Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury.

A prospective, longitudinal study of 100 people with traumatic spinal cord injury (SCI) was performed to determine the time of onset. prevalence and severity of different types of pain (musculoskeletal, visceral, neuropathic at level, neuropathic below level) at 2, 4, 8, 13 and 26 weeks following SCI. In addition, we sought to determine the relationship between physical factors such as level of lesion, completeness and clinical SCI syndrome and the presence of pain. At 6 months following SCI, 40% of people had musculoskeletal pain, none had visceral pain, 36% had neuropathic at level pain and 19% had neuropathic below level pain. When all types of pain were included, at 6 months following injury, 64% of people in the study had pain, and 21% of people had pain that was rated as severe. Those with neuropathic below level pain were most likely to report their pain as severe or excruciating. There was no relationship between the presence of pain overall and level or completeness of lesion, or type of injury. Significant differences were found, however, when specific types of pain were examined. Musculoskeletal pain was more common in people with thoracic level injuries. Neuropathic pain associated with allodynia was more common in people who had incomplete spinal cord lesions, cervical rather than thoracic spinal cord lesions, and central cord syndrome. Therefore, this study suggests that most people continue to experience pain 6 months following spinal cord injury and 21% of people continue to experience severe pain. While the presence or absence of pain overall does not appear to be related to physical factors following SCI, there does appear to be a relationship between physical factors and pain when the pain is classified into specific types.     

Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury

At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine-induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above-level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI.

Different underlying pain mechanisms despite identical pain characteristics: a case report of a patient with spinal cord injury

Pain following spinal cord injury has been classified as nociceptive (musculoskeletal, visceral) or neuropathic (above, at, below level). There is no clear relation between the etiology and reported symptoms. Thus, due to different underlying mechanisms, the treatment is often ineffective. We report on a patient with spinal cord injury with neurological level of injury at T8 suffering from bilateral burning and prickling pain in the T9-11 dermatomes bilaterally (at-level pain), as well as diffusely in both legs from below the torso (below-level pain), accompanied by musculoskeletal low back pain. Bilateral comparison of quantitative sensory testing (QST) and skin biopsy revealed completely different findings in the dermatome T9 despite identical at-level pain characteristics. On the right side, QST revealed a normal sensory profile; the intraepidermal nerve fiber density (IENFD) was reduced, but not as severe as the contralateral side. On the left side there was a severe sensory loss with a stronger reduction of the IENDF, similar to the areas below the neurological level. These findings were significantly related to the treatment results. Pregabalin induced unilateral pain relief only in the area with remaining sensory function, whereas the left-sided at-level pain was unchanged. Thus, 2 different underlying mechanisms leading to bilaterally neuropathic pain with identical symptoms and with different treatment success were demonstrated in a single patient. The at-level pain in areas with remaining sensory function despite IENFD reduction could be relieved by pregabalin. Thus, in an individual case, QST may be helpful to better understand pain-generating mechanisms and to initiate successful treatment.     

Characterization of Hyperacute Neuropathic Pain after Spinal Cord Injury: A Prospective Study

There is currently a lack of information regarding neuropathic pain in the very early stages of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) for the patient's worst pain within the first 5 days of injury (i.e., hyperacute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time frame (i.e., 5 days), at- and below-level neuropathic pain were reported as the worst pain in 23% (n = 18) and 5% (n = 4) of individuals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late presenting neuropathic pain was characterized by more intense painful electrical and cold sensations, but less itching sensations. Phenotypic differences between acute and late neuropathic pain support the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuropathic pains, with the former potentially masking the latter. This may lead to an underestimation of the incidence of neuropathic pain during the very early, hyperacute time points post-injury.Trial registrationClinicalTrials.gov (Identifier: NCT01279811)PerspectiveThis article presents distinct pain phenotypes of hyperacute and late presenting neuropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute phase after injury. This information may be relevant to clinical trial design and broaden our understanding of neuropathic pain mechanisms after spinal cord injury.     

Pain during in-patient rehabilitation after traumatic spinal cord injury

In this prospective study, we surveyed the pain experience of 40 participants during the in-patient rehabilitation period following traumatic spinal cord injury (SCI). Twenty-eight patients (70% of the study population) had musculoskeletal (MS) pain or neuropathic (NP) pain. Pain responded positively to physical therapy and analgesics. A numerical pain scale decreased from a mean of 6.36+/-1.7 on admission to 3.2+/-1.94 on discharge (P<0.001). Paraplegic patients were more likely to have MS pain (P=0.001) and NP pain (P=0.046). There was no relationship between completeness of injury, or spinal surgery, and type of pain encountered. There was also no significant difference in the modified Barthel index between patients with and without pain on admission and discharge. We conclude that pain is a common experience in SCI patients and that it can be reduced significantly by the end of in-patient rehabilitation.     

Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain.

Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of gamma-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.     

Movement imagery increases pain in people with neuropathic pain following complete thoracic spinal cord injury

Spinal cord injury (SCI) results in deafferentation and the onset of neuropathic pain in a substantial proportion of people. Based on evidence suggesting motor cortex activation results in attenuation of neuropathic pain, we sought to determine whether neuropathic SCI pain could be modified by imagined movements of the foot. Fifteen subjects with a complete thoracic SCI (7 with below-level neuropathic pain and 8 without pain) were instructed in the use of movement imagery. Movement imagery was practiced three times daily for 7days. On the eighth day, subjects performed the movement imagery in the laboratory and recorded pain ratings during the period of imagined movement. Six out of 7 subjects with neuropathic pain reported an increase in pain during imagined movements from 2.9+/-0.7 during baseline to 5.0+/-1.0 during movement imagery (p<0.01). In SCI subjects without neuropathic pain, movement imagery evoked an increase in non-painful sensation intensity from a baseline of 1.9+/-0.7 to 4.8+/-1.3 during the movement imagery (p<0.01). Two subjects without a history of pain or non-painful phantom sensations had onset of dysesthesia while performing imagined movements. This study reports exacerbation of pain in response to imagined movements and it contrasts with reports of pain reduction in people with peripheral neuropathic pain. The potential mechanisms underlying this sensory enhancement with movement imagery are discussed.     

Brain circuitry underlying pain in response to imagined movement in people with spinal cord injury

Pain following injury to the nervous system is characterized by changes in sensory processing including pain. Although there are many studies describing pain evoked by peripheral stimulation, we have recently reported that pain can be evoked in subjects with complete spinal cord injury (SCI) during a motor imagery task. In this study, we have used functional magnetic resonance imaging to explore brain sites underlying the expression of this phenomenon. In 9 out of 11 subjects with complete thoracic SCI and below-level neuropathic pain, imagined foot movements either evoked pain in a previously non-painful region or evoked a significant increase in pain within the region of on-going pain (3.2 ± 0.7–5.2 ± 0.8). In both controls (n = 19) and SCI subjects, movement imagery evoked signal increases in the supplementary motor area and cerebellar cortex. In SCI subjects, movement imagery also evoked increases in the left primary motor cortex (MI) and the right superior cerebellar cortex. In addition, in the SCI subjects, the magnitude of activation in the perigenual anterior cingulate cortex and right dorsolateral prefrontal cortex was significantly correlated with absolute increases in pain intensity. These regions expanded to include right and left anterior insula, supplementary motor area and right premotor cortex when percentage change in pain intensity was examined. This study demonstrates that in SCI subjects with neuropathic pain, a cognitive task is able to activate brain circuits involved in pain processing independently of peripheral inputs.     

A role for peripheral afferents in the pathophysiology and treatment of at-level neuropathic pain in spinal cord injury? A case report

At-level neuropathic pain is a frequent symptom following spinal cord injury, but the underlying pathophysiology is not completely understood. We report a patient suffering from treatment-resistant at-level pain characterized by ongoing pain and mechanical allodynia for three years after an incomplete spinal lesion. Quantitative sensory testing revealed severe thermosensory deficits in the neuropathic pain area. However, topical application of capsaicin in the neuropathic pain area induced a burning pain sensation, a marked decrease in heat pain threshold and an increase in mechanical allodynia. Treatment with topical lidocaine patches (5%) led to considerable pain relief. These results indicate a functional connection between peripheral, spinal and supraspinal nociceptive pathways and that peripheral afferents may contribute to at-level neuropathic pain after spinal cord injury in this patient. Lesioned peripheral afferents in combination with central neuronal hyperexcitability are discussed as a likely underlying pain mechanism.     

What is the efficacy of physical therapeutics for treating neuropathic pain in spinal cord injury patients?

