J Head Trauma Rehabil Vol. 30, No. 6, pp. E40–E46 c 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright
The Relation Between Injury of the Spinothalamocortical Tract and Central Pain in Chronic Patients With Mild Traumatic Brain Injury Jin Hyun Kim, MD; Sang Ho Ahn, MD; Yoon Woo Cho, MD; Seong Ho Kim, MD; Sung Ho Jang, MD Objectives: Little is known about the pathogenetic etiology of central pain in patients with traumatic brain injury (TBI). We investigated the relation between injury of the spinothalamocortical tract (STT) and chronic central pain in patients with mild TBI. Design: Retrospective survey. Participants: We recruited 40 consecutive chronic patients with mild TBI and 21 normal control subjects: 8 patients were excluded by the inclusion criteria and the remaining 32 patients were finally recruited. The patients were classified according to 2 groups based on the presence of central pain: the pain group (22 patients) and the nonpain group (10 patients). Methods: Diffusion tensor tractography for the STT was performed using the Functional Magnetic Resonance Imaging of the Brain Software Library. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of each STT were measured. Results: Lower FA value and tract volume were observed in the pain group than in the nonpain group and the control group (P < .05). By contrast, higher MD value was observed in the pain group than in the nonpain group and the control group (P < .05). However, no significant differences in all diffusion tensor imaging parameters were observed between the nonpain group and the control group (P > .05). Conclusions: Decreased FA and tract volume and increased MD of the STTs in the pain group appeared to indicate injury of the STT. As a result, we found that injury of the STT is related to the occurrence of central pain in patients with mild TBI. We believe that injury of the STT is a pathogenetic etiology of central pain following mild TBI. Key words: central pain, diffusion tensor imaging, spinothalamocortical tract, traumatic brain injury
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RAUMATIC BRAIN INJURY (TBI), which is a major cause of disability, is classified as mild, moderate, and severe, based on the severity;1 70% to 90% of cases of TBI are classified as mild TBI.2–4 Chronic pain is a common sequela in patients with TBI: prevalence of chronic pain of greater than 50% has been reported in patients with whole TBI and it became worse in patients with mild TBI, up to 75%.5,6 Many studies have reported
Author Affiliations: Department of Physical Medicine and Rehabilitation (Drs Kim, Ahn, Cho, and Jang) and Department of Neurosurgery (Dr Kim), College of Medicine, Yeungnam University, Taegu, Republic of Korea. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A4A01001873). The authors declare no conflicts of interest. Corresponding Author: Sung Ho Jang, MD, Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University 317-1, Daemyungdong, Namku, Taegu, 705-717, Republic of Korea ([email protected]). DOI: 10.1097/HTR.0000000000000121
on the various pathogenetic etiologies of chronic pain following TBI.7–9 These include musculoskeletal, vascular, neurogenic, visceral, and iatrogenic mechanisms.7–9 Central pain presents the characteristics of neuropathic pain, characterized by stimulation-independent pain: shooting, lancinating, burning, electric shock-like sensation, and paresthesia (crawling, itching, tingling sensation); stimulus evoked pain: hyperalgesia or allodynia.10–13 Central pain is caused by a lesion or dysfunction arisen from the central nervous system, including brain and spinal cord.8,9,14 Clinically, the diagnosis of central pain would be very important because the management strategy and prognosis differ significantly from those for other pain ascribed to other pathogenetic etiologies. However, research on central pain in patients with TBI has been neglected.8,9,15,16 Many previous studies have reported a close association of injury of the spinothalamocortical tract (STT) with development of central poststroke pain.17–22 In addition, injury of the STT has been regarded as the main pathogenetic mechanism of central pain following spinal cord injury (SCI).23,24 A few studies have
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Injury of the Spinothalamocortical Tract in Mild TBI described central pain in patients with TBI.9,16 In 2006, Son et al16 reported on a patient suffering from central pain (a burning sensation and heaviness in his right leg and arm) after severe TBI, whose clinical picture of the pain was similar to that of central poststroke pain. Subsequently, Ofek and Defrin,9 who investigated the characteristics of chronic central pain in 15 chronic patients with central pain after TBI, reported that development of central pain had a relatively late onset (average 6.6 months); was almost exclusively unilateral; and reported as pricking, throbbing, and burning. However, the pathogenetic mechanism of central pain in patients with TBI has not been clearly elucidated.25,26 Diffusion tensor tractography (DTT), which is derived from diffusion tensor imaging (DTI), provides 3-dimensional visualization and estimation of the STT, which carries information on pain and touch from the contralateral extremities and body.27–29 Several studies using DTT have demonstrated that injury of the STT is the pathogenetic mechanism of central pain in patients with stroke.19,21,17,22 However, only a few studies using DTT have reported on central pain following injury of the STT in patients with TBI.25,26 Consequently, the relation between injury of the STT and central pain in patients with TBI has not been clearly elucidated. In this study, we hypothesized that injury of the STT is the pathogenetic mechanism of central pain in patients with mild TBI. In this study, using DTT, we attempted to investigate the relation between injury of the STT and central pain in chronic patients with mild TBI. MATERIALS AND METHODS Subjects Forty patients (13 men, 27 women; mean age = 49.42 ± 14.16 years, range: 