Injury of the Spinothalamic Tract Following Whiplash Injury: A Diffusion Tensor Tractography Study.

OBJECTIVES: Using diffusion tensor tractography (DTT), we demonstrated the spinothalamic tract (STT) injury in patients with central pain following whiplash injury. Our primary hypothesis is that fractional anisotropy (FA) and tract volume (TV) of the STT in injured people differ from non-injured people. Our secondary hypothesis is that the direction of the collision results in a different type of injury. METHODS: Nineteen central pain patients following whiplash injury and 19 normal control subjects were recruited. The STT was reconstructed by the DTT, the FA and TV of the STT were measured. In addition, different characteristics of the STT injury according to the collision direction were investigated. RESULTS: The FA value did not differ significantly between the patient and control groups (p > 0.05). However, the significantly lower value of the TV was observed in patient group than the control group (p < 0.05). The onset of central pain was significantly delayed (13.5 days) in patients who were involved in a frontal collision, compared to patients with rear-end collision (0.6 days) (p < 0.05). In contrast, the Visual Analogue Scale was higher in the patients with rear-end collision (p < 0.05). CONCLUSIONS: We found the STT injury mild traumatic brain injury (TBI) who suffered central pain after whiplash injury, using DTT. In addition, we demonstrated different characteristics of the STT injury according to the collision direction. We believe that injury of the STT would be usefully detected by DTT following whiplash injury.

Diagnostic sensitivity of traumatic axonal injury of the spinothalamic tract in patients with mild traumatic brain injury.

ABSTRACT: Diffusion tensor tractography (DTT) can detect traumatic axonal injury (TAI) in patients whose conventional brain magnetic resonance imaging results are negative. This study investigated the diagnostic sensitivity of TAI of the spinothalamic tract (STT) in patients with a mild traumatic brain injury (TBI) suffering from central pain symptoms, using DTT.Thirty-five patients with central pain following mild TBI and 30 healthy control subjects were recruited for this study. After DTT-based reconstruction of the STT, we analyzed the STT in terms of configuration (narrowing and/or tearing) and the DTT parameters (fractional anisotropy and tract volume).Thirty-three (94.3%) patients had at least 1 DTT parameter value at 1 standard deviation below the control group value, and 20 (57.1%) patients had values at 2 standard deviations, below the control group value. All 35 patients showed STT abnormalities (tearing, narrowing, or both) on DTT.A high diagnostic sensitivity of TAI of the STT in patients with mild TBI was achieved. However, the small number of subjects who visited the university hospital and the limitations of DTT should be considered when generalizing the results of this study.

Microglial deactivation by adeno-associated virus expressing small-hairpin GCH1 has protective effects against neuropathic pain development in a spinothalamic tract-lesion model.

AIMS: Neuropathic pain after spinal cord injury is one of the most difficult clinical problems after the loss of mobility, and pharmacological or neuromodulation therapy showed limited efficacy. In this study, we examine the possibility of pain modulation by a recombinant adeno-associated virus (rAAV) encoding small-hairpin RNA against GCH1 (rAAV-shGCH1) in a spinal cord injury model in which neuropathic pain was induced by a spinothalamic tract (STT) lesion. METHODS: Micro-electric lesioning was used to damage the left STT in rats (n = 32), and either rAAV-shGCH1 (n = 19) or rAAV control (n = 6) was injected into the dorsal horn of the rats at the same time. On postoperative days 3, 7, and 14, we evaluated neuropathic pain using a behavioral test and microglial activation by immunohistochemical staining. RESULTS: A pain modulation effect of shGCH1 was observed from postoperative days 3 to 14. The mechanical withdrawal threshold was 13.0 ± 0.95 in the shGCH1 group, 4.3 ± 1.37 in the control group, and 3.49 ± 0.85 in sham on postoperative day 3 (p < 0.0001) and continued to postoperative day 14 (shGCH1 vs. control: 11.4 ± 1.1 vs. 2.05 ± 0.60, p < 0.001 and shGCH1 vs. sham: 11.4 ± 1.1 vs. 1.43 ± 0.54, p < 0.001). Immunohistochemical staining of the spinal cord dorsal horn showed deactivation of microglia in the shGCH1 group without any change of delayed pattern of astrocyte activation as in STT model. CONCLUSIONS: Neuropathic pain after spinal cord injury can be modulated bilaterally by deactivating microglial activation after a unilateral injection of rAAV-shGCH1 into the dorsal horn of a STT lesion spinal cord pain model. This new attempt would be another therapeutic approach for NP after SCI, which once happens; there is no clear curative options still now.