ObjectiveEvaluate the place and level of proof of physical therapeutics for treating neuropathic pain in spinal cord injury (SCI) patients.MethodLiterature review from three databases: PubMed, Embase, Pascal. The following keywords were selected: chronic neuropathic pain/non-pharmacological treatment; transcutaneous electrical nerve stimulation, physiotherapy, acupuncture, physical therapy, transcranial magnetic stimulation, heat therapy, ice therapy, cold therapy, massage, ultrasound, alternative treatment, complementary treatment, occupational therapy. The articles were analyzed using the double-reading mode.ResultsThree techniques emerge from the literature: magnetic or electrical transcranial stimulation, transcutaneous electrical nerve stimulation and acupuncture. Even though the first method is not easily accessible on a daily basis it is the one that yields the most promising results validated by Grade B studies. Healthcare professionals remain faithful to pain-relieving transcutaneous neurostimulation for both segmental neuropathic pain and below-level central neuropathic pain. Acupuncture is advocated by Canadian teams and could offer some interesting options; however, to this day, it does not have the methodological support and framework required to validate its efficacy. All other physical therapies are used in a random way. Only below-level massages are advocated by the patients themselves.ConclusionTo this day, no study can validate the integration of physical therapy as part of the array of therapeutics used for treating neuropathic pain in SCI patients. In the future, it will require controlled and randomized therapeutic studies on homogenous groups of SCI patients, to control the various confusion factors.     

Above-level mechanical hyperalgesia in rats develops after incomplete spinal cord injury but not after cord transection, and is reversed by amitriptyline, morphine and gabapentin

Spinal cord injury (SCI) is a major cause of persistent neuropathic pain of central origin. Recent evidence suggests neuropathic pain in clinically complete SCI patients correlates with limited sensory function below the lesion (sensory discomplete). On this basis we examined if the onset of mechanical hyperalgesia was different in rodents after a severe incomplete clip-compression SCI versus a complete spinal cord transection at thoracic segment T13. Above-level withdrawal behaviors evoked by forepaw stimulation provided evidence of mechanical hyperalgesia after incomplete but not complete SCI, whereas below-level responses evoked by hindpaw stimulation revealed hypersensitivity after both injuries. The latency of the above-level response was 4-5 wks but was longer after a moderate clip-compression injury. Mechanical hyperalgesia was fully reversed by three analgesic drugs used in treating neuropathic SCI pain, but their duration of action differed significantly, showing a rank order of amitriptyline (24-48 h) ? morphine (6 h) > gabapentin (2 h). Evidence of central sensitization in cervical spinal cord segments that receive sensory projections from the forelimbs was provided by immunohistochemistry for Zif268, a functional marker of neuroplasticity. Zif268-immunoreactive neurons in laminae I/II increased in response to repetitive noxious forepaw stimulation in the incomplete SCI group, and this response was reduced in the complete transection and sham-operated groups. These data are consistent with the hypothesis that neuropathic pain of cord origin is more likely to develop after SCI when there is an incomplete loss of axons traversing the lesion.     

Dermatomal Scratching After Intramedullary Quisqualate Injection: Correlation With Cutaneous Denervation

Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation.PerspectiveThis study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.     

Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: Evaluation of pain-like behavior

Pain is a frequent consequence of spinal cord injury (SCI) which may profoundly impair the patients’ quality of life. Valid experimental models and methods are therefore desirable in the search for better treatments. Usually, experimental pain assays depend on stimulus-evoked withdrawal responses; however, this spinal-mediated reflex response may be particularly problematic when evaluating below-level SCI pain due to the development of hyperactive reflex circuitries. In this study, we applied and compared assays measuring cold (acetone), static (von Frey filaments), and dynamic mechanical (soft brush) hypersensitivity at different levels of the neuroaxis at and below the level of injury in a rat model of SCI. We induced an experimental SCI (MASCIS 25 mm weight-drop) and evaluated the development of spinal reflexes (withdrawal), spinal-brainstem-spinal reflexes (licking, guarding, struggling, vocalizing, jumping, and biting) and cerebral-dependent behavior (place escape/avoidance paradigm (PEAP)). We demonstrated increased brainstem reflexes and cerebrally mediated aversive reactions to stimuli applied at the level of SCI, suggesting development of at-level evoked pain behavior. Furthermore, stimulation below-level increased innate reflex responses without increasing brainstem reflexes or aversive behavior in the PEAP, suggesting development of the spasticity syndrome rather than pain-like behavior. While spinal reflex measures are acceptable for studying changes in the spinal reflex pathways and spinal cord, they are not suited as nociceptive behavioral measures. Measuring brainstem organized responses eliminates the bias associated with the spastic syndrome, but pain requires cortical involvement. Methods depending on cortical structures, as the PEAP, are therefore optimal endpoints in animal models of central pain.     