19–72) with TBI who were admitted to the rehabilitation department of a university hospital and 21 normal control subjects (8 men, 13 women; mean age = 45.05 ± 14.02 years, range: 20– 74) were recruited. Forty consecutive patients with TBI were recruited according to the following criteria: (1) loss of consciousness (LOC) for less than 30 minutes, initial Glasgow Coma Scale (GCS) score of 13 to 15, and posttraumatic amnesia (PTA) for 24 or less hours30,31 ; (2) more than 3 months after onset of TBI; and (3) no history of head trauma or neurologic or psychiatric disease. We excluded patients according to the following exclusion criteria: (1) brain lesion on conventional magnetic resonance imaging (MRI) (T1-weighted, T2weighted, fluid-attenuated inversion recovery, and T2weighted gradient recall echo images), (2) evidence of radiculopathy or peripheral neuropathy on electromyography and nerve conduction study, and (3) evidence of myelopathy on spinal MRI or central motor conduction
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time. Two patients who showed a brain lesion (one patient: concurrent intracranial hemorrhage and the other patient: an old cerebral infarct) were excluded. In addition, 3 patients who showed radiculopathy and 3 other patients who showed myelopathy were also excluded. Thus, finally, the remaining 32 patients were recruited for this study. This study was conducted retrospectively, and the study protocol was approved by the institutional review board of a university hospital. We classified patients according to 2 groups based on the presence of neuropathic pain, which had developed after TBI:10–13 the pain group included patients who suffered from neuropathic pain, and the nonpain group included patients who did not show neuropathic pain. Clinical evaluation Neuropathic pain of patients was rated using the visual analog scale (VAS).32,33 The reliability and validity of the VAS is well-established.32,33 The Wechsler Intelligence Scale (WAIS) and the Memory Assessment Scale (MAS) were used for evaluation of cognitive function. The WAIS is the most standardized intelligence test. Full Scale Intelligence Index (Full IQ) derived from Verbal and Performance Intelligence Indices was obtained.34 The MAS is a comprehensive standardized memory assessment battery, consisting of 4 memory subsets, including short-term memory, verbal memory, visual memory, and total memory derived from verbal and visual memory.35 The reliability and validity of WAIS and MAS are well-established.34,35 Diffusion tensor image Diffusion tensor image was performed at an average of 11.1 months (range: 3–28 months) after onset of TBI using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Ltd, Best, the Netherlands) with single-shot echo-planar imaging. For each of the 32 noncollinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissure (AC)-posterior commissure (PC) line. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed to matrix = 192 × 192 matrix; field of view = 240 mm × 240 mm; TR = 10,726 ms; TE = 76 ms; parallel imaging reduction factor (SENSE factor) = 2; EPI factor = 59; b = 1000 s/mm2 ; NEX = 1; slice gap = 0 mm; and a slice thickness = 2.5 mm (acquired isotropic voxel size = 2.5 mm × 2.5 mm × 2.5 mm). Fiber tracking The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain Software Library (FSL; www.fmrib.ox.ac.uk/fsl) was used for analysis of diffusion-weighted imaging data, and affine multiscale 2-dimensional registration was used to correct for head www.headtraumarehab.com
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motion effects and image distortions due to eddy currents. A probabilistic tractography method, based on a multifiber model, was used in performance of fiber tracking, which was applied in the current study utilizing tractography routines implemented in Functional Magnetic Resonance Imaging of the Brain diffusion (5000 streamline samples, 0.5-mm step lengths, curvature thresholds = 0.2).36,37 The STTs were reconstructed by selection of fibers passing through regions of interest (ROIs). The seed ROI was placed in the STT of the posterolateral medulla, which was posterior to the inferior olivary nucleus, anterior to the inferior cerebellar peduncle, and lateral to the medial lemniscus on an axial slice.29 The first target ROI was drawn around the ventral posterior lateral nucleus of the thalamus, which was placed at onethird of the AC-PC line from the PC for the anteroposterior direction and three-fourths of the thalamus from the AC-PC line for the mediolateral direction, where this ROI was located in the purple area on a color-coded primary diffusion map.29,38 The second target ROI was placed at the primary somatosensory cortex (S1) on
an axial slice.29 Out of 5000 samples generated from each seed voxel, the STT was visualized at a minimum threshold of 1 streamline (see Figure 1). The values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of the reconstructed STT were measured in both hemispheres. Total brain voxel was also measured39 (Fig 1). Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 18.0 (SPSS, Chicago, Illinois). For determination of the demographic and clinical variances between the pain group and the nonpain group, the independent t test was used for age, duration after the onset of TBI, duration of LOC, duration of PTA, initial GCS score, WAIS (full IQ), and MAS (short-term memory, verbal memory, visual memory, and total memory), and the chi-square test was used for gender and mechanism of injury. The values of the FA, MD, and tract volume of both STTs, and total brain voxel were used in performance of 1-way analysis
Figure 1. A, The spinothalamocortical tract (STT) for a patient (53-year-old women) in the pain group. The STTs in both hemispheres are thinner than those of a patient in the nonpain group and a subject in the control group. B, The STT for a patient in the nonpain group (50-year-old women). Both STTs are similar in appearance to those of a control subject (54-year-old women). C, The STT for a subject in the control group.
