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Journal of Personalized Medicine

Article Alteration of in Patients with Central Post-

Jung Geun Park 1 , Bo Young Hong 1 , Hae-Yeon Park 2 , Yeun Jie Yoo 1, Mi-Jeong Yoon 1 , Joon-Sung Kim 1 and Seong Hoon Lim 1,*

1 Department of Rehabilitation Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Korea; [email protected] (J.G.P.); [email protected] (B.Y.H.); [email protected] (Y.J.Y.); [email protected] (M.-J.Y.); [email protected] (J.-S.K.) 2 Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-31-249-8952; Fax: +82-31-251-4481

Abstract: A stroke may be followed by central post-stroke pain (CPSP), which is characterized by chronic neuropathic pain. The exact mechanism has not yet been fully uncovered. We investigated alterations in the white matters in patients with CPSP, compared with stroke patients without CPSP and normal controls. Our retrospective cross-sectional, case-control study participants were assigned to three groups: CPSP (stroke patients with CPSP (n = 17)); stroke control (stroke patients without CPSP (n = 26)); and normal control (normal subjects (n = 34)). The investigation of white matter for CPSP was focused on the values of fiber numbers (FN) and fractional anisotrophy (FA) for (STT), anterior thalamic radiation (ATR), superior thalamic radiation (STR) and posterior thalamic radiation (PTR), and (CST) was measured. The FA for the STT   and STR of the CPSP group were lower than those for the stroke control and normal control groups. The FA of CST and ATR did not differ between the CPSP and stroke groups, but both differed from Citation: Park, J.G.; Hong, B.Y.; Park, the normal control. The FA of PTR in the stroke control group differed from the normal control group, H.-Y.; Yoo, Y.J.; Yoon, M.-J.; Kim, J.-S.; but not from the CPSP group. The FN of CST, STT, ATR, and STR for the CPSP and stroke control Lim, S.H. Alteration of White Matter in Patients with Central Post-Stroke groups did not differ from each other, but both differed from those of normal controls. FN of PTR Pain. J. Pers. Med. 2021, 11, 417. did not differ between the CPSP and normal control groups. The alterations in the spinothalamic https://doi.org/10.3390/jpm11050417 tract and superior thalamic radiation after stroke would play a role in the pathogenesis of CPSP.

Academic Editor: Won Hyuk Chang Keywords: central post-stroke pain; stroke; thalamic pain; spinothalamic tract; anterior thalamic radiation; superior thalamic radiation; white mater; diffusion tensor imaging; DTI Received: 15 April 2021 Accepted: 13 May 2021 Published: 15 May 2021 1. Introduction Publisher’s Note: MDPI stays neutral Central post-stroke pain (CPSP) can occur after a cerebrovascular accident and is with regard to jurisdictional claims in characterized by neuropathic pain syndrome [1]. It has characteristics of stimulation- published maps and institutional affil- independent pain, such as shooting, burning, or electric shock-like sensations and pares- iations. thesia [1–3]. The prevalence of CPSP is about 8% in all stroke patients but is as high as 18% among sensory deficit stroke patients [1]. Thermal or pinprick hypersensitivity is more common in CPSP than in non-CPSP patients, which indicates that spinothalamic tract hyperexcitability might be an underlying mechanism of CPSP [4]. Copyright: © 2021 by the authors. Several theories suggest that regions such as the somatosensory , inferior Licensee MDPI, Basel, Switzerland. , cingulate , lateral , and medial meniscus are responsible for This article is an open access article the pathophysiologic mechanism of CPSP [5–8]. Theories about the pathogenesis of CPSP distributed under the terms and include disinhibition, central sensitization, alterations in spinothalamic tract function, conditions of the Creative Commons and thalamic changes [5,6,9–11]. Disinhibition theory suggests that a lesion in the lateral Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ thalamus causes disinhibition of the medial spinothalamic tract pain signaling pathway, 4.0/). which ultimately causes CPSP [12]. The explanation in terms of central sensitization

