
==== Front
J Clin Neurol
J Clin Neurol
JCN
Journal of Clinical Neurology (Seoul, Korea)
1738-6586
2005-5013
Korean Neurological Association

39227334
10.3988/jcn.2024.0015
Original Article
Customized Visual Discrimination Digital Therapy According to Visual Field Defects in Chronic Stroke Patients
https://orcid.org/0000-0002-1279-4499
Namgung Eun a*
https://orcid.org/0009-0008-0102-6890
Kim Hana b*
https://orcid.org/0000-0002-9275-199X
Kim Yong-Hwan b*
https://orcid.org/0009-0006-8494-7008
Kim Young-Sun b
https://orcid.org/0000-0001-8047-1029
Lee Eun-Jae c
https://orcid.org/0009-0008-7973-4571
Lee Jee-Hyun b
https://orcid.org/0000-0002-0061-0250
Sasaki Yuka d
https://orcid.org/0000-0002-4562-5376
Watanabe Takeo d
https://orcid.org/0000-0002-2999-485X
Kang Dong-Wha bc
a Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
b Nunaps Inc., Seoul, Korea.
c Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
d Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, RI, USA.
Correspondence: Dong-Wha Kang, MD, PhD. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel +82-2-3010-3968, Fax +82-2-474-4691, dwkang@amc.seoul.kr
*These authors contributed equally to this work.

9 2024
02 8 2024
20 5 509518
08 1 2024
19 6 2024
21 6 2024
Copyright © 2024 Korean Neurological Association
2024
Korean Neurological Association
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background and Purpose

Visual perceptual learning (VPL) may improve visual field defects (VFDs) after chronic stroke, but the optimal training duration and location remain unknown. This prospective study aimed to determine the efficacy of 8 weeks of VFD-customized visual discrimination training in improving poststroke VFDs.

Methods

Prospectively enrolled patients with poststroke VFDs initially received no training for 8 weeks (no-training phase). They subsequently underwent our customized VPL program that included orientation-discrimination tasks in individualized blind fields and central letter-discrimination tasks three times per week for 8 weeks (training phase). We analyzed the luminance detection sensitivity and deviation as measured using Humphrey visual field tests before and after the no-training and training phases. The vision-related quality of life was assessed at baseline and at a 16-week follow-up using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25).

Results

Changes in mean total deviation (MTD) scores were greater during the training phase than during the no-training phase (defective hemifield, p=0.002; whole field, p=0.004). The MTD scores improved during the training phase (defective hemifield, p=0.004; whole field, p=0.016), but not during the no-training phase (defective hemifield, p=0.178; whole field, p=0.178). The difference between the improved and worsened areas (≥6 dB changes in luminance detection sensitivity) was greater during the training phase than during the no-training phase (p=0.009). The vision-specific social functioning subscore of the NEI-VFQ-25 improved after the 16-week study period (p=0.040).

Conclusions

Our 8-week VFD-customized visual discrimination training protocol may effectively improve VFDs and vision-specific social functioning in chronic stroke patients.

Graphical Abstract

visual perception
vision disorders
stroke
cortical blindness
Korea Medical Device Development Fund https://doi.org/10.13039/100019266 1711197973 RS-2023-00222139 Korea Health Industry Development Institute https://doi.org/10.13039/501100003710 HR18C0016 National Research Foundation of Korea https://doi.org/10.13039/501100003725 2022R1F1A1060778 National Institutes of Health https://doi.org/10.13039/100000002
==== Body
pmcINTRODUCTION

Damage to the primary visual cortex results in vision loss and is referred to as cortical blindness. This presents as a defect in half (hemianopia) or one-quarter (quadrantanopia) of the visual field.12 Visual field defects (VFDs) are estimated to affect approximately 20% of people with stroke due to damage to the primary visual cortex.13 Cortical blindness impairs the ability to perform the activities of daily living due to difficulties in noticing obstacles in blind fields.45

While spontaneous recovery of VFDs may occur shortly after a stroke, sequelae remain in most patients with VFDs at 6 months after the onset if the underlying disorders are not addressed.16 Current rehabilitation methods for cortical blindness mostly focus on substitution with optical aids, such as prisms or compensatory scanning strategies.178 Vision restoration therapies have recently received increasing interest due to their efficacy in improving long-term outcomes and vision in blind fields.2910

Visual perceptual learning (VPL), defined as long-term improvement in visual performance after repeated visual training, could be a promising tool for vision recovery as a manifestation of sensory plasticity.11121314 Recent trials have shown that VPL involving at least 3 months of training may effectively occur in the blind visual fields associated with cortical blindness, leading to recovery from VFDs.9151617

However, the responses to VPL can differ between individuals, which is partly due to interindividual variations in the types and severities of cortical blindness.9151617 The optimal type and location of visual stimuli and duration of VPL training remain unclear for treating poststroke VFDs, and hence further investigations are needed. A short VPL program (lasting <3 months) that targets individualized blind fields is needed to effectively induce recovery in various types of poststroke VFDs.