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Injury of the Spinothalamocortical Tract in Mild TBI of variance for determination of variances between the pain group, the nonpain group, and the control group. Tukey’s post hoc test was used for evaluation of differences in data among the 3 groups. Statistical significance was accepted for P < .05. RESULTS A summary of the patients’ demographic and clinical data is shown in see Table 1. Out of 32 patients, 22 (68.75%) patients were enrolled in the pain group (7 men, 15 women; mean age 47.25 ± 10.91 years) and 10 (31.25%) patients were enrolled in the nonpain group (5 men, 5 women; mean age: 48.38 ± 17.78 years). In the pain group, mean VAS was 4.87 ± 1.74, and 20 of the 22 patients received medications such as gabapentin for relief of their central pain. No significant differences in all demographic and clinical data were observed between the pain group and nonpain group, except VAS and the number of patients who received medications for central pain (P > .05) (see Table 1). Significantly decreased FA value was observed for the pain group (0.420 ± 0.021) compared with the nonpain group (0.438 ± 0.018) and the control group (0.447 ± 0.020) (P < .05). By contrast, significantly increased MD value was observed for the pain group (0.925 ± 0.051) compared with the nonpain group (0.896 ± 0.065) and the control group (0.892 ± 0.044) (P < .05). However, no significant differences in FA and MD values were observed between the nonpain group and the control group (P > .05). The tract volume of the pain group TABLE 1
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(1105 ± 541) was significantly lower than that of the nonpain group (1738 ± 892) and the normal control group (1915 ± 718) (P < .05). No significant difference in tract volume was observed between the nonpain group and the control group (P > .05). In addition, no significant difference in total brain voxel was observed between the pain group, the nonpain group, and the control group (see Table 2and Figure 2). DISCUSSION In this study, we observed a significant difference in DTT parameters (FA, MD, and tract volume) of the STT in the pain group compared to the nonpain group and the normal control group. In detail, lower FA and tract volume and higher MD was observed in the pain group than in the nonpain group and the normal control group. However, no differences in all DTT parameters of the STT were observed between the nonpain group and the normal control group. The FA value indicates the degree of directionality of water diffusion, with a range of zero (completely isotropic diffusion) to 1 (completely anisotropic diffusion).40–43 It represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures such as axon, myelin, and microtubule.40–43 A decreased FA value might be related to impaired integration of a neural tract. The MD value represents the magnitude of water diffusion, which can increase with some forms of pathology, particularly vasogenic edema or accumulation of cellular debris from neuronal injury.40–43 In
Patients’ demographic and clinical dataa
Patients, n (%) Age, y Sex Duration after onset of TBI, mo Duration of LOC, min Duration of PTA, h Initial GCS score VAS Mechanism of injury Motor vehicle accident Bicycle accident Falling object accident WAIS MAS Short-term memory Verbal memory Visual memory Total memory
Pain group
Nonpain group
22 (68.75%) 47.25 ± 10.91 7 men, 15 women 11.95 ± 8.36 7.77 ± 10.25 1.48 ± 4.99 14.73 ± 0.62 4.87 ± 1.74
10 (31.25%) 48.38 ± 17.78 5 men, 5 women 9.1 ± 6.63 6.3 ± 6.87 0.83 ± 1.74 14.8 ± 0.60 0
18 3 1 100.18 ± 11.10
7 1 2 97.70 ± 12.71
89.96 ± 17.71 81.59 ± 12.07 90.36 ± 13.88 82.32 ± 11.85
90.60 ± 21.38 85.90 ± 15.75 87.20 ± 14.83 83.40 ± 17.67
are presented as mean ± standard deviation. Abbreviations: GCS, Glasgow Coma Scale; LOC, loss of consciousness; MAS, Memory Assessment Scale; PTA, posttraumatic amnesia; TBI, traumatic brain injury; VAS, visual analog scale; WAIS, Wechsler Intelligence Scale.
a Values
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Comparison of diffusion tensor imaging parameters of both spinothalamocortical tracts between the pain, nonpain, and control groupsa TABLE 2
Patients
FA MD (×10−3 mm2 /s) Tract volume Total brain voxel
Pain group
Nonpain group
Control group
0.420 ± 0.021b 0.925 ± 0.051b 1105 ± 541b 4 86 624 ± 74 292
0.438 ± 0.018 0.896 ± 0.065 1738 ± 892 4 92 359 ± 85 026
0.447 ± 0.020 0.892 ± 0.044 1915 ± 718 4 78 780 ± 75 746
Abbreviations: FA, fractional anisotropy; MD, mean diffusivity. a Values are presented as mean ± standard deviation. Tukey’s post hoc test was used for comparisons of diffusion tensor image parameters. b Significantly different compared to the nonpain and control group at P < .05.