Abdominal pain due to the spinothalamic tract injury in patients with mild traumatic brain injury: a case report.

BACKGROUND: We report on a patient with a mild traumatic brain injury (TBI) who developed abdominal pain due to spinothalamic tract (STT) injuries revealed by diffusion tensor tractography (DTT). CASE PRESENTATION: A 53-year-old female patient suffered head trauma resulting from a backward fall. While bathing at a public bathhouse, she fell backward and struck the occipital area of her head against the floor. After the head trauma, she experienced pain in the abdomen and in both hands and feet. She underwent evaluations including conventional brain MRI, abdominal and pelvic ultrasonography, and stomach and intestine endoscopy. No abnormality was observed in her brain or abdomen. In addition, her abdominal pain had not been relieved by medical management. When she came to our hospital 4 years after the head trauma, her pain characteristics and severity were as follows: intermittent pain without allodynia or hyperalgesia; squeezing and warm creeping-like pain in the abdomen (visual analog scale score: 7); tingling pain in both hands and feet (visual analog scale score: 7). She was prescribed pregabalin and gabapentin, and her abdominal and limb pain was well-controlled at a tolerable level. On DTT 4 years after head trauma, the upper portion of the spinothalamic tracts (STTs) in both hemispheres showed partial tearing. DISCUSSION AND CONCLUSIONS: Injury of the STT was demonstrated by using DTT in a patient who showed abdominal pain that was refractory to medical management following mild TBI. Our results suggest that central pain due to STT injury might be suspected in patients with abdominal pain that is refractory to medical management following TBI.

Headache due to spinothalamic tract injury in patients with mild traumatic brain injury: Two case reports.

RATIONALE: Headache is the most common physical complaint reported by the following traumatic brain injury (TBI). Several studies using diffusion tensor tractography (DTT) have demonstrated that injury of the spinothalamic tract (STT) is a pathogenetic mechanism of central pain following TBI. However, no study of headache due to injury of the STT has been reported. PATIENT CONCERNS: Patient 1 was a 52-year-old female who suffered head trauma resulting from an in-car traffic crash. While sitting in a passenger seat in a moving vehicle, another vehicle suddenly hit the car from the right side. Her head hit the door and she suffered a flexion-hyperextension-rotation injury. She began to feel headaches in both fronto-parieto-occipital areas approximately 2 weeks after the crash. The characteristics and severity of pain were as follows: constant tingling and intermittent stabbing pain without allodynia or hyperalgesia (visual analogue scale score: 7). Patient 2 was a 50-year-old male who suffered head trauma from a flexion-hyperextension injury that occurred after being hit from behind by a vehicle while driving his car. He began to feel headache in both fronto-parieto-occipital areas the day after the crash: constant tingling pain without allodynia or hyperalgesia (visual analogue scale score: 6). DIAGNOSES: The patient 1 was diagnosed as mild TBI due to head flexion-hyperextension-rotation injury. The patient 2 was diagnosed as mild TBI due to head flexion-hyperextension injury. INTERVENTIONS: Clinical assessment and DTT were performed at 5 months (patient 1) and 10 months (patient 2) after the initial injury. OUTCOMES: On DTTs of patient 1 and 2, the STTs showed narrowing in both hemispheres. In addition, discontinuations at the subcortical white matter were observed in both hemispheres in patient 2. LESSONS: Headache due to injury of the STT was diagnosed in patients with mild TBI. Precise diagnosis of central pain from other types of pain is clinically important because the management of central pain is quite different from those for other types of pain. Our results suggest that headache might be ascribed to the injury of the STT in patients with mild TBI. Therefore, we recommend evaluation of the STT using DTT in patients with mild TBI who complain of headache having the characteristics of neuropathic pain.

