Abstract
This study aimed to analyze the compromised cortical and subcortical brain structures and quantify the volume of ischemic lesions in patients with hemispatial neglect after stroke treated with transcranial direct current stimulation (tDCS). This cross-sectional study was conducted using data from the ELETRON Trial. Computed tomography (CT) images of 23 patients who underwent anodal tDCS (A-tDCS), cathodal tDCS (C-tDCS), or placebo (sham-tDCS) were included. Lesion mapping based on high-resolution volumetric CT images was performed using an automated anatomical labeling atlas. The proportion of damage in each region and brain damage between groups were compared using chi-squared and Fisher's exact tests. The behavioral inattention test (BIT-C) score was significantly higher in the C-tDCS group than in sham-tDCS group (P=0.03). Gray matter analysis revealed that lesion extension in the A-tDCS group was 325.580 mm3, in C-tDCS was 231.700 mm3, and in the sham-tDCS was 241.574 mm3. The lesion extension in the white matter was 37.076 mm3 in the A-tDCS group, 22.258 mm3 in the C-tDCS group, and 40.556 mm3 in the sham-tDCS, all centered on the superior longitudinal fasciculus. Overall, the A-tDCS group presented with a larger lesion area in the gray matter than the C-tDCS group (P=0.046). The C-tDCS group showed a smaller proportion of areas with white matter damage than the A-tDCS (P=0.011) and S-tDCS (P=0.002) groups. Hemispatial neglect was significantly improved after C-tDCS; however, the extent of gray and white matter damage was smaller for this group.
Key words: Stroke, Transcranial direct current stimulation, Hemispatial neglect, Voxel-based lesion mapping, Non-invasive brain stimulation
Introduction
Hemispatial neglect is defined as a prevalent perceptual and cognitive impairment following stroke in the right hemisphere (1,2). This condition is a negative predictor of both functional outcomes (3,4) and quality of life (5). Various rehabilitation therapies have been investigated with the aim of mitigating perceptual deficits and improving functional recovery in patients with hemispatial neglect (6- 8). Recent clinical trials and meta-analyses have indicated that non-invasive brain stimulation, particularly transcranial direct current stimulation (tDCS) targeted at the right posterior parietal lobe, can reduce the severity of hemispatial neglect after stroke (9- 11). Transcranial DCS is a non-invasive stimulation technique that aims to modulate cortical excitability following a stroke. Several studies have explored different methods for improving the efficacy of tDCS in post-stroke rehabilitation protocols (12- 14).
Several factors can contribute to the positive or negative responses to tDCS. The positive effects of tDCS on motor recovery depend on the corticospinal tract integrity and baseline motor impairment (13). However, the factors contributing to a positive response to tDCS in perceptual-cognitive recovery after stroke remain unclear. Hemispatial neglect is a complex syndrome involving several cortical and subcortical regions, which is primarily characterized by the disconnection of the right frontoparietal network (15), notably affecting fascicular regions (superior and inferior occipitofrontal and superior longitudinal), basal ganglia, insula, gyri (inferior frontal, superior, and middle temporal), inferior parietal lobe, and operculum (16). Damage to the superior longitudinal and inferior fronto-occipital fasciculi is associated with hemispheric neglect in patients with right hemispheric stroke (17). Disconnection of the posterior portion (splenium) of the corpus callosum has also been shown to increase the severity and persistence of unilateral spatial neglect (USN) following stroke (18).
Volumetric analysis of the damage has revealed that the variability in responses to non-invasive brain stimulation using theta burst transcranial magnetic stimulation (cTBS) is contingent upon the integrity of interhemispheric connections within the corpus callosum, particularly the parieto-parietal connections (19). Typically, patients with intact interhemispheric connectivity demonstrate significant improvement and acceleration in hemispatial neglect recovery and positive functional outcomes following cTBS over the contralesional posterior parietal cortex. However, in the ELETRON Trial clinical study (11), some patients failed to demonstrate satisfactory responses. This raises the question of whether there could be an association between the injured cortical network and response to tDCS in patients with hemispatial neglect after stroke. Indeed, studies have shown that a diminished white matter integrity can negatively affect functional outcomes. Use of tDCS for hemispatial neglect after stroke is not new. However, volumetric analyses and automated anatomical labeling atlas (AAL) in the methods may offer a novel contribution to the literature. Therefore, the present study aimed to examine the compromised cortical and subcortical brain structures, and to quantify the volume of ischemic lesions in patients undergoing tDCS while participating in the ELETRON trial. The present study posited that the extent of lesions in the cortical and/or subcortical pathways may diminish the response to tDCS in patients with hemispheric neglect following a stroke.
