Visual Snow Syndrome Improves With Modulation of Resting-State Functional MRI Connectivity After Mindfulness-Based Cognitive Therapy: An Open-Label Feasibility Study

Supplemental Digital Content is Available in the Text.

cognitive therapy customized for visual symptoms (MBCTvision) can treat VSS and modulate functional dysregulation in vision-related pathways.
Mindfulness is the nonjudgmental awareness of the present moment.Studies on mindfulness-based interventions have shown changes in neural networks and improved psychological resilience. 2 The clinical application of mindfulness is based on the training of attention, awareness, and self-regulation.
MBCT is a clinical intervention related to mindfulnessbased stress reduction and cognitive-behavioral therapy (CBT), originally for major depression. 3MBCT is an 8week program that develops skills of mindfulness and CBT strategies through weekly small-group participation and structured daily practice between sessions.MBCT trains attention, awareness, and emotional regulation, while embodying nonjudgment, curiosity, kindness, and friendliness. 3The facilitated group discussions on mindfulness practices are designed to develop cognitive-behavioral skills.

METHODS
We performed a prospective open-label feasibility study of VSS, defined by the International Classification of Headache Disorders-3 diagnostic criteria.All participants were screened by the principal investigator (PI), a neuroophthalmologist (S.H.W.) before study recruitment.
Participants were enrolled into an 8-week program of MBCT-vision delivered by an experienced MBCT teacher (J.W.) and assisted by the PI and an MBCT teacher (S.H.W.).The standard MBCT protocol was customized to the MBCT-vision protocol by replacing structured discussions about preventing depression with structured discussions related to the impact of and response to visual symptoms. 3roup sizes were limited to facilitate effective group learning and engagement.The MBCT-vision intervention was delivered in 3 groups to enable sufficient study sample size.The first group met in-person; the second and third groups met online because of the COVID-19 pandemic.
Primary outcome measures were changes in self-reported visual symptom severity and impact of symptoms on daily life, comparing scores at baseline, Week 9 (1 week after MBCT-vision completion), and Week 20 (i.e., 3 months after MBCT-vision intervention to evaluate sustained treatment response).The self-reported ratings were determined from an ordinal scale with a range of 0-10, where 0 indicated no symptoms or impact, and 10 indicated maximum severity or impact.Statistical analysis used nonparametric 2-tailed Wilcoxon signed-rank tests, with a nominal P value of significance of 0.0182, 4 resulting in an overall significance level of 0.05.
Secondary outcome measures were the overall WHO-5 Wellbeing questionnaire score measured on a scale of 0-100 5 and the overall CORE-10 Psychological Distress questionnaire score measured on a scale of 0-40, 6 comparing baseline with Week 9 and Week 20.Statistical analyses for these primary and secondary outcomes used nonparametric 2-tailed Wilcoxon signed-rank tests, with a nominal P value of significance of 0.0182, 4 resulting in an overall significance level of 0.05.
Quantitative MRI was performed for the second and third groups after funding was obtained after an interim report on the first group. 7Secondary MRI outcomes included resting-state functional connectivity and diffusion MRI microstructural metrics compared between baseline and Week 20.Healthy control MRI data were compared with VSS to investigate fMRI and diffusion-related alterations at baseline only.
Preprocessing of rs-fMRI data was performed using fMRIPrep 20.2.6 8 and included correction for head motion, susceptibility distortions and slice-timing, registration to the T1w volumes, and denoising to minimize residual nonneuronal variability (See Supplemental Digital Content, Supplementary Material, http://links.lww.com/WNO/A781).Preprocessed fMRI data were imported into the functional connectivity (CONN) toolbox (v.21.b, http://www.nitrc.org/projects/conn)for the subsequent analyses.We used CONN's independent component analysis (ICA) implementation (including temporal concatenation across multiple subjects, group-level dimensionality reduction using principal component analysis, FastICA to obtain 10 spatially independent components, and subject-specific back projection using dual regression) 9 to identify the visual network (VN).Subjectlevel VN maps entered second-level analyses, where we tested in a general linear model framework: (i) within-subject modifications of FC before and after MBCT-vision, (ii) associations between pre-post FC changes and clinical improvement (defined as a self-rated symptom severity score delta .2),and (iii) cross-sectional differences between VSS patients at baseline and healthy controls (HCs).For all analyses, significance level was set at a = 0.05, familywise error (FWE)-corrected at cluster level.
DTI and NODDI models were fitted to the DWI data, after eddy current, distortion, and motion correction, using FSL 10 and the MATLAB (MathWorks, Inc, Natick, MA) NODDI toolboxes (http://nitrc.org/projects/noddi_toolbox).We assessed voxelwise differences in core white matter voxels of DTI (fractional anisotropy and mean diffusivity) and NODDI (neurite density index, orientation dispersion index, and isotropic volume fraction) metrics (i) between VSS patients at baseline and HCs and (ii) within VSS patients before and after intervention using the tractbased spatial statistics (TBSS) toolbox. 11Threshold-free cluster enhancement was used, and FWE-corrected P values less than 0.05 were considered statistically significant.
This study received ethics approval from the National Research Ethics Committee (London-South East, 19/LO/ 1615) and registered on ClinicalTrials.gov(Identifier: NCT04184726).Written informed consent was obtained from all participants, and the appropriate institutional forms have been archived.

Data Availability
Anonymized data beginning 12 months and ending 3 years after publication of this article can be made available on request from a qualified researchers whose proposed use of the data is approved by the PI and the institution's research governance committee, and requesters will need to sign a data access agreement.

RESULTS
Twenty-one participants (14 male participants, median age 30 years, range 22-56 years) with VSS were recruited from January 2020 to October 2021.Two participants (9.5%) did not complete the 8-week program citing work-related reasons and dropped out of the study.Pre-existing migraine was present in 12/21 (57%) and anxiety in 9/21(43%).

com/WNO/ A781) post-MBCT-vision (Week 20) compared with pre-MBCT-vision (baseline).
There was a significant association between the improvement in self-reported severity score and increased VNrelated FC within the right striatum (size = 70 mL, clusterlevel FWE-corrected P value = 0.03) (Fig. 4, See Supplemental Digital Content, Table 2, http://links.lww.com/WNO/A781).For the between-group analysis (VSS vs HC, N = 13 vs 16), VSS subjects at baseline showed reduced VN-related FC within the left lateral occipital cortex (cluster size = 118 mL, cluster-level FWE-corrected P value = 0.01) compared with HCs (Fig. 5, See Supplemental Digital Content, Table 4, http://links.lww.com/WNO/A781).No significant differences were found for DTI (fractional isotropy and mean diffusivity) and NODDI (neurite density index, orientation dispersion index, and isotropic volume fraction) metrics between VSS patients at baseline and controls and VSS patients before and after intervention.

DISCUSSION
There are no other previous intervention study on VSS with rs-fMRI as a neural outcome correlate, confirmed on a