We developed a customized 8-week VPL program that involves dual tasks of visual discrimination in individualized blind visual fields and simultaneous central fixation. We investigated the efficacy of our 8-week VFD-customized visual discrimination training protocol in improving VFDs of chronic stroke patients relative to an 8-week no-training phase.

METHODS

Participants and study design

This prospective study was approved by the Institutional Review Board of Asan Medical Center (approval number: 2014-1174) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each participant or their legally authorized representatives.

The inclusion criteria were patients who 1) were older than 20 years, 2) had VFDs such as homonymous hemianopia or quadrantanopia due to chronic stroke (at least 6 months after stroke onset), 3) were in a clinically stable status as confirmed by a neurologist (D-W. Kang), and 4) had a corrected visual acuity of ≥0.7. The exclusion criteria were 1) cognitive impairment (score of <24 points on the Korean version of the Mini–Mental State Examination18) or 2) ophthalmic disorders such as cataracts, glaucoma, or macular degeneration.

VPL program

The screened patients first received an 8-week no-training period (no-training phase), before undergoing 24 sessions of a VFD-customized visual discrimination training over an 8-week period with 3 sessions per week (training phase). Humphrey visual field (HVF) tests were conducted before and after both the no-training and training phases. The National Eye Institute Visual Function Questionnaire-25 (NEI–VFQ-25) was administered at baseline and at a 16-week follow-up. A schematic of the training program is shown in Fig. 1A.

A modified orientation-discrimination task that was customized to personalized VFD locations was used to elicit VPL. Based on the HVF test results at baseline, the training location of the orientation-discrimination tasks was determined individually for each defective quadrant (referred to as the training location; green box in Fig. 1B and C), which was located along the border of the blind and normal fields. There were two trained quadrants for hemianopia (both upper and lower quadrants) and one trained quadrant for quadrantanopia (either the upper or lower quadrant depending on the defective quadrant). Each training session consisted of 384 trials for patients with hemianopia and 264 trials for patients with quadrantanopia (26 trials for each defective quadrant and 6 trials for each normal quadrant for each task; patients performed 6 tasks during each training session). During the training sessions, peripheral visual stimuli were randomly presented in blind or normal fields at a 26:6 ratio (Fig. 1C).

The target screen (an LCD monitor) displayed a centrally located fixation letter (either “ㅋ” or “ㅌ” Korean letters) within a circle (radius=0.8 degrees) and a peripherally located square grating pattern (with a horizontal or vertical orientation, size 10×10 degrees2), with the location of the peripheral stimulus along the border of the blind fields determined based on the results of the baseline HVF test. The central fixation letter and the peripheral orientation stimuli were presented simultaneously. The purpose of the letter task was to ensure that the subject’s gaze was fixated on the center of the screen. The gray color values of the background, fixation circle, and letters were 127, 100, and 140, respectively, on a 256 RGB grayscale from 0 to 255. The peripheral stimulus was filled with horizontally or vertically oriented grating patterns comprising a 2.5-Hz sine wave. The spatial length of the intensity changes (i.e., λ) covered 4 degrees of the visual field.

While keeping their eyes fixated at the center of the fixation point, patients were asked to respond twice by pressing two of four buttons on a response button box in each trial: one to identify the fixation letter (“ㅋ” or “ㅌ”) and the other to indicate the orientation (horizontal or vertical) of the grating pattern (Fig. 1C). Visual stimuli were presented on the screen at a viewing distance of 40 cm, and covered 37×30 cm2, corresponding to visual angles of 50×40 degrees2 that spanned 25 degrees of the visual field horizontally and 20 degrees vertically from the center of the screen. Each trial involved the sequential presentation of the fixation for 500 ms followed by the target for 150 ms, with the response then monitored for a maximum of 8,000 ms. The subsequent trial was started immediately after a response had been elicited. The accuracy of the peripheral orientation task was analyzed with trials in which the fixation task was correct.

Assessment of VFDs

The HVF test (30-2 SITA-FAST protocol; Humphrey Field Analyzer 750i, Zeiss-Humphrey, Leandro, CA, USA) was used for the quantitative analysis of VFDs. The type and side of VFDs were evaluated according to a total deviation probability of <5% for the baseline HVF test results.1920 Patients with a fixation loss of >30% in any HVF test were excluded from the final analysis.21

The Humphrey Field Analyzer provides total deviation scores and luminance detection sensitivity at each tested HVF position. The total deviation scores are luminance detection thresholds in decibels relative to age-normative values.