contrast, the tract volume indicates the included number of voxels in a neural tract.44,45 Therefore, these changes of DTT parameters (decrement of FA and tract volume, and increment of MD) in the pain group appear to indicate injury of the STT. All patients in the pain group showed neuropathic pain; however, no definite brain lesion was observed on conventional brain MRI. Radiculopathy, myelopathy, and peripheral neuropathy were also ruled out. Therefore, it appears that injury of the STT was related to the occurrence of central pain in patients in the pain group. The traumatic axonal injury
appeared to be the most likely pathogenetic mechanism for injury of the STT. Since introduction of DTI, several studies have reported on development of central pain in various brain pathologies, including stroke, SCI, and multiple sclerosis.19,21,17,22,46–48 In 2005, Seghier et al22 reported on a patient with central poststroke pain who showed selective decreased fibers of the STT (visually), whereas medial lemniscus was preserved on DTT. In 2008, Goto et al21 demonstrated injury of the STT (visually) on DTT in 13 out of 17 patients with central poststroke pain. In
Figure 2. Group data plots for diffusion tensor imaging parameters of the spinothalamocortical tract. FA indicates fractional anisotropy; MD, mean diffusivity.
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Injury of the Spinothalamocortical Tract in Mild TBI 2010, Hong et al19 demonstrated that injury of the STT was a requirement for development of central poststroke pain irrespective of medial lemniscus state in 30 chronic stroke patients. In 2012, Hong et al17 reported that partial injury of the STT was more vulnerable to development of central poststroke pain than complete injury of the STT in 52 chronic stroke patients. In this study, we found that a large portion of patients, 22 (68.75%) of 32 consecutive patients, showed partial injury of the STT with preserved integrity of the STT (Fig 1). Therefore, we think that our result is in agreement with that of a previous study (Hong et al, 2012) of stroke patients.17 Ofek and Defrin9 also reported high prevalence rate of central pain in patients with chronic pain following TBI: 15 (48%) of 31 patients. Regarding patients with SCI, in 2010, Gustin et al46 reported that 12 out of 23 patients with complete thoracic SCI presenting with below-level central pain showed significant changes of the MD value in pain-related brain regions. Yoon et al47 recently reported decreased MD value in the brain regions of the STT in 10 patients with central pain after SCI. On the contrary, in 2013, Deppe et al48 reported on a patient with central pain due to multiple sclerosis who showed local alterations of FA and MD values in the left thalamus on follow up DTI, and these alterations showed correlation with his episodic central pain and sensory deficits. Regarding TBI, only a few studies have reported on central pain following TBI using DTT.25,26 In 2013, Seo and Jang25 reported on a patient with injury of the STT at the ventroposterolateral nucleus of the thalamus after TBI. The patient had suffered from tingling sensation and pain in her right arm and leg, and DTT for the left STT showed decreased FA value at the thalamic level. Seo and Jang26 recently reported on a patient with mild TBI who showed injury of STTs in both hemispheres. The patient complained of central pain in multiple areas (both subscapular areas, posterior head and neck, both upper trapezius areas, and right arm and leg), and decreased tract volume of the STTs was observed in both hemispheres on DTT. On the basis of the aforementioned studies, this study is the first original study to investigate the relation between injury of the STT and the presence of central pain in a large number of
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consecutive patients with mild TBI. However, the limitations of this study should be considered. First, the study included a relatively small number of subjects, particularly in the nonpain group. Therefore, there was a possibility for potential instability of the image analysis. This study was conducted retrospectively; therefore, conduct of further prospective studies including larger numbers of subjects should be encouraged. Second, we recruited patients who had been admitted for rehabilitation. Therefore, it is possible that among all patients with mild TBI, we recruited patients with severe clinical manifestations. Third, DTI is a powerful anatomic imaging tool, which can demonstrate gross fiber architecture; however, due to crossing fiber or partial volume effect, DTI can produce both false positive and negative results throughout the white matter of the brain.49,50 Finally, this study was conducted at a 1.5tesla magnetic field strength with 32 diffusion gradient; however, this method provides relatively lower signalto-noise ratio and resolution compared to higher tesla magnetic field strength with more diffustion gradients.51 Therefore, conduct of further complementary DTI study should be encouraged to overcome these limitations. CONCLUSION We investigated the relation between injury of the STT and central pain in chronic patients with mild TBI, using DTT. We found that the injury of the STT was related to the occurrence of central pain in patients with mild TBI. As a result, we believe that the injury of the STT is a pathogenetic etiology of central pain following mild TBI. Therefore, we recommend evaluation of the STT using DTT when a patient with head trauma complains of pain having the characteristics of central pain, even in patients with mild TBI. In addition, we believe that central pain should be ruled out when the patient with mild TBI is refractory to routine management for pain of already known etiology. On the contrary, because the patients were recruited from patients with mild TBI who had been admitted for rehabilitation, it is possible that among all patients with mild TBI, we recruited patients with severe clinical manifestations. As a result, we consider this is a pilot study.
