Effectiveness of NIBS and Perceptual Learning for Improving Visual Performance in Patients With Glaucoma

Study Overview
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Brief Summary
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Glaucoma is a complex disease that can result in progressive vision loss. It is the second leading cause of blindness, accounting for 23% of permanent blindness in Hong Kong. There are no treatments that restore vision lost to glaucoma. However, recent studies have shown that vision can be improved by non-invasive brain stimulation (NIBS) and visual training. This study will examine the effect of perceptual learning and NIBS on improving quality of life, visual function and functional performance in patients with peripheral field loss due to glaucoma.

Detailed Description
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Study design: This study uses a prospective, double-masked, randomized, placebo-controlled training RCT design. The eligible participants will be randomly allocated into 3 groups: (A) Placebo-Perceptual learning + Sham-NIBS; (B) Real-Perceptual learning + Sham-NIBS; (C) Real-Perceptual learning + Real-NIBS. All participants will complete forty-three study visits: Visit 1: Eligibility assessment (refer to the recruitment criteria); Visit 2-3: Outcome measures (Pre-intervention/ baseline); Visit 4-13: 10 sessions intervention (1st batch); Visit 14-15: Interim 1 Outcome measures; Visit 16-25: 10 sessions intervention (2nd batch); Visit 26-27: Interim 2 Outcome measures; Visit 28-37: 10 sessions intervention (3rd batch); Visit 38-39: Post-training 1 Outcome measures; Visit 40-41: Post-training 2 Outcome measures (to evaluate the retention effect after 1 month); Visit 42-43: Post-training 3 Outcome measures (to evaluate the retention effect after 2 months). Six sessions of assessment will be conducted: (1) Baseline; (2) Interim-1 (after 10-sessions training); (3) Interim-2 (after 20-sessions training); (4) Post-1 (after 30-sessions training); (5) Post-2 (1-month post training); and (6) Post-3 (2-month post training).

Official Title
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Improving Vision and Quality of Life in Patients With Glaucoma Using Non-invasive Brain Stimulation and Perceptual Learning: A Randomized Clinical Trial