J. Pers. Med. 2021, 11, 417. https://doi.org/10.3390/jpm11050417 https://www.mdpi.com/journal/jpm J. Pers. Med. 2021, 11, 417 2 of 8

suggests that anatomical, neurochemical, and inflammatory changes in Central (CNS) lesions trigger neuronal excitability, which generates central sensitization and [13]. Investigations such as this into the pathogenesis of CPSP are underway, but the pathophysiologic mechanism of CPSP has yet to be fully explained. Recently, several reports have demonstrated that structural changes in the spinothalamic tract might be associated with CPSP development [14–16]. In addition, hypometabolism of the ipsilesional primary has been reported in patients with CPSP [17]. Thus, we hypothesized that central pain after stroke may be based on morphological and structural changes in the white matter of the thalamus, primary , and . We investigated alterations in the spinothalamic tract (STT) and thalamocortical tract; anterior thalamic radiation (ATR), superior thalamic radiation (STR), and posterior thalamic radiation (PTR); and the corticospinal tract (CST) in three groups: stroke patients with CPSP, stroke patients without CPSP, and normal controls.

2. Materials and Methods 2.1. Study Design and Participants This was a retrospective case—control study. Subjects were assigned to three groups (Table1): CPSP (stroke patients with CPSP ( n = 17)); stroke control (stroke patients without CPSP (n = 26)); and normal controls (n = 34). The CPSP and stroke control groups comprised 43 patients with first-ever supratentorial unilateral stroke involving the thalamus or , and all met the following criteria: (1) diagnosed with first-ever supratentorial unilateral stroke involving the thalamus or basal ganglia and (2) 3.0-T magnetic resonance imaging (MRI) scan and brain diffusion tensor imaging (DTI) performed 6 months after onset. Exclusion criteria were: (1) recurrent stroke; (2) diagnosis of brain complications after stroke, such as ; (3) underlying degenerative brain disease, such as Parkinson’s disease; and (4) other pain syndrome, such as complex regional pain syndrome, fibromyalgia, or other rheumatologic disease. Normal controls were age- and sex-matched subjects chosen from the data from the Health Promotion Center of our institution [18].

Table 1. Participants’ demographic data.

CPSP Stroke Control Normal Control p Subjects, n 17 26 34 Age, years 57.3 (51.75–62.25) 53.17 (44.0–67.25) 57.9 (51.0–64.0) Female sex, n (%) 4 (23.5) 8 (30.8) 10 (29.4) 0.867 Stroke type, n (%) Hemorrhage 9 (52.9) 14 (53.8) N/A 0.954 Infarction 8 (47.1) 12 (46.2) N/A Brain injury location, n (%) Basal ganglia 10 (58.8) 15 (57.7) N/A 0.810 Thalamus 6 (35.3) 8 (30.8) N/A Both 1 (5.9) 3 (11.5) N/A Stroke side, Left/Right, n (%) 12/5 (70.6/29.4) 18/8 (69.2/30.8) N/A 0.925 Comorbidity Diabetus Mellitus 4 (23.5) 1 (3.8) 5(14.7) 0.159 9 (52.9) 16 (61.5) 12 (35.3) 0.118 Arterial fibrillation 0 (0) 2 (7.7) 0 (0) 0.133 Values are the median (interquartile range: first–third quartiles), or number (n) (%). p-values were tested using Pearson’s chi-square test, CPSP; central post-stroke pain, N/A; not applicable.

CPSP on the hemiplegic side was defined using as a score of 4 or higher on a 10-point visual analog scale (VAS), completed at 6 months after onset. The stroke control group included patients without central post-stroke pain at 6 months after onset. Visual analog scales (VAS) were used for evaluations during outpatient visits; patients were instructed to rate their pain from zero to 10, where zero represented no pain and 10 was the worst pain imaginable. Patients with central pain of ≤3 on the VAS were excluded from the study to avoid ambiguity in group assignments. Potential normal controls were excluded J. Pers. Med. 2021, 11, 417 3 of 8

for: (1) a history of determined through medical examination and (2) structural abnormalities on their scan. Considering the process of neurologic recovery, 6 months after stroke onset was defined as the completion of neurological recovery [19]. The present study was an observational investigation of CPSP, so the exact sample size was not calculated beforehand. However, the sample sizes of previous studies varied from 2 to 14 [16,20,21]; thus, it was determined that the sample size for this study would be more than 14 subjects. Moreover, to increase the accuracy of our results, we decided to include a stroke control group 1.5 times the size of the CPSP group and a normal control group twice the size of the CPSP group. The study protocol was reviewed and approved by the Institutional Review Board of Catholic University, College of Medicine (Registry No. VC20RASI0185); the requirement for informed consent was waived by the board.

