Probing the role of the right inferior frontal gyrus during Pain‐Related empathy processing: Evidence from fMRI and TMS

Recent studies have suggested that the right inferior frontal gyrus (rIFG) may be involved in pain‐related empathy. To verify the role of the rIFG, we performed a functional magnetic resonance imaging (fMRI) experiment to replicate previous research and further designed a noninvasive repetitive transcranial magnetic stimulation (rTMS) experiment to probe the causal role of the rIFG in pain‐related empathy processing. We assigned 74 volunteers (37 females) to three groups. Group 1 (n = 26) performed a task in which participants were required to perceive pain in others (task of pain: TP) and we used fMRI to observe the activity of the rIFG during pain‐related empathy processing. Then, we applied online rTMS to the rIFG and the vertex site (as reference site) to observe the performance of Group 2 (n = 24; performing TP) and Group 3 (n = 24; performing a control task of identifying body parts; task of body: TB). fMRI experiment demonstrated stronger activation in the rIFG than in the vertex during the perception of pain in others (p < .0001, Bonferroni‐corrected). rTMS experiment indicated that when the rIFG was temporarily disrupted, participants perceived pain in others significantly more slowly (p < .0001, Bonferroni‐corrected) than when the vertex was disrupted. Our results provide evidence that the rIFG is involved in pain‐related empathy processing, which yields insights into how the brain perceives pain in others.     

Cross‐sectional assessment of pain and physical function in skeletal dysplasia patients

Short stature skeletal dysplasia (SD) patients have orthopedic and neurologic complications causing significant pain and physical disability. We conducted a large cross‐sectional online survey in 361 people with short stature SD (>10 years) to describe pain prevalence, characteristics, and the relationship between pain and function. Chronic pain prevalence per Brief Pain Inventory (BPI) was 70.3%. Women reported more pain than men (73% vs 63% p = 0.04). Pain Severity Score (average of current, worst, least and average pain) averaged 3.3 ± 2, while the Pain Interference Score (with daily activities) averaged 3.4 ± 2.7 on a 10‐point scale. Per Bleck scale, 20.5% had little or no functional capacity. Increasing age and decreased ambulation independently predicted chronic pain. Chronic pain is prevalent in