Material and Methods
Design, setting, and participants
This retrospective study was based on data from the previous multicenter randomized double-blind ELETRON trial (11). The inclusion criteria were patients who completed the ELETRON trial protocol (aged 18 years or older and had suffered hemispatial neglect after ischemic stroke within 6 months of the onset of stroke symptoms) with available high-resolution computed tomography (CT) images. CT images exhibiting technical failures, individuals who did not undergo CT during the clinical trial, or participants who did not complete the protocol were excluded. Ethical approval was obtained from the Botucatu Medical School institutional review board and all participants provided informed consent.
Procedures
The detailed methods of the ELETRON trial have been described elsewhere (11). In brief, patients were randomly assigned to receive anodal tDCS (A-tDCS), cathodal tDCS (C-tDCS), or a placebo (sham-tDCS), in combination with physical therapy training. For A-tDCS, the anode was placed over the right parietal posterior region (P4), while the cathode was placed over the left supraorbital area (Fp1). For C-tDCS, the cathode was placed over the left parietal posterior region (P3), and the cathode was placed over the right supraorbital area (Fp2). In both the A-tDCS and C-tDCS groups, a constant current of 1 mA was applied for 20 min with a 30-s ramp-up and ramp-down period. For participants in the sham-tDCS group, the stimulator was turned on, but current intensity gradually increased for 30 s, and then tapered off over 30 s. All participants underwent the tDCS protocol for 15 sessions twice a week for a total of 7.5 weeks. Immediately after each tDCS session, all participants underwent 1 h of physical therapy.
The primary outcome of the ELETRON trial was the degree of USN, evaluated by analyzing the differences between the baseline and post-intervention session values of the behavioral inhibition test (BIT-C). The BIT-C is the gold-standard scale used to assess USN in tasks involving drawing and copying figures and line bisection tests. This test comprises six conventional subtests: line cancellation, letter cancellation, star cancellation, line bisection, copying figures and forms, and figure representation. Higher BIT-C scores are associated with fewer perceptual impairments and a smaller degree of hemispatial neglect.
Lesion mapping and analysis
High-resolution CT was performed during the clinical trial. Only patients with volumetric images were included in the analysis. Imaging was performed using a Toshiba Aquilion (Japan) device with voxels of maximum size 0.46×0.46×1.25 mm. The lesions were semi-automatically segmented using the ITK-SNAP program (20). Subsequently, the images and lesions were registered in the Montreal Neurological Institute standard space using the Clinical Toolbox (21) and SPM8 (Statistical Parametric Mapping, www.fil.ion.ucl.ac.uk/spm/) (22) tools running on the MATLAB® platform (MATrixLABoratory) (23). At this stage, images were transformed into isotropic voxels measuring 1 mm. Finally, overlay maps of the images and locations of the damaged areas were generated using the MRICRON software (24). The lesions were mapped using an automated anatomical labeling atlas (AAL) (25). Gray matter damage analysis in the right hemisphere encompassed a total area of 633.221 mm3 with 43 anatomical regions of interest. White matter damage was mapped according to the JHU atlas, which comprises 18 regions of interest and a total area of 85.891 mm3.
Statistical analysis
Data normality was assessed using the Shapiro-Wilk test. Comparisons of clinical and demographic data among the groups were conducted using the Kruskal-Wallis' test (Dunn post hoc test) for continuous variables and Fisher's exact test for categorical data. Comparison of the proportion of damage in each region of interest and brain damage among the groups was performed using chi-squared and Fisher's exact tests. Statistical significance was set at P<0.05, with Bonferroni correction applied for multiple comparisons. SPSS version 25.0 (IBM Corp., USA) software was used for all statistical analyses.