2.2. Diffusion Tensor Imaging Acquisition and Image Processing Diffusion tensor imaging was performed using a 3.0-T magnetic resonance imager (MAGNETOM® Verio, Siemens, Erlangen, Germany) equipped with a six-channel head coil. Data were acquired in the form of single-shot spin-echo echo-planar images, with axial slices covering the whole brain across 76 interleaved slices of 2.0 mm thickness (no gap; repetition time/echo time = 14,300/84 ms; field of view = 224 × 224 mm2; matrix 224 × 224; voxel size 1 × 1 × 2 mm3 (isotropic); number of excitations = 1). Diffusion sensitizing gradients were applied in 64 noncollinear directions with a b-value of 1000 ms/mm2. The b = 0 images were scanned before acquisition of the diffusion-weighted images, with 65 volumes in total [22,23]. Fiber tracking was based on the fiber assignment continuous tracking (FACT) algo- rithm and a multiple regions of interest (ROIs) approach using DTI-studio [24,25]. The termination criteria were fractional anisotropy (FA) < 0.2 and an angle change > 60 de- grees [25].

2.3. Diffusion Tensor To reconstruct the CST, the seed ROI was placed on the mid- portion of the CST in the axial plane, and the target ROI was the primary motor cortex (Supplementary Materials Figure S1) [22]. STT was reconstructed using two ROIs, with the seed ROI placed on the posterolateral medulla (posterior to the inferior olivary , anterior to the inferior , and lateral to the medial ) in the axial plane, and the target ROI was the primary somatosensory cortex (Supplementary Materials Figure S2) [26,27]. For reconstruction of the ATR, the seed ROI was located on the anterior part of the thalamus in the coronal plane where the first appears, and the target ROI was at the slice level where the frontal and temporal lobes were separated in the coronal plane (Supplementary Materials Figure S3) [28]. PTR was reconstructed using two ROIs, with the seed ROI placed on the posterior thalamus at the slice level where the posterior tip of the lies in the coronal plane, and the target ROI was the below the parieto-occipital (Supplementary Materials Figure S4). To reconstruct STR, the seed ROI was on the middle thalamus in the coronal plane at the midpoint slice level between the ATR and PTR seed ROI, and the target ROI was the entire ipsilateral hemisphere within a transverse section above the in the axial plane (Supplementary Materials Figure S5) [29]. As the seed and target ROIs of ATR and PTR were complicated, specific anatomical locations are provided in Figure1. The FA values were measured in the seed ROIs of each tract in both hemispheres, and FN values were measured in both hemispheres of all patients. The normalization ratios for FN and FA values were calculated using the following formula in the CPSP and non-CPSP groups: data of affected side/data of non-affected side [25]. For the control group, the normalization ratio for FN and FA values was calculated as left/right [22]. J. Pers. Med. 2021, 11, x FOR PEER REVIEW 4 of 8

were complicated, specific anatomical locations are provided in Figure 1. The FA values were measured in the seed ROIs of each tract in both hemispheres, and FN values were measured in both hemispheres of all patients. The normalization ratios for FN and FA J. Pers. Med. 2021, 11, 417 values were calculated using the following formula in the CPSP and non-CPSP groups:4 of 8 data of affected side/data of non-affected side [25]. For the control group, the normaliza- tion ratio for FN and FA values was calculated as left/right [22].

