Transcranial Direct Current Stimulation and Cognitive Remediation Therapy for Interictal Dysfunction in Epilepsy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate whether tDCS enhances the effect of cognitive remediation therapy on cognition and functional outcome in patients with epilepsy. There has been evidence that working memory performance is enhanced in healthy subjects. Acute tDCS studies have found improvements in working memory performance in subjects with other neurological diseases. To date, there have been no published studies examining whether can enhance learning during multi-session cognitive remediation over 2 weeks in subjects with epilepsy. This study could have potential application as a non-invasive clinical intervention for interictal dysfunction in epilepsy.

Detailed Description
-----------------
Epilepsy is a chronic neurological disorder affecting 50 million people worldwide. Patients suffer not only from recurring seizures, but also from cognitive deficits despite adequate treatment control. Cognitive remediation therapy (CRT) is a therapeutic intervention that has recently shown promise in improving cognitive impairment in many neuropsychological disorders. Transcranial direct current stimulation (tDCS) is a non-invasive method that modulates cortical excitability. It works by applying weak electrical currents to the scalp that induce acute modifications of neuronal membrane potentials, producing long-lasting changes in the bioelectric activity of underlying brain tissue. It is postulated that tDCS enhances benefit gained through cognitive remediation therapy. These interventions have yet to be combined with each other for the treatment of interictal dysfunction in patients with epilepsy. The goal of the study is to investigate whether the introduction of tDCS in addition to CRT is effective in the treatment of cognitive impairment in patients suffering from epilepsy.

Official Title
-----------------
Transcranial Direct Current Stimulation and Cognitive Remediation Therapy for Interictal Dysfunction in Epilepsy