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The Relation Between Injury of the Spinothalamocortical Tract and Central Pain in Chronic Patients With Mild Traumatic Brain Injury Jin Hyun Kim, MD; Sang Ho Ahn, MD; Yoon Woo Cho, MD; Seong Ho Kim, MD; Sung Ho Jang, MD Objectives: Little is known about the pathogenetic etiology of central pain in patients with traumatic brain injury (TBI). We investigated the relation between injury of the spinothalamocortical tract (STT) and chronic central pain in patients with mild TBI. Design: Retrospective survey. Participants: We recruited 40 consecutive chronic patients with mild TBI and 21 normal control subjects: 8 patients were excluded by the inclusion criteria and the remaining 32 patients were finally recruited. The patients were classified according to 2 groups based on the presence of central pain: the pain group (22 patients) and the nonpain group (10 patients). Methods: Diffusion tensor tractography for the STT was performed using the Functional Magnetic Resonance Imaging of the Brain Software Library. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of each STT were measured. Results: Lower FA value and tract volume were observed in the pain group than in the nonpain group and the control group (P < .05). By contrast, higher MD value was observed in the pain group than in the nonpain group and the control group (P < .05). However, no significant differences in all diffusion tensor imaging parameters were observed between the nonpain group and the control group (P > .05). Conclusions: Decreased FA and tract volume and increased MD of the STTs in the pain group appeared to indicate injury of the STT. As a result, we found that injury of the STT is related to the occurrence of central pain in patients with mild TBI. We believe that injury of the STT is a pathogenetic etiology of central pain following mild TBI. Key words: central pain, diffusion tensor imaging, spinothalamocortical tract, traumatic brain injury
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RAUMATIC BRAIN INJURY (TBI), which is a major cause of disability, is classified as mild, moderate, and severe, based on the severity;1 70% to 90% of cases of TBI are classified as mild TBI.2–4 Chronic pain is a common sequela in patients with TBI: prevalence of chronic pain of greater than 50% has been reported in patients with whole TBI and it became worse in patients with mild TBI, up to 75%.5,6 Many studies have reported
Author Affiliations: Department of Physical Medicine and Rehabilitation (Drs Kim, Ahn, Cho, and Jang) and Department of Neurosurgery (Dr Kim), College of Medicine, Yeungnam University, Taegu, Republic of Korea. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A4A01001873). The authors declare no conflicts of interest. Corresponding Author: Sung Ho Jang, MD, Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University 317-1, Daemyungdong, Namku, Taegu, 705-717, Republic of Korea ([email protected]). DOI: 10.1097/HTR.0000000000000121
on the various pathogenetic etiologies of chronic pain following TBI.7–9 These include musculoskeletal, vascular, neurogenic, visceral, and iatrogenic mechanisms.7–9 Central pain presents the characteristics of neuropathic pain, characterized by stimulation-independent pain: shooting, lancinating, burning, electric shock-like sensation, and paresthesia (crawling, itching, tingling sensation); stimulus evoked pain: hyperalgesia or allodynia.10–13 Central pain is caused by a lesion or dysfunction arisen from the central nervous system, including brain and spinal cord.8,9,14 Clinically, the diagnosis of central pain would be very important because the management strategy and prognosis differ significantly from those for other pain ascribed to other pathogenetic etiologies. However, research on central pain in patients with TBI has been neglected.8,9,15,16 Many previous studies have reported a close association of injury of the spinothalamocortical tract (STT) with development of central poststroke pain.17–22 In addition, injury of the STT has been regarded as the main pathogenetic mechanism of central pain following spinal cord injury (SCI).23,24 A few studies have
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Injury of the Spinothalamocortical Tract in Mild TBI described central pain in patients with TBI.9,16 In 2006, Son et al16 reported on a patient suffering from central pain (a burning sensation and heaviness in his right leg and arm) after severe TBI, whose clinical picture of the pain was similar to that of central poststroke pain. Subsequently, Ofek and Defrin,9 who investigated the characteristics of chronic central pain in 15 chronic patients with central pain after TBI, reported that development of central pain had a relatively late onset (average 6.6 months); was almost exclusively unilateral; and reported as pricking, throbbing, and burning. However, the pathogenetic mechanism of central pain in patients with TBI has not been clearly elucidated.25,26 Diffusion tensor tractography (DTT), which is derived from diffusion tensor imaging (DTI), provides 3-dimensional visualization and estimation of the STT, which carries information on pain and touch from the contralateral extremities and body.27–29 Several studies using DTT have demonstrated that injury of the STT is the pathogenetic mechanism of central pain in patients with stroke.19,21,17,22 However, only a few studies using DTT have reported on central pain following injury of the STT in patients with TBI.25,26 Consequently, the relation between injury of the STT and central pain in patients with TBI has not been clearly elucidated. In this study, we hypothesized that injury of the STT is the pathogenetic mechanism of central pain in patients with mild TBI. In this study, using DTT, we attempted to investigate the relation between injury of the STT and central pain in chronic patients with mild TBI. MATERIALS AND METHODS Subjects Forty patients (13 men, 27 women; mean age = 49.42 ± 14.16 years, range: 19–72) with TBI who were