Figure 1. Specific anatomical locations of seed and target ROIs of ATR and PTR in slice levels in brain MR images. (a) Figure 1. Specific anatomical locations of seed and target regions of interest (ROIs) of anterior thalamic radiation (ATR) and Target ROI of ATR where the frontal and temporal lobes are separated. Equivalent slice level to (a) in Supplementary posterior thalamic radiation (PTR) in slice levels in brain MR images. (A) Sagittal view for ROIs, (B) Axial view for ROIs. Materials Figure S3. (b) Seed ROI of ATR located on the anterior part of the thalamus where the substantia nigra first appears.(a) Target Equivalent ROI of ATR slice where level the to frontal(b) in Supplementary and temporal lobesMateri areals separated. Figure S3. Equivalent (c) Seed ROI slice of levelPTR located to (a) in on Supplementary the posterior partMaterials of the Figurethalamus, S3. where (b) Seed the ROI posterior of ATR tip located of the putamen on the anterior lies. Equivalent part of the slice thalamus level to where(c) in Supplementary the substantia nigraMaterials first Figureappears. S4. Equivalent (d) Target ROI slice of level PTR to located (b) in Supplementarybelow the parieto-occipital Materials Figure sulcus. S3. Equivalent (c) Seed ROI slice of level PTR to located (d) in onSupplementary the posterior Materialspart of the Figure thalamus, S4. where the posterior tip of the putamen lies. Equivalent slice level to (c) in Supplementary Materials Figure S4. (d) Target ROI of PTR located below the parieto-occipital sulcus. Equivalent slice level to (d) in Supplementary Materials Figure S4. 2.4. Statistical Analysis The FN and FA values in the three groups are presented as the median (interquartile range:2.4. Statistical first–third Analysis quartiles). The Kruskal–Wallis test was conducted to evaluate differ- encesThe among FN the and three FA values groups, in thefollowed three groupsby the Mann–Whitney are presented as U-test the median with the (interquartile Bonferroni correction.range: first–third The Mann–Whitney quartiles). The U-test Kruskal–Wallis and the Bo testnferroni was conducted correction to were evaluate two-tailed, differences and pamong-values the≤ 0.0166 three were groups, deemed followed significant. by the All Mann–Whitney statistical analyses U-test were with performed the Bonferroni using SPSScorrection. software The for Mann–Whitney Windows (ver. U-test 21.0; SPSS, and the Inc., Bonferroni Chicago, correction IL, USA). were two-tailed, and p-values ≤ 0.0166 were deemed significant. All statistical analyses were performed using 3.SPSS Results software for Windows (ver. 21.0; SPSS, Inc., Chicago, IL, USA).

3. ResultsDemographic and clinical characteristics of the three groups are presented in Table 1. The distributions of stroke type, brain injury location, and comorbidity did not differ Demographic and clinical characteristics of the three groups are presented in Table1 . among the three groups. The FN and FA values of the CST, STT, ATR, STR, and PTR for The distributions of stroke type, brain injury location, and comorbidity did not differ all three groups are presented in Table 2. among the three groups. The FN and FA values of the CST, STT, ATR, STR, and PTR for all threeTable groups 2. FN, FA are values presented of CST, in STT, Table ATR,2. STR, PTR by group. The normalized FA values of STT in the CPSP group were lower than those in the Values CPSPstroke control group P1 and Stroke normal Control control groups; P2 0.79 for Normal CPSP, 0.98 Control for non-CPSP, P3 0.98 FN 0.31 (0.06–0.76)for control (Figure0.8812 A). The0.33 normalized (0.05–0.71) FA values0.003 of STR in0.86 the (0.46–1.14) CPSP group were0.001 lower CST FA 0.75 (0.65–0.94)than those in the 0.881 stroke control 0.79 (0.73–0.90) group and normal <0.001 control groups;0.96 (0.91–1.03) 0.88 for CPSP, <0.001 1.00 for FN 0.47 (0.31–0.69)non-CPSP, 0.970.728 for control0.40 (Figure (0.09–0.86)2B). There were<0.001 no differences1.4 (0.59–2.73) in the FA values<0.001 of STT STT FA 0.79 (0.68–0.85)and STR * between <0.001 the stroke 0.98 control (0.85–1.11) and normal * 0.994control groups. 0.98 (0.91–1.10) The normalized * FN <0.001 values of STT and STR were lower in the CPSP and stroke control group than in the normal control FN 0.76 (0.65–0.94) 0.823 0.68 (0.60–1.10) 0.005 1.00 (0.90–1.26) 0.002 ATR group. However, there was no significant difference between the CPSP and stroke control FA 0.96 (0.83–1.09) 0.593 0.99 (0.85–1.09) 0.551 1.01 (0.95–1.06) 0.337 for the normalized FN of STT and STR. Representative DTIs of STT in all three groups are STR FN 0.45 (0.28–0.62)shown in Figure 0.7853, and those 0.34 of (0.17–0.70) STR in Figure 4. <0.001 0.91 (0.67–1.40) <0.001

