Longitudinal structural brain changes after Scharioth macula lens implantation in patients with age-related macular degeneration

Longitudinal structural brain changes after Scharioth macula lens implantation in patients with age-related macular degeneration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Longitudinal structural brain changes after Scharioth macula lens implantation in patients with age-related macular degeneration Jakub Bochnička, Juhana Hakumäki, Naďa Jirásková, Jan Kremláček This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9110944/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Purpose Age-related macular degeneration (AMD) is associated with visual impairment and with structural and functional brain changes. The extent to which AMD affects cerebral structure and whether visual rehabilitation, including implantation of the Scharioth macula lens (SML), is associated with structural brain changes, remains incompletely understood. This study aimed to investigate regional brain volume alterations in patients with AMD and to assess longitudinal changes after SML implantation. Materials and Methods Ten patients with AMD (mean age 78.8 ± 5.6 years) underwent a structural brain MRI at 3T before and 6 months after SML implantation. Regional brain volumes were quantified using a fully automated AI-assisted multi-atlas segmentation tool (cNeuro cMRI). The results were expressed as absolute volumes and normative percentile values relative to an age-matched healthy MRI reference database. Primary analyses focused on a predefined extended visual network. In addition, exploratory whole-brain analyses were performed with correction for multiple comparisons. A vision-related quality-of-life questionnaire was administered, and changes in composite scores were associated with pre-implantation volumes. Results At baseline, pronounced atrophy was observed in the posterior visual cortex, most prominently in the occipital pole, and most of the patients showed reduced normative percentiles. Longitudinal analyses revealed overall structural stability in the visual network. Region-specific changes were identified, including significant decreases in percentile values in the left middle occipital gyrus and the precuneus, along with an increase in the volume of the occipital pole and the percentile ranking. Exploratory analyses outside the visual network identified heterogeneous uncorrected changes; however, none survived the false discovery rate correction. Visual quality-of-life composites showed modest mean improvements in 6 months, but no association with volume was statistically significant after correction for multiple comparisons. Conclusions AMD is associated with regionally specific structural alterations in the posterior visual cortex. Following SML implantation and visual rehabilitation, the visual network regions demonstrated general stability with heterogeneous regional changes, while no evidence of generalized brain involvement was observed. These findings support the involvement of central visual pathways in AMD and suggest preserved cortical plasticity even in advanced age. age-related macular degeneration magnetic resonance imaging artificial intelligence brain segmentation longitudinal changes Scharioth macula lens Figures Figure 1 1 INTRODUCTION Age-related macular degeneration (AMD) is the leading cause of visual impairment and severe vision loss worldwide. It affects approximately 10% of the population over 60 years of age, with prevalence increasing to up to 25% in individuals older than 75 years 1 . AMD causes substantial difficulties in daily life by altering activities that require fine spatial resolution, such as reading, face recognition, and object identification 2 . Beyond visual impairment, AMD has been associated with higher rates of cognitive decline, poorer performance on cognitive tests - even those not directly involving visual processing - and an increased risk of dementia 3 . Retinal nerve cell apoptosis in AMD, particularly in the macular region, can induce changes in the properties of brain tissue through transsynaptic degeneration 4 . This process leads to reduced visual input to the cortex and may influence behavioral factors related to visually dependent activities, including social interaction and reading 5 . Sensory deprivation related to AMD can result in region-specific structural and functional brain changes through multiple mechanisms. These include reduced cognitive stimulation, diminished feedback from visual cortical areas, and adaptive reorganization of visual pathways. Such changes have been reflected in altered functional connectivity patterns, increased metabolic demands in specific regions of the brain, and reduced cognitive performance 6 . Importantly, visual rehabilitation aimed at improving visual function has been shown to promote functional cerebral reorganization, particularly within the primary visual cortex and fronto-parietal control networks 7 . The Scharioth macula lens (SML) was developed as a visual rehabilitation option for patients with advanced AMD. Its design is based on an established concept of sulcus-fixation in pseudophakic eyes. SML has been used clinically for several years and is characterized by a relatively simple implantation procedure and a low complication rate 8 . In this retrospective study, our aim was to investigate whether patients with AMD develop specific structural regional changes in the cerebral areas and then whether implantation of the Scharioth macula lens, combined with postoperative visual rehabilitation, is associated with changes in these alterations. We employed a two-level analytical strategy combining exploratory structural mapping with confirmatory brain–behavior modeling. The hypothesis was that AMD is associated with structural changes that predominantly affect visual cortical regions, and that improved retinal input may modulate these changes. By exploring this relationship, we hope to improve the understanding of the anatomical and clinical manifestation of macular degeneration and potentially improve clinical management strategies for these patients. 2 MATERIALS AND METHODS 2.1 Study design The study included 10 patients (3 females and 7 males), with an age range of 72–86 years (AVG 78.8, SD 5.6). The selection criteria for implantation were based on the recommendations of the SML manufacturer (Medicontur International, Geneva, Switzerland): age over 55 years, best-corrected distant visual acuity (BCVA) of 0.4 to 1.3 logMAR (i.e. 0.4 to 0.05 in the decimal fraction), stabilized maculopathy, and pseudophakic eye. Exclusion criteria were a photopic pupil size less than 2.5 mm, severe zonulopathy, an anterior chamber depth less than 2.8 mm, narrow-angle or severe ocular pathology, or previous retinal surgery. Patient selection, surgery, clinical care, and some of the examinations were conducted in the Department of Ophthalmology of the University Hospital in Hradec Kralove, Czech Republic. The study was approved by the Ethics Committee of the University Hospital in Hradec Kralove. All principles of the Declaration of Helsinki were followed, and all patients gave their informed consent. All participants underwent the implantation of a + 6-diopter macular intraocular lens (SML). All patients underwent standard postoperative treatment with a topical antibiotic for 1 week and a topical steroid for 1 month. To facilitate postoperative functional vision, all participants completed supervised visual rehabilitation during the first 3 postoperative weeks (30 min/day). Rehabilitation was explicitly aimed at improving visual fixation stability and reading performance and comprised structured training in fixation strategies, reading exercises, and graphomotor practice to support functional use of restored near-vision capacity. All patients contributed paired structural MRI data acquired before implantation (approximately 27 days, median in the range 5 to 49 days) and 6 months after implantation. 2.2 Quality of life A vision-specific quality-of-life questionnaire was used to evaluate how the intervention affected participants’ vision-related quality of life. Localized for Czech conditions 9 , The National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) 10 was administered on two occasions: prior to SML implantation and again 6 months postoperatively. To ensure independence, the questionnaire was read aloud by a healthcare professional who had not participated in any previous assessments or rehabilitation, and who recorded the responses of the participants. The NEI VFQ-25 comprises 12 brief subscales, which range from 0 to 100, with higher scores indicating a better quality of life. A composite score is typically computed as the mean of 11 subscales, omitting the vision-nonspecific general health subscale. As none of the participants were able to drive, the driving subscale was also excluded. Given the small sample size and the mechanistic focus of the intervention (fixation/reading), the VFQ-25 domains were summarized a priori into a reduced set. VFQ Near (primary functional target): near activities . VFQ Psychosocial (secondary): mean of vision-specific depend ency, role difficulties , mental health , and social functioning . VFQ Overall (excluding general health): mean of all available VFQ domain scores excluding general health , to avoid conflating global health status with vision-specific outcomes. All VFQ scores were analyzed at baseline, at 6 months, and as change scores (Δ = post − pre). The quality-of-life assessment served a confirmatory role within the overall analytical framework. While the volumetric analyses were primarily exploratory with hypothesis-driven regional emphasis, the quality-of-life composites were used to evaluate whether structural patterns in functionally relevant networks showed coherent associations with the intervention’s behavioral targets (reading, fixation stability, social adaptation). These outcomes were integrated into pre-specified mechanistic regression models, linking baseline structural organization to functional change. 2.3 MRI acquisition Magnetic resonance imaging (MRI) was performed in CEITEC MAFIL Brno on a 3-T whole-body MRI system (MAGNETOM Prisma, Siemens Healthineers, Erlangen, Germany) using a three-dimensional T1-weighted magnetization-prepared rapid gradient-echo (3D MPRAGE) sequence. The imaging parameters were as follows: repetition time (TR) = 2300 ms, echo time (TE) = 2.33 ms, inversion-prepared gradient-echo readout and flip angle = 8°. The images were acquired in the sagittal plane with an isotropic spatial resolution of 1 × 1 × 1 mm³, a slice thickness of 1 mm, and an in-plane acquisition matrix of 224 × 224. The field of view resulted in 224 slices that covered the entire brain. One signal average was used. The sequence used Siemens' proprietary MPRAGE implementation (sequence name tfl3d1) and was reconstructed using the vendor’s standard normalization pipeline (syngo MR E11). 2.4 Voxel-based morphometric analysis: cMRI cNeuro Regional brain volumes were determined at both time points using a fully automated multi-atlas segmentation tool cNeuro (Combinostics Ltd, Tampere, Finland) from 3D T1 MRI images 11 . The cNeuro method was used as a fully automated AI-assisted segmentation and volumetry tool for measuring brain atrophy, with CE marking and wide clinical application, in cooperation with Kuopio University Hospital. The segmentation method described by Koikkalainen et al. 12 , and Wang et al. 13 , was used to compute volumes of anatomical areas from 3D T1-weighted magnetic resonance images. In total, 258 anatomical biomarkers, such as total brain volume, white and gray matter volumes, cerebellum, CSF spaces, and deep gray matter structures, including their volume composites and atrophy scores, were extracted with normalization for age, sex, and head size. This method provides the evaluation of the severity of brain changes at the individual patient level without the need for control groups (the software contains an internal control database of 1,923 normal individuals - age range 18–94 years, 57% females) and is validated for use in both clinical and research settings. The tool provides the percentiles for both the left- and right-sided structures, when applicable, and the total volume of the anatomical structures, which was utilized in this study. 