Does exergaming promote neurofunctional changes in Parkinson´s disease? A pilot clinical study

Abstract Introduction Previous studies have demonstrated beneficial effects in people with Parkinson´s disease trained with exergames. However, to the best of our knowledge, none of them evaluated whether these effects are sustained by neurofunctional changes. Objective To evaluate neurofunctional effects of a training, by means of functional magnetic resonance imaging, in people with Parkinson´s disease. Methods This study was a blind, randomized, and controlled pilot clinical trial with crossover design. The participants were submitted to an evaluation including cognitive performance and functional magnetic resonance imaging before and after the WiiTM or control trainings. Trainings were applied for 10 days, in two consecutive weeks. Participants starting with WiiTM training were then moved to the control training and vice versa. A wash-out period of 45 days between the trainings was respected. Results Memory, executive and visuo-spatial functions, and attention were significantly improved compared to baseline (p < 0.05). No differences were observed in cognition compared to the control training. Though not significant, results of functional magnetic resonance imaging analyses suggested that WiiTM training could promote improvements on the brain functional connectivity especially in areas involved in motor execution, planning, visual, memory and somatosensory functions. Conclusion In people with Parkinson´s disease, an intensive WiiTM training improved cognitive performance that underlined neurofunctional changes in areas involved in cognitive processing.


Introduction
Parkinson's disease (PD) is a chronic, degenerative, and progressive condition characterized by motor (stiffness, tremor, bradykinesia, postural instability) and cognitive symptoms (attention, executive, and visuospatial functions impairments).1 Cognitive symptoms lead to increased disability and hinder the treatment of motor symptoms.2 Treatment of PD involves medication, surgery, and rehabilitation.As medications and surgery may not prevent the progression of the disease or improve cognitive functions, the role of rehabilitation has become increasingly important.3,4 Among treatment modalities, virtual reality (VR) training has become a resource in cognitive-motor rehabilitation.VR allows the patient to interact with an artificial reality through computer simulation, 5 providing real-time feedback on performance in the virtual task and offering control over the intensity of exercises and an environment rich in sensory stimulation.5,6 In the last decade, commercial exergames, due to low cost, positive effect on motivation and potential for home using, 7,8 have become an alternative to more sophisticated VR systems and might be considered a new intervention tool.
Previous studies have shown that videogame training is beneficial, economical, and safe for PD patients, 8,9 demanding non only motor but cognitive skills such as memory, attention, and visuospatial functions.9 Among the commercial exergaming systems, potentially useful as rehabilitation tool, the most used is the Nintendo Wii Fit Plus™.It is a portable low-cost device, easy to handle and with good reliability.10 Its interface incorporates manual wireless controls and a force platform, the Wii Balance Board (WBB), capturing the weight shifting and users´ resulting movements, and transferring them to the games in real time.11 Some studies have used the Wii™ confirming it as an effective intervention tool in people with PD.Functional magnetic resonance imaging (fMRI) has been applied to PD to enhance the understanding of pathophysiological changes, including functional connectivity (FC), by detecting variations in cerebral blood flow.Among these, resting state (RS-fMRI) evaluates regional interactions and functional connectivity when the subject is not performing a specific task.Fast stationary walk and suddenly stopping.
Response inhibition and planning.

Basic step
Alternate steps according to the game's music rhythm and visual stimuli.
Alternate, coordinated steps.Sustained attention, divided attention and visuospatial capacity.

Rhythm parade
Marching in place to the sound of a beat while moving arms according to the visual stimuli.
Alternate coordinated steps while moving arms.
Divided attention.

Tightrope walk
Keep balance while walking on a tightrope and avoid obstacles.
Shift center of gravity latero-laterally.
Sustained attention and decision making.
dos Santos Mendes et al.

RS-fMRI acquisition and preprocessing
All participants underwent brain scan using a As a statistical analysis, the different component maps are tested voxel-wise for statistically significant differences between the groups using FSL dual regression, which allows for a voxel-wise comparison of RS-fMRI.19 Correction for multiple comparisons across space was applied assuming an overall significance of p < 0.05, using permutation testing and TFCE.No significant differences were observed in the participants' performances in any other cognitive test (Table 3).

Results
No dropouts occurred during the study.Both WG and WLG trainings were well tolerated.
A significant improvement in cognitive performance (Table 3) was observed after both trainings, in the Rey List tests (immediate and later recall), Trail Making Test  The dual regression analysis did not show any statistically significant RS-Functional Connectivity changes using a p-value of 0.05 and a cluster threshold of 0.95.However, by lowering the cluster threshold significance to 0.