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J. Pers. Med. 2021FA, 11 , 417 0.88 (0.83–0.93) * 0.004 1.00 (0.90–1.07) * 0.836 0.97 (0.91–1.04) * 0.0015 of 8 FN 0.32 (0.18–0.86) 0.172 0.60 (0.40–1.22) 0.748 0.69 (0.25–1.27) 0.223 PTR FAFA 0.88 0.93 (0.83–0.93) (0.87–1.00) * 0.0040.087 1.001.03 (0.90–1.07) (0.93–1.12) * 0.8360.005 0.970.91 (0.91–1.04) (0.84–0.98) * 0.0010.734 Values are the median (interquartile range: first–third quartiles) and normalized. Normalized values of FA, FN in CPSP FN 0.32 (0.18–0.86)Table 2. FN, FA0.172 values of CST,0.60 STT,(0.40–1.22) ATR, STR, PTR0.748 by group. 0.69 (0.25–1.27) 0.223 PTRand non-CPSP group are shown as affected/non-affected. For normal control, normalized values are shown as left/right. FA 0.93 (0.87–1.00) 0.087 1.03 (0.93–1.12) 0.005 0.91 (0.84–0.98) 0.734 CST, corticospinal tract; STT, spinothalamic tract; ATR, anterior thalamic radiation; STR, superior thalamic radiation; PTR, Values areValues the median (interquartile CPSP range: first–third P1 quartiles) Stroke and Control normalized. Normalized P2 Normalvalues of Control FA, FN in CPSP P3 posterior thalamic radiation; FA, fractional anisotropy; FN, fiber number. * p < 0.05, three groups were compared using and non-CPSP group are shown as affected/non-affected. For normal control, normalized values are shown as left/right. the Kruskal–WallisFN test. P1; 0.31 comparison (0.06–0.76) between 0.881 CPSP and 0.33 non-CPSP (0.05–0.71) groups with 0.003 the Mann–Whitney 0.86 (0.46–1.14) U-test with 0.001the CSTCST, corticospinal tract; STT, spinothalamic tract; ATR, anterior thalamic radiation; STR, superior thalamic radiation; PTR, Bonferroni correctionFA (p ≤ 0.750.0166 (0.65–0.94) deemed to be 0.881significant). 0.79P2; comparis (0.73–0.90)on between <0.001 non-CPSP 0.96 and (0.91–1.03) control groups <0.001with posterior thalamicFN radiation; 0.47 FA, (0.31–0.69) fractional anisotropy; 0.728 FN, 0.40fiber (0.09–0.86) number. * p < 0.05, <0.001 three groups 1.4 (0.59–2.73)were compared using <0.001 STTthe Mann–Whitney U-test with the Bonferroni correction (p ≤ 0.0166 deemed to be significant). P3; comparison between the Kruskal–WallisFA test. P1; 0.79 comparison (0.68–0.85) between * <0.001 CPSP and 0.98 non-CPSP (0.85–1.11) groups * with 0.994 the Mann–Whitney 0.98 (0.91–1.10) U-test * with <0.001 the control and CPSP groups with the Mann–Whitney U-test with the Bonferroni correction (p ≤ 0.0166 deemed to be signifi- Bonferroni correctionFN (p ≤ 0.760.0166 (0.65–0.94) deemed to be significant). 0.823 P2; 0.68 comparis (0.60–1.10)on between 0.005 non-CPSP 1.00 and (0.90–1.26) control groups with 0.002 ATRcant). the Mann–WhitneyFA U-test 0.96with (0.83–1.09) the Bonferroni correction 0.593 (p 0.99≤ 0.0166 (0.85–1.09) deemed to be 0.551 significant). 1.01 P3; (0.95–1.06)comparison between 0.337 control and CPSPFN groups with 0.45 (0.28–0.62)the Mann–Whitne 0.785y U-test with 0.34 the (0.17–0.70) Bonferroni correction <0.001 (p ≤ 0.0166 0.91 (0.67–1.40)deemed to be signifi- <0.001 STR The normalized FA values of STT in the CPSP group were lower than those in the cant). FA 0.88 (0.83–0.93) * 0.004 1.00 (0.90–1.07) * 0.836 0.97 (0.91–1.04) * 0.001 FN 0.32stroke (0.18–0.86) control group 0.172 and normal 0.60 (0.40–1.22)control groups; 0.7480.79 for CPSP, 0.69 (0.25–1.27)0.98 for non-CPSP, 0.223 0.98 PTR FA 0.93 (0.87–1.00) 0.087 1.03 (0.93–1.12) 0.005 0.91 (0.84–0.98) 0.734 for controlThe normalized (Figure 2A). FA The values normalized of STT in FA the values CPSP of group STR in were the CPSPlower groupthan those were inlower the Values are the median (interquartilestrokethan range:those control first–third in the group stroke quartiles) and control normal and normalized. group control and Normalizedgrou normalps; 0.79 control values for of CPSP,groups; FA, FN 0.98 in 0.88 CPSP for for and non-CPSP, CPSP, non-CPSP 1.00 0.98 for group are shown as affected/non-affected.non-CPSP, For 0.97 normal for control control, normalized (Figure 2B). values There are shown were asno left/right. differences CST, corticospinalin the FA values tract; STT, of STT spinothalamic tract; ATR, anteriorfor thalamiccontrol radiation; (Figure STR,2A). superior The normalized thalamic radiation; FA values PTR, posterior of STR thalamic in the CPSP radiation; group FA, fractional were lower anisotropy; FN, fiber number. *thanandp < 0.05, STRthose three between in groups the stroke the were stroke compared control control usinggroup theand and Kruskal–Wallis norm normalal control control test. P1;groups. groups; comparison The 0.88 betweennormalized for CPSP, CPSP and1.00FN val- for non-CPSP groups with the Mann–Whitneynon-CPSP,ues of STT U-test 0.97and for withSTR control thewere Bonferroni lower (Figure correctionin 2B).the CPSPThere (p ≤ 0.0166 andwere stroke deemed no differences control to be significant). group in the than P2;FA comparison valuesin the normalof STT between non-CPSP and control groupscontrol with group. the Mann–Whitney However, there U-test withwas theno Bonferronisignificant correction difference (p ≤ 0.0166 between deemed the to CPSP be significant). and stroke P3; comparison between controland and CPSPSTR between groups with the the stroke Mann–Whitney control U-test and with norm theal Bonferroni control correctiongroups. (Thep ≤ 0.0166 normalized deemed to FN be val- significant). uescontrol of STT for andthe STRnormalized were lower FN ofin STTthe CPSPand STR. and strokeRepresentative control group DTIs thanof STT in thein all normal three controlgroups group.are shown However, in Figure there 3, andwas thoseno signif of STRicant in difference Figure 4. between the CPSP and stroke control for the normalized FN of STT and STR. Representative DTIs of STT in all three groups are shown in Figure 3, and those of STR in Figure 4.