Central poststroke pain: A systematic review.

Background Physical, psychological, and/or social impairment can result after a stroke and can be exacerbated by pain. One type of pain after stroke, central poststroke pain, is believed to be due to primary central nervous system mechanisms. Estimated prevalence of central poststroke pain ranges widely from 8% to 55% of stroke patients, suggesting a difficulty in reliably, accurately, and consistently identifying central poststroke pain. This may be due to the absence of a generally accepted definition. Aim We aimed to clarify the role of thalamic strokes and damage to the spinothalamic pathway in central poststroke pain patients. Also, we aimed to gain a current understanding of anatomic substrates, brain imaging, and treatment of central poststroke pain. Summary of review Two independent reviewers identified 10,144 publications. Based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we extracted data from 23 papers and categorized the articles' aims into four sections: somatosensory deficits, pathway stimulation, clinical trials, and brain imaging. Conclusions Our systematic review suggests that damage to the spinothalamic pathway is associated with central poststroke pain and this link could provide insights into mechanisms and treatment. Moreover, historical connection of strokes in the thalamic region of the brain and central poststroke pain should be reevaluated as many studies noted that strokes in other regions of the brain have high occurrence of central poststroke pain as well.

Central pain due to spinothalamic tract injury caused by indirect head trauma following a pratfall.

OBJECTIVES: This study reports on patients who showed central pain due to injury of the spinothalamic tract (STT) caused by fall without direct head trauma. DESIGN: Prospective study. PARTICIPANTS: Two patients with mild traumatic brain injury (TBI) resulting from a fall were enrolled. Patient 1 was a 21-year-old female who had suffered a pratfall with no history of direct head trauma. She had begun to feel pain in both upper trunk and lower back and the left leg since ~ 5 days after onset: constant tingling and throbbing sensation with allodynia. Patient 2 was a 39-year-old male who had suffered a pratfall without direct head trauma. He had begun to feel pain in both arms and legs since ~ 4 days after the fall: constant tingling and pricking sensation without allodynia or hyperalgesia. RESULTS: On diffusion tensor tractograhpy (DTT) of patient 1, partial tearing of the right STT was observed at the subcortical white matter. On DTT of patient 2, partial tearing at the subcortical white matter was observed in the right STT and partial narrowing at the subcortical white matter was observed in the left STT. CONCLUSIONS: This study demonstrated injury of the STT in patients who suffered from central pain following a fall. The results suggest that minor indirect head trauma can cause traumatic axonal injury of the brain.

Degeneration of an injured spinothalamic tract in a patient with mild traumatic brain injury.

OBJECTIVES: This study reports on a patient who developed degeneration of an injured spinothalamic tract (STT) detected on diffusion tensor tractography (DTT) following mild traumatic brain injury (TBI). CASE DESCRIPTION: A 56-year-old female had suffered from head trauma resulting from a pedestrian car accident. The patient did not experience loss of consciousness or post-traumatic amnesia and the patient's Glasgow Coma Scale score was 15. She had begun to feel pain in her left hand and foot at ~ 7 days after onset. The characteristics and severity of pain were as follows: constant tingling and pricking sensation without allodynia or hyperalgesia (Visual Analogue Scale score: 3~4). No specific focal lesion was observed on brain and spine MRI and an electromyography study showed no evidence of peripheral nerve injury or radiculopathy. At 6 months after onset, the central pain in the left hand and foot became aggravated, with a Visual Analogue Scale score of 6. RESULTS: On 1-month DTT, partial tearing was observed in both STTs. In contrast, both partially torn STTs had become atrophy on 9-month DTT. CONCLUSIONS: This study recommends further studies conducted on the prognosis (regeneration or degeneration) of injured STTs and on the effect of change of an injured STT on central pain.