admitted to the rehabilitation department of a university hospital and 21 normal control subjects (8 men, 13 women; mean age = 45.05 ± 14.02 years, range: 20– 74) were recruited. Forty consecutive patients with TBI were recruited according to the following criteria: (1) loss of consciousness (LOC) for less than 30 minutes, initial Glasgow Coma Scale (GCS) score of 13 to 15, and posttraumatic amnesia (PTA) for 24 or less hours30,31 ; (2) more than 3 months after onset of TBI; and (3) no history of head trauma or neurologic or psychiatric disease. We excluded patients according to the following exclusion criteria: (1) brain lesion on conventional magnetic resonance imaging (MRI) (T1-weighted, T2weighted, fluid-attenuated inversion recovery, and T2weighted gradient recall echo images), (2) evidence of radiculopathy or peripheral neuropathy on electromyography and nerve conduction study, and (3) evidence of myelopathy on spinal MRI or central motor conduction
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time. Two patients who showed a brain lesion (one patient: concurrent intracranial hemorrhage and the other patient: an old cerebral infarct) were excluded. In addition, 3 patients who showed radiculopathy and 3 other patients who showed myelopathy were also excluded. Thus, finally, the remaining 32 patients were recruited for this study. This study was conducted retrospectively, and the study protocol was approved by the institutional review board of a university hospital. We classified patients according to 2 groups based on the presence of neuropathic pain, which had developed after TBI:10–13 the pain group included patients who suffered from neuropathic pain, and the nonpain group included patients who did not show neuropathic pain. Clinical evaluation Neuropathic pain of patients was rated using the visual analog scale (VAS).32,33 The reliability and validity of the VAS is well-established.32,33 The Wechsler Intelligence Scale (WAIS) and the Memory Assessment Scale (MAS) were used for evaluation of cognitive function. The WAIS is the most standardized intelligence test. Full Scale Intelligence Index (Full IQ) derived from Verbal and Performance Intelligence Indices was obtained.34 The MAS is a comprehensive standardized memory assessment battery, consisting of 4 memory subsets, including short-term memory, verbal memory, visual memory, and total memory derived from verbal and visual memory.35 The reliability and validity of WAIS and MAS are well-established.34,35 Diffusion tensor image Diffusion tensor image was performed at an average of 11.1 months (range: 3–28 months) after onset of TBI using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Ltd, Best, the Netherlands) with single-shot echo-planar imaging. For each of the 32 noncollinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissure (AC)-posterior commissure (PC) line. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed to matrix = 192 × 192 matrix; field of view = 240 mm × 240 mm; TR = 10,726 ms; TE = 76 ms; parallel imaging reduction factor (SENSE factor) = 2; EPI factor = 59; b = 1000 s/mm2 ; NEX = 1; slice gap = 0 mm; and a slice thickness = 2.5 mm (acquired isotropic voxel size = 2.5 mm × 2.5 mm × 2.5 mm). Fiber tracking The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain Software Library (FSL; www.fmrib.ox.ac.uk/fsl) was used for analysis of diffusion-weighted imaging data, and affine multiscale 2-dimensional registration was used to correct for head www.headtraumarehab.com
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motion effects and image distortions due to eddy currents. A probabilistic tractography method, based on a multifiber model, was used in performance of fiber tracking, which was applied in the current study utilizing tractography routines implemented in Functional Magnetic Resonance Imaging of the Brain diffusion (5000 streamline samples, 0.5-mm step lengths, curvature thresholds = 0.2).36,37 The STTs were reconstructed by selection of fibers passing through regions of interest (ROIs). The seed ROI was placed in the STT of the posterolateral medulla, which was posterior to the inferior olivary nucleus, anterior to the inferior cerebellar peduncle, and lateral to the medial lemniscus on an axial slice.29 The first target ROI was drawn around the ventral posterior lateral nucleus of the thalamus, which was placed at onethird of the AC-PC line from the PC for the anteroposterior direction and three-fourths of the thalamus from the AC-PC line for the mediolateral direction, where this ROI was located in the purple area on a color-coded primary diffusion map.29,38 The second target ROI was placed at the primary somatosensory cortex (S1) on
an axial slice.29 Out of 5000 samples generated from each seed voxel, the STT was visualized at a minimum threshold of 1 streamline (see Figure 1). The values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of the reconstructed STT were measured in both hemispheres. Total brain voxel was also measured39 (Fig 1). Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 18.0 (SPSS, Chicago, Illinois). For determination of the demographic and clinical variances between the pain group and the nonpain group, the independent t test was used for age, duration after the onset of TBI, duration of LOC, duration of PTA, initial GCS score, WAIS (full IQ), and MAS (short-term memory, verbal memory, visual memory, and total memory), and the chi-square test was used for gender and mechanism of injury. The values of the FA, MD, and tract volume of both STTs, and total brain voxel were used in performance of 1-way analysis
Figure 1. A, The spinothalamocortical tract (STT) for a patient (53-year-old women) in the pain group. The STTs in both hemispheres are thinner than those of a patient in the nonpain group and a subject in the control group. B, The STT for a patient in the nonpain group (50-year-old women). Both STTs are similar in appearance to those of a control subject (54-year-old women). C, The STT for a subject in the control group.