2.5 Statistical analysis All statistical analyses were performed in R (version 4.5.1). The analysis pipeline was designed to accommodate the small sample size and potential non-normality of the data, with emphasis on effect sizes and confidence intervals. Statistical analyses were performed using paired within-subject comparisons to assess longitudinal changes in brain structure before and after implantation of the Scharioth macula lens. Absolute regional brain volumes and the corresponding percentile values normalized for age, sex, and head size were obtained from the cNeuro analysis and used for all statistical tests. Baseline abnormalities were descriptively evaluated using percentile values derived from a comparison with an age-matched healthy MRI reference database. Percentile values below the 25th percentile were considered indicative of reduced regional volume relative to normative data. The analyses focused on a priori defined visual regions of interest (ROIs), including the primary and associative visual cortices (calcarine cortex, cuneus, lingual gyrus, fusiform gyrus, occipital gyri, and occipital pole). Secondary regions related to visuospatial integration (precuneus and superior parietal lobule) were included for supportive analyses. For each ROI, pre–post changes were evaluated using paired statistical tests. The normality of the paired differences was assessed with the Shapiro-Wilk test. When the assumption of normality was met, a paired t-test was applied; otherwise, a Wilcoxon signed-rank test was used. Primary ROIs were analyzed without correction for multiple comparisons due to their hypothesis-driven selection. All remaining regions were analyzed exploratorily with correction for the false discovery rate (FDR) using the Benjamini–Hochberg procedure. Effect sizes were reported for all inferential tests. For paired t-tests, Cohen’s dz with 95% confidence intervals was calculated. For Wilcoxon tests, the effect size was expressed as Wilcoxon r , with point estimates and 95% confidence intervals obtained by bootstrap resampling of paired observations (5,000 iterations) to ensure stability in small samples. Descriptive statistics were reported conditional on the test applied: mean (SD) for parametric analyses and median [Q1, Q3] for nonparametric analyses. Statistical significance was set at p < 0.05. To integrate structural findings with functional targets of the intervention and to limit model complexity at n = 10, regional measures were reduced a priori into three minimally overlapping ROI-level indices representing mechanistically relevant networks. These networks were computed as the mean normative percentile across constituent regions, using total-volume metrics only to avoid redundancy from left/right duplication. ROI membership was defined by atlas-derived region names and documented explicitly in a supplementary ROI membership table. The three minimally overlapping ROIs were: i) Ventral stream / occipito-temporal ROI (central vision / reading-related visual cortex): total-volume measures of calcarine cortex, cuneus, lingual gyrus, occipital fusiform gyrus, inferior occipital gyrus, and middle occipital gyrus. ii) Dorsal attention / oculomotor ROI (fixation and attentional control): total-volume measures of precuneus, superior parietal lobule, superior frontal gyrus, middle frontal gyrus, and supplementary motor cortex. iii) Limbic / affect ROI (psychosocial/QoL-related circuitry): total-volume measures of amygdala, hippocampus, posterior cingulate gyrus, subcallosal area, and ventral diencephalon. For each ROI, a baseline ROI mean percentile and a 6-month ROI mean percentile were computed, together with the corresponding change score (ΔROI = post − pre). Mechanistically motivated multivariable relationships were evaluated using a small set of pre-specified regression models: M1: ΔVFQ Near ~ baseline Ventral-stream ROI + baseline Dorsal-attention ROI; M2: ΔVFQ Near ~ baseline Ventral-stream ROI + baseline Limbic/affect ROI; M3: ΔVFQ Psychosocial ~ baseline Limbic/affect ROI. Regression coefficient uncertainty was quantified using bootstrap resampling at the participant level (5,000 bootstrap samples) with 95% confidence intervals. Model fit was summarized using R². All analyses prioritize robustness, transparency, and clinical interpretability. The complete analysis pipeline can be provided upon request in the R script to ensure reproducibility. 3 RESULTS 3.1 Baseline abnormalities At baseline, a percentile-based comparison with the healthy magnetic resonance imaging database revealed marked deviations in the posterior visual regions, with the strongest abnormality observed in the occipital pole. The mean percentile of the occipital pole was 12.15 ± 14.17, with 8 subjects < 25th percentile and 6 subjects < 10th percentile, indicating consistent sub-normative structural values in this region. Additional baseline reductions (mean percentile < 35) were observed in ventral and lateral visual association regions, including the following: Occipital fusiform gyrus: 26.87 ± 22.61; Middle temporal gyrus: 28.13 ± 22.40; Lingual gyrus: 29.83 ± 19.29; Cuneus: 31.57 ± 26.62. In contrast, several regions (e.g., calcarine cortex, inferior temporal gyrus) showed mean percentiles closer to normative ranges at baseline. 3.2 Longitudinal changes in the visual network The longitudinal paired analyses revealed region-specific changes within the predefined extended visual network during the 6-month follow-up period (Table 1). Although most of the visual cortical regions demonstrated general structural stability, statistically significant changes at the uncorrected level were observed in selected posterior cortical areas. A significant decrease in percentile values was detected in the left middle occipital gyrus (mean ± SD: 39.11 ± 28.18 pre vs. 31.02 ± 24.56 post; p = 0.004; dz = -1.23), indicating a reduction relative to the normative reference. Furthermore, the precuneus (total) showed a modest but statistically significant decrease in the percentile ranking (35.54 ± 29.93 pre vs. 31.57 ± 28.28 post; p = 0.034; dz = -0.79). In contrast, the occipital pole (total) demonstrated a statistically significant increase in percentile values (median [Q1, Q3]: 6.22 [2.65, 14.03] pre vs. 11.15 [4.78, 20.49] post; Wilcoxon signed-rank test, p = 0.033; r = 0.68), reflecting a directional shift towards a higher normative ranking. The left and right occipital pole subregions showed consistent increases in mean percentile values; however, these hemispheric changes did not reach statistical significance individually. All remaining regions of the visual network, including the calcarine cortex, cuneus, lingual gyrus, superior and inferior occipital gyri, fusiform gyrus, and compounds of the occipital lobe, showed small changes in the mixed direction that did not reach statistical significance (all p > 0.05). No region within the visual network survived correction for multiple comparisons. These findings indicate heterogeneous longitudinal changes within the posterior visual cortex, characterized by relative preservation or improvement in the occipital pole alongside localized decreases in adjacent extrastriate regions. Table 1. Primary ROI analysis (pre vs post implantation) Region n Test Shapiro–Wilk p Pre Post p Effect (95% CI) p Middle occipital gyrus (left) 10 Paired t-test 0.115 39.11 (28.18) 31.02 (24.56) 0.004 dz = -1.23 [-2.05, -0.38] p Occipital pole (total) 10 Wilcoxon signed-rank 0.008 6.22 [2.65, 14.03] 11.15 [4.78, 20.49] 0.033 r = 0.68 [0.23, 0.87] p Precuneus (total) 10 Paired t-test 0.658 35.54 (29.93) 31.57 (28.28) 0.034 dz = -0.79 [-1.49, -0.06] p Occipital lobe (left) 10 Wilcoxon signed-rank 0.017 24.37 [2.88, 38.68] 14.61 [1.71, 27.96] 0.053 r = -0.61 [-0.87, 0.19] p Occipital lobe (total) 10 Paired t-test 0.193 21.94 (25.04) 18.48 (22.07) 0.064 dz = -0.67 [-1.34, 0.04] p Precuneus (left) 10 Paired t-test 0.977 44.27 (31.77) 39.16 (28.35) 0.077 dz = -0.63 [-1.30, 0.07] p Calcarine cortex (right) 10 Paired t-test 0.822 44.26 (33.51) 39.05 (31.40) 0.092 dz = -0.60 [-1.26, 0.09] p Calcarine cortex (total) 10 Paired t-test 0.204 50.11 (36.26) 46.18 (34.55) 0.105 dz = -0.57 [-1.23, 0.12] p Lingual gyrus (right) 10 Wilcoxon signed-rank 0.038 37.40 [11.93, 54.98] 27.48 [7.81, 35.14] 0.126 r = -0.52 [-0.87, 0.10] p Occipital pole (left) 10 Paired t-test 0.763 16.45 (15.16) 21.35 (20.24) 0.127 dz = 0.53 [-0.15, 1.18] p Occipital pole (right) 10 Paired t-test 0.579 14.98 (17.41) 20.36 (18.59) 0.127 dz = 0.53 [-0.15, 1.18] p Lingual gyrus (total) 10 Paired t-test 0.775 29.83 (19.29) 23.27 (18.51) 0.131 dz = -0.53 [-1.18, 0.15] p Occipital fusiform gyrus (left) 10 Paired t-test 0.120 30.05 (22.59) 36.69 (28.55) 0.186 dz = 0.45 [-0.21, 1.09] p Superior occipital gyrus (right) 10 Paired t-test 0.906 41.00 (24.48) 36.56 (25.91) 0.241 dz = -0.40 [-1.03, 0.26] p Middle occipital gyrus (right) 10 Paired t-test 0.670 32.42 (26.17) 36.37 (29.87) 0.249 dz = 0.39 [-0.26, 1.02] p Calcarine cortex (left) 10 Paired t-test 0.370 56.43 (37.21) 54.08 (35.87) 0.259 dz = -0.38 [-1.01, 0.27] p Precuneus (right) 10 Paired t-test 0.466 30.90 (27.37) 27.93 (26.08) 0.330 dz = -0.33 [-0.95, 0.32] p Superior occipital gyrus (total) 10 Paired t-test 0.771 34.47 (25.04) 30.80 (26.00) 0.363 dz = -0.30 [-0.93, 0.34] p Lingual gyrus (left) 10 Paired t-test 0.962 27.84 (14.13) 23.78 (17.86) 0.385 dz = -0.29 [-0.91, 0.35] p Cuneus (left) 10 Paired t-test 0.608 36.11 (30.96) 32.46 (30.64) 0.402 dz = -0.28 [-0.90, 0.36] p Occipital lobe (right) 10 Paired t-test 0.068 20.34 (23.03) 18.74 (20.14) 0.433 dz = -0.26 [-0.88, 0.38] p Middle occipital gyrus (total) 10 Wilcoxon signed-rank 0.031 35.88 [6.55, 42.11] 30.05 [4.32, 42.16] 0.476 r = 0.00 [-0.71, 0.52] p Fusiform gyrus (right) 10 Paired t-test 0.892 49.73 (25.43) 46.73 (23.40) 0.478 dz = -0.23 [-0.86, 0.40] p Inferior occipital gyrus (total) 10 Paired t-test 0.979 34.08 (26.79) 37.31 (31.53) 0.517 dz = 0.21 [-0.42, 0.84] p Fusiform gyrus (total) 10 Paired t-test 0.193 45.23 (28.72) 43.20 (27.56) 0.550 dz = -0.20 [-0.82, 0.44] p Superior occipital gyrus (left) 10 Paired t-test 0.629 32.30 (23.66) 29.64 (25.28) 0.589 dz = -0.18 [-0.80, 0.45] p Cuneus (total) 10 Paired t-test 0.489 31.57 (26.62) 29.53 (28.01) 0.612 dz = -0.17 [-0.79, 0.46] p Inferior occipital gyrus (right) 10 Paired t-test 0.599 35.60 (25.07) 38.18 (30.04) 0.657 dz = 0.15 [-0.48, 0.76] p Occipital fusiform gyrus (total) 10 Wilcoxon signed-rank 0.005 22.52 [12.12, 33.80] 32.39 [15.52, 50.06] 0.683 r = -0.03 [-0.55, 0.68] p Superior parietal lobule (left) 10 Paired t-test 0.656 49.35 (33.42) 47.05 (25.38) 0.687 dz = -0.13 [-0.75, 0.49] p Cuneus (right) 10 Paired t-test 0.405 30.99 (20.90) 29.86 (24.11) 0.756 dz = -0.10 [-0.72, 0.52] p Superior parietal lobule (right) 10 Paired t-test 0.495 55.57 (25.00) 57.48 (23.14) 0.777 dz = 0.09 [-0.53, 0.71] p Fusiform gyrus (left) 10 Paired t-test 0.558 44.02 (30.25) 44.83 (30.11) 0.831 dz = 0.07 [-0.55, 0.69] p Occipital fusiform gyrus (right) 10 Wilcoxon signed-rank 0.008 22.66 [11.89, 53.69] 40.71 [17.58, 57.66] 0.838 r = -0.16 [-0.87, 0.52] p Inferior occipital gyrus (left) 10 Paired t-test 0.406 39.07 (28.46) 38.51 (35.15) 0.923 dz = -0.03 [-0.65, 0.59] p Superior parietal lobule (total) 10 Paired t-test 0.240 52.71 (28.65) 52.77 (20.91) 0.992 dz = 0.00 [-0.62, 0.62] Note. Percentiles are relative to the normative reference. Descriptives are reported as mean (SD) for regions analyzed with paired t-tests, and as median [Q1, Q3] for regions analyzed with Wilcoxon signed-rank tests. Effect sizes: dz for paired t-tests; r for Wilcoxon tests (bootstrap point estimate and 95% percentile CI). 3.3 Changes outside the visual network An exploratory analysis was performed to assess longitudinal changes in brain regions outside of the predefined extended visual network. Multiple regions demonstrated pre–post differences at an uncorrected significance level (p < 0.05), encompassing parietal, temporal, limbic, subcortical, cerebellar and ventricular structures. These changes were heterogeneous in both anatomical distribution and direction, with some regions showing decreases and others increases in percentile values relative to the normative reference (Table 2). Specifically, uncorrected decreases were observed in parietal regions (total and right parietal lobe), posterior midline structures (posterior cingulate gyrus and precuneus), temporal and limbic regions (anterolateral temporal cortex, entorhinal cortex, hippocampus and amygdala), as well as global cerebral gray matter measures. In contrast, increases in percentile values were observed in selected regions, including the inner temporal lobe, the cerebellar vermal lobules VI–VII, and the right accumbens area. Importantly, after correction for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure, none of the observed changes outside the visual network remained statistically significant (all FDR-adjusted p FDR ≥ 0.35). The effect sizes for the uncorrected findings ranged from moderate to large; however, given the small sample size, the absence of FDR-surviving effects, and the lack of a coherent anatomical pattern, these results should be interpreted cautiously. Accordingly, the observed non-visual changes are reported as exploratory and hypothesis-generating and were not considered as evidence of systematic or generalized brain involvement. Table 2. Exploratory analysis across all other regions (FDR-corrected) Region n Test Shapiro–Wilk p Pre Post p p (FDR) Effect (95% CI) p Temporal horn (Lateral ventricle) (right) 10 Wilcoxon signed-rank 0.030 84.17 [63.67, 97.15] 87.70 [67.68, 98.08] 0.006 0.353 r = 0.87 [0.87, 0.88] p Temporal horn (Lateral ventricle) (total) 10 Wilcoxon signed-rank 0.002 91.71 [59.92, 97.47] 92.59 [72.24, 98.10] 0.006 0.353 r = 0.87 [0.87, 0.88] p Parietal lobe (total) 10 Paired t-test 0.100 31.53 (26.31) 26.38 (23.86) 0.008 0.353 dz = -1.06 [-1.83, -0.26] p Inner Temporal lobe Calculated MTA (left) 10 Wilcoxon signed-rank 0.002 83.53 [54.79, 94.50] 90.11 [68.02, 95.66] 0.009 0.353 r = 0.83 [0.72, 0.88] p Cerebral cortical grey matter (right) 10 Paired t-test 0.774 23.14 (23.06) 19.41 (21.93) 0.012 0.353 dz = -1.00 [-1.75, -0.21] p Cerebral grey matter (right) 10 Paired t-test 0.382 22.84 (23.65) 19.09 (22.30) 0.013 0.353 dz = -0.98 [-1.72, -0.20] p Inner Temporal lobe Calculated MTA (right) 10 Wilcoxon signed-rank 0.002 78.46 [57.72, 96.77] 80.97 [62.87, 98.53] 0.014 0.353 r = 0.78 [0.60, 0.88] p Parietal lobe Calculated GCA (right) 10 Wilcoxon signed-rank 0.029 86.68 [74.04, 96.72] 94.15 [85.31, 98.25] 0.014 0.353 r = 0.78 [0.39, 0.88] p Cerebellar vermal lobules VI-VII (total) 10 Paired t-test 0.443 45.97 (32.92) 54.16 (34.55) 0.017 0.353 dz = 0.92 [0.16, 1.65] p Posterior cingulate gyrus (total) 10 Paired t-test 0.906 44.05 (36.12) 38.46 (31.57) 0.018 0.353 dz = -0.91 [-1.64, -0.15] p Parietal lobe (right) 10 Paired t-test 0.714 35.19 (27.52) 28.45 (23.60) 0.023 0.353 dz = -0.87 [-1.59, -0.12] p Vessel (left) 10 Paired t-test 0.112 53.01 (26.99) 41.17 (25.69) 0.023 0.353 dz = -0.86 [-1.58, -0.11] p Antero lateral temporal (left) 10 Paired t-test 0.774 38.47 (27.96) 28.82 (23.88) 0.025 0.353 dz = -0.85 [-1.57, -0.10] p Cerebral cortical grey matter (total) 10 Wilcoxon signed-rank 0.041 19.16 [4.80, 28.99] 12.18 [4.13, 25.59] 0.025 0.353 r = -0.71 [-0.88, -0.29] p Amygdala (total) 10 Paired t-test 0.643 39.28 (31.53) 26.07 (28.32) 0.025 0.353 dz = -0.85 [-1.56, -0.10] p Posterior insula (right) 10 Paired t-test 0.326 28.30 (35.43) 22.93 (30.45) 0.026 0.353 dz = -0.84 [-1.55, -0.10] p Transverse temporal gyrus (left) 10 Paired t-test 0.821 46.08 (35.14) 39.53 (30.17) 0.027 0.353 dz = -0.83 [-1.54, -0.09] p Temporal horn (Lateral ventricle) (left) 10 Wilcoxon signed-rank < .001 93.19 [72.56, 97.78] 93.73 [80.06, 97.70] 0.032 0.353 r = 0.68 [0.26, 0.88] p Entorhinal area (left) 10 Paired t-test 0.962 43.55 (31.92) 33.62 (23.50) 0.037 0.353 dz = -0.77 [-1.47, -0.04] p Posterior cingulate gyrus (left) 10 Paired t-test 0.403 39.52 (35.84) 34.26 (32.11) 0.038 0.353 dz = -0.77 [-1.47, -0.04] p Amygdala (right) 10 Paired t-test 0.070 40.15 (28.63) 24.68 (24.15) 0.038 0.353 dz = -0.77 [-1.47, -0.04] p Vessel (total) 10 Paired t-test 0.384 53.91 (21.47) 46.05 (21.22) 0.039 0.353 dz = -0.76 [-1.46, -0.04] p Accumbens area (right) 10 Wilcoxon signed-rank 0.031 18.38 [9.51, 40.46] 32.76 [14.55, 49.58] 0.041 0.353 r = 0.65 [0.16, 0.88] p Cerebral grey ja whiten matter (total) 10 Wilcoxon signed-rank 0.001 17.84 [4.79, 52.75] 14.48 [3.13, 52.65] 0.041 0.353 r = -0.68 [-0.87, 0.13] p Cerebral grey matter (total) 10 Wilcoxon signed-rank 0.018 19.55 [3.83, 27.71] 13.34 [3.28, 22.64] 0.041 0.353 r = -0.65 [-0.88, 0.00] p Transverse temporal gyrus (total) 10 Wilcoxon signed-rank 0.027 40.59 [12.74, 83.32] 34.94 [8.78, 68.92] 0.041 0.353 r = -0.68 [-0.88, -0.16] p Middle temporal gyrus (left) 10 Paired t-test 0.067 37.31 (29.72) 26.52 (25.99) 0.044 0.360 dz = -0.74 [-1.43, -0.02] p Hippocampus (total) 10 Paired t-test 0.181 33.64 (28.46) 30.24 (27.55) 0.046 0.363 dz = -0.73 [-1.42, -0.01] p Cerebral cortical grey matter (left) 10 Paired t-test 0.090 23.82 (23.96) 20.52 (23.97) 0.059 0.446 dz = -0.68 [-1.36, 0.02] p Angular gyrus (total) 10 Wilcoxon signed-rank 0.031 47.38 [16.90, 64.46] 40.08 [8.96, 59.86] 0.067 0.446 r = -0.58 [-0.88, -0.00] Note. Percentiles are relative to the normative reference. Descriptives are reported as mean (SD) for regions analyzed with paired t-tests, and as median [Q1, Q3] for regions analyzed with Wilcoxon signed-rank tests. Effect sizes: dz for paired t-tests; r for Wilcoxon tests (bootstrap point estimate and 95% percentile CI). FDR = Benjamini–Hochberg correction. 3.4 Confirmatory analysis among reduced dimensions In the reduced-dimension analysis (Wilcoxon signed-rank tests; n = 10), the limbic/affect ROI composite showed a significant pre–post decrease in normative brain percentile values (pre: 42.30; post: 38.42; mean change = − 3.87; median change = − 3.19; W = 3, p = 0.014; rank-biserial r = − 0.891), indicating a large effect in the negative direction. After controlling multiple comparisons across the reduced set using FDR correction, this effect did not remain significant (p = 0.0866), but it represented the strongest change among the tested dimensions. VFQ-25 scores showed numerical improvements from pre to post that did not reach statistical significance. The VFQ-25 overall score excluding general health increased from 56.24 to 62.89 (mean change = 6.65; median change = 2.67; W = 38, p = 0.308; r = 0.382; p FDR = 0.610). Near activities improved from 33.33 to 42.08 (mean change = 8.75; median change = 14.58; W = 31, p = 0.343; r = 0.378; p FDR = 0.610), and the psychosocial composite increased from 45.68 to 55.05 (mean change = 9.38; median change = 0.26; W = 28, p = 0.554; r = 0.244; p FDR = 0.610). The remaining brain composites showed minimal to small decreases with small effect sizes and no evidence of statistical change: the ventral-stream ROI remained essentially unchanged (pre: 31.16; post: 31.07; mean change = − 0.09; W = 22, p = 0.610; r = − 0.200), and the dorsal attention/oculomotor ROI decreased modestly (pre: 44.23; post: 41.64; mean change = − 2.58; W = 22, p = 0.610; r = − 0.200), with both effects non-significant after FDR correction (p FDR = 0.610). Targeted multivariable regression models yielded no stable predictors; all bootstrap 95% confidence intervals for coefficients crossed zero. 4 DISCUSSION In this retrospective longitudinal magnetic resonance imaging study, we investigated structural brain changes in patients with age-related macular degeneration and assessed whether implantation of the Scharioth macula lens, combined with postoperative visual rehabilitation, was associated with changes in these alterations. By combining exploratory structural mapping with theory-driven dimensional reduction and confirmatory regression modeling, the present study aimed to distinguish descriptive volumetric patterns from mechanistically interpretable structure–function relationships. The main findings were the following: first, patients with AMD demonstrated pronounced baseline structural deviations in the posterior visual cortex relative to a healthy MRI reference database, most prominently in the occipital pole. Second, over a 6-month follow-up period after SML implantation, visual network regions showed overall structural stability with region-specific changes. Third, exploratory analyses outside the visual network revealed that no changes survived correction for multiple comparisons, which does not support evidence of generalized brain involvement over the studied interval. The absence of robust associations between baseline network organization and quality-of-life improvements suggests that functional adaptation after SML implantation may not be directly predictable from baseline macrostructural measures alone. 4.1 Visual cortex abnormalities in AMD The most prominent baseline abnormality was the markedly reduced occipital pole percentile, with most patients falling below the 25th percentile and more than half below the 10th percentile relative to normative data. This finding is consistent with previous studies on voxel-based morphometry and morphometric magnetic resonance imaging reporting gray matter reductions in the posterior visual cortex in AMD, particularly near the occipital pole and the calcarine sulcus 14 , 15 . These structural alterations are compatible with transsynaptic degeneration secondary to chronic loss of retinal input, as well as reduced visual stimulation and altered participation in visually guided behaviors 4 . Additional baseline reductions were observed in ventral and lateral visual association regions, including the lingual gyrus, the occipital fusiform gyrus, and the middle temporal gyrus, supporting the concept that AMD affects an extended visual network rather than the primary visual cortex alone 15 , 16 . At the same time, several visual regions, such as the calcarine cortex and inferior temporal gyrus, showed percentile values closer to normative ranges, highlighting regional heterogeneity in vulnerability within the posterior visual cortex. 4.2 Longitudinal stability and trends after SML implantation Over the 6-month follow-up period, most regions of the extended visual network demonstrated overall structural stability. This finding is notable given the advanced age of the cohort, in which age-related cortical atrophy is typically expected. Nevertheless, statistically significant longitudinal changes were observed in selected posterior cortical regions. Specifically, a significant decrease in percentile values was detected in the left middle occipital gyrus, an extrastriate region involved in higher-order visual processing and visual integration. In addition, the precuneus demonstrated a modest but significant decrease in percentile ranking. Both regions are involved in visuospatial integration and visual attention and have been reported to be affected in previous neuroimaging studies of AMD and visual deprivation 15 , 16 . In contrast, the occipital pole demonstrated a consistent directional increase in both absolute volume and percentile ranking. Given that the occipital pole corresponds to the representation of the central visual field, this trend may reflect relative preservation or partial normalization of the cortical structure in the region, which is most directly related to improved retinal image quality after SML implantation and visual rehabilitation. Although causal inference is not possible, this pattern is compatible with previous functional and structural imaging studies that show experience-dependent plasticity in the visual cortex, even in older adults 7 . The coexistence of decreases in the extrastriate and posterior midline regions along with a trend toward preservation in the occipital pole underscores the heterogeneous nature of cortical adaptation in AMD. Rather than indicating a uniform treatment effect, these findings suggest region-specific responses within the visual network, likely reflecting differences in functional specialization and susceptibility to sensory deprivation. 4.3 Changes outside the visual network Exploratory analyses identified multiple uncorrected longitudinal changes in regions outside the visual network, including parietal, posterior midline, temporal, limbic, subcortical, cerebellar, and ventricular structures. These changes were heterogeneous in both anatomical distribution and direction. However, none of these effects survived the false discovery rate correction. The absence of corrected significance outside the visual network argues against systematic or generalized brain involvement over the 6-month interval. Although uncorrected decreases were observed in regions such as the parietal lobe, the posterior cingulate gyrus, and the precuneus - areas implicated in higher-order visual integration and default mode network function, the lack of correction-surviving effects and the absence of a coherent anatomical pattern suggest that these findings are best regarded exploratory. Similarly, uncorrected limbic findings involving the hippocampus and amygdala should be interpreted with caution. Given their small effect sizes, the lack of correction for multiple comparisons, and the absence of convergent cognitive or clinical evidence, these observations do not support the presence of generalized neurodegeneration or Alzheimer-type pathology. This interpretation is consistent with population-based and genetic studies that have failed to demonstrate a clear causal association between AMD and Alzheimer’s disease 17 , 18 . 4.4 Limitations Several limitations should be acknowledged. The sample size was relatively small, which limits the statistical power and increases the susceptibility to Type II error. Therefore, findings should be interpreted as preliminary and hypothesis-generating, particularly with respect to regression modeling. In addition, postoperative visual rehabilitation was performed in all patients, making it impossible to separate the effects of the intraocular lens from those of training. The absence of a non-implanted AMD comparison group limits causal inference regarding the effect of SML versus natural disease progression. Finally, structural MRI does not capture functional or microstructural changes that can precede volumetric alterations. Despite these limitations, the longitudinal within-subject design, the use of a validated AI-based segmentation tool, and the comparison with a large normative MRI database strengthen the validity of the findings. Automated segmentation methods are sensitive to image quality and anatomical variability. To mitigate this limitation, an experienced neuroradiologist (J.H.) visually inspected all automated segmentations for anatomical plausibility, paying particular attention to posterior visual cortical regions. Furthermore, an independent segmentation using FreeSurfer was performed in selected cases to qualitatively verify the anatomical location and directional consistency of key regional findings. Because cNeuro and FreeSurfer rely on different parcellation schemes and normalization strategies, FreeSurfer results were not used for quantitative statistical analysis, but served as cross-pipeline validation. 5 CONCLUSIONS Patients with age-related macular degeneration show pronounced structural deviations in the posterior visual cortex, particularly in the occipital pole, compared to the age-matched healthy MRI database. These findings are consistent with regionally specific central nervous system involvement in AMD, which predominantly affects the posterior visual cortex. Longitudinal changes after the implantation of the Scharioth macula lens were heterogeneous, with relative preservation of the structure of the occipital pole in conjunction with localized decreases in adjacent extrastriate regions. The absence of robust changes outside the visual network argues against generalized neurodegeneration and underscores the need for larger prospective multimodal imaging studies for further explanation of cortical plasticity in AMD. Declarations Grant Support The work was supported by ERDF-Project „BraDy“ No. CZ.02.01.01/00/22_008/0004643 and by Ministry of Health of the Czech Republic, Grant no. AZV NV18-06-00484. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to the content of this article. Author contributions J. Bochnička: Conceptualization, cNeuro analysis, Writing – original draft; J. Hakumäki: Conceptualization, cNeuro analysis, Supervision, Writing – editing; N. Jirásková: Conceptualization, Patient selection and treatment, Writing – editing; J. Kremláček: Conceptualization, Data acquisition, Statistical analysis, Supervision, Writing – review and editing Data availability The anonymized data can be made available upon request. References Mitchell P, Liew G, Gopinath B, Wong TY (2018) Age-related macular degeneration. Lancet 392:1147–1159 Stelmack JA, Szlyk JP, Stelmack TR, Demers-Turco P, Williams RT, Moran D, Massof RW (2004) Psychometric properties of the veterans affairs low-vision visual functioning questionnaire. Invest Ophthalmol Visual Sci, 45 Zhuang J, Madden DJ, Duong-Fernandez X, Chen Nkuei, Cousins SW, Potter GG, Diaz MT, Whitson HE (2018) Language processing in age-related macular degeneration associated with unique functional connectivity signatures in the right hemisphere, Neurobiology of Aging, vol. 63, pp. 65–74, 3 Prins D, Hanekamp S, Cornelissen FW (2016) Structural brain mri studies in eye diseases: Are they clinically relevant? a review of current findings Zuo X, Zhuang J, Chen Nkuei, Cousins S, Cunha P, Lad EM, Madden DJ, Potter G, Whitson HE (2020) Relationship between neural functional connectivity and memory performance in age-related macular degeneration. Neurobiol Aging, 95 Whitson HE, Chou YH, Potter GG, Diaz MT, Chen NK, Lad EM, Johnson MA, Cousins SW, Zhuang J, Madden DJ (2015) Phonemic fluency and brain connectivity in age-related macular degeneration: A pilot study. Brain Connect, 5 Masuda Y, Dumoulin SO, Nakadomari S, Wandell BA (2008) V1 projection zone signals in human macular degeneration depend on task, not stimulus. Cereb Cortex, 18 Scharioth GB (2015) New add-on intraocular lens for patients with age-related macular degeneration. J Cataract Refractive Surg, 41 Nekolova J, Kremlacek J, Lukavsky J, Sikl R, Sin M, Langrova J, Szanyi J, Jiraskova N (1 2023) The intraocular implant and visual rehabilitation improve the quality of life of elderly patients with geographic atrophy secondary to age-related macular degeneration. 261:263–272 Graefe’s Archive for Clinical and Experimental Ophthalmology Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD, for the National Eye Institute Visual Function Questionnaire Field Test Investigators (07 2001) Development of the 25-list-item national eye institute visual function questionnaire. Arch Ophthalmol 119:1050–1058 Lotjonen JM, Wolz R, Koikkalainen JR, Thurfjell L, Waldemar G, Soininen H, Rueckert D (2010) Fast and robust multi-atlas segmentation of brain magnetic resonance images. NeuroImage 49(3):2352–2365 Koikkalainen J, Rhodius-Meester H, Tolonen A, Barkhof F, Tijms B, Lemstra AW, Tong T, Guerrero R, Schuh A, Ledig C, Rueckert D, Soininen H, Remes AM, Waldemar G, Hasselbalch S, Mecocci P, van der Flier W, L¨otj¨onen J (2016) Differential diagnosis of neurodegenerative diseases using structural mri data. NeuroImage: Clin 11:435–449 Wang Y, Catindig JA, Hilal S, Soon HW, Ting E, Wong TY, Venketasubramanian N, Chen C, Qiu A (2012) Multi-stage segmentation of white matter hyperintensity, cortical and lacunar infarcts. NeuroImage 60(4):2379–2388 Boucard CC, Hernowo AT, Maguire RP, Jansonius NM, Roerdink JBTM, Hooymans JMM, Cornelissen FW (7 2009) Changes in cortical grey matter density associated with long-standing retinal visual field defects. Brain 132:1898–1906 Hernowo AT, Prins D, Baseler HA, Plank T, Gouws AD, Hooymans JM, Morland AB, Greenlee MW, Cornelissen FW (2014) Morphometric analyses of the visual pathways inmacular degeneration. Cortex, 56 Shen Y-K, Ge Q-M, Pan Y-C, Shu H-Y, Zhang L-J, Li Q-Y, Liang R-B, Shao Y, Yu Y (10 2021) Decreased gray matter volume and increased white matter volume in patients with neovascular age-related macular degeneration: a voxel-based morphometry study. Aging 13:23182–23192 Proitsi P, Lupton MK, Dudbridge F, Tsolaki M, Hamilton G, Daniilidou M, Pritchard M, Lord K, Martin BM, Craig D, Todd S, McGuinness B, Hollingworth P, Harold D, Kloszewska I, Soininen H, Mecocci P, Velas B, Gill M, Lawlor B, Rubinsztein DC, Brayne C, Passmore PA, Williams J, Lovestone S, Powell JF (2012) Alzheimer’s disease and age-related macular degeneration have different genetic models for complement gene variation. Neurobiol Aging, 33 Keenan TD, Goldacre R, Goldacre MJ, Hyman L (2014) Associations between age-related macular degeneration, alzheimer disease, and dementia: Record linkage study of hospital admissions. JAMA Ophthalmol, 132 Additional Declarations The authors declare no competing interests. Supplementary Files supplementaryROItable1.docx Supplementary ROI table Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9110944","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":605456224,"identity":"66b19dc5-a874-45f9-a5e0-a5eb7fec8a0d","order_by":0,"name":"Jakub Bochnička","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYBACAwYGNhDJzMDe3PCZ4QBIjLGBSC08Bxtnk6AFBCQSYVoIAHP25mePCwrs2PlnPmxsLjjDIG9wu7mB4ccf3Fose46ZG88wSGaWuJ3Y2DzjBoPhhjsHGxh7ePA47EYOmzSPwQFmhtuJ7Y95PjAkGNxIbGBmkCBCi/zNg43NCC0GRGgxuMEI1HIDpiUBr1/MgFqSmQ3PAP3Cc0bCcCZQy8GeA7i1gEJMmuePXbLc8cMHm3mO2cjz3Uh/+ABfiMFAMpSGeBuPHQhgR4yiUTAKRsEoGKEAABPBUdRXsR6TAAAAAElFTkSuQmCC","orcid":"","institution":"Charles University","correspondingAuthor":true,"prefix":"","firstName":"Jakub","middleName":"","lastName":"Bochnička","suffix":""},{"id":605456513,"identity":"e4b0645a-a30e-4828-89a6-18ad30c4f265","order_by":1,"name":"Juhana Hakumäki","email":"","orcid":"","institution":"University of Eastern Finland","correspondingAuthor":false,"prefix":"","firstName":"Juhana","middleName":"","lastName":"Hakumäki","suffix":""},{"id":605456629,"identity":"1d5f7a03-f7c2-4fa6-8e1f-01d48760fba2","order_by":2,"name":"Naďa Jirásková","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Naďa","middleName":"","lastName":"Jirásková","suffix":""},{"id":605456630,"identity":"4b2763c2-c0ba-4831-afc0-37eadaefdac6","order_by":3,"name":"Jan Kremláček","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Kremláček","suffix":""}],"badges":[],"createdAt":"2026-03-13 06:29:49","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9110944/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9110944/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104694036,"identity":"491d9623-037e-45ea-bbf1-ae6391cec328","added_by":"auto","created_at":"2026-03-16 06:57:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1346478,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eScatterplots show each participant’s pre-implantation percentile (x-axis) versus 6-month post-implantation percentile (y-axis) relative to the normative reference (cNeuro database); the dashed diagonal indicates no change (points above/below denote increase/decrease). Panels outlined in red indicate a statistically significant post-implantation decrease, green a statistically significant increase, and yellow indicates that most participants are below the 25th normative percentile (baseline abnormality).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1highresolution.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9110944/v1/b0f54c60dcfe5ec35c47a3ad.jpg"},{"id":104782732,"identity":"99a91601-b2a1-4e95-9271-139f4531944c","added_by":"auto","created_at":"2026-03-17 07:57:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2474058,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9110944/v1/a4f3fe0d-6e04-4db7-9295-a1ac73aaf8b0.pdf"},{"id":104694041,"identity":"2c04defa-6dfd-4a48-8d8b-c5d67d1f8120","added_by":"auto","created_at":"2026-03-16 06:57:39","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":22857,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary ROI table\u003c/p\u003e","description":"","filename":"supplementaryROItable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9110944/v1/09a4e372a96212f836872a86.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eLongitudinal structural brain changes after Scharioth macula lens implantation in patients with age-related macular degeneration\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1 INTRODUCTION","content":"\u003cp\u003eAge-related macular degeneration (AMD) is the leading cause of visual impairment and severe vision loss worldwide. It affects approximately 10% of the population over 60 years of age, with prevalence increasing to up to 25% in individuals older than 75 years\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. AMD causes substantial difficulties in daily life by altering activities that require fine spatial resolution, such as reading, face recognition, and object identification\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Beyond visual impairment, AMD has been associated with higher rates of cognitive decline, poorer performance on cognitive tests - even those not directly involving visual processing - and an increased risk of dementia\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Retinal nerve cell apoptosis in AMD, particularly in the macular region, can induce changes in the properties of brain tissue through transsynaptic degeneration\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. This process leads to reduced visual input to the cortex and may influence behavioral factors related to visually dependent activities, including social interaction and reading\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Sensory deprivation related to AMD can result in region-specific structural and functional brain changes through multiple mechanisms. These include reduced cognitive stimulation, diminished feedback from visual cortical areas, and adaptive reorganization of visual pathways. Such changes have been reflected in altered functional connectivity patterns, increased metabolic demands in specific regions of the brain, and reduced cognitive performance\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Importantly, visual rehabilitation aimed at improving visual function has been shown to promote functional cerebral reorganization, particularly within the primary visual cortex and fronto-parietal control networks\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe Scharioth macula lens (SML) was developed as a visual rehabilitation option for patients with advanced AMD. Its design is based on an established concept of sulcus-fixation in pseudophakic eyes. SML has been used clinically for several years and is characterized by a relatively simple implantation procedure and a low complication rate\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e In this retrospective study, our aim was to investigate whether patients with AMD develop specific structural regional changes in the cerebral areas and then whether implantation of the Scharioth macula lens, combined with postoperative visual rehabilitation, is associated with changes in these alterations. We employed a two-level analytical strategy combining exploratory structural mapping with confirmatory brain\u0026ndash;behavior modeling. The hypothesis was that AMD is associated with structural changes that predominantly affect visual cortical regions, and that improved retinal input may modulate these changes.\u003c/p\u003e \u003cp\u003eBy exploring this relationship, we hope to improve the understanding of the anatomical and clinical manifestation of macular degeneration and potentially improve clinical management strategies for these patients.\u003c/p\u003e"},{"header":"2 MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e2.1 Study design\u003c/h2\u003e\n\u003cp\u003eThe study included 10 patients (3 females and 7 males), with an age range of 72\u0026ndash;86 years (AVG 78.8, SD 5.6). The selection criteria for implantation were based on the recommendations of the SML manufacturer (Medicontur International, Geneva, Switzerland): age over 55 years, best-corrected distant visual acuity (BCVA) of 0.4 to 1.3 logMAR (i.e. 0.4 to 0.05 in the decimal fraction), stabilized maculopathy, and pseudophakic eye. Exclusion criteria were a photopic pupil size less than 2.5 mm, severe zonulopathy, an anterior chamber depth less than 2.8 mm, narrow-angle or severe ocular pathology, or previous retinal surgery. Patient selection, surgery, clinical care, and some of the examinations were conducted in the Department of Ophthalmology of the University Hospital in Hradec Kralove, Czech Republic. The study was approved by the Ethics Committee of the University Hospital in Hradec Kralove. All principles of the Declaration of Helsinki were followed, and all patients gave their informed consent. All participants underwent the implantation of a\u0026thinsp;+\u0026thinsp;6-diopter macular intraocular lens (SML). All patients underwent standard postoperative treatment with a topical antibiotic for 1 week and a topical steroid for 1 month. To facilitate postoperative functional vision, all participants completed supervised visual rehabilitation during the first 3 postoperative weeks (30 min/day). Rehabilitation was explicitly aimed at improving visual fixation stability and reading performance and comprised structured training in fixation strategies, reading exercises, and graphomotor practice to support functional use of restored near-vision capacity. All patients contributed paired structural MRI data acquired before implantation (approximately 27 days, median in the range 5 to 49 days) and 6 months after implantation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003e2.2 Quality of life\u003c/h2\u003e\n\u003cp\u003eA vision-specific quality-of-life questionnaire was used to evaluate how the intervention affected participants\u0026rsquo; vision-related quality of life. Localized for Czech conditions\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, The National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e was administered on two occasions: prior to SML implantation and again 6 months postoperatively. To ensure independence, the questionnaire was read aloud by a healthcare professional who had not participated in any previous assessments or rehabilitation, and who recorded the responses of the participants. The NEI VFQ-25 comprises 12 brief subscales, which range from 0 to 100, with higher scores indicating a better quality of life. A composite score is typically computed as the mean of 11 subscales, omitting the vision-nonspecific general health subscale. As none of the participants were able to drive, the driving subscale was also excluded. Given the small sample size and the mechanistic focus of the intervention (fixation/reading), the VFQ-25 domains were summarized a priori into a reduced set.