Spinal Cord Injuries Containing Asymmetrical Damage in the Ventrolateral Funiculus Is Associated With a Higher Incidence of At-Level Allodynia

Approximately 70% of male rats receiving severe T8 spinal contusions develop allodynia in T5-7 dermatomes (at-level) beginning 2 weeks after injury. In contrast, rats having either complete transections or dorsal hemisections do not develop allodynia at-level after chronic spinal cord injury (SCI). In the present study, incomplete laceration and contusion injuries were made to test for neuroanatomical correlates between areas of white matter damage/sparing at the lesion epicenter and the presence/absence of allodynia. After incomplete laceration lesions and 6 weeks of behavioral testing, histological reconstruction and analysis of the lesion epicenters revealed a significant difference (P < .001) in the amount of ventrolateral funiculus (VLF) asymmetry between rats showing pain-like responses evoked by touch (74.5% ± 8.4% side-to-side difference in VLF damage) versus those not responding to touch (11.3% ± 4.4% side-to-side difference in VLF damage). A 5-week mean allodynia score for each rat that incorporates a full range of forces that are all innocuous in intact controls revealed that the degree of hypersensitivity at level is related to the extent of VLF asymmetry after SCI. No other damaged spinal white matter or gray matter area was correlated with sensitivity to touch. Similar findings were obtained for rats receiving T8 contusions, a more clinically relevant injury. These data suggest that different extents of damage/sparing between the 2 sides of VLF probably are a requisite for the development of allodynia after SCI.PerspectiveA side-to-side lesion asymmetry after chronic SCI in a rodent model was found to be highly correlated with the presence and degree of allodynia. Greater insight of key factors contributing to the development and maintenance of chronic neuropathic pain is important for improving quality of life.     

Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states

Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca_vα2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca_vα2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca_vα2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca_vα2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca_vα2δ-1 protein upregulation by intrathecal Ca_vα2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca_vα2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients.     

The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury

Spinal cord injury (SCI) results in the development of mechanical allodynia immediately rostral to the lesion site, within the dermatome border of normal sensation and sensory loss (at-level mechanical allodynia). We propose that an observed threefold increase in serotonergic fibre immunoreactivity within spinal segments corresponding to these allodynic dermatomes facilitates the maintenance of chronic neuropathic pain via activation of the 5-HT(3) receptor (5-HT(3)-R). Serotonin (5-HT), the non-selective 5-HT(1)/5-HT(2) receptor antagonist, methysergide, the 5-HT(3)-R agonist, m-chlorophenylbiguanide (m-CPBG) or the 5-HT(3)-R antagonist, ondansetron were intrathecally administered five weeks following SCI in rats. Ondansetron produced a robust, long-term reduction of at-level mechanical allodynia, while m-CPBG exacerbated allodynia. Exogenous 5-HT transiently reduced at-level mechanical allodynia. This effect was opposed by methysergide, which enhanced mechanical allodynia. Co-administration of 5-HT and ondansetron produced a short-lasting partial summation of effects, further decreasing mechanical allodynia while co-administration of methysergide attenuated the anti-allodynic effect of ondansetron. Depletion of spinal 5-HT via 5,7-dihydroxytryptamine (5,7-DHT) resulted in decreased at-level mechanical allodynia. The reduction of allodynia by ondansetron was lost following 5,7-DHT administration, suggesting that reduced allodynia following intrathecal ondansetron is via blockade of 5-HT-induced excitation of the 5-HT(3)-R. These results suggest that increased 5-HT fibre density immediately rostral to the SCI lesion site could have transient effects to reduce mechanical allodynia via actions at 5-HT(1) and/or 5-HT(2) receptors. However, the more long-lasting effects of this enhanced serotonergic input may facilitate chronic, at-level allodynia via the 5-HT(3)-R.     

Spinal Cord Injury Pain: Mechanisms and Management

Patients with spinal cord injury (SCI) may experience several types of chronic pain, including peripheral and central neuropathic pain, pain secondary to overuse, painful muscle spasms, and visceral pain. An accurate classification of the patient's pain is important for choosing the optimal treatment strategy. In particular, neuropathic pain appears to be persistent despite various treatment attempts. In recent years, we have gained increasing knowledge of SCI pain mechanisms from experimental models and clinical studies. Nevertheless, treatment remains difficult and inadequate. In line with the recommendations for peripheral neuropathic pain, evidence from randomized controlled treatment trials suggests that tricyclic antidepressants and pregabalin are first-line treatments. This review highlights the diagnosis and classification of SCI pain and recent improvements in the understanding of underlying mechanisms, and provides an update on treatment of SCI pain.     

Thalamic activity and biochemical changes in individuals with neuropathic pain after spinal cord injury

There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain.