mTBI are often not mild in regard to disability with up to 22 of patients reporting functional impairment at one year following injury In particular executive functions such as working memory set shifting and response inhibition appear to be more sensitive to TBI damage and have a greater impact on overall functioning Despite advances in our understanding of PPCS no single treatment yet targets putative TBI mechanisms Medications such as methylphenidate while modestly helpful carry adverse consequences such as disinhibition and cardiovascular effects and little evidence currently exists to recommend any other class of medication Cognitive rehabilitation is only mildly helpful Since the 2009 meeting of the Defense Centers for Excellence of Psychological Health and Traumatic Brain Injury little consensus has been reached regarding the utility or optimum means of delivery for therapist-based rehabilitation of cognitive deficits Importantly several limitations in the evidence base have impeded progress toward a standardized approach to post-TBI cognitive symptoms including 1 varied rehabilitation interventions used ie therapist-based computer-based 2 varied outcome measures studied and 3 lack of generalization of benefits to global functioning The most recent trials of cognitive rehabilitation interventions in military populations have attempted to compare these different rehabilitation approaches While these studies demonstrate that cognitive rehabilitation interventions can improve subjective symptoms and quality of life after mTBI it is not clear how this benefit is achieved nor if it is actually targeting a mTBI related mechanism
Neuromodulation can accelerate cognitive recovery Multiple studies have described use of tDCS in TBI for cognitive performance nearly all targeting the left DLPFC node of the CCN with variable improvements noted from a variety of different stimulation protocols Of note a recent meta-analysis of tDCS for working memory in neuropsychiatric populations showed that anodal tDCS produces significant improvement in online during stimulation working memory accuracy standardized mean difference 077
rTMS also shows promise for treating mTBI rTMS is a powerful neuromodulation technique that induces robust neuroplasticity effectively treats disease and is better characterized in terms of its mechanism of action Recently several small naturalistic and controlled studies have been reported indicating that both excitatory and inhibitory rTMS are safe in the mTBI population and can improve post concussive headaches chronic pain tinnitus and depression A recent negative trial of non-specific rTMS for cognition in severe TBI highlights the important need for more precise methods of patient selection treatment selection and target engagement
Study procedures involve a baseline testing visit 16 treatment visits and a post-treatment testing visit Participants will also be contacted at 3 months and 6 months post treatment for follow-up
Baseline Testing Visit Study assessments for collecting demographic information history and TBI data symptom severity information and neuropsychological testing will be completed at the baseline testing visit Testing will be performed by trained study personnel under direct supervision of the study Co-Investigators
Baseline Visit MRI scanning Subjects will undergo a 60-minute MRI using a 3T Siemens Prisma scanner at both the Albuquerque MRN and Minneapolis CMRR sites High-resolution T1- and T2-weighted images 1 x 1 x 1 mm resolution DTI pCASL resting state fMRI and task-related fMRI will be collected All anatomical data will be reviewed by a board-certified neuroradiologist blinded to group identification All positive findings will be coded for presence location severity and pathology of each abnormality consistent with the imaging CDEs Participants will undergo structural and functional MRI scanning at rest and during a multisensory working memory task The MMWM is a continuous performance test in which subjects respond to simultaneous sequences of visual squares on a grid and auditory spoken numbers stimuli by pressing a button if stimuli in either or both sensory modalities match a previous stimulus 1-back or 2-back
Neuromodulation Training Sessions 16 total 1 hr each In Albuquerque following completion of the Baseline Visit participants will receive either active HD-tDCS active rTMS or sham stimulation to the left DLPFC for a total of 30 minutes 4 daysweek for 4 consecutive weeks During neuromodulation sessions subjects will describe physical sensations such as tingling or itching using a 10-point anchored Likert scale Administration of HD-tDCS will be stopped immediately if subjects report 8 or above for discomfort or if subjects wish to stop at any time Subjects will have their mood energy pain and arousal levels assessed using visual analog 10-point scales These checks will occur every ten minutes during the stimulation session