Conditions
-----------------
Epilepsy

Intervention / Treatment
-----------------
* Device: transcranial direct current stimulation
* Other: Cognitive Remediation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-64 Epilepsy diagnosis confirmed by the UMN Comprehensive Epilepsy Center Complete seizure logs of the type in standard clinic use at the UMN Comprehensive Epilepsy Center for at least 12 weeks prior to study entry Stable CNS medications for the 2 weeks prior to the initiation visit and expected to continue with current medication doses for the two weeks of the intervention No diagnosis of mental retardation (IQ not less than 70) or pervasive developmental disorder At least one subtest of learning and memory less than --1.5 SD Sufficient spoken English so as to be able to comprehend testing procedures Competent and willing to provide consent Exclusion Criteria: Occurrence of generalized convulsive status epilepticus or of complex partial status epilepticus within 1 year prior to study entry Occurrence of more than 1 generalized tonic-clonic (GTC) seizure per month, or more than 4 complex partial (CP) seizures per week, as reported in the subject's seizure logs for 12 weeks prior to study entry Occurrence of GTC seizure within 48 hours before testing Any anti-epileptic medication changes or hospitalizations in the previous 4 weeks Additional neurologic disorder other epilepsy and cognitive dysfunctions History of metallic cranial plates, screws, or implanted devices History of craniotomy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active tDCS<br>There will be a total of 14 visits in the study: will complete a screening visit, an initial visit, 10 session visits with active tDCS(transcranial direct current stimulation) andcognitive remediation therapy, and follow--up visits immediately (within 5 days), 1 and 3 months after the last intervention. Subjects will be informed of their group assignment at the end of the study. | Device: transcranial direct current stimulation<br>* The anode will be placed over left DLPFC at F3, according to the 10-20 international system for EEG electrode placement. The cathode will be placed over the contralateral supraorbital area. They will be placed via two saline soaked electrode sponges (3 cm x 4.5 cm).After electrodes have been placed, the participants will be instructed to log into CRT software using a unique patient identifier. The CRT software that will be used will be Cogmed working memory training program (Pearson Education, Inc.)Active tDCS will be applied at a ramp-like fashion from 0 to 2mA over 10 seconds, and will be ramped down for the last 10 seconds of stimulation. Active tDCS will last 20 minutes each session. The sham procedure involves only 30 seconds of stimulation at 2mA.<br>* Other names: Neuroelectrics Starstim;Other: Cognitive Remediation Therapy<br>* The CRT software that will be used will be Cogmed working memory training program (Pearson Education, Inc.). Cogmed is a targeted computerized training program that has been shown to improve working memory and attention. (Spencer-Smith 2015).<br>* Other names: Cogmed;|
| Sham Comparator: Sham tDCS<br>There will be a total of 14 visits in the study: will complete a screening visit, an initial visit, 10 session visits with sham tDCS and cognitive remediation therapy, and follow--up visits immediately (within 5 days), 1 and 3 months after the last intervention. Subjects will be informed of their group assignment at the end of the study. | Other: Cognitive Remediation Therapy<br>* The CRT software that will be used will be Cogmed working memory training program (Pearson Education, Inc.). Cogmed is a targeted computerized training program that has been shown to improve working memory and attention. (Spencer-Smith 2015).<br>* Other names: Cogmed;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cogstate Brief Battery | The Cogstate Battery is a computerized cognitive assessment program which measures a wide range of cognitive functions (e.g. psychomotor speed, reaction time, working memory, divided attention, learning), which can be repeated with little to none observed practice effects (Falleti 2006). All tasks within the battery were adaptations of standard neuro-psychological and experimental psychological tests. Time to administer requires approximately 15-20 minutes consists of 8 tasks in the form of card games that are presented in succession. | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 
| Rey Auditory Verbal Learning Test (AVLT) | The Rey Auditory Verbal Learning Test (AVLT) is a measure of immediate auditory and verbal memory as well as delayed recall. Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes. Approximately 45-50 minutes is required for the procedure. (Loring et al. 2008, Strauss 2006) | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 
| Picture Sequence Memory Test | The Picture Sequence Memory Test (PSMT) is a measure for use in the assessment of episodic memory. Participants are asked to recall, in increasing length, a series of illustrated objects and activities that are presented in a particular order on the computer screen. The participants are asked to recall the sequence of pictures that is demonstrated over two learning trials. The number of pictures may vary depending on the age. The test takes approximately 7 minutes to administer. (Dikmen et al. 2014) | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 
| Flanker Inhibitory Control and Attention Task | This task measures both a participant's attention and inhibitory control. The test requires the participant to focus on a given arrow while inhibiting attention to other arrows surrounding it. (Heaton et al. 2014) Sometimes the middle stimulus is pointing in the same direction as the flankers (congruent) and sometimes in the opposite direction (incongruent). Scoring is based on a combination of accuracy and reaction time. The test takes approximately 3 minutes to administer. | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 
| Dimensional Change Card Sort Test | DCCS is an assessment to measure of cognitive flexibility. Two target pictures are presented that vary along two dimensions (e.g., shape and color). Participants are asked to match a series of bivalent test pictures (e.g., yellow balls and blue trucks) to the target pictures, first according to one dimension (e.g., color) and then, after a number of trials, according to the other dimension(e.g., shape). Switch trials are also employed, in which the participant must change the dimension being matched. For example, after 4 straight trials matching on shape,the participant may be asked to match on color on the next trial and then go back to shape, thus requiring the cognitive flexibility to quickly choose the correct stimulus. Scoring is based on a combination of accuracy and reaction time. This test takes approximately 4 minutes to administer. | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral Symbol Digit Test | This instrument is a measure of processing speed. (Denboer et al. 2014). The participant is presented with a set of nine symbols on the computer screen, each associated with a number 1-9, and is then presented with a series of symbols without numbers and is asked to orally say each number that should go with that symbol, without skipping any. The score is equal to the number of symbols correctly identified orally within two minutes. This takes approximately 3 minutes. | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 
| Cogstate Brief Battery | The Cogstate Battery is a computerized cognitive assessment program which measures a wide range of cognitive functions (e.g. psychomotor speed, reaction time, working memory, divided attention, learning), which can be repeated with little to none observed practice effects (Falleti 2006). All tasks within the battery were adaptations of standard neuro-psychological and experimental psychological tests. Time to administer requires approximately 15-20 minutes consists of 8 tasks in the form of card games that are presented in succession. | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 
| Quality of Life | To asses quality of life the Quality of Life in Epilepsy Inventory 31 will be administered. | Change from baseline to 5 days, 1 month, and 3 months after last intervention visit. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Interictal, Cognitive, Dysfunction, tDCS, transcranial direct current stimulation