Conclusion
In conclusion, we observed that an intensive Regarding the results of the RS-fMRI, small changes in connectivity were detected in different networks, in T1.Thus, RS-fMRI analysis did not show any statistically significant RS-FC changes when using a p-value of 0.05 and a cluster threshold of 0.95.However, by lowering the cluster threshold significance to 0.7 and considering only those clusters equal or higher to five voxels, some interesting results has emerged.Thus, considering the relevance and novelty of the results, we will discuss the results speculatively, highlighting those ones in which there were an increase in the connectivity in participants Study designParticipants first underwent cognitive tests and RS-fMRI (T0 the week prior to the beginning of the first training).They were then randomly allocated into the Nintendo Wii Group (WG) or the Wii-like Group (WLG).After completion of the first part of training, patients of both groups underwent cognitive evaluation and RS-fMRI (T1, the week after the end of the first training).After a 45 days interval, the two groups started the second exercise sessions: those who initially started with Wii™ training completed the study with "Wii-like" exercises, and vice versa.When the second training session was completed, the two groups repeated cognitive evaluation and RS-fMRI (T2, the week after the end of the second training).

Figure 1
Figure 1 illustrates the stages of the study.The participants were instructed not to reveal to the evaluator about their allocation.The same physiotherapist was involved in both types of training.

Figure 1 -
Figure 1 -Flowchart of the study procedures.

Fisioter
Mov. 2023;36:e36120 6 Wii-like training: WLG performed a set of exercises based on the same motor demands (described in Table 2), with similar number of repetitions, movement velocities and duration required by each of the four games selected for the Wii training.The same Wii´s controls and platform were used, but turned off, to increase the similarity with Wii training.Wii-like training occurred without the provision of external cues, feedback, or cognitive stimulation, offered by the games.Cognitive performance assessment A comprehensive battery of neuropsychological tests was applied, with a total duration of 1 hour, in a room reserved exclusively to the evaluator and to the patient.All tests were applied through forms A and B to avoid learning effects.The following tests were applied: Attention and working memory: digit span forward; attentive matrix test; trail making test parts A and B; symbol digit modalities test; Executive functions: frontal assessment battery; phonemic fluency (letters P, F and L); cognitive estimation test; Visuo-spatial functions: Test of the Rey-Osterrieth C Com-plex Figure, that evaluates immediate and late recall; Verbal memory: Rey´s list -immediate and late recall; revocation of the complex figure of Rey-Osterrieth; Language: semantic fluency test (animals).

1. 5 T
MRI scanner (Signa HDxt; GE Medical System, Milwaukee, Wisconsin, USA) at the Radiology Section of the University Hospital of Palermo.An eight-channel brain phased array coil was used.Foam pads were placed on both sides of the head, within the head coil, to limit head motion during the scan.Structural images were obtained via a T1-weighted sagittal three-dimensional (3D), ultra-fast gradient echo 1mm thick Brain Volume Imaging (BRAVO) isotropic sequence (acquisition matrix 256 x 256; FOV 25.6 x 25.6; slice thickness 1 mm; TR 12.4 ms; TE 5.1 ms; IT 450 ms; FA 20; parallel imaging method: Array coil Spatial Sensitivity Encoding, ASSET).RS-fMRI data were acquired with a two-dimensional (2D) axial T2*-weighted gradientecho Echo-Planar (EP) pulse sequence parallel to the anterior commissure-posterior commissure (AC-PC) line over the entire brain (acquisition matrix 64 x 64; 33 slices; slice thickness 3 mm; gap 1 mm; TR 3000 ms; TE 60 ms; FA 90); the first five scans were discarded to allow T1 saturation to reach equilibrium.All participants were explicitly instructed not to move during the MRI scan and quietly rest in the scanner with their eyes open and not to think of anything specific.A ten-minute (200 volumes) fMRI scan was performed on each participant.Scan parameters were consistent for all imaging sessions.All the preprocessing was performed at the Department of Physics and Chemistry of the University of Palermo, using FSL's recommended preprocessing pipeline from FMRIB's Software Library (FSL version 5.0.9).The following preprocessing procedure was applied by employing different modules of the FSL-software package.The preprocessing of the resting-state data consisted of the standard FSL steps.1819 Statistical analysis All analyses were performed using the statistical package SPSS 21.0 (SPSS Inc., Chicago, IL, USA).Kolmogorov-Smirnov, Levene and Mauchly tests were used to assess normality, variance homogeneity and data sphericity, respectively.Demographic and clinical characteristics were presented as descriptive measures.Results of the cognitive tests were analyzed by means of a repeated measure two-way Anova (group [WG x WLG]x time [pre x post]), followed by the post hoc Bonferroni test.The significance level was p < 0.05.The analyses related to the processing of functional magnetic resonance images were made through FSL's MELODIC software, using independent component analysis (ICA).ICA was carried out using FSL's MELODIC toolbox implementing probabilistic independent component analysis (PICA).Multi-session temporal concatenated ICA (Concat-ICA) approach, as recommended for RS-fMRI data analysis was chosen.20We tested Resting State-Functional Connectivity (RS-FC) by performing a dual regression analysis in six different conditions: Baseline x Wii (stat1); Wii x Baseline (stat2); Baseline x Wii-Like (stat3); Wii-Like x Baseline (stat4); Wii x Wii-Like (stat5); Wii-Like x Wii (stat6).
are represented as mean and standard deviation.p = Bonferroni post hoc test to compare post-training evaluation with pre-training evaluation.FAB = Frontal Batery Assessment; DSF = Digit Span forward; Rey-I = List of Rey-immediate evocation; Rey-D = List of Rey-late evocation; TMT-A = Trail Making Test part A; TMT-B = Trail Making Test part B; AM = Attentive Matrix; SD = Symbol digit Modalities Test; CET = Cognitive Estimation Test; FF = Phonetic Fluency Test; FS = Semantic Fluency Test; Rey Fig Cop = Rey-Osterrieth Complex Figure Copy Test; Rey Fig Rec = Revocation of the Complex Figure of Rey-Osterrieth.For all tests, the higher the score, the better the performance, except for TMT-A and TMT-B.dos Santos Mendes et al.Fisioter Mov.2023;36:e36120 8Neurofunctional changesVisual inspection of IC maps allowed us to identify common RS-fMRI networks reported in literature.21,22