FigureFigure 2.2. NormalizedNormalized fractionalfractional anisotropyanisotropy (FA)(FA)values valuesof of the the spinothalamic spinothalamic tract tract (STT) and superior and superior thalamic thalamic radiation. radiation The (STR).median The values median with values quartiles with are quartiles shown are as shownlines. For as lines.all values, For all the values, rectan thegular rectangular shape shows shape the shows range the between range betweenthe first and third quartiles. The FA value of STT in the CPSP group was lower than those in the stroke control and normal control theFigure first 2. and Normalized third quartiles. fractional (A) FAanisotropy values for (FA) STT values for all of groups. the spinothalamic The FA value tract of STT and in superior the CPSP thalamic group was radiation. lower thanThe groups (left, p-value < 0.001). The FA value of STR in the CPSP group was lower than those in the stroke control and thosemedian in values the stroke with control quartiles and are normal shown control as lines. groups For (allp-value values, < 0.001).the rectan (B)gular FA values shape for shows STR forthe all range groups. between The FA the value first normal control groups (right, p-values 0.03, and 0.01, respectively). ofand STR third in thequartiles. CPSP The group FA was value lower of STT than in thosethe CPSP in the group stroke wa controls lower and than normal those in control the stroke groups control (p-values and normal 0.03, and control 0.01, respectively).groups (left, p-value < 0.001). The FA value of STR in the CPSP group was lower than those in the stroke control and normal control groups (right, p-values 0.03, and 0.01, respectively).