\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eVFQ Near (primary functional target): \u003cem\u003enear activities\u003c/em\u003e.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eVFQ Psychosocial (secondary): mean of \u003cem\u003evision-specific depend\u003c/em\u003eency, \u003cem\u003erole difficulties\u003c/em\u003e, \u003cem\u003emental health\u003c/em\u003e, and \u003cem\u003esocial functioning\u003c/em\u003e.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eVFQ Overall (excluding general health): mean of all available VFQ domain scores excluding \u003cem\u003egeneral health\u003c/em\u003e, to avoid conflating global health status with vision-specific outcomes.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eAll VFQ scores were analyzed at baseline, at 6 months, and as change scores (\u0026Delta;\u0026thinsp;=\u0026thinsp;post\u0026thinsp;\u0026minus;\u0026thinsp;pre).\u003c/p\u003e\n\u003cp\u003eThe quality-of-life assessment served a confirmatory role within the overall analytical framework. While the volumetric analyses were primarily exploratory with hypothesis-driven regional emphasis, the quality-of-life composites were used to evaluate whether structural patterns in functionally relevant networks showed coherent associations with the intervention\u0026rsquo;s behavioral targets (reading, fixation stability, social adaptation). These outcomes were integrated into pre-specified mechanistic regression models, linking baseline structural organization to functional change.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003e2.3 MRI acquisition\u003c/h2\u003e\n\u003cp\u003eMagnetic resonance imaging (MRI) was performed in CEITEC MAFIL Brno on a 3-T whole-body MRI system (MAGNETOM Prisma, Siemens Healthineers, Erlangen, Germany) using a three-dimensional T1-weighted magnetization-prepared rapid gradient-echo (3D MPRAGE) sequence. The imaging parameters were as follows: repetition time (TR)\u0026thinsp;=\u0026thinsp;2300 ms, echo time (TE)\u0026thinsp;=\u0026thinsp;2.33 ms, inversion-prepared gradient-echo readout and flip angle\u0026thinsp;=\u0026thinsp;8\u0026deg;. The images were acquired in the sagittal plane with an isotropic spatial resolution of 1 \u0026times; 1 \u0026times; 1 mm\u0026sup3;, a slice thickness of 1 mm, and an in-plane acquisition matrix of 224 \u0026times; 224. The field of view resulted in 224 slices that covered the entire brain. One signal average was used. The sequence used Siemens' proprietary MPRAGE implementation (sequence name tfl3d1) and was reconstructed using the vendor\u0026rsquo;s standard normalization pipeline (syngo MR E11).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003e2.4 Voxel-based morphometric analysis: cMRI cNeuro\u003c/h2\u003e\n\u003cp\u003eRegional brain volumes were determined at both time points using a fully automated multi-atlas segmentation tool cNeuro (Combinostics Ltd, Tampere, Finland) from 3D T1 MRI images\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The cNeuro method was used as a fully automated AI-assisted segmentation and volumetry tool for measuring brain atrophy, with CE marking and wide clinical application, in cooperation with Kuopio University Hospital. The segmentation method described by Koikkalainen et al.\u003csup\u003e12\u003c/sup\u003e, and Wang et al.\u003csup\u003e13\u003c/sup\u003e, was used to compute volumes of anatomical areas from 3D T1-weighted magnetic resonance images. In total, 258 anatomical biomarkers, such as total brain volume, white and gray matter volumes, cerebellum, CSF spaces, and deep gray matter structures, including their volume composites and atrophy scores, were extracted with normalization for age, sex, and head size. This method provides the evaluation of the severity of brain changes at the individual patient level without the need for control groups (the software contains an internal control database of 1,923 normal individuals - age range 18\u0026ndash;94 years, 57% females) and is validated for use in both clinical and research settings. The tool provides the percentiles for both the left- and right-sided structures, when applicable, and the total volume of the anatomical structures, which was utilized in this study.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e\n\u003cp\u003eAll statistical analyses were performed in R (version 4.5.1). The analysis pipeline was designed to accommodate the small sample size and potential non-normality of the data, with emphasis on effect sizes and confidence intervals. Statistical analyses were performed using paired within-subject comparisons to assess longitudinal changes in brain structure before and after implantation of the Scharioth macula lens. Absolute regional brain volumes and the corresponding percentile values normalized for age, sex, and head size were obtained from the cNeuro analysis and used for all statistical tests.\u003c/p\u003e\n\u003cp\u003eBaseline abnormalities were descriptively evaluated using percentile values derived from a comparison with an age-matched healthy MRI reference database. Percentile values below the 25th percentile were considered indicative of reduced regional volume relative to normative data.\u003c/p\u003e\n\u003cp\u003eThe analyses focused on a priori defined visual regions of interest (ROIs), including the primary and associative visual cortices (calcarine cortex, cuneus, lingual gyrus, fusiform gyrus, occipital gyri, and occipital pole). Secondary regions related to visuospatial integration (precuneus and superior parietal lobule) were included for supportive analyses. For each ROI, pre\u0026ndash;post changes were evaluated using paired statistical tests. The normality of the paired differences was assessed with the Shapiro-Wilk test. When the assumption of normality was met, a paired t-test was applied; otherwise, a Wilcoxon signed-rank test was used. Primary ROIs were analyzed without correction for multiple comparisons due to their hypothesis-driven selection. All remaining regions were analyzed exploratorily with correction for the false discovery rate (FDR) using the Benjamini\u0026ndash;Hochberg procedure.\u003c/p\u003e\n\u003cp\u003eEffect sizes were reported for all inferential tests. For paired t-tests, Cohen\u0026rsquo;s \u003cem\u003edz\u003c/em\u003e with 95% confidence intervals was calculated. For Wilcoxon tests, the effect size was expressed as Wilcoxon \u003cem\u003er\u003c/em\u003e, with point estimates and 95% confidence intervals obtained by bootstrap resampling of paired observations (5,000 iterations) to ensure stability in small samples. Descriptive statistics were reported conditional on the test applied: mean (SD) for parametric analyses and median [Q1, Q3] for nonparametric analyses. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003cp\u003eTo integrate structural findings with functional targets of the intervention and to limit model complexity at n\u0026thinsp;=\u0026thinsp;10, regional measures were reduced a priori into three minimally overlapping ROI-level indices representing mechanistically relevant networks. These networks were computed as the mean normative percentile across constituent regions, using total-volume metrics only to avoid redundancy from left/right duplication. ROI membership was defined by atlas-derived region names and documented explicitly in a supplementary ROI membership table. The three minimally overlapping ROIs were: i) Ventral stream / occipito-temporal ROI (central vision / reading-related visual cortex): total-volume measures of calcarine cortex, cuneus, lingual gyrus, occipital fusiform gyrus, inferior occipital gyrus, and middle occipital gyrus. ii) Dorsal attention / oculomotor ROI (fixation and attentional control): total-volume measures of precuneus, superior parietal lobule, superior frontal gyrus, middle frontal gyrus, and supplementary motor cortex. iii) Limbic / affect ROI (psychosocial/QoL-related circuitry): total-volume measures of amygdala, hippocampus, posterior cingulate gyrus, subcallosal area, and ventral diencephalon.\u003c/p\u003e\n\u003cp\u003eFor each ROI, a baseline ROI mean percentile and a 6-month ROI mean percentile were computed, together with the corresponding change score (\u0026Delta;ROI\u0026thinsp;=\u0026thinsp;post\u0026thinsp;\u0026minus;\u0026thinsp;pre). Mechanistically motivated multivariable relationships were evaluated using a small set of pre-specified regression models: M1: \u0026Delta;VFQ Near ~\u0026thinsp;baseline Ventral-stream ROI\u0026thinsp;+\u0026thinsp;baseline Dorsal-attention ROI; M2: \u0026Delta;VFQ Near ~\u0026thinsp;baseline Ventral-stream ROI\u0026thinsp;+\u0026thinsp;baseline Limbic/affect ROI; M3: \u0026Delta;VFQ Psychosocial\u0026thinsp;~\u0026thinsp;baseline Limbic/affect ROI.\u003c/p\u003e\n\u003cp\u003eRegression coefficient uncertainty was quantified using bootstrap resampling at the participant level (5,000 bootstrap samples) with 95% confidence intervals. Model fit was summarized using R\u0026sup2;.\u003c/p\u003e\n\u003cp\u003eAll analyses prioritize robustness, transparency, and clinical interpretability. The complete analysis pipeline can be provided upon request in the R script to ensure reproducibility.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Baseline abnormalities\u003c/h2\u003e\n \u003cp\u003eAt baseline, a percentile-based comparison with the healthy magnetic resonance imaging database revealed marked deviations in the posterior visual regions, with the strongest abnormality observed in the occipital pole. The mean percentile of the occipital pole was 12.15\u0026thinsp;\u0026plusmn;\u0026thinsp;14.17, with 8 subjects \u0026lt;\u0026thinsp;25th percentile and 6 subjects \u0026lt;\u0026thinsp;10th percentile, indicating consistent sub-normative structural values in this region.\u003c/p\u003e\n \u003cp\u003eAdditional baseline reductions (mean percentile\u0026thinsp;\u0026lt;\u0026thinsp;35) were observed in ventral and lateral visual association regions, including the following: Occipital fusiform gyrus: 26.87\u0026thinsp;\u0026plusmn;\u0026thinsp;22.61; Middle temporal gyrus: 28.13\u0026thinsp;\u0026plusmn;\u0026thinsp;22.40; Lingual gyrus: 29.83\u0026thinsp;\u0026plusmn;\u0026thinsp;19.29; Cuneus: 31.57\u0026thinsp;\u0026plusmn;\u0026thinsp;26.62.\u003c/p\u003e\n \u003cp\u003eIn contrast, several regions (e.g., calcarine cortex, inferior temporal gyrus) showed mean percentiles closer to normative ranges at baseline.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Longitudinal changes in the visual network\u003c/h2\u003e\n \u003cp\u003eThe longitudinal paired analyses revealed region-specific changes within the predefined extended visual network during the 6-month follow-up period (Table\u0026nbsp;1). Although most of the visual cortical regions demonstrated general structural stability, statistically significant changes at the uncorrected level were observed in selected posterior cortical areas.\u003c/p\u003e\n \u003cp\u003eA significant decrease in percentile values was detected in the left middle occipital gyrus (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 39.11\u0026thinsp;\u0026plusmn;\u0026thinsp;28.18 pre vs. 31.02\u0026thinsp;\u0026plusmn;\u0026thinsp;24.56 post; p\u0026thinsp;=\u0026thinsp;0.004; dz = -1.23), indicating a reduction relative to the normative reference. Furthermore, the precuneus (total) showed a modest but statistically significant decrease in the percentile ranking (35.54\u0026thinsp;\u0026plusmn;\u0026thinsp;29.93 pre vs. 31.57\u0026thinsp;\u0026plusmn;\u0026thinsp;28.28 post; p\u0026thinsp;=\u0026thinsp;0.034; dz = -0.79).\u003c/p\u003e\n \u003cp\u003eIn contrast, the occipital pole (total) demonstrated a statistically significant increase in percentile values (median [Q1, Q3]: 6.22 [2.65, 14.03] pre vs. 11.15 [4.78, 20.49] post; Wilcoxon signed-rank test, p\u0026thinsp;=\u0026thinsp;0.033; r\u0026thinsp;=\u0026thinsp;0.68), reflecting a directional shift towards a higher normative ranking. The left and right occipital pole subregions showed consistent increases in mean percentile values; however, these hemispheric changes did not reach statistical significance individually.\u003c/p\u003e\n \u003cp\u003eAll remaining regions of the visual network, including the calcarine cortex, cuneus, lingual gyrus, superior and inferior occipital gyri, fusiform gyrus, and compounds of the occipital lobe, showed small changes in the mixed direction that did not reach statistical significance (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). No region within the visual network survived correction for multiple comparisons.\u003c/p\u003e\n \u003cp\u003eThese findings indicate heterogeneous longitudinal changes within the posterior visual cortex, characterized by relative preservation or improvement in the occipital pole alongside localized decreases in adjacent extrastriate regions.\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;1. Primary ROI analysis (pre vs post implantation)\u003c/p\u003e\n \u003ctable width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRegion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eShapiro\u0026ndash;Wilk p\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePre\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePost\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEffect (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Middle occipital gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.11 (28.