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Injury of the Spinothalamocortical Tract in Mild TBI of variance for determination of variances between the pain group, the nonpain group, and the control group. Tukey’s post hoc test was used for evaluation of differences in data among the 3 groups. Statistical significance was accepted for P < .05. RESULTS A summary of the patients’ demographic and clinical data is shown in see Table 1. Out of 32 patients, 22 (68.75%) patients were enrolled in the pain group (7 men, 15 women; mean age 47.25 ± 10.91 years) and 10 (31.25%) patients were enrolled in the nonpain group (5 men, 5 women; mean age: 48.38 ± 17.78 years). In the pain group, mean VAS was 4.87 ± 1.74, and 20 of the 22 patients received medications such as gabapentin for relief of their central pain. No significant differences in all demographic and clinical data were observed between the pain group and nonpain group, except VAS and the number of patients who received medications for central pain (P > .05) (see Table 1). Significantly decreased FA value was observed for the pain group (0.420 ± 0.021) compared with the nonpain group (0.438 ± 0.018) and the control group (0.447 ± 0.020) (P < .05). By contrast, significantly increased MD value was observed for the pain group (0.925 ± 0.051) compared with the nonpain group (0.896 ± 0.065) and the control group (0.892 ± 0.044) (P < .05). However, no significant differences in FA and MD values were observed between the nonpain group and the control group (P > .05). The tract volume of the pain group TABLE 1
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(1105 ± 541) was significantly lower than that of the nonpain group (1738 ± 892) and the normal control group (1915 ± 718) (P < .05). No significant difference in tract volume was observed between the nonpain group and the control group (P > .05). In addition, no significant difference in total brain voxel was observed between the pain group, the nonpain group, and the control group (see Table 2and Figure 2). DISCUSSION In this study, we observed a significant difference in DTT parameters (FA, MD, and tract volume) of the STT in the pain group compared to the nonpain group and the normal control group. In detail, lower FA and tract volume and higher MD was observed in the pain group than in the nonpain group and the normal control group. However, no differences in all DTT parameters of the STT were observed between the nonpain group and the normal control group. The FA value indicates the degree of directionality of water diffusion, with a range of zero (completely isotropic diffusion) to 1 (completely anisotropic diffusion).40–43 It represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures such as axon, myelin, and microtubule.40–43 A decreased FA value might be related to impaired integration of a neural tract. The MD value represents the magnitude of water diffusion, which can increase with some forms of pathology, particularly vasogenic edema or accumulation of cellular debris from neuronal injury.40–43 In
Patients’ demographic and clinical dataa
Patients, n (%) Age, y Sex Duration after onset of TBI, mo Duration of LOC, min Duration of PTA, h Initial GCS score VAS Mechanism of injury Motor vehicle accident Bicycle accident Falling object accident WAIS MAS Short-term memory Verbal memory Visual memory Total memory
Pain group
Nonpain group
22 (68.75%) 47.25 ± 10.91 7 men, 15 women 11.95 ± 8.36 7.77 ± 10.25 1.48 ± 4.99 14.73 ± 0.62 4.87 ± 1.74
10 (31.25%) 48.38 ± 17.78 5 men, 5 women 9.1 ± 6.63 6.3 ± 6.87 0.83 ± 1.74 14.8 ± 0.60 0
18 3 1 100.18 ± 11.10
7 1 2 97.70 ± 12.71
89.96 ± 17.71 81.59 ± 12.07 90.36 ± 13.88 82.32 ± 11.85
90.60 ± 21.38 85.90 ± 15.75 87.20 ± 14.83 83.40 ± 17.67
are presented as mean ± standard deviation. Abbreviations: GCS, Glasgow Coma Scale; LOC, loss of consciousness; MAS, Memory Assessment Scale; PTA, posttraumatic amnesia; TBI, traumatic brain injury; VAS, visual analog scale; WAIS, Wechsler Intelligence Scale.
a Values
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Comparison of diffusion tensor imaging parameters of both spinothalamocortical tracts between the pain, nonpain, and control groupsa TABLE 2
Patients
FA MD (×10−3 mm2 /s) Tract volume Total brain voxel
Pain group
Nonpain group
Control group
0.420 ± 0.021b 0.925 ± 0.051b 1105 ± 541b 4 86 624 ± 74 292
0.438 ± 0.018 0.896 ± 0.065 1738 ± 892 4 92 359 ± 85 026
0.447 ± 0.020 0.892 ± 0.044 1915 ± 718 4 78 780 ± 75 746
Abbreviations: FA, fractional anisotropy; MD, mean diffusivity. a Values are presented as mean ± standard deviation. Tukey’s post hoc test was used for comparisons of diffusion tensor image parameters. b Significantly different compared to the nonpain and control group at P < .05.