Results
Of the 46 patients included in the ELETRON trial, 23 were excluded due to poor image quality or technical processing failure. Subsequently, a total of 23 patients were included in the lesion mapping imaging study and divided into the A-tDCS (n=8), C-tDCS (n=8), and sham-tDCS (n=7) groups. The clinical and demographic data of the participants included in the study are presented in Table 1. No significant differences were observed in clinical or demographic data between the groups. No significant differences were observed in BIT scores between groups at baseline (F=8.5; P=0.09); however, post-intervention scores showed a significant difference (F=14.7; P=0.02), with post hoc analysis showing a difference between the C-tDCS and sham groups (mean difference [MD], 29.8; P=0.03).
Table 1. Clinical and demographic data of the three groups.
| A-tDCS (n=8) | C-tDCS (n=8) | Sham-tDCS (n=7) | P | |
|---|---|---|---|---|
| Demographic variables | ||||
| Age (year)1 | 67.0 (40.0-80.0) | 66.0 (42.0-84.0) | 65.5 (35.0-80.0) | 0.26 |
| Female sex n, (%)2 | 5 (62.5) | 4 (50.0) | 4 (57.1) | 0.88 |
| White race n, (%)2 | 4 (50.0) | 4 (50.0) | 3 (42.8) | 0.95 |
| Medical history n, (%) | ||||
| Prior stroke/TIA n, (%)2 | 2 (25.0) | 2 (25.0) | 2 (28.5) | 0.98 |
| Diabetes mellitus n, (%)2 | 5 (62.5) | 5 (33.3) | 5 (71.4) | 0.92 |
| Hypertension n, (%)2 | 7 (87.5) | 6 (80.0) | 6 (85.7) | 0.78 |
| Currents or past tobacco use n, (%)2 | 6 (75.0) | 5 (53.3) | 4 (57.1) | 0.75 |
| Obesity n, (%)2 | 2 (25.0) | 2 (25.0) | 1 (14.3) | 0.84 |
| Heart disease n, (%)2 | 2 (25.0) | 2 (25.0) | 1 (14.3) | 0.84 |
| Hospitalization | ||||
| Thrombolysis n, (%)2 | 2 (25.0) | 2 (25.0) | 2 (28.5) | 0.98 |
| Time of hospitalization (days)1 | 9.0 (1.0-20.0) | 9.0 (2.0-15.0) | 9.0 (1.0-15.0) | 0.86 |
| NIHSS (hospital discharge)1 | 6.0 (4.0-15.0) | 4.0 (1.0-14.0) | 4.0 (0.0-15.0) | 0.67 |
| mRS (hospital discharge)1 | 3.0 (1.0-4.0) | 3.0 (1.0-4.0) | 3.0 (1.0-5.0) | 0.88 |
| Time after stroke (days)1 | 45.0 (15.0-60.0) | 42.0 (10.0-55.0) | 40.0 (17.0-70.0) | 0.52 |
| Body impairments | ||||
| Right hemiplegia n, (%)2 | 8 (100.0) | 8 (100.0) | 8 (100.0) | 1.00 |
| Anosognosia n, (%)2 | 2 (25.0) | 0 (0.0) | 0 (0.0) | 0.11 |
| Pusher syndrome n, (%)2 | 1 (12.5) | 0 (0.0) | 1 (12.5) | 0.58 |
| BIT-C | ||||
| Baseline1 | 80.5 (46-116) | 106.3 (30-126) | 95.3 (44-125) | 0.35 |
| After intervention1 | 119.8 (80-139) | 129.1 (94-146) | 99.3 (53-124) | 0.002 |
Data are reported as median and interquartile interval. 1ANOVA; 2chi-squared test. A-tDCS: anodal transcranial direct current stimulation: C-tDCS: cathodal tDCS; TIA: transient ischemic attack; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin scale; BIT-C: Behavioral Inattention Test (conventional).
Figure 1 shows the total extent of the lesions in each group. In the A-tDCS group, the lesion extension in the gray matter was 325.580 mm3 (51% of all regions of interest [ROIs]), primarily centered in the opercular Rolandic area (x=42, y=-13, z=17) and involving all 43 ROIs (100%). In the C-tDCS group, the lesion extension in the gray matter was 231.700 mm3 (37% of all ROIs), centered on the amygdala (x=38, y=-10, z=6), and involved 37/43 ROIs (86%). In the sham-tDCS group, the lesion extension was 241.574 mm3 (38% of all ROIs), centered on the insula (x=37, y=-7, z=17), and involved 41/43 ROIs (95%).