Mean total deviation (MTD) scores for the defective hemifield (Fig. 1B, red box) and the whole field (Fig. 1B, black box) were calculated by averaging the total deviation scores for the defective hemifield and the whole field, respectively, for both eyes. The luminance detection sensitivity in the whole visual field was averaged for both eyes.

Changes in the MTD scores and luminance detection sensitivity were calculated by subtracting the baseline scores from the 8-week scores during the no-training phase and by subtracting the 8-week scores from the 16-week scores during the training phase. The outcome measures included MTD scores for the defective hemifield and the whole field measured at baseline and at the 8-week and 16-week follow-ups as well as the changes in MTD scores during the no-training and training phases.

A cutoff of 6 dB for the test–retest HVF variability (which represents a doubling) was chosen to define a significant change in the luminance sensitivity for the whole visual field.152223 The outcome measures were improved areas where the sensitivity increased by ≥6 dB, worsened areas where the sensitivity decreased by ≥6 dB, and differences between the improved and worsened areas (improved minus worsened area).

The impact of the VFDs on the quality of life was assessed at baseline and at the 16-week follow-up using the NEI-VFQ-25.2425 Visual acuity, peripheral vision, color vision, and the ability to perform the activities of daily living were assessed using the 25 questions in the questionnaire, with each question scored from 0 to 100. The composite and subscale scores were calculated, with higher scores indicating better vision-related quality of life.

Assessment of ischemic stroke lesion volumes

Ischemic stroke lesions were automatically segmented in T1-weighted images using the LINDA (Lesion Identification with Neighborhood Data Analysis) software at baseline.26 The lesion masks in the T1 space were normalized to the standard space, and then inversely registered onto the individual T1 space using the inverse matrix for calculating the individual ischemic stroke lesion volume. The lesion volume was calculated separately for the entire brain and the visual cortex.

Statistical analyses

Wilcoxon signed-rank tests were used to compare MTD scores for the defective hemifield and the whole field between pre- and postassessment during the no-training and training phases. Wilcoxon signed-rank tests were also used to compare NEI-VFQ-25 scores between baseline and the 16-week follow-up.

Linear mixed-effects models for repeated measures were used to compare the fixed effects of the VPL training (no-training vs. training) on changes in MTD scores for the defective hemifield and the whole field during the 8-week follow-up. These models included a random subject effect and the respective preassessment raw score as a covariate. Differences in the changes in the whole area (improved area, worsened area, and improved minus worsened area with ≥6 dB changes in sensitivity) between VPL training and no-training were analyzed using a linear mixed-effects model. This model included VPL training (no-training vs. training) as a fixed effect, a within-individual random effect, and the sensitivity score at the preassessment as a covariate.

Robust regression analyses were performed to examine how patient characteristics may affect changes in the HVF measures during the 8-week training phase while correcting for outliers and noise. Independent variables included age, stroke lesion age, entire brain lesion volume, and lesion volume in the visual cortex of each patient. Dependent variables included changes in MTD scores for the defective hemifield and the whole field as well as the improved area, worsened area, and improved minus worsened area with ≥6 dB changes in sensitivity during the 8-week training phase.

Robust regression was also used to examine how changes in HVF measures during the 8-week training phase may affect changes in the NEI-VFQ-25 composite score during the 16-week follow-up. The independent variables included changes in MTD scores for the defective hemifield and the whole field as well as the improved area, worsened area, and improved minus worsened area with ≥6 dB changes in sensitivity during the 8-week training phase. The dependent variable included changes in the NEI-VFQ-25 composite score during the 16-week follow-up.

We considered that p<0.05 indicated statistical significance. All statistical analyses were conducted using Stata software (Stata Corporation, College Station, TX, USA).

RESULTS

Participant characteristics

Screening resulted in the enrollment of 18 patients who completed the study program consisting of the no-training phase for 8 weeks followed by VFD-customized visual discrimination training for 8 weeks (Fig. 1). No patient complained of side effects associated with the 8-week customized VPL training program. Four patients were excluded from the analyses due to low HVF test reliability with a fixation loss exceeding 30%.

The patient demographics, type of VFDs, stroke lesion age, and stroke lesion volume are presented in Table 1. The patients included in the final analysis (n=14) had a mean age of 53.9 years, and most of them were male (92.9%). Regarding the VFD characteristics, 57.1% of the patients had hemianopia and 64.3% of the patients had VFDs on the left side. The mean stroke lesion age was 10.1 months. Calculated based on magnetic resonance imaging data, the mean entire brain stroke lesion volume was 28.4 cc, while the mean lesion volume in the visual cortex was 18.3 cc.

Age, stroke lesion age, entire brain lesion volume, and lesion volume in the visual cortex of the 14 patients were not significantly associated with any of the changes in HVF measures during the 8-week training phase, including changes in the MTD scores for the defective hemifield and the whole field as well as the improved area, worsened area, and improved minus worsened area with ≥6 dB changes in sensitivity (Table 2).

