*2.6. Data Analysis*

Diffusion MRI connectometry [28] analyses were carried out using DSI Studio (http: //dsi-studio.labsolver.org, version 7 April 2021). Connectometry was used to derive the correlational tractography that has longitudinal QA changes correlated with Group. To do

this, two nonparametric multiple regression models were used to identify local connectome (i.e., QA) changes across time (TP2 > TP1 and TP3 > TP2) between the groups (AB and BA). Local connectomes exceeding a *t*-statistic threshold of 2 were selected and tracked using a deterministic fibre tracking algorithm [40] to obtain correlational tractography. The tracks were filtered by topology-informed pruning [42] with 4 iterations, and a length threshold of 20 voxel distance was used to identify significant tracts. Bootstrap resampling with 10,000 randomized permutations was used to obtain the null distribution of the track length and estimate the false discovery rates (FDR).

To evaluate whether the intervention-induced longitudinal QA changes were associated with behavioural gains in executive function, the mean QA change in the network of significant connectometry results was extracted for each patient and exported to SPSS (IBM SPSS Statistics for Windows, v.27.0. IBM Corp.: Armonk, NY, USA). Then, nonparametric correlations (Spearman, two-tailed) were calculated over the whole sample between the longitudinal mean QA change in the significant connectometry results and the longitudinal FAB score change to determine the structural relationship with behavioural gains. To control for multiple comparisons, FDR-correction was applied.

#### **3. Results**

The demographic, clinical, and musical background information of the patients is presented in Table 1. There were no significant differences between the AB (*n* = 16) and BA (*n* = 9) groups.


**Table 1.** Demographic, clinical, and musical background information (*n* = 25).

<sup>a</sup> 3–8 = severe, 9–12 = moderate, 13–15 = minor; <sup>b</sup> 1 = mild (<1 day), 2 = moderate (1–7 days), 3 = severe (>1 weeks); <sup>c</sup> Based on MRI findings; <sup>d</sup> Glasgow Outcome Scale Extended; <sup>e</sup> Neurological Outcome Scale for TBI.

The connectometry analyses comparing the QA changes from baseline (TP1) to 3 month (TP2) stage between the groups revealed that the group receiving the NMT (AB) showed greater QA increase (TP2 > TP1) compared to the group receiving only standard care (BA) in the right dorsal pathways (arcuate fasciculus, superior longitudinal fasciculus, frontal aslant tract) and in the right thalamic radiation and corticostriatal tract (FDR = 0.005; d = 0.97, Figure 2A). The mean increased QA in this network of results correlated with

increased FAB score (r = 0.46, *p* = 0.021). No significant QA increases from TP1 to TP2 were observed in the BA group compared to the AB group.

**Figure 2.** Music therapy induced structural white matter connectometry changes. Significant connectometry changes showing increased structural white matter connectivity between (**A**) music therapy and control group (TP2 > TP1) and (**B**) music therapy and control group (TP3 > TP2). Mean longitudinal QA change correlations (Spearman, two-tailed) to FAB score change are shown with scatter plots. Bar plots for mean QA in the significant connectivity results for both groups are shown: bar = mean, error-bar = standard error of mean, d = Cohen's d, L = left, QA = quantitative anisotropy, R = Right, TP = time point.

Similar findings were observed when comparing the groups between from the 3-month (TP2) to the 6-month (TP3) stage: the group receiving the NMT (BA) showed greater QA increase (TP3 > TP2) in the right dorsal pathways (arcuate fasciculus, superior longitudinal fasciculus, frontal aslant tract) and in the right corticostriatal tract as well as in the corpus callosum (FDR = 0.009; d = 0.65, Figure 2B) compared to the group receiving only standard care (AB). Significant correlations between the mean increased QA and increased FAB score were not observed. There were no significant QA increases from TP2 to TP3 in the AB group compared to the BA group.