Figure 1. Overlap of the lesion maps for each group investigated group using an axial magnetic resonance imaging template and 3D rendering. The color scale indicates the number of affected individuals. Group 1: anodal transcranial direct current stimulation (A-tDCS); Group 2: cathodal tDCS (C-tDCS); Group 3: Sham-tDCS.
In the A-tDCS group, the lesion extension in the white matter was 37.076 mm3 (43% of all ROIs), centered on the superior longitudinal fasciculus (SLF) (x=42, y=-13, z=17), and involved 18/18 regions of interest (100%). In the C-tDCS group, the lesion extension in the white matter was 22.258 mm3 (26% of all ROIs), centered on the SLF (x=38, y=-10, z=25), and involved 15/18 regions of interest (83%). In the sham-tDCS group, the lesion extension in the white matter was 40.556 mm3 (47% of all ROIs), centered on the SLF (x=37, y=-7, z=17), and involved 18/18 ROIs (100%).
Tables 2 and 3 show the brain regions of interest, total number of voxels, number of voxels with lesions, and equivalent percentages for each group. In general, the A-tDCS group exhibited a larger lesion area in the gray matter than the C-tDCS group (P=0.046). Furthermore, the C-tDCS group demonstrated a lower proportion of areas with white matter damage than the A-tDCS (P=0.011) and sham-tDCS (P=0.002) groups. Regarding the overall injured brain area (gray and white matter), the A-tDCS group measured 362.656 mm3 (50%), the C-tDCS group measured 253.958 mm3 (35%), and the sham-tDCS group measured 282.130 mm3 (39%), with statistically significant differences between the A-tDCS and C-tDCS groups (P=0.03).
Table 2. Overview of the gray matter regions of interest showing the total number of voxels, the number of voxels with lesions, and the equivalent percentage for each group.
| Brain region | A-tDCS (1) | C-tDCS (2) | Sham-tDCS (3) | P value (post hoc) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total voxels | Voxel with lesion | % lesion | Voxel with lesion | % lesion | Voxel with lesion | % lesion | 1 vs 2 | 2 vs 3 | 1 vs 3 | |
| Precentral gyrus | 27058 | 16592 | 61 | 17218 | 64 | 10122 | 37 | 0.37 | 0.013 | 0.08 |
| Superior frontal gyrus | 32089 | 9537 | 30 | 15114 | 47 | 7801 | 24 | 0.39 | 0.079 | 0.29 |
| Superior frontal gyrus (pars orbitaris) | 7859 | 957 | 12 | 48 | 1 | 1672 | 21 | 0.13 | <0.0001 | 0.44 |
| Middle frontal gyrus | 40374 | 30380 | 75 | 26763 | 66 | 14561 | 36 | 0.33 | <0.0001 | <0.0001 |
| Middle frontal gyrus (pars orbitaris) | 8057 | 2129 | 26 | 391 | 5 | 2211 | 27 | <0.0001 | <0.0001 | 0.09 |
| Inferior frontal gyrus (pars opercularis) | 11174 | 11170 | 100 | 5107 | 46 | 10453 | 94 | <0.0001 | <0.0001 | 0.08 |
| Inferior frontal gyrus (pars triangularis) | 17132 | 17131 | 100 | 15328 | 89 | 14857 | 87 | <0.0001 | 0.08 | 0.013 |
| Inferior frontal gyrus (pars orbitaris) | 13747 | 9092 | 66 | 8891 | 65 | 11275 | 82 | 0.55 | 0.79 | 0.23 |
| Rolandic operculum | 10733 | 10649 | 99 | 8360 | 78 | 10184 | 95 | <0.0001 | <0.0001 | 0.07 |