HVF score changes in the defective visual hemifield after VPL

The MTD scores for the defective hemifield did not change significantly during the no-training phase (-22.9±7.4 [mean±standard deviation] and -23.6±6.8 at pre- and postassessment, respectively; Wilcoxon signed-rank test: p=0.178) (Fig. 2A). The MTD scores for the defective hemifield improved during the training phase (-23.6±6.8 and -22.5±7.1 at pre- and postassessment, respectively; Wilcoxon signed-rank test: p=0.004) (Fig. 2B).

Moreover, 8-week changes in the MTD scores for the defective hemifield were significantly larger during the training phase than during the no-training phase (1.04±1.45 vs. -0.65±1.60; linear mixed-effects model for repeated measures: p=0.002) (Fig. 2C).

HVF score changes in the whole visual field after VPL

The MTD scores for the whole field did not change significantly during the no-training phase (-12.4±4.1 and -12.8±3.6 at pre- and postassessment, respectively; Wilcoxon signed-rank test: p=0.178) (Fig. 3A). The MTD scores for the whole field improved during the training phase (-12.8±3.6 and -12.1±4.1 at pre- and postassessment, respectively; Wilcoxon signed-rank test: p=0.016) (Fig. 3B).

Moreover, 8-week changes in the MTD scores for the whole field were significantly larger during the training phase than during the no-training phase (0.689±0.934 vs. -0.441±1.185; linear mixed-effects model for repeated measures: p=0.004) (Fig. 3C).

Changes in the whole visual field after VPL

The area in which the luminance detection sensitivity improved by ≥6 dB was 157±119 degrees2 during the training phase and 95.1±99.5 degrees2 during the no-training phase, with no significant difference between the two phases (linear mixed-effects model for repeated measures: p=0.063) (Fig. 4A).

The area in which the luminance detection sensitivity worsened by ≥6 dB was significantly larger during the no-training phase (144±153 degrees2) than during the training phase (61.7±55.5 degrees2) (linear mixed-effects model for repeated measures: p=0.029) (Fig. 4B).

Moreover, the difference between the improved and worsened areas (improved minus worsened area with ≥6 dB changes in sensitivity) was significantly larger during the training phase (95.1±130.6 degrees2) than during the no-training phase (-48.9±177.3 degrees2) (linear mixed-effects model for repeated measures: p=0.009) (Fig. 4C).

Changes in quality of life related to VFD

The composite score of the NEI-VFQ-25 and its subscale scores other than the driving score increased after 16 weeks during the no-training and training phases (Table 3). The vision-specific social functioning subscore improved significantly during the 16-week follow-up (Wilcoxon signed-rank test: p=0.040).

The change in the composite score of the NEI-VFQ-25 during the 16-week follow-up was positively associated with an improved area with ≥6 dB changes in sensitivity (standardized β=0.494; robust regression: p<0.001) and the changes in MTD scores for the whole field (standardized β=0.718; robust regression: p=0.003) during the 8-week training phase.

However, the change in the composite score of the NEI-VFQ-25 during the 16-week follow-up was not significantly associated with the worsened area (standardized β=0.320; robust regression: p=0.302), improved minus worsened area (standardized β=0.039; robust regression: p=0.911), or changes in MTD score for the defective hemifield (standardized β=0.540; robust regression: p=0.074) during the 8-week training phase.

DISCUSSION

This study has notably demonstrated that our 8-week VFD-customized visual discrimination training program that provided peripheral orientation tasks in patient-specific blind fields with central fixation reduced the size of poststroke VFDs. MTD scores in the defective hemifield and the whole field were improved after the training phase but not after the no-training phase. The improved minus worsened area in the whole field was significantly larger during the training phase than during the no-training phase. Vision-specific social functioning improved after the 16-week study period.

It is also noteworthy that our 8-week VFD-customized visual discrimination training program targeting patient-specific blind fields with central fixation led to recovery in damaged visual areas. The letter and orientation-discrimination tasks were effective at improving visual perception by reweighting between low-level visual processing and higher decision-making.912152728 Our orientation-discrimination task with Gabor stimuli in individualized blind fields that were aligned with the receptive fields may efficiently target the lesioned visual cortex to enhance tuning specificity and lead to focused improvement in blind visual fields.13142930 Our VFD-customized visual discrimination training program that requires repeated decision-making in blind fields has a major strength in noninvasively targeting neuroplasticity of the damaged primary visual cortex and inducing visual restoration.1314 Regarding the underlying brain mechanisms, altered connectivity of the lesioned visual cortex with an intact contralateral visual cortex or higher regions involved in decision-making was previously suggested to underlie VPL-induced VFD recovery.6283132