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31.02 (24.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -1.23 [-2.05, -0.38]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital pole (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.22 [2.65, 14.03]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11.15 [4.78, 20.49]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.68 [0.23, 0.87]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Precuneus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.658\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35.54 (29.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31.57 (28.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.79 [-1.49, -0.06]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital lobe (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.37 [2.88, 38.68]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.61 [1.71, 27.96]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.61 [-0.87, 0.19]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital lobe (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.94 (25.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.48 (22.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.67 [-1.34, 0.04]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Precuneus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.977\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.27 (31.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.16 (28.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.63 [-1.30, 0.07]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Calcarine cortex (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.822\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.26 (33.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.05 (31.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.60 [-1.26, 0.09]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Calcarine cortex (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e50.11 (36.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46.18 (34.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.57 [-1.23, 0.12]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Lingual gyrus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e37.40 [11.93, 54.98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.48 [7.81, 35.14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.52 [-0.87, 0.10]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital pole (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.763\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.45 (15.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.35 (20.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.53 [-0.15, 1.18]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital pole (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.579\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.98 (17.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.36 (18.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.53 [-0.15, 1.18]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Lingual gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.775\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.83 (19.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.27 (18.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.53 [-1.18, 0.15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital fusiform gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.05 (22.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.69 (28.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.45 [-0.21, 1.09]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Superior occipital gyrus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e41.00 (24.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.56 (25.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.40 [-1.03, 0.26]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Middle occipital gyrus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.670\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.42 (26.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.37 (29.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.249\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.39 [-0.26, 1.02]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Calcarine cortex (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e56.43 (37.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e54.08 (35.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.38 [-1.01, 0.27]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Precuneus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.466\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.90 (27.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.93 (26.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.33 [-0.95, 0.32]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Superior occipital gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.47 (25.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.80 (26.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.30 [-0.93, 0.34]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Lingual gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.962\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.84 (14.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.78 (17.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.29 [-0.91, 0.35]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cuneus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.608\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.11 (30.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.46 (30.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.402\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.28 [-0.90, 0.36]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital lobe (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.34 (23.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.74 (20.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.26 [-0.88, 0.38]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Middle occipital gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35.88 [6.55, 42.11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.05 [4.32, 42.16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.476\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.00 [-0.71, 0.52]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Fusiform gyrus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.892\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e49.73 (25.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46.73 (23.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.478\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.23 [-0.86, 0.40]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Inferior occipital gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.979\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.08 (26.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e37.31 (31.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.21 [-0.42, 0.84]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Fusiform gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45.23 (28.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e43.20 (27.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.550\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.20 [-0.82, 0.44]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Superior occipital gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.30 (23.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.64 (25.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.18 [-0.80, 0.45]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cuneus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.489\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31.57 (26.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.53 (28.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.17 [-0.79, 0.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Inferior occipital gyrus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35.60 (25.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38.18 (30.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.657\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.15 [-0.48, 0.76]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital fusiform gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22.52 [12.12, 33.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.39 [15.52, 50.06]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.683\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.03 [-0.55, 0.68]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Superior parietal lobule (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.656\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e49.35 (33.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e47.05 (25.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.687\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.13 [-0.75, 0.49]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cuneus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.99 (20.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.86 (24.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.756\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.10 [-0.72, 0.52]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Superior parietal lobule (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e55.57 (25.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e57.48 (23.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.777\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.09 [-0.53, 0.71]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Fusiform gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.558\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.02 (30.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.83 (30.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.07 [-0.55, 0.69]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Occipital fusiform gyrus (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22.66 [11.89, 53.69]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40.71 [17.58, 57.66]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.16 [-0.87, 0.52]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Inferior occipital gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.406\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.07 (28.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38.51 (35.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.03 [-0.65, 0.59]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Superior parietal lobule (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.240\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e52.71 (28.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e52.77 (20.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.992\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.00 [-0.62, 0.62]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eNote. Percentiles are relative to the normative reference. Descriptives are reported as mean (SD) for regions analyzed with paired t-tests, and as median [Q1, Q3] for regions analyzed with Wilcoxon signed-rank tests. Effect sizes: dz for paired t-tests; r for Wilcoxon tests (bootstrap point estimate and 95% percentile CI).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Changes outside the visual network\u003c/h2\u003e\n \u003cp\u003eAn exploratory analysis was performed to assess longitudinal changes in brain regions outside of the predefined extended visual network. Multiple regions demonstrated pre\u0026ndash;post differences at an uncorrected significance level (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), encompassing parietal, temporal, limbic, subcortical, cerebellar and ventricular structures. These changes were heterogeneous in both anatomical distribution and direction, with some regions showing decreases and others increases in percentile values relative to the normative reference (Table\u0026nbsp;2).\u003c/p\u003e\n \u003cp\u003eSpecifically, uncorrected decreases were observed in parietal regions (total and right parietal lobe), posterior midline structures (posterior cingulate gyrus and precuneus), temporal and limbic regions (anterolateral temporal cortex, entorhinal cortex, hippocampus and amygdala), as well as global cerebral gray matter measures. In contrast, increases in percentile values were observed in selected regions, including the inner temporal lobe, the cerebellar vermal lobules VI\u0026ndash;VII, and the right accumbens area.\u003c/p\u003e\n \u003cp\u003eImportantly, after correction for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure, none of the observed changes outside the visual network remained statistically significant (all FDR-adjusted p\u003csub\u003eFDR\u003c/sub\u003e \u0026ge; 0.35). The effect sizes for the uncorrected findings ranged from moderate to large; however, given the small sample size, the absence of FDR-surviving effects, and the lack of a coherent anatomical pattern, these results should be interpreted cautiously. Accordingly, the observed non-visual changes are reported as exploratory and hypothesis-generating and were not considered as evidence of systematic or generalized brain involvement.