Aromatase inhibition exacerbates pain and reactive gliosis in the dorsal horn of the spinal cord of female rats caused by spinothalamic tract injury.

Central pain syndrome is characterized by severe and excruciating pain resulting from a lesion in the central nervous system. Previous studies have shown that estradiol decreases pain and that inhibitors of the enzyme aromatase, which synthesizes estradiol from aromatizable androgens, increases pain sensitivity. In this study we have assessed whether aromatase expression in the dorsal horns of the spinal cord is altered in a rat model of central pain syndrome, induced by the unilateral electrolytic lesion of the spinothalamic tract. Protein and mRNA levels of aromatase, as well as the protein and mRNA levels of estrogen receptors α and ß, were increased in the dorsal horn of female rats after spinothalamic tract injury, suggesting that the injury increased estradiol synthesis and signaling in the dorsal horn. To determine whether the increased aromatase expression in this pain model may participate in the control of pain, mechanical allodynia thresholds were determined in both hind paws after the intrathecal administration of letrozole, an aromatase inhibitor. Aromatase inhibition enhanced mechanical allodynia in both hind paws. Because estradiol is known to regulate gliosis we assessed whether the spinothalamic tract injury and aromatase inhibition regulated gliosis in the dorsal horn. The proportion of microglia with a reactive phenotype and the number of glial fibrillary acidic protein-immunoreactive astrocytes were increased by the injury in the dorsal horn. Aromatase inhibition enhanced the effect of the injury on gliosis. Furthermore, a significant a positive correlation of mechanical allodynia and gliosis in the dorsal horn was detected. These findings suggest that aromatase is up-regulated in the dorsal horn in a model of central pain syndrome and that aromatase activity in the spinal cord reduces mechanical allodynia by controlling reactive gliosis in the dorsal horn.

Injury of the spinothalamic tract in a patient with mild traumatic brain injury: diffusion tensor tractography study.

OBJECTIVE: To report on a patient found to have injury of the spinothalamic tract on diffusion tensor tractography following traumatic brain injury. CASE DESCRIPTION: A 29-year-old male patient with head trauma resulting from a pedestrian car accident presented with pain in multiple areas (both subscapular areas, posterior head and neck, both upper trapezius areas, and the right arm and leg). His pain had not improved with various types of conservative management. RESULTS: Evaluations (conventional brain magnetic resonance imaging, electromyography, and whole spine magnetic resonance imaging), performed 2 years after the head trauma, did not reveal any specific abnormality. Fibromyalgia and myofascial pain syndrome were ruled out by physical examination. Injuries of the spinothalamic tracts in both hemispheres were observed on diffusion tensor imaging in terms of the configuration (thinning) and diffusion tensor tractography parameters (decreased fractional anisotropy or tract volume). CONCLUSION: Some of the pain in the trunk and extremities in this patient could be ascribed to central pain caused by injury of both spinothalamic tracts. We conclude that diffusion tensor tractography provides a useful means of detecting injury of the spinothalamic tract in patients with traumatic brain injury.

Enhancing K-Cl co-transport restores normal spinothalamic sensory coding in a neuropathic pain model.