HD-tDCS The Star-Stim 8 high-definition transcranial electrical stimulator will be used to administer HD-tDCS Targeting of the left DLPFC will be done by utilizing a standard EEG cap fitted snugly to the subjects head Several 10-20 EEG system positions will be measured and confirmed to ensure that the cap is correctly oriented on the head Round 1 cm2 HD-tDCS electrodes will be utilized to deliver anodal current and receive cathodal current Two anodal electrodes will be placed on the scalp over the functionally determined DLPFC delivering approximately 1 mA of current each in order to reduce overall sensation Six return electrodes will be placed in various positions around the anodes Precise electrode placement for each subject will be determined according to current modeling software that will use each individuals MRI T1 images to construct a 3-dimensional finite element model aiming to maximize current density within the DLPFC while minimizing current density outside of it Current for the treatment condition will be applied at 20 mA for 30 minutes for a total delivered charge of 60 mA-min Current will be ramped up over 1 minute at initiation and ramped down over 1 minute with termination Impedances are monitored in real-time for each channel to ensure that they do not exceed recommended limits eg 200 kilo-ohms
rTMS Participants will receive 16 sessions of TMS to the functional area in the DLPFC identified with fMRI while performing a working memory task A Magventure MagPro Transcranial Magnetic Stimulator Albuquerque NM and a Magstim Rapid 2 Transcranial Magnetic Stimulator Minneapolis MN will be used to administer active and sham rTMS to the left dorsolateral prefrontal cortex in 54 Veterans and Warfighters 36 active 18 sham with mTBI and cognitive postconcussive symptoms At the first session dose titration will be performed After sitting comfortably in the chair the subjects head is held with a moldable pillow and they are given earplugs to protect against coil discharge noise Surface electromyography leads will be applied to clean skin over the right hand over the first dorsal interosseous FDI muscle The motor cortex hotspot for the muscle will be identified with single-pulse TMS delivered to the contralateral hemisphere Resting motor threshold will be determined to be the lowest stimulation intensity necessary to elicit a motor-evoked potential meeting TMS Clinical Society conventional criteria of 50 uV peak-to-peak on 5 out of 10 trials The subjects fMRI data is loaded into the neuronavigation tracking computer to locate the functional hotspot within the DLPFC An infrared camera connected to the targeting computer will track the three-dimensional positions of the subjects head and the TMS coil in real time via affixed tracking markers The TMS coil is then positioned over the left forehead using the co-registered MRI data and identified head landmarks In each session up to 1800 pulses will be delivered according to conventional parameters for excitatory TMS eg 60 trains of 10 triplet pulses frequency 5 Hz train duration 2 seconds intertrain interval 8 seconds Magnetic field strength will be 120 of resting motor threshold Ramp up of magnetic field strength may be utilized in the first session for tolerability Side effects will be monitored and coil angle adjusted to improve tolerability if necessary without compromising placement
Sham The sham group n36 total will be split half n18 will receive sham HD-tDCS and half n18 will receive sham rTMS Participants receiving sham HD-tDCS will receive a current ramp up to the intensity of the real intervention in 30 seconds then the current will ramp down to 01 mA an amount that has been shown not to have any physiologic effect With 1 minute left in the stimulation session the current will ramp up to full strength in 30 seconds then ramp down in 30 seconds This paradigm is used as a control condition rather than the absence of stimulation to equate aspects of the procedure preparation and application of electrodes and to give the participant a degree of physical sensation that is somewhat similar to that of the real stimulation group while remaining well below the level sufficient to affect brain function and behavior To accomplish a double blind the HD-tDCS machine is programmed to randomize sham versus active stimulation and keeps track of the stimulation protocol for later querying Sham rTMS is delivered with a sham coil which delivers no physiologically active magnetic fields to the brain It creates a similar sound as the active rTMS coil and features electrodes that contact the skin and deliver a mild electrical current which resembles the sensations caused by typical rTMS pulses Double blind is maintained through use of randomized program codes assigned to each subject and which dictate the choice of coil for the participant
Cognitive Training Tasks For all groups participants will be administered the APT-3 training battery for 30 minutes at each session during treatment and sham Each sessions material will be determined by the study staff in advance according to a predetermined syllabus and the participant will proceed through the material as efficiently as they can If rTMS is given the training will take place after rTMS is completed If HD-tDCS is given the training will take place concurrently while the stimulation is occurring
Post-treatment Visit After the 16 neuromodulation training sessions are completed the testing and assessments from the Baseline Visit is repeated for the Post-treatment Visit including neuropsychological testing symptom assessment and MRI Demographic information will not be repeated
Long term follow-up 30 min each At 3 months and 6 months after receiving neuromodulation and cognitive training subjects will be contacted via telephone and administered symptom burden and quality of life assessment tools
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
True
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None