\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;2. Exploratory analysis across all other regions (FDR-corrected)\u003c/p\u003e\n \u003ctable width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRegion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTest\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eShapiro\u0026ndash;Wilk p\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePre\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePost\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep (FDR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEffect (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Temporal horn (Lateral ventricle) (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e84.17 [63.67, 97.15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e87.70 [67.68, 98.08]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.87 [0.87, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Temporal horn (Lateral ventricle) (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e91.71 [59.92, 97.47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e92.59 [72.24, 98.10]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.87 [0.87, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Parietal lobe (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31.53 (26.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.38 (23.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -1.06 [-1.83, -0.26]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Inner Temporal lobe Calculated MTA (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e83.53 [54.79, 94.50]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e90.11 [68.02, 95.66]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.83 [0.72, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebral cortical grey matter (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.774\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.14 (23.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.41 (21.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -1.00 [-1.75, -0.21]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebral grey matter (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22.84 (23.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.09 (22.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.98 [-1.72, -0.20]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Inner Temporal lobe Calculated MTA (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.46 [57.72, 96.77]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80.97 [62.87, 98.53]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.78 [0.60, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Parietal lobe Calculated GCA (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e86.68 [74.04, 96.72]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e94.15 [85.31, 98.25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.78 [0.39, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebellar vermal lobules VI-VII (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.443\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45.97 (32.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e54.16 (34.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = 0.92 [0.16, 1.65]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Posterior cingulate gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e44.05 (36.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38.46 (31.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.91 [-1.64, -0.15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Parietal lobe (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35.19 (27.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.45 (23.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.87 [-1.59, -0.12]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Vessel (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e53.01 (26.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e41.17 (25.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.86 [-1.58, -0.11]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Antero lateral temporal (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.774\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e38.47 (27.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.82 (23.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.85 [-1.57, -0.10]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebral cortical grey matter (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.16 [4.80, 28.99]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.18 [4.13, 25.59]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.71 [-0.88, -0.29]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Amygdala (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.643\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.28 (31.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.07 (28.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.85 [-1.56, -0.10]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Posterior insula (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.30 (35.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22.93 (30.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.84 [-1.55, -0.10]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Transverse temporal gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46.08 (35.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.53 (30.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.83 [-1.54, -0.09]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Temporal horn (Lateral ventricle) (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; .001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e93.19 [72.56, 97.78]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e93.73 [80.06, 97.70]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.68 [0.26, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Entorhinal area (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.962\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e43.55 (31.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33.62 (23.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.77 [-1.47, -0.04]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Posterior cingulate gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.403\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.52 (35.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.26 (32.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.77 [-1.47, -0.04]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Amygdala (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40.15 (28.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.68 (24.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.77 [-1.47, -0.04]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Vessel (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.384\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e53.91 (21.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46.05 (21.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.76 [-1.46, -0.04]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Accumbens area (right)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.38 [9.51, 40.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.76 [14.55, 49.58]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = 0.65 [0.16, 0.88]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebral grey ja whiten matter (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.84 [4.79, 52.75]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.48 [3.13, 52.65]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.68 [-0.87, 0.13]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebral grey matter (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.55 [3.83, 27.71]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.34 [3.28, 22.64]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.65 [-0.88, 0.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Transverse temporal gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40.59 [12.74, 83.32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.94 [8.78, 68.92]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.68 [-0.88, -0.16]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Middle temporal gyrus (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e37.31 (29.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.52 (25.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.74 [-1.43, -0.02]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Hippocampus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33.64 (28.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.24 (27.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.73 [-1.42, -0.01]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Cerebral cortical grey matter (left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePaired t-test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.82 (23.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.52 (23.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003edz = -0.68 [-1.36, 0.02]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ep Angular gyrus (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWilcoxon signed-rank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e47.38 [16.90, 64.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40.08 [8.96, 59.86]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er = -0.58 [-0.88, -0.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eNote. Percentiles are relative to the normative reference. Descriptives are reported as mean (SD) for regions analyzed with paired t-tests, and as median [Q1, Q3] for regions analyzed with Wilcoxon signed-rank tests. Effect sizes: dz for paired t-tests; r for Wilcoxon tests (bootstrap point estimate and 95% percentile CI). FDR = Benjamini\u0026ndash;Hochberg correction.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Confirmatory analysis among reduced dimensions\u003c/h2\u003e\n \u003cp\u003eIn the reduced-dimension analysis (Wilcoxon signed-rank tests; n\u0026thinsp;=\u0026thinsp;10), the limbic/affect ROI composite showed a significant pre\u0026ndash;post decrease in normative brain percentile values (pre: 42.30; post: 38.42; mean change\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;3.87; median change\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;3.19; W\u0026thinsp;=\u0026thinsp;3, p\u0026thinsp;=\u0026thinsp;0.014; rank-biserial r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.891), indicating a large effect in the negative direction. After controlling multiple comparisons across the reduced set using FDR correction, this effect did not remain significant (p\u0026thinsp;=\u0026thinsp;0.0866), but it represented the strongest change among the tested dimensions.\u003c/p\u003e\n \u003cp\u003eVFQ-25 scores showed numerical improvements from pre to post that did not reach statistical significance. The VFQ-25 overall score excluding general health increased from 56.24 to 62.89 (mean change\u0026thinsp;=\u0026thinsp;6.65; median change\u0026thinsp;=\u0026thinsp;2.67; W\u0026thinsp;=\u0026thinsp;38, p\u0026thinsp;=\u0026thinsp;0.308; r\u0026thinsp;=\u0026thinsp;0.382; p\u003csub\u003eFDR\u003c/sub\u003e = 0.610). Near activities improved from 33.33 to 42.08 (mean change\u0026thinsp;=\u0026thinsp;8.75; median change\u0026thinsp;=\u0026thinsp;14.58; W\u0026thinsp;=\u0026thinsp;31, p\u0026thinsp;=\u0026thinsp;0.343; r\u0026thinsp;=\u0026thinsp;0.378; p\u003csub\u003eFDR\u003c/sub\u003e = 0.610), and the psychosocial composite increased from 45.68 to 55.05 (mean change\u0026thinsp;=\u0026thinsp;9.38; median change\u0026thinsp;=\u0026thinsp;0.26; W\u0026thinsp;=\u0026thinsp;28, p\u0026thinsp;=\u0026thinsp;0.554; r\u0026thinsp;=\u0026thinsp;0.244; p\u003csub\u003eFDR\u003c/sub\u003e = 0.610).\u003c/p\u003e\n \u003cp\u003eThe remaining brain composites showed minimal to small decreases with small effect sizes and no evidence of statistical change: the ventral-stream ROI remained essentially unchanged (pre: 31.16; post: 31.07; mean change\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.09; W\u0026thinsp;=\u0026thinsp;22, p\u0026thinsp;=\u0026thinsp;0.610; r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.200), and the dorsal attention/oculomotor ROI decreased modestly (pre: 44.23; post: 41.64; mean change\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;2.58; W\u0026thinsp;=\u0026thinsp;22, p\u0026thinsp;=\u0026thinsp;0.610; r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.200), with both effects non-significant after FDR correction (p\u003csub\u003eFDR\u003c/sub\u003e = 0.610).\u003c/p\u003e\n \u003cp\u003eTargeted multivariable regression models yielded no stable predictors; all bootstrap 95% confidence intervals for coefficients crossed zero.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 DISCUSSION","content":"\u003cp\u003eIn this retrospective longitudinal magnetic resonance imaging study, we investigated structural brain changes in patients with age-related macular degeneration and assessed whether implantation of the Scharioth macula lens, combined with postoperative visual rehabilitation, was associated with changes in these alterations. By combining exploratory structural mapping with theory-driven dimensional reduction and confirmatory regression modeling, the present study aimed to distinguish descriptive volumetric patterns from mechanistically interpretable structure\u0026ndash;function relationships. The main findings were the following: first, patients with AMD demonstrated pronounced baseline structural deviations in the posterior visual cortex relative to a healthy MRI reference database, most prominently in the occipital pole. Second, over a 6-month follow-up period after SML implantation, visual network regions showed overall structural stability with region-specific changes. Third, exploratory analyses outside the visual network revealed that no changes survived correction for multiple comparisons, which does not support evidence of generalized brain involvement over the studied interval. The absence of robust associations between baseline network organization and quality-of-life improvements suggests that functional adaptation after SML implantation may not be directly predictable from baseline macrostructural measures alone.