Figure 3. Representative diffusion tensor tractography images of the spinothalamic tract in typical subjects from the (A) CPSP, (B) stroke control, and (C) normal control groups. The non-affected tract is shown in red, and the affected tract in yellow. Figure 3. Representative diffusion tensor tractography images of the spinothalamic tract in typical subjects from the (A) Figure 3. Representative diffusion tensor tractography images of the spinothalamic tract in typical subjects from the (A) CPSP, (B) stroke control, and (C) normal control groups. The non-affected tract is shown in red, and the affected tract in CPSP, (B) stroke control, and (C) normal control groups. The non-affected tract is shown in red, and the affected tract in yellow. yellow.

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Figure 4. Representative diffusion tensor tractography images of superior thalamic radiation in typical subjects from the Figure 4. Representative diffusion tensor tractography images of superior thalamic radiation in typical subjects from the (A) (A) CPSP group, (B) stroke control, and (C) normal control groups. The non-affected tract is shown in red, and the affected CPSP group, (B) stroke control, and (C) normal control groups. The non-affected tract is shown in red, and the affected tract tract in yellow. in yellow. The normalized FA values of CST were lower in the CPSP and stroke control group The normalized FA values of CST were lower in the CPSP and stroke control group than in the normal control group. No significant difference was shown between CPSP and than in the normal control group. No significant difference was shown between CPSP and strokestroke controlcontrol forfor normalized normalized FA FA values values of CST.of CST. There There was nowas significant no significant difference difference among amongall three all groups three groups for normalized for normalized FA values FA valu of ATR.es of TheATR. FN The values FN va oflues CST ofand CST ATR and wereATR werelower lower in the in CPSP the CPSP and strokeand stroke control control group group than inthan the in normal the normal control control group, group, and there and therewasno was difference no difference between between CPSP andCPSP stroke and control.stroke control. The normalized The normalized FA and FNFA valueand FN of valuePTR among of PTR threeamong groups three weregroups not were different not different from each from other. each other.

4.4. Discussion Discussion InIn conceptualizing conceptualizing this this study, study, we we consider considereded that structural structural changes in several several white white mattersmatters involved involved in the sensory pathway,pathway, i.e., i.e., STT, STT, ATR, ATR, STR, STR, and and PTR, PTR, would would be be related related to tothe the pathogenesis pathogenesis of of CPSP. CPSP. Consistent Consistent with with our our results, results, aa recentrecent studystudy demonstrated that partialpartial injury injury of of the the STT STT in in patients with hemorrhage may may be be related related to to the pathogenesispathogenesis of of CPSP CPSP [14]. [14]. The The ventral ventral poster posterolateralolateral nucleus nucleus of of the the thalamus thalamus is is closely closely relatedrelated to to CPSP, CPSP, as as the the superior superior thalamic thalamic radi radiationation projects projects fibers fibers from from the the ventral ventral nucleus nucleus groupgroup of of the the thalamus thalamus to to the the precentral precentral and and postcentral [30]. [30]. Our Our results results show show that that thethe FA valuesvalues of of STT STT and and STR STR in thein the CPSP CPSP group group were were lower lower than thosethan inthose the strokein the controlstroke controland normal and normal control groups.control groups. Our results Our are results consistent are consistent with the with anatomical the anatomical function offunc- the tionthalamus of the in thalamus finding thatin finding neural that injury neural of STR injury in the of thalamocortical STR in the thalamocortical pathway is associated pathway iswith associated the pathophysiologic with the pathophysiologic mechanismof mechanism CPSP. of CPSP. ConsideringConsidering a previous studystudy thatthat foundfound hypometabolismhypometabolism of of the the primary primary motor motor cortex cor- texin CPSPin CPSP [17 ],[17], we we also also investigated investigated changes changes in thein the CST CST in relationin relation to CPSP.to CPSP. However, However, the theCST CST values values inthe in the CPSP CPSP group group did did not not differ differ from from those those in the in strokethe stroke control control group, group, and andthe CSTthe CST values values of the of CPSP the CPSP and stroke and stroke control control groups groups were lowerwere thanlower those than of those the normal of the normalcontrols, controls, as expected. as expected. Thus, weThus, suggest we suggest that changes that changes in STT in and STT STR and may STR be may related be re- to latedCPSP. to Despite CPSP. metabolicDespite metabolic changes inchanges the motor in the cortex, motor the cortex, white the matter white was matter not altered was not by alteredthe development by the development of CPSP. of CPSP. OurOur study study had several limitations,limitations, such such as as a a relatively relatively small small sample sample size, size, the the subjective subjec- tivenature nature of pain, of pain, and and the the cross-sectional cross-sectional design design itself. itself. Thus, Thus, we we used used several several methods methods to toovercome overcome bias. bias. First, First, for for overcoming overcoming the the relatively relativelysmall small samplesample size,size, we undertook the analysesanalyses by comparing threethree groups:groups: CPSP, CPSP, stroke stroke control, control, and and normal normal control. control. In addition,In addi- tion,we enrolled we enrolled the larger the numberslarger numbers of sample of sizesample compared size compared to previous to studiesprevious [16 studies,20,21]. Thus, we drew out the alterations of white matter for CPSP. Second, for reducing bias [16,20,21]. Thus, we drew out the alterations of white matter for CPSP. Second, for reduc- relevant to subjective nature of pain itself, we excluded patients with ambiguous pain ing bias relevant to subjective nature of pain itself, we excluded patients with ambiguous levels, as measured by VAS scores between one and three. However, the participants’ pain, pain levels, as measured by VAS scores between one and three. However, the participants’ especially neuropathic pain, is necessarily measured subjectively using a self-reported pain, especially neuropathic pain, is necessarily measured subjectively using a self-re- measure, making it difficult to present it an objective or quantified manner. In addition, ported measure, making it difficult to present it an objective or quantified manner. In ad- sensory abnormalities in stroke patients could be expressed as abnormal sensations of pain dition, sensory abnormalities in stroke patients could be expressed as abnormal sensations or as thermal, touch, or vibration abnormalities. Various types of sensations should be of pain or as thermal, touch, or vibration abnormalities. Various types of sensations considered in further studies to clarify the specific mechanism of CPSP. Finally, our study should be considered in further studies to clarify the specific mechanism of CPSP. Finally, our study was a cross-sectional study and, therefore, did not reveal longitudinal changes