| Supplementary motor area | 18885 | 218 | 1 | 2078 | 11 | 4934 | 26 | 0.26 | 0.79 | <0.0001 |
| Olfactory | 2286 | 163 | 7 | 163 | 7 | 599 | 26 | 0.13 | 0.026 | 0.026 |
| Frontal superior medial | 16979 | 1011 | 6 | 58 | 0 | 612 | 4 | NS | NS | NS |
| Rectus | 5930 | 121 | 2 | 0 | 0 | 550 | 9 | NS | 0.264 | NS |
| Insula | 14128 | 14037 | 99 | 14009 | 99 | 14128 | 100 | 0.89 | 0.92 | 0.88 |
| Hippocampus | 7606 | 5995 | 79 | 1914 | 25 | 3445 | 45 | <0.0001 | <0.0001 | <0.0001 |
| Parahippocampal gyrus | 9028 | 857 | 9 | 268 | 3 | 1521 | 17 | NS | 0.1188 | NS |
| Amygdala | 1965 | 1716 | 87 | 721 | 37 | 1908 | 97 | <0.0001 | <0.0001 | NS |
| Calcarine gyrus | 14885 | 423 | 3 | 0 | 0 | 0 | 0 | NS | NS | NS |
| Cuneus | 11323 | 375 | 3 | 0 | 0 | 0 | 0 | NS | NS | NS |
| Lingual | 18450 | 124 | 1 | 0 | 0 | 0 | 0 | NS | NS | NS |
| Superior occipital gyrus | 11149 | 1820 | 16 | 1224 | 11 | 834 | 7 | NS | NS | NS |
| Middle occipital gyrus | 16512 | 10209 | 62 | 7101 | 43 | 5826 | 35 | 0.079 | NS | <0.0001 |
| Inferior occipital gyrus | 7929 | 942 | 12 | 0 | 0 | 0 | 0 | 0.039 | NS | 0.039 |
| Fusiform | 20227 | 2300 | 11 | 488 | 2 | 548 | 3 | NS | NS | NS |
| Postcentral gyrus | 30652 | 20221 | 66 | 24665 | 80 | 13584 | 44 | NS | <0.0001 | 0.13 |
| Superior parietal lobule | 17554 | 7357 | 42 | 7175 | 41 | 4216 | 24 | NS | NS | 0.79 |
| Inferior parietal lobule | 10763 | 10763 | 100 | 6011 | 56 | 9054 | 84 | <0.0001 | <0.0001 | <0.0001 |
| Supra marginal | 15770 | 15754 | 100 | 10024 | 64 | 12415 | 79 | <0.0001 | NS | <0.0001 |
| Angular | 14009 | 13416 | 96 | 4827 | 34 | 13010 | 93 | <0.0001 | <0.0001 | NS |
| Precuneus | 26083 | 1311 | 5 | 857 | 3 | 162 | 1 | 0.92 | 0.96 | 0.79 |
| Paracentral lobule | 6693 | 106 | 2 | 95 | 1 | 548 | 8 | 0.89 | 0.66 | 0.72 |
| Caudate | 7941 | 4443 | 56 | 1335 | 17 | 7547 | 95 | <0.0001 | <0.0001 | <0.0001 |
| Putamen | 8510 | 8066 | 95 | 6504 | 76 | 8510 | 100 | 0.0132 | <0.0001 | 0.69 |
| Pallidum | 2188 | 2035 | 93 | 1353 | 62 | 2188 | 100 | <0.0001 | <0.0001 | 0.81 |
| Thalamus | 8399 | 2994 | 36 | 804 | 10 | 2362 | 28 | <0.0001 | 0.13 | 0.82 |
| Heschl | 1936 | 1930 | 100 | 1773 | 92 | 1917 | 99 | 0.39 | NS | NS |
| Superior temporal gyrus | 25258 | 24612 | 97 | 15816 | 63 | 16643 | 66 | <0.0001 | NS | <0.0001 |
| Superior temporal polar gyrus | 10654 | 7688 | 72 | 6645 | 62 | 8403 | 79 | 0.82 | 0.79 | 0.93 |
| Middle temporal gyrus | 35484 | 34511 | 97 | 14847 | 42 | 13448 | 38 | <0.0001 | 0.08 | <0.0001 |
| Middle temporal polar gyrus | 9470 | 3761 | 40 | 2435 | 26 | 5526 | 58 | 0.28 | <0.0001 | 0.11 |
| Inferior temporal gyrus | 28468 | 18402 | 65 | 560 | 2 | 3835 | 13 | <0.0001 | 0.39 | <0.0001 |
| Total | 633221 | 325580 | 51 | 231700 | 37 | 241574 | 38 | 0.046 | 0.88 | 0.06 |
ANOVA and Bonferroni correction for multiple comparisons; NS: non-significant. A-tDCS: anodal transcranial direct current stimulation: C-tDCS: cathodal tDCS.