The mean improved minus worsened whole area (Fig. 4C) and changes in MTD scores (Figs. 2C and 3C) suggest that VFDs, which naturally tend to deteriorate over a 2-month period, could recover even after only 2 months of our customized VPL training. This is comparable to the efficacy of previously described longer VPL training procedures lasting 3 months to 6 months.151722 Moreover, the mean improved area after the training phase (157 degrees2) and the mean worsened area after the no-training phase (144 degrees2) are meaningful changes over an 8-week period, especially considering the three HVF test points (108 degrees2) cutoff for significant visual deterioration in glaucoma.33 While acknowledging variations in methodology between research studies, such as in the training durations and HVF analysis methods, the magnitude of the VFD improvement in the present study was comparable to that for previous orientation-discrimination training protocols (improved areas ranging from 101 to 288 degrees2) and superior to previous untrained controls (improved areas ranging from 16 to 72 degrees2) in poststroke VFDs.9152227 Specifically, using a different HVF methodology from ours, the orientation discrimination task with Gabor stimuli over 6 months improved poststroke VFDs, with a mean improved area of 101 degrees2.15 We previously found that applying peripheral orientation-central letter discrimination tasks for 3 months improved poststroke VFDs with a median improved area of 288 degrees2.9

The correlations between an enhanced vision-related quality of life and improved whole visual field posttraining were observed alongside improved vision-specific social functioning. These findings related to subjective visual experiences suggest that VPL-induced improvements in the whole visual field will enhance the quality of life, particularly in terms of observing the reactions of others and in social interactions.45 As a future promising digital therapeutic intervention, our 8-week VFD-customized visual discrimination training program specifically targets individualized blind fields based on the baseline HVF tests, along with controlled central fixation and minimized eye movements. The program applied in this study involved the simultaneous presentation of visual central and peripheral stimuli for a very brief duration (150 ms) and randomly presented peripheral stimuli in blind or normal fields at a 26:6 ratio. Our program with central fixation may be effective at providing sufficient visual stimulation to defective visual fields, rather than to intact fields. Moreover, we used an objective measure of VFDs—the HVF test quantifies visual field sensitivity with controlled fixation1522 using 6 dB as a conservative threshold for meaningful visual field changes.152223 The same patients were compared between the training and no-training phases in order to minimize potential confounding effects of patient demographic and clinical characteristics.

Some limitations need to be considered when interpreting the current results. Future studies are needed to investigate whether balanced stimuli presentation in normal and blind visual fields for a longer training period would be more beneficial, considering that learning transfer effects occur in repetitive and easier tasks. Despite the efficacy of our VFD-customized VPL program, our training duration (2 months) might have been too short relative to those applied in previous studies (with at least 3 months of training).151617 Another limitation is the absence of a sham program during the no-training phase for the first 8 weeks, which might have impaired its reliability as a scientific control. Although our study did not use an eye tracker, potential eye movements were controlled using simultaneous central and peripheral visual stimuli for a very brief duration and by excluding participants with >30% of fixation losses from the analysis. Given the smallness of the sample, the predominant inclusion of males, and the potential learning effects of training, future larger randomized controlled trials are warranted to confirm the most-effective protocol—in terms of stimuli location and training duration—to be used in VFD-customized visual discrimination training for poststroke VFDs.

In conclusion, our 8-week VFD-customized visual discrimination training program that includes dual tasks for peripheral orientation-discrimination tasks of individualized blind fields and central fixation may be an effective therapy for improving VFDs, particularly in the blind fields of patients with chronic stroke. Personalized digital therapeutic interventions for cortical blindness may be developed based on our method of VFD-customized VPL through individualized programs (in terms of stimuli type and location, training duration, and difficulties) so as to maximize the efficacy of rehabilitation.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.

Fig. 1 Study design and customized VPL program. A: The enrolled patients underwent an 8-week period without training (no-training phase) followed by 24 sessions of a VFD-customized VPL program over 8 weeks implemented as 3 training sessions per week (training phase). HVF tests (gray box) were conducted before and after both the no-training and training phases. The NEI-VFQ-25 (blue box) was administered at baseline and at the 16-week follow-up. B: For one patient with quadrantanopia, an example blind field from the HVF test is shown along with the stimulus location for the VPL (green box). The defective hemifield (red box) and the whole field (black box) are also displayed. C: Our customized VPL program included orientation-discrimination training in the individualized blind field, based on the baseline HVF test, as well as letter-discrimination training for central fixation. HVF, Humphrey visual field; NEI-VFQ-25, National Eye Institute Visual Function Questionnaire-25; VFD, visual field defect; VPL, visual perceptual learning.