Conditions
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Glaucoma

Intervention / Treatment
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* Other: Real-PL training + Real-NIBS(tDCS)
* Other: Real-PL training + Sham-NIBS (tDCS)
* Other: Placebo-PL training + Sham-NIBS (tDCS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range from 18 to 80 years; Diagnosis of primary open angle or normal tension glaucoma with relative scotoma in both eyes; A relative scotoma defined as a Humphrey Field Analyser (HFA) threshold perimetry loss (mean deviation of -6dB) within the central 24 degree of the visual field for at least one eye; Best-corrected distance visual acuity of 6/12 or better (equivalent to 0.3 logMAR acuity or better to confirm that participant's central vision is preserved). Stable vision and visual field loss for at least 3 months; With a cognitive functional score of 22 or above in the Montreal Cognitive Assessment - Hong Kong version (HK-MoCA) (to confirm participant's intact cognitive function). Exclusion Criteria: Ocular diseases other than glaucoma (e.g. age-related macular degeneration, diabetic retinopathy, moderate to severe cataract) or severe hearing impairment (to ensure that participant can hear the instructions clearly during assessments and training); Severe medical problems (e.g. stroke, Parkinson's disease) or self-reported neurological (e.g. brain surgery, brain tumor, peripheral neuropathy), or cognitive disorders (e.g. diagnosed dementia or cognitive impairment); Self-reported vestibular or cerebellar dysfunction, history of vertigo; Using any medications for any neurological conditions or psychiatric drugs (e.g. sedative, hypnotic) that might interfere motor control; Contraindications for non-invasive brain stimulation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: A prospective, double-masked, randomized, placebo-controlled training RCT design
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Real-PL + Real-NIBS (tDCS)<br>Participant will receive 30 training sessions with real PL and real NIBS (tDCS): 3-4 sessions per week, about 1 hour per session | Other: Real-PL training + Real-NIBS(tDCS)<br>* PLtraining : around 40mins, tDCS: 20mins<br>|
| Experimental: Real-PL + Sham-NIBS (tDCS)<br>Participant will receive 30 training sessions with real PL and sham NIBS (tDCS): 3-4 sessions per week, about 1 hour per session | Other: Real-PL training + Sham-NIBS (tDCS)<br>* PL training : around 40mins, tDCS: 20mins<br>|
| Placebo Comparator: Placebo-PL + Sham-NIBS (tDCS)<br>Participant will receive 30 training sessions with placebo PL and sham NIBS (tDCS): 3-4 sessions per week , about 1 hour per session | Other: Placebo-PL training + Sham-NIBS (tDCS)<br>* PL training : around 40mins, tDCS: 20mins<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral visual function (high-resolution perimetry & conventional perimetry) | Peripheral visual function will be evaluated monocularly by high-resolution perimetry (HRP) along with conventional perimetry using the program SITA-Standard 24-2 of the HFA. These are two common outcome measures adopted in previous glaucoma RCTs | Change from baseline at 5weeks, change from baseline at 10weeks, change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks | 
| Electroencephalography (EEG) | 64-channel electroencephalography(EEG) recordings from Neuroscan will be used to understand the electrophysiological changes in the intervention. A standard visual evoked potential task (VEP) and a specific designed SSVEP task will be used to assess the functional integrity of central vision and peripheral function. Besides, resting-state EEG will be recorded to measure the functional connectivity at different timepoints. ERP components (such as P100, N1 and N2) in VEP, tagging frequency response in SSVEP, and the power correlation in resting state will be analyzed as physiological indicators. | Change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Questionnaires for QoL | National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ 25) and Low Vision Quality of Life (LVQoL) will be used to evaluate the patient-perceived outcome of the intervention on daily living. In NEI-VFQ 25, more positive person measures indicates greater visual ability, and more negative person measures have less visual ability. In the LVQoL, the completion results in a summed score between 0 (a low quality of life) and 125 (a high quality of life). | Change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks | 
| Balance function | Balance function will be evaluated for the following two conditions: Static Balance: Participants will be asked to stand on a force place with a foam while performing visual searching. Parameters including maximum antero-posterior amplitude (mm), maximum medio-lateral amplitude (mm), total sway path (mm), and root mean square sway (mm/s) will be analyzed. Perturbed Balance: Participants will be asked to stand on a force place which will translate forward or backward while performing visual searching. Parameters including latency (ms) reacting to the perturbation, maximum antero-posterior amplitude (mm), maximum medio-lateral amplitude (mm), total sway path (mm), and root mean square sway (mm/s) will be analyzed. | Change from baseline at 5weeks, change from baseline at 10weeks, change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks | 
| Gait Test | All participants will be asked to walk along a 7-m walkway at their normal pace. Two disturbing factors will be introduced while walking: visual searching task and obstacle crossing. For trials with visual search, visual stimuli will be presented on the monitor (located at the end of the walkway) when the participant crosses the obstacle. For trials with obstacle crossing, an obstacle with two different colors (grey for low contrast and yellow for high contrast obstacle) of two different heights (2.5x60x5 cm or 2.5x60x15 cm) are positioned at the middle of the walkway. Participants' gait parameters including hip flexion/extension (degree), knee Min/Max (degree), ankle flexion/extension (degree), head flexion/extension (degree), walking speed (mm/s), step width (mm), and toe clearance(mm) will be measured and analyzed for each condition. | Change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks | 
| Questionnaire of psychological state | Perceived Stress Scale (PSS-10) and Patient Health Questionnaire - 9 (PHQ9) will be used to evaluated the stress and depression severity of the outcome of the intervention of participant. Individual scores on the PSS-10 can range from 0 to 40 with higher scores indicating higher perceived stress. In PHQ9, the completion results in a summed score between 0 (none minimal) to 27 (severe). | Change from baseline at 15weeks, change from baseline at 19weeks, change from baseline at 23weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glaucoma, transcranial direct current stimulation (tDCS), perceptual learning (PL)