J. Pers. Med. 2021, 11, 417 7 of 8

was a cross-sectional study and, therefore, did not reveal longitudinal changes in white matter. Further research is needed to address the remaining questions regarding CPSP. In conclusion, changes in STT and STR may play a role in CPSP among patients with chronic supratentorial stroke.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/jpm11050417/s1, Figure S1: (ROIs) used to reconstruct the corticospinal tract (CST) on DTI and representative DTT images of the corticospinal tract; Figure S2: Regions of interest (ROIs) used to reconstruct the spinothalamic tract (STT) on DTI and representative DTT images of the spinothalamic tract; Figure S3: Regions of interest (ROIs) used to reconstruct anterior thalamic radiation (ATR) on DTI and representative DTT images of anterior thalamic radiation; Figure S4: Regions of interest (ROIs) used to reconstruct the posterior thalamic radiation (PTR) on DTI and representative DTT images of posterior thalamic radiation; Figure S5: Regions of interest (ROIs) used to reconstruct the superior thalamic radiation (STR) on DTI and representative DTT images of superior thalamic radiation. Author Contributions: Conceptualization, J.G.P. and S.H.L.; methodology, J.G.P., B.Y.H. and H.-Y.P.; software, J.G.P. and H.-Y.P.; validation, B.Y.H. and Y.J.Y.; formal analysis, J.G.P. and S.H.L.; investi- gation, J.G.P. and S.H.L.; resources, S.H.L.; data curation, J.G.P. and S.H.L.; writing—original draft preparation, J.G.P. and S.H.L.; writing—review and editing, S.H.L.; visualization, J.G.P.; supervision, B.Y.H., M.-J.Y. and J.-S.K.; project administration, S.H.L.; funding acquisition, S.H.L. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT, Ministry of Science and ICT) (No. 2021R1A2C1012113). Institutional Review Board Statement: In The study protocol was reviewed and approved by the Institutional Review Board of Catholic University, College of Medicine (Registry No. VC20RASI0185). Informed Consent Statement: The requirement for informed consent was waived by the board. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Conflicts of Interest: The authors declare no conflict of interest.

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