Fig. 2 Changes in the defective visual hemifield after the customized VPL program. A: MTD scores for the defective hemifield did not change significantly during the no-training phase (p=0.178). Line graphs with scores (white circles) at baseline and at the 8-week follow-up are shown for each patient. B: MTD scores for the defective hemifield improved significantly after VFD-customized VPL training for 8 weeks (p=0.004). Line graphs with scores (black circles) at the 8- and 16-week follow-ups are shown for each patient. C: Changes in MTD scores after 8 weeks for the defective hemifield were significantly larger during the training phase than during the no-training phase (p=0.002). The bar graph shows the changes in scores as mean and standard-error values. *Statistical significance at p<0.05. MTD, mean total deviation; VFD, visual field defect; VPL, visual perceptual learning.

Fig. 3 Changes in the whole visual field after the customized VPL program. A: MTD scores for the whole field did not change significantly during the no-training phase (p=0.178). Line graphs with scores (white circles) at baseline and at the 8-week follow-up are shown for each patient. B: MTD scores for the whole field improved significantly after VFD-customized VPL training for 8 weeks (p=0.016). Line graphs with scores (black circles) at the 8- and 16-week follow-ups are shown for each patient. C: Eight-week-induced changes in MTD scores for the whole field were significantly larger during the training phase than during the no-training phase (p=0.004). The bar graph shows the changes in scores as mean and standard-error values. *Statistical significance at p<0.05. MTD, mean total deviation; VFD, visual field defect; VPL, visual perceptual learning.

Fig. 4 Changes in whole area after the customized VPL program. A: The area in which sensitivity improved by ≥6 dB after VPL did not differ significantly between the no-training and training phases (95.1±99.5 degrees2 vs. 157±119 degrees2, p=0.063). The bar graph shows the improved area as mean and standard-error values. B: The area in which sensitivity worsened by ≥6 dB after VPL was significantly larger during the no-training phase than during the training phase (144±153 degrees2 vs. 61.7±55.5 degrees2, p=0.029). The bar graph shows the worsened area as mean and standard-error values. C: The area in which the improved minus worsened sensitivity was ≥6 dB after VPL was significantly larger during the training phase than during the no-training phase (95.1±130.6 degrees2 vs. -48.9±177.3 degrees2, p=0.009). The bar graph shows the change in scores as mean and standard-error values. *Statistical significance at p<0.05. VPL, visual perceptual learning.

Table 1 Baseline characteristics of the 14 included participants

Characteristic	Value	
Migraine treatment, prescriptions per person-years	8.04	
Combination therapy with >1 distinct migraine medications	556,158 (73.05)	
Migraine treatment regimen		
	Prophylactic treatment	442,809 (58.16)	
		Antidepressants	129,581 (17.02)	
			Amitriptyline	103,130 (13.55)	
			Venlafaxine	2,191 (0.29)	
			Nortriptyline	31,696 (4.16)	
		Anticonvulsants	101,259 (13.30)	
			Divalproex sodium	24,730 (3.25)	
			Valproate	8,750 (1.15)	
			Topiramate	79,760 (10.48)	
		Beta blockers	195,162 (25.63)	
			Propranolol	185,953 (24.42)	
			Atenolol	1,783 (0.23)	
			Nadolol	12,412 (1.63)	
		CCBs		
			Flunarizine	280,857 (36.89)	
		RAAS inhibitors	2,288 (0.30)	
			Candesartan	2,285 (0.30)	
			Lisinopril	3 (0.00)	
	Acute treatment	702,686 (92.29)	
		Ergotamine	149,583 (19.65)	
		Triptans	214,446 (28.17)	
			Sumatriptan	104,948 (13.78)	
			Zolmitriptan	24,776 (3.25)	
			Almotriptan	44,752 (5.88)	
			Frovatriptan	34,226 (4.50)	
			Naratriptan	60,178 (7.90)	
		Aspirin	1,930 (0.25)	
		Acetaminophen	380,675 (50.00)	
		NSAIDs	532,194 (69.90)	
		Antiemetics	1,110 (0.15)	
		Opioids	9,645 (1.27)	
Data are n (%) or mean±standard deviation values.

VFD, visual field defect.

Table 2 Relationships between patient characteristics and changes in HVF measures during the training phase

	Changes in MTD scores for the defective hemifield	Changes in MTD scores for the whole field	Improved area	Worsened area	Improved minus worsened area	
β	p	β	p	β	p	β	p	β	p	
Age	0.071	0.592	0.171	0.591	0.262	0.410	-0.277	0.375	0.364	0.219	
Stroke lesion age	0.054	0.723	-0.554	0.070*	-0.109	0.747	-0.150	0.643	-0.010	0.976	
Entire brain lesion volume	-0.099	0.394	-0.281	0.376	-0.417	0.180	0.114	0.714	-0.367	0.226	
Lesion volume in visual cortex	-0.092	0.420	-0.224	0.489	-0.422	0.176	0.225	0.475	-0.215	0.506	
Robust regression analyses were performed to determine how patient characteristics may affect changes in HVF measures during the 8-week training phase while correcting for outliers. Independent variables included age, stroke lesion age, entire brain lesion volume, and lesion volume in the visual cortex of each participant. Dependent variables included changes in MTD scores for the defective hemifield and the whole field as well as the improved area, worsened area, and improved minus worsened area with ≥6 dB changes in sensitivity during the 8-week training phase.