Neuropathic pain is a widespread and highly debilitating condition commonly resulting from injury to the nervous system, one main sequela of which is tactile allodynia, a pain induced by innocuous mechanical stimulation of the skin. Yet, the cellular mechanisms and neuronal substrates underlying this pathology have remained elusive. We studied this by quantifying and manipulating behavioural and neuronal nociceptive thresholds in normal and pathological pain conditions. We found that, in both control rats and those with pain hypersensitivity induced by nerve injury, the nociceptive paw withdrawal threshold matches the response threshold of nociceptive-specific deep spinothalamic tract neurons. In contrast, wide dynamic range or multimodal spinothalamic tract neurons showed no such correlation nor any change in properties after nerve injury. Disrupting Cl(-) homeostasis by blocking K(+)-Cl(-) co-transporter 2 replicated the decrease in threshold of nociceptive-specific spinothalamic tract neurons without affecting wide dynamic range spinothalamic tract cells. Accordingly, only combined blockade of both GABAA- and glycine-gated Cl(-) channels replicated the effects of nerve injury or K(+)-Cl(-) co-transporter 2 blockade to their full extent. Conversely, rescuing K(+)-Cl(-) co-transporter 2 function restored the threshold of nociceptive-specific spinothalamic tract neurons to normal values in animals with nerve injury. Thus, we unveil a tight association between tactile allodynia and abnormal sensory coding within the normally nociceptive-specific spinothalamic tract. Thus allodynia appears to result from a switch in modality specificity within normally nociceptive-specific spinal relay neurons rather than a change in gain within a multimodal ascending tract. Our findings identify a neuronal substrate and a novel cellular mechanism as targets for the treatment of pathological pain.

In vivo microdialysis of glutamate in ventroposterolateral nucleus of thalamus following electrolytic lesion of spinothalamic tract in rats.

Central pain is one of the most important complications after spinal cord injury (SCI), and thereby, its treatment raises many challenges. After SCI, in a cascade of molecular events, a marked increase in glutamate at the injury site results in secondary changes which may impact on supraspinal regions, mainly ventroposterolateral (VPL). There is little information about the changes in glutamate metabolism in the VPL and whether it contributes to SCI-related central pain. The present study was performed to evaluate glutamate release in the VPL following electrolytic lesion of spinothalamic tract (STT). A laminectomy was performed at spinal segments of T9-T10 in male rats, and then, unilateral electrolytic lesions were made in the STT. Glutamate concentrations in ipsilateral VPL dialysate were measured by HPLC method at days 3, 7, 14, 21 and 28 post-injury. Tactile pain and motor activity were also examined. Glutamate levels were significantly increased in ipsilateral VPL of spinal-cord-injured rats 2 weeks after SCI and remained high up to day 28 post-surgery. The STT lesions had no marked effect on our measures of motor activity, but there was a significant decrease in paw withdrawal threshold in the hind paws at day 14 post-SCI. These findings suggest that an increased release of glutamate in VPL plays a role in secondary pathologic changes, leading to neuronal hyperexcitation and neuropathic pain after SCI.

Role of microglia and astrocyte in central pain syndrome following electrolytic lesion at the spinothalamic tract in rats.

Central pain syndrome (CPS) is a debilitating state and one of the consequences of spinal cord injury in patients. Many pathophysiological aspects of CPS are not well documented. Spinal glia activation has been identified as a key factor in the sensory component of chronic pain. In this study, the role of glial subtypes in the process of CPS induced by unilateral electrolytic lesion of spinothalamic tract (STT) is investigated. Male rats received a laminectomy at T8-T9 and then unilateral electrolytic lesion centered on the STT. Thermal and mechanical thresholds as well as locomotor function were measured on days 0, 3, 7, 14, 21, and 28 post-injuries by tail flick, von Frey filament, and open field tests, respectively. To investigate the spinal glial activation following denervation in STT-lesioned groups, Iba1 and GFAP were detected by immunohistochemistry and Western blotting at the same time points. Data showed that STT lesion significantly decreased thermal pain at day 3 in comparison with sham groups. Significant bilateral allodynia appeared in hind paws at day 14 after spinal cord injury and continued to day 28 (P < 0.05). Additionally, electrolytic spinal lesion attenuated locomotor function of injured animals after 7 days (P < 0.05). In both histological assessments and Western blotting, Iba1 increased at days 3 and 7 while increased GFAP occurred from day 14 to 28 after lesion. It appears that microglial activation is important in the early stages of pain development and astrocytic activation occurs later. These events may lead to behavioral outcomes especially central neuropathic pain.