contrast, the tract volume indicates the included number of voxels in a neural tract.44,45 Therefore, these changes of DTT parameters (decrement of FA and tract volume, and increment of MD) in the pain group appear to indicate injury of the STT. All patients in the pain group showed neuropathic pain; however, no definite brain lesion was observed on conventional brain MRI. Radiculopathy, myelopathy, and peripheral neuropathy were also ruled out. Therefore, it appears that injury of the STT was related to the occurrence of central pain in patients in the pain group. The traumatic axonal injury
appeared to be the most likely pathogenetic mechanism for injury of the STT. Since introduction of DTI, several studies have reported on development of central pain in various brain pathologies, including stroke, SCI, and multiple sclerosis.19,21,17,22,46–48 In 2005, Seghier et al22 reported on a patient with central poststroke pain who showed selective decreased fibers of the STT (visually), whereas medial lemniscus was preserved on DTT. In 2008, Goto et al21 demonstrated injury of the STT (visually) on DTT in 13 out of 17 patients with central poststroke pain. In
Figure 2. Group data plots for diffusion tensor imaging parameters of the spinothalamocortical tract. FA indicates fractional anisotropy; MD, mean diffusivity.
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Injury of the Spinothalamocortical Tract in Mild TBI 2010, Hong et al19 demonstrated that injury of the STT was a requirement for development of central poststroke pain irrespective of medial lemniscus state in 30 chronic stroke patients. In 2012, Hong et al17 reported that partial injury of the STT was more vulnerable to development of central poststroke pain than complete injury of the STT in 52 chronic stroke patients. In this study, we found that a large portion of patients, 22 (68.75%) of 32 consecutive patients, showed partial injury of the STT with preserved integrity of the STT (Fig 1). Therefore, we think that our result is in agreement with that of a previous study (Hong et al, 2012) of stroke patients.17 Ofek and Defrin9 also reported high prevalence rate of central pain in patients with chronic pain following TBI: 15 (48%) of 31 patients. Regarding patients with SCI, in 2010, Gustin et al46 reported that 12 out of 23 patients with complete thoracic SCI presenting with below-level central pain showed significant changes of the MD value in pain-related brain regions. Yoon et al47 recently reported decreased MD value in the brain regions of the STT in 10 patients with central pain after SCI. On the contrary, in 2013, Deppe et al48 reported on a patient with central pain due to multiple sclerosis who showed local alterations of FA and MD values in the left thalamus on follow up DTI, and these alterations showed correlation with his episodic central pain and sensory deficits. Regarding TBI, only a few studies have reported on central pain following TBI using DTT.25,26 In 2013, Seo and Jang25 reported on a patient with injury of the STT at the ventroposterolateral nucleus of the thalamus after TBI. The patient had suffered from tingling sensation and pain in her right arm and leg, and DTT for the left STT showed decreased FA value at the thalamic level. Seo and Jang26 recently reported on a patient with mild TBI who showed injury of STTs in both hemispheres. The patient complained of central pain in multiple areas (both subscapular areas, posterior head and neck, both upper trapezius areas, and right arm and leg), and decreased tract volume of the STTs was observed in both hemispheres on DTT. On the basis of the aforementioned studies, this study is the first original study to investigate the relation between injury of the STT and the presence of central pain in a large number of
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consecutive patients with mild TBI. However, the limitations of this study should be considered. First, the study included a relatively small number of subjects, particularly in the nonpain group. Therefore, there was a possibility for potential instability of the image analysis. This study was conducted retrospectively; therefore, conduct of further prospective studies including larger numbers of subjects should be encouraged. Second, we recruited patients who had been admitted for rehabilitation. Therefore, it is possible that among all patients with mild TBI, we recruited patients with severe clinical manifestations. Third, DTI is a powerful anatomic imaging tool, which can demonstrate gross fiber architecture; however, due to crossing fiber or partial volume effect, DTI can produce both false positive and negative results throughout the white matter of the brain.49,50 Finally, this study was conducted at a 1.5tesla magnetic field strength with 32 diffusion gradient; however, this method provides relatively lower signalto-noise ratio and resolution compared to higher tesla magnetic field strength with more diffustion gradients.51 Therefore, conduct of further complementary DTI study should be encouraged to overcome these limitations. CONCLUSION We investigated the relation between injury of the STT and central pain in chronic patients with mild TBI, using DTT. We found that the injury of the STT was related to the occurrence of central pain in patients with mild TBI. As a result, we believe that the injury of the STT is a pathogenetic etiology of central pain following mild TBI. Therefore, we recommend evaluation of the STT using DTT when a patient with head trauma complains of pain having the characteristics of central pain, even in patients with mild TBI. In addition, we believe that central pain should be ruled out when the patient with mild TBI is refractory to routine management for pain of already known etiology. On the contrary, because the patients were recruited from patients with mild TBI who had been admitted for rehabilitation, it is possible that among all patients with mild TBI, we recruited patients with severe clinical manifestations. As a result, we consider this is a pilot study.
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