Table 3. Overview of the white matter regions of interest and the total number of voxels, the number of voxels with lesions, and the equivalent percentage for each group.
| Brain region | A-tDCS (1) | C-tDCS (2) | Sham-tDCS (3) | P value (post hoc) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total voxels | Voxel withlesion | % lesion | Voxel withlesion | % lesion | Voxel withlesion | % lesion | 1 vs 2 | 2 vs 3 | 1 vs 3 | |
| Corpus callosum (genus) | 8851 | 152 | 2 | 0 | 0 | 1532 | 17 | NS | <0.0001 | 0.01 |
| Corpus callosum (body) | 13711 | 548 | 4 | 15 | 0 | 2444 | 18 | NS | NS | 0.057 |
| Corpus callosum (splenium) | 12729 | 8 | 0 | 0 | 0 | 10 | 0 | NS | NS | NS |
| Internal capsule (anterior limb) | 3018 | 2643 | 88 | 1079 | 36 | 3012 | 100 | <0.0001 | <0.0001 | 0.01 |
| Internal capsule (posterior limb) | 3752 | 3275 | 87 | 1580 | 42 | 2906 | 77 | <0.0001 | <0.0001 | NS |
| Internal capsule (retrolentiform) | 2469 | 2053 | 83 | 990 | 40 | 1824 | 74 | <0.0001 | <0.0001 | NS |
| Corona radiata (anterior) | 6852 | 4725 | 69 | 540 | 8 | 5430 | 79 | <0.0001 | <0.0001 | NS |
| Corona radiata (superior) | 7508 | 5077 | 68 | 5492 | 73 | 7179 | 96 | NS | 0.0003 | <0.0001 |
| Corona radiata (posterior) | 3714 | 987 | 27 | 420 | 11 | 1950 | 53 | 0.22 | <0.0001 | 0.005 |
| Posterior thalamic radiation | 3978 | 2369 | 60 | 654 | 16 | 137 | 3 | <0.0001 | 0.09 | <0.0001 |
| Sagittal stratum* | 2231 | 1964 | 88 | 598 | 27 | 942 | 42 | <0.0001 | NS | <0.0001 |
| External capsule | 5587 | 5429 | 97 | 4806 | 86 | 5587 | 100 | 0.28 | 0.005 | NS |
| Fornix | 1125 | 939 | 83 | 286 | 25 | 328 | 29 | <0.0001 | NS | <0.0001 |
| Superior longitudinal fasciculus | 6605 | 5807 | 88 | 5209 | 79 | 6380 | 97 | NS | 0.005 | NS |
| Superior fronto-occipital fasciculus | 507 | 507 | 100 | 224 | 44 | 507 | 100 | <0.0001 | <0.0001 | NS |
| Tapetum | 600 | 74 | 12 | 0 | 0 | 9 | 2 | 0.017 | NS | 0.31 |
| Total | 85891 | 37076 | 43 | 22258 | 26 | 40556 | 47 | 0.011 | 0.002 | 0.56 |
*Includes the inferior longitudinal and inferior frontooccipital fasciculi; ANVOA and Bonferroni correction for multiple comparisons; NS: non-significant. A-tDCS: anodal transcranial direct current stimulation: C-tDCS: cathodal tDCS.
Discussion
The present study mapped the ischemic areas of the gray and white matter in a subset of patients from the ELETRON trial (11). In this subset, larger lesion areas were observed in the A-tDCS group. The C-tDCS group further demonstrated a superior improvement in BIT-C scores compared to the sham group. The white matter damage observed in all three groups was centered on the SLF, which was particularly prominent in the A-tDCS group. In terms of gray matter damage, the A-tDCS group exhibited damage centered in the opercular Rolandic area, the C-tDCS had damage in the amygdala, and the sham-tDCS in the insula. However, the overall extent of gray and white matter damage was smaller in the C-tDCS group.