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Visual cortex abnormalities in AMD\u003c/h2\u003e \u003cp\u003eThe most prominent baseline abnormality was the markedly reduced occipital pole percentile, with most patients falling below the 25th percentile and more than half below the 10th percentile relative to normative data. This finding is consistent with previous studies on voxel-based morphometry and morphometric magnetic resonance imaging reporting gray matter reductions in the posterior visual cortex in AMD, particularly near the occipital pole and the calcarine sulcus\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. These structural alterations are compatible with transsynaptic degeneration secondary to chronic loss of retinal input, as well as reduced visual stimulation and altered participation in visually guided behaviors\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAdditional baseline reductions were observed in ventral and lateral visual association regions, including the lingual gyrus, the occipital fusiform gyrus, and the middle temporal gyrus, supporting the concept that AMD affects an extended visual network rather than the primary visual cortex alone\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. At the same time, several visual regions, such as the calcarine cortex and inferior temporal gyrus, showed percentile values closer to normative ranges, highlighting regional heterogeneity in vulnerability within the posterior visual cortex.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Longitudinal stability and trends after SML implantation\u003c/h2\u003e \u003cp\u003eOver the 6-month follow-up period, most regions of the extended visual network demonstrated overall structural stability. This finding is notable given the advanced age of the cohort, in which age-related cortical atrophy is typically expected. Nevertheless, statistically significant longitudinal changes were observed in selected posterior cortical regions.\u003c/p\u003e \u003cp\u003eSpecifically, a significant decrease in percentile values was detected in the left middle occipital gyrus, an extrastriate region involved in higher-order visual processing and visual integration. In addition, the precuneus demonstrated a modest but significant decrease in percentile ranking. Both regions are involved in visuospatial integration and visual attention and have been reported to be affected in previous neuroimaging studies of AMD and visual deprivation\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn contrast, the occipital pole demonstrated a consistent directional increase in both absolute volume and percentile ranking. Given that the occipital pole corresponds to the representation of the central visual field, this trend may reflect relative preservation or partial normalization of the cortical structure in the region, which is most directly related to improved retinal image quality after SML implantation and visual rehabilitation. Although causal inference is not possible, this pattern is compatible with previous functional and structural imaging studies that show experience-dependent plasticity in the visual cortex, even in older adults\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe coexistence of decreases in the extrastriate and posterior midline regions along with a trend toward preservation in the occipital pole underscores the heterogeneous nature of cortical adaptation in AMD. Rather than indicating a uniform treatment effect, these findings suggest region-specific responses within the visual network, likely reflecting differences in functional specialization and susceptibility to sensory deprivation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Changes outside the visual network\u003c/h2\u003e \u003cp\u003eExploratory analyses identified multiple uncorrected longitudinal changes in regions outside the visual network, including parietal, posterior midline, temporal, limbic, subcortical, cerebellar, and ventricular structures. These changes were heterogeneous in both anatomical distribution and direction. However, none of these effects survived the false discovery rate correction.\u003c/p\u003e \u003cp\u003eThe absence of corrected significance outside the visual network argues against systematic or generalized brain involvement over the 6-month interval. Although uncorrected decreases were observed in regions such as the parietal lobe, the posterior cingulate gyrus, and the precuneus - areas implicated in higher-order visual integration and default mode network function, the lack of correction-surviving effects and the absence of a coherent anatomical pattern suggest that these findings are best regarded exploratory.\u003c/p\u003e \u003cp\u003eSimilarly, uncorrected limbic findings involving the hippocampus and amygdala should be interpreted with caution. Given their small effect sizes, the lack of correction for multiple comparisons, and the absence of convergent cognitive or clinical evidence, these observations do not support the presence of generalized neurodegeneration or Alzheimer-type pathology. This interpretation is consistent with population-based and genetic studies that have failed to demonstrate a clear causal association between AMD and Alzheimer\u0026rsquo;s disease\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Limitations\u003c/h2\u003e \u003cp\u003eSeveral limitations should be acknowledged. The sample size was relatively small, which limits the statistical power and increases the susceptibility to Type II error. Therefore, findings should be interpreted as preliminary and hypothesis-generating, particularly with respect to regression modeling. In addition, postoperative visual rehabilitation was performed in all patients, making it impossible to separate the effects of the intraocular lens from those of training. The absence of a non-implanted AMD comparison group limits causal inference regarding the effect of SML versus natural disease progression. Finally, structural MRI does not capture functional or microstructural changes that can precede volumetric alterations.\u003c/p\u003e \u003cp\u003eDespite these limitations, the longitudinal within-subject design, the use of a validated AI-based segmentation tool, and the comparison with a large normative MRI database strengthen the validity of the findings.\u003c/p\u003e \u003cp\u003eAutomated segmentation methods are sensitive to image quality and anatomical variability. To mitigate this limitation, an experienced neuroradiologist (J.H.) visually inspected all automated segmentations for anatomical plausibility, paying particular attention to posterior visual cortical regions. Furthermore, an independent segmentation using FreeSurfer was performed in selected cases to qualitatively verify the anatomical location and directional consistency of key regional findings. Because cNeuro and FreeSurfer rely on different parcellation schemes and normalization strategies, FreeSurfer results were not used for quantitative statistical analysis, but served as cross-pipeline validation.\u003c/p\u003e \u003c/div\u003e"},{"header":"5 CONCLUSIONS","content":"\u003cp\u003ePatients with age-related macular degeneration show pronounced structural deviations in the posterior visual cortex, particularly in the occipital pole, compared to the age-matched healthy MRI database.\u003c/p\u003e \u003cp\u003eThese findings are consistent with regionally specific central nervous system involvement in AMD, which predominantly affects the posterior visual cortex. Longitudinal changes after the implantation of the Scharioth macula lens were heterogeneous, with relative preservation of the structure of the occipital pole in conjunction with localized decreases in adjacent extrastriate regions. The absence of robust changes outside the visual network argues against generalized neurodegeneration and underscores the need for larger prospective multimodal imaging studies for further explanation of cortical plasticity in AMD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eGrant Support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by ERDF-Project „BraDy“ No. CZ.02.01.01/00/22_008/0004643 and by Ministry of Health of the Czech Republic, Grant no. AZV NV18-06-00484.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest related to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ. Bochnička: Conceptualization, cNeuro analysis, Writing – original draft; J. Hakumäki: Conceptualization, cNeuro analysis, Supervision, Writing – editing; N. Jirásková: Conceptualization, Patient selection and treatment, Writing – editing; J. Kremláček: Conceptualization, Data acquisition, Statistical analysis, Supervision, Writing – review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe anonymized data can be made available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMitchell P, Liew G, Gopinath B, Wong TY (2018) Age-related macular degeneration. Lancet 392:1147\u0026ndash;1159\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStelmack JA, Szlyk JP, Stelmack TR, Demers-Turco P, Williams RT, Moran D, Massof RW (2004) Psychometric properties of the veterans affairs low-vision visual functioning questionnaire. 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JAMA Ophthalmol, 132\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"617fed6f-8efd-4eb3-9dbf-a301069fcc27","identifier":"10.13039/501100008530","name":"European Regional Development Fund","awardNumber":"CZ.02.01.01/00/22_008/0004643","order_by":0},{"identity":"f57418bd-d008-496a-a969-e3e0cb6315e2","identifier":"10.13039/501100003243","name":"Ministerstvo Zdravotnictví Ceské Republiky","awardNumber":"AZV NV18-06-00484","order_by":1}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Charles University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"age-related macular degeneration, magnetic resonance imaging, artificial intelligence, brain segmentation, longitudinal changes, Scharioth macula lens","lastPublishedDoi":"10.21203/rs.3.rs-9110944/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9110944/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and Purpose\u003c/h2\u003e \u003cp\u003eAge-related macular degeneration (AMD) is associated with visual impairment and with structural and functional brain changes. The extent to which AMD affects cerebral structure and whether visual rehabilitation, including implantation of the Scharioth macula lens (SML), is associated with structural brain changes, remains incompletely understood. This study aimed to investigate regional brain volume alterations in patients with AMD and to assess longitudinal changes after SML implantation.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eTen patients with AMD (mean age 78.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6 years) underwent a structural brain MRI at 3T before and 6 months after SML implantation. Regional brain volumes were quantified using a fully automated AI-assisted multi-atlas segmentation tool (cNeuro cMRI). The results were expressed as absolute volumes and normative percentile values relative to an age-matched healthy MRI reference database. Primary analyses focused on a predefined extended visual network. In addition, exploratory whole-brain analyses were performed with correction for multiple comparisons. A vision-related quality-of-life questionnaire was administered, and changes in composite scores were associated with pre-implantation volumes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt baseline, pronounced atrophy was observed in the posterior visual cortex, most prominently in the occipital pole, and most of the patients showed reduced normative percentiles. Longitudinal analyses revealed overall structural stability in the visual network. Region-specific changes were identified, including significant decreases in percentile values in the left middle occipital gyrus and the precuneus, along with an increase in the volume of the occipital pole and the percentile ranking. Exploratory analyses outside the visual network identified heterogeneous uncorrected changes; however, none survived the false discovery rate correction. Visual quality-of-life composites showed modest mean improvements in 6 months, but no association with volume was statistically significant after correction for multiple comparisons.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAMD is associated with regionally specific structural alterations in the posterior visual cortex. Following SML implantation and visual rehabilitation, the visual network regions demonstrated general stability with heterogeneous regional changes, while no evidence of generalized brain involvement was observed. These findings support the involvement of central visual pathways in AMD and suggest preserved cortical plasticity even in advanced age.\u003c/p\u003e","manuscriptTitle":"Longitudinal structural brain changes after Scharioth macula lens implantation in patients with age-related macular degeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 06:56:49","doi":"10.21203/rs.3.rs-9110944/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c55459e-78ac-4b73-b3aa-2e42aff33153","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T06:56:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 06:56:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9110944","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9110944","identity":"rs-9110944","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}