Original Contribution
PubMed search.We show MBCT-vision is a feasible treatment for VSS, with subjective improvements and fMRI-associated changes.
Subjective improvements in symptom severity and impact of symptoms were sustained at three months after intervention.Although there was no treatment control group for comparison because of the study's open-label feasibility design, such a sustained improvement is unexpected from natural history studies, showing that VSS persists without spontaneous improvement. 13ur primary outcomes were an ordinal scale (0-10) for the rating of the severity of VSS and the impact of this on daily life.This was a pragmatic study design because of the lack of validated rating scales for VSS.Participants were advised to respond based on all aspects of their VSS.Future studies validating a VSS rating scale that differentiates all aspects of VSS, including the primary symptom of visual snow and other visual symptoms such as afterimages and floaters, are necessary to advance research in VSS.
We showed objective fMRI reorganization of the visual network, involving both visual and extravisual areas in the neocortex and cerebellum, after MBCT-vision intervention.
Alterations of FC in VSS have previously involved both intranetwork dysconnectivity of vision-related brain regions and aberrant coupling with other functional systems, including the default mode network (DMN) and the thalami/basal ganglia. 14ur findings of reduced VN-related FC in the extrastriate visual cortex in VSS patients compared with HC are consistent with this.Moreover, we found that MBCTvision intervention was associated with functional reorganization of the VN within the visual extrastriate regions of the lateral occipital cortex, the posterior cerebellar areas implicated in visual processing and attentional mechanisms, 15 and the posterior hub of the DMN.These findings support the hypothesis that the alteration of VN-related FC within visual areas and association networks may underpin disruptions between the integration of internally generated visual information and the processing of salient environmental stimuli, resulting in a constant "noise-like" perception. 14he modulation of FC within the right striatum was related to clinical improvement.There is evidence that the basal ganglia influence visual perception, although the visual corticostriatal loop 16 and altered functional coupling between visual hubs and the caudate nuclei have also been FIG.4. Cluster of significant association between pre-post VN-related FC increase and clinical improvement (defined as a self-rated symptom severity score delta .2),displayed as a binary mask (i.e., thresholded and binarized statistical map) on a 3D glass brain representation (See Supplemental Digital Content, Table 3, http://links.lww.com/WNO/A781).FC indicates functional connectivity; VN, visual network.FIG. 5. Cluster of significant between-group (VSS , HC) difference in terms of VN-related FC, displayed as a binary mask (i.e., thresholded and binarized statistical map) on a 3D glass brain representation.FC indicates functional connectivity; HC, healthy controls; VN, visual network; VSS, visual snow syndrome.
reported with VSS. 14 We therefore speculate that MBCTvision improved visual snow symptoms by modulating FC between the VN and the striatum.
There is emerging understanding of the role of the cerebellum in processing not only motor functions, but also cognitive and associative functions. 17Of note, MBCTvision intervention modulated functional connectivity of the VIIb/VIII cerebellar lobule.Considering that the cerebellum has a role in prediction and somatosensory state estimation as well as in cognitive control, 18 it is possible that the MBCT-vision intervention could have modulated the response of the cerebellum to visual stimuli.The cerebellum also impacts on brain dynamics, at whole-brain network level. 19Therefore, one could hypothesize that changes in lobule VIIb/VIII may have driven visual network changes.Future research in advanced signal analysis, such as dynamic causal modeling of resting-state data, will be of interest to clarify how MBCT-vision acts on different cortical areas.
Mindfulness-based approaches such as MBCT empower patients with skillsets that enable self-efficacy for the management of their conditions. 3This may explain the significant reduction of the impact of symptoms on daily life of any ongoing symptoms after MBCT-vision intervention.In addition, participants had significant improvements in the WHO-5 Wellbeing Index 5 and the CORE-10 Psychological Distress scale. 6In comparison, the natural history of VSS is associated with unchanged levels of anxiety and depression. 13ur study showed MBCT-vision intervention resulted in changes to the visual and its associated default mode networks using fMRI.The neurological network dysfunction of VSS affects the visual, attentional, and salience networks. 1he salience network and default mode networks are closely associated, where the default mode network reflects the baseline state of connectivity.Mindfulness meditations have been shown to modulate these networks. 2This observation of change in the default mode network was also seen in a similar study on tinnitus, which is often associated with VSS, whereby MBCT intervention resulted in changes of the default mode network on fMRI. 20In line with this, a systematic review of mindfulness-based interventions on tinnitus showed a decrease in tinnitus distress scores. 21 possible conclusion is that MBCT-vision improves VSS symptoms but not the underlying condition itself.However, a strength of our study is the inclusion of objective fMRI measures, which showed modulation of visual network areas, suggesting a material change in the underlying condition.
Limitations of this study include the lack of a treatment control group.This will be addressed in an upcoming randomized controlled trial (RCT) which has been made possible after this feasibility study (ClinicalTrials.govidentifier: NCT06018103, www.MBCT-vision.co.uk).Another limitation is the lack of detailed evaluation of nonvisual symptoms, e.g., auditory, vestibular, and somaesthetic symptoms; this is also planned in the upcoming RCT.

Conclusions
MBCT-vision is a potential treatment for VSS, with benefits that translate to quality of life, self-efficacy, and wellbeing.This feasibility study supports the rationale for a randomized controlled trial that includes MBCT-vision as a treatment arm (ClinicalTrials.govidentifier: NCT06018103, www.MBCT-vision.co.uk).Our study showed that mindfulness intervention can change organization of functional networks on fMRI, an objective observation raising the possibility of mindfulness therapy in the treatment of other neurological conditions.