Stroke affecting the non-dominant hemisphere, typically the right hemisphere, particularly fascicular regions (superior and inferior occipitofrontal and superior longitudinal), basal ganglia, insula, inferior frontal gyrus, superior temporal gyrus, middle temporal gyrus, inferior parietal lobe, and operculum, is associated with attention and visuospatial dysfunction (17,26,27). In our analysis of gray matter regions, the sham group exhibited a greater number of lesions centered on the insula, a region involved in somatosensory and auditory processing, and connected to the inferior parietal and lateral prefrontal cortices (26). Insular lesions may manifest as non-visual hemispatial neglect symptoms, such as impairment of body exploration or tactile extinction (27). The A-tDCS group displayed a larger lesion centered on the Rolandic operculum. Several studies have linked the rolandic operculum to emotional processing, with high-degree lesions in this region being associated with apathy, depression, and anxiety following a stroke (28). Additionally, lesions in the rolandic operculum are associated with anosognosia following a stroke (29), resulting in multiple concomitant deficits in sensation, attention, interoceptive bodily representations, motor programming, error monitoring, memory, and affective processing (30). The C-tDCS group exhibited greater damage to the amygdala than the control group. The amygdala plays a fundamental role in emotional processing (31), and has an attentional network capable of enhancing perceptual processing, potentially facilitating the conscious perception of undetected stimuli (32).
In the analysis of the white matter regions, all groups exhibited lesions in the SLF, albeit to a lesser extent in the C-tDCS group, which showed a better therapeutic response in reducing hemispheric neglect following stroke. The SLF links the superior parietal region and the adjacent medial parietal cortex with the supplementary and premotor areas in the frontal lobe (33). Functional MRI studies have previously demonstrated coactivation of the parietal and frontal areas when performing a broad range of visual-spatial tasks (34). Damage to the parietofrontal projections is the strongest predictive factor for chronic spatial neglect following a stroke (35). Similar to the association between cortico-spinal tract integrity and improved motor recovery, as well as the therapeutic effects of post-stroke tDCS (13), this study underscores the importance of white matter integrity, particularly in the SLF, for perceptual recovery and selective indication of tDCS in patients with hemispatial neglect.
The ELETRON trial revealed the superiority of A-tDCS over sham treatment in terms of BIT-C (11). However, our subgroup analysis, which excluded patients due to technical failures in imaging, revealed a larger lesion area in both the gray and white matter in the A-tDCS group. However, this benefit was not sustained, suggesting that the efficacy of tDCS may be more pronounced in patients with gray and white matter integrity. Looking at the maxim “A car may start, but without a fit driver or a clear road, it won't reach its destination”, the car represents tDCS, the driver represents the qualified therapist, and the road represents intact cortical and subcortical pathways for conducting the stimulus.
This study had some limitations. First, this was a subgroup of patients included in a previous randomized clinical trial. Therefore, the results have reduced statistical power due to loss of patients. Second, the sample size was reduced because of technical image limitations such as segmentation errors, inadequate image quality, hemorrhage, microangiopathy, and unsatisfactory resolution. The main issue encountered was that for some patients, the boundary between recent and previous lesions was unclear. In such cases, the segmentation algorithm fails and is unable to accurately classify the damaged tissue. This problem may be challenging to address even with visual analysis using CT scans. Third, the use of CT rather than magnetic resonance imaging may have limited anatomical precision. Despite these limitations, this study offers valuable insights into the factors influencing individual responses to tDCS. Future studies should individualize the location of brain stimulation based on neuroimaging studies, while patient selection for tDCS should be explored in large-scale phase III clinical trials.
Conclusion
The extent of white matter damage was centered on the SLF in all three groups. Individuals in the A-tDCS group exhibited gray matter damage centered on the opercular Rolandic area, whereas those in the C-tDCS group exhibited gray matter damage centered on the amygdala. However, the overall extent of gray and white matter damage was lower in the C-tDCS group. In this sub-study, patients in the C-tDCS group showed significant improvement compared with those in the sham-tDCS group, an effect which was attributable to the smaller extent of damage in the white matter regions.
Funding Statement
Brazilian National Council for Scientific and Technological Development (CNPq; 423924/2016-8 - R. Bazan) and the São Paulo Research Foundation (FAPESP; 2015/14231-0 - R. Bazan).
Footnotes
Funding: Brazilian National Council for Scientific and Technological Development (CNPq; 423924/2016-8 - R. Bazan) and the São Paulo Research Foundation (FAPESP; 2015/14231-0 - R. Bazan).
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