Figure 2 -
Figure 2 -Functional magnetic resonance imaging at resting state.
exergaming training is efficacious to improve cognitive performance, particularly memory functions, executive functions, attention, and visuospatial function, without advantages on the conventional training.Despite the low significance of the neurofunctional changes observed through RS-fMRI exams, cognitive improvement underlined neurofunctional changes of brain connectivity among areas involved in specific cognitive domains.
of the WG in relation to those of WLG.An increase in the FC was detected in the left precentral gyrus and left cingulate gyrus, in the motor and default mode networks.Such data suggest a global increase in the connectivity of the area involved in motor control (pre-central area) and in processing of emotions and behavior regulation (cingulate gyrus).An increase in the FC was detected also in the left cerebellar crus II, left lingual gyrus and left retrosplenial cortex (hippocampus tail), in the cerebellar and visual networks, respectively.Some studies 26,27 found increased FC of the cerebellum with motor and sensorimotor areas in people with PD compared to healthy controls.28 This increase observed after Wii training, in the present study, could therefore reflect a beneficial effect of exergaming, promoting a greater cerebellar neurofunctional activity, helping in motor planning in this population.Additionally, the increase in the FC lingual gyrus could be related to gains in the visual function, possibly linked to the high visual stimulation of the games used.Guimarães et al. have already showed that the retrosplenial cortex is associated with verbal memory performance in people with PD. 29 So, we could infer that the repetitive stimulation promoted by the exergaming training could have improved this function in our sample.Taken together, these findings can reflect the results in the cognitive clinical tests performed, in which we were able to verify in both groups improvements in memory and visuospatial functions.Finally, we found increased FC in the left postcentral gyrus, in the frontoparietal network, greater in the WG in relation to the WLG.Guimarães et al. 29 have showed that people with mild PD symptoms already present cortical structural and functional damage.In PD, areas such as the postcentral gyrus present cortical thinning.Therefore, considering the increase in FC in this area, verified in the present study, it is plausible to infer that the Wii training

Table 1 -
Demographic and clinical characteristics of the participants 16By means of RS-fMRI,16it has been demonstrated that one training session, with high intensity exercises, was able to promote changes in the brain activity of people with PD previously trained.consecutivas.Os participantes que começaram o treinamento com Wii® foram depois movidos para o treinamento de controle e vice-versa.Respeitou-se um período de wash-out de 45 dias entre os treinamentos.Resultados: Memória, funções executivas e visuoespaciais e atenção melhoraram significativamente em comparação com a linha de base (p < 0,05).Não foram observadas diferenças na cognição em comparação com o treinamento de controle.Embora não significativos, os resultados das análises de ressonância magnética funcional sugeriram que o treinamento com Wii® poderia promover melhorias na Exclusion criteria Having other neurological disorders or organic pathological conditions that prevented participation in the trainings; having previous experience with Wii games; attending another specialized rehabilitation program; having absolute or relative contraindications to MRI.Note: m-H&Y = Modified Scale of Hoehn and Yahr; UPDRS = Unified Parkinson's Disease Rating Scale; MMSE = Mini Mental State Examination; SD = standard deviation.dos Santos Mendes et al.Fisioter Mov.2023;36:e36120 4

Table 2 -
Main games tasks and demands GamesTasks Main motor demands Main cognitive demandsObstacle courseWalk as fast as possible and stop ona course, avoiding obstacles.

Table 3 -
Performance of participants in cognitive tests, in the pre-and post-intervention moments, for each training modality