*Corrected for one outlier with a change in the MTD score of 1.40 for the whole field and a stroke lesion age of 18 months, with a Cook’s distance of 2.22.

HVF, Humphrey visual field; MTD, mean total deviation.

Table 3 Changes in quality of life related to VFDs

	Baseline	16-week follow-up	p	
n	Score	n	Score	
Composite score	13	62.4±20.1	13	68.5±18.6	0.124	
	General health	13	32.7±21.4	13	48.1±31.4	0.109	
	General vision	13	53.8±15.0	13	56.9±7.5	0.480	
	Ocular pain	13	75.0±22.8	13	80.8±16.6	0.520	
	Near activities	13	60.9±22.9	13	69.2±24.1	0.084	
	Distance activities	13	62.8±21.1	13	72.4±18.8	0.084	
	Vision-specific social functioning	12	65.6±22.7	12	78.1±22.1	0.040	
	Vision-specific mental health	13	58.8±30.0	13	65.9±26.0	0.134	
	Vision-specific role difficulties	13	49.0±26.3	13	59.6±30.3	0.180	
	Vision-specific dependency	13	74.4±25.3	13	77.6±19.4	0.911	
	Driving	10	55.4±39.4	10	49.6±43.2	0.816	
	Color vision	12	68.8±18.8	12	81.3±21.7	0.056	
	Peripheral vision	13	61.5±24.2	13	69.2±20.8	0.103	
Data are mean±standard deviation values. Quality of life related to VFDs was assessed using the National Eye Institute Visual Function Questionnaire-25 at baseline and at the 16-week follow-up. The composite score and subscale scores at baseline and at the 16-week follow-up were compared using Wilcoxon signed-rank tests.

VFDs, visual field defects.

Author Contributions: Conceptualization: Dong-Wha Kang.

Formal analysis: Eun Namgung, Hana Kim, Yong-Hwan Kim.

Funding acquisition: Eun Namgung, Yuka Sasaki, Takeo Watanabe, Dong-Wha Kang.

Investigation: Jee-Hyun Lee.

Methodology: Eun Namgung, Hana Kim, Yong-Hwan Kim.

Supervision: Yuka Sasaki, Takeo Watanabe, Dong-Wha Kang.

Validation: Young-Sun Kim, Eun-Jae Lee.

Visualization: Eun Namgung, Hana Kim, Yong-Hwan Kim.

Writing—original draft: Eun Namgung, Hana Kim, Yong-Hwan Kim, Dong-Wha Kang.

Writing—review & editing: Young-Sun Kim, Eun-Jae Lee, Jee-Hyun Lee, Yuka Sasaki, Takeo Watanabe.

Conflicts of Interest: Eun-Jae Lee, a contributing editor of the Journal of Clinical Neurology, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.

Funding Statement: This research was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711197973, RS-2023-00222139); a grant from the Korea Health Technology R&D Project, through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HR18C0016); a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (2022R1F1A1060778), Republic of Korea; and grants from the NIH (EY031705, R01 EY027841, R01 EY019466), USA.
==== Refs
1 Pollock A Hazelton C Henderson CA Angilley J Dhillon B Langhorne P Interventions for visual field defects in patients with stroke Cochrane Database Syst Rev 2019 5 CD008388 31120142
2 Saionz EL Busza A Huxlin KR Rehabilitation of visual perception in cortical blindness Handb Clin Neurol 2022 184 357 373 35034749
3 Sand KM Wilhelmsen G Naess H Midelfart A Thomassen L Hoff JM Vision problems in ischaemic stroke patients: effects on life quality and disability Eur J Neurol 2016 23 Suppl 1 1 7
4 Gall C Franke GH Sabel BA Vision-related quality of life in first stroke patients with homonymous visual field defects Health Qual Life Outcomes 2010 8 33 20346125
5 Papageorgiou E Hardiess G Schaeffel F Wiethoelter H Karnath HO Mallot H Assessment of vision-related quality of life in patients with homonymous visual field defects Graefes Arch Clin Exp Ophthalmol 2007 245 1749 1758 17653566
6 Kim YH Cho AH Kim D Kim SM Lim HT Kwon SU Early functional connectivity predicts recovery from visual field defects after stroke J Stroke 2019 21 207 216 31161764
7 de Haan GA Melis-Dankers BJ Brouwer WH Tucha O Heutink J The effects of compensatory scanning training on mobility in patients with homonymous visual field defects: a randomized controlled trial PLoS One 2015 10 e0134459 26275160
8 Sabel BA Vision restoration therapy and raising red flags too early Br J Ophthalmol 2006 90 659 660
9 Lee EJ Kim D Kim YH Namgung E Lee JH Sasaki Y Digital therapeutics with visual discrimination training for cortical blindness in patients with chronic stroke J Stroke 2023 25 409 412 37554076
10 Mueller I Mast H Sabel BA Recovery of visual field defects: a large clinical observational study using vision restoration therapy Restor Neurol Neurosci 2007 25 563 572 18334773
11 Gilbert CD Li W Adult visual cortical plasticity Neuron 2012 75 250 264 22841310
12 Kang DW Kim D Chang LH Kim YH Takahashi E Cain MS Structural and functional connectivity changes beyond visual cortex in a later phase of visual perceptual learning Sci Rep 2018 8 5186 29581455
13 Sagi D Perceptual learning in vision research Vision Res 2011 51 1552 1566 20974167
14 Sasaki Y Nanez JE Watanabe T Advances in visual perceptual learning and plasticity Nat Rev Neurosci 2010 11 53 60 19953104
15 Cavanaugh MR Huxlin KR Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness Neurology 2017 88 1856 1864 28404802
16 Huxlin KR Martin T Kelly K Riley M Friedman DI Burgin WS Perceptual relearning of complex visual motion after V1 damage in humans J Neurosci 2009 29 3981 3991 19339594
17 Sahraie A Trevethan CT MacLeod MJ Murray AD Olson JA Weiskrantz L Increased sensitivity after repeated stimulation of residual spatial channels in blindsight Proc Natl Acad Sci U S A 2006 103 14971 14976 17000999
18 Tombaugh TN McIntyre NJ The mini-mental state examination: a comprehensive review J Am Geriatr Soc 1992 40 922 935 1512391
19 Acton JH Smith RT Greenberg JP Greenstein VC Comparison between MP-1 and Humphrey visual field defects in glaucoma and retinitis pigmentosa Optom Vis Sci 2012 89 1050 1058 22733099
20 Barkana Y Leshno A Stern O Singer R Russ H Oddone F Visual field endpoints based on subgroups of points may be useful in glaucoma clinical trials: a study with the Humphrey field analyzer and compass perimeter J Glaucoma 2021 30 661 665 33899809
21 Yang Y Dunbar H Clinical perspectives and trends: microperimetry as a trial endpoint in retinal disease Ophthalmologica 2021 244 418 450 33567434
22 Cavanaugh MR Blanchard LM McDermott M Lam BL Tamhankar M Feldon SE Efficacy of visual retraining in the hemianopic field after stroke: results of a randomized clinical trial Ophthalmology 2021 128 1091 1101 33242498
23 Saionz EL Tadin D Melnick MD Huxlin KR Functional preservation and enhanced capacity for visual restoration in subacute occipital stroke Brain 2020 143 1857 1872 32428211
24 Heo JW Yoon HS Shin JP Moon SW Chin HS Kwak HW [A validation and reliability study of the Korean version of National Eye Institute visual function questionnaire 25] J Korean Ophthalmol Soc 2010 51 1354 1367 Korean
25 Mangione CM Lee PP Pitts J Gutierrez P Berry S Hays RD Psychometric properties of the National Eye Institute visual function questionnaire (NEI-VFQ) Arch Ophthalmol 1998 116 1496 1504 9823352
26 Pustina D Coslett HB Turkeltaub PE Tustison N Schwartz MF Avants B Automated segmentation of chronic stroke lesions using LINDA: lesion identification with neighborhood data analysis Hum Brain Mapp 2016 37 1405 1421 26756101
27 Das A Tadin D Huxlin KR Beyond blindsight: properties of visual relearning in cortically blind fields J Neurosci 2014 34 11652 11664 25164661
28 Kim YH Kang DW Kim D Kim HJ Sasaki Y Watanabe T Real-time strategy video game experience and visual perceptual learning J Neurosci 2015 35 10485 10492 26203143
29 Cowey A Stoerig P The neurobiology of blindsight Trends Neurosci 1991 14 140 145 1710851
30 Watanabe T Sasaki Y Perceptual learning: toward a comprehensive theory Annu Rev Psychol 2015 66 197 221 25251494
31 Namgung E Kim YH Lee EJ Sasaki Y Watanabe T Kang DW Functional connectivity interacts with visual perceptual learning for visual field recovery in chronic stroke Sci Rep 2024 14 3247 38332042
32 Namgung E Lee EJ Kim YH Kang DW White matter structural connectivity associated with visual field recovery after stroke J Stroke 2024 26 116 120 38246721
33 Leske MC Heijl A Hyman L Bengtsson B Early manifest glaucoma trial: design and baseline data Ophthalmology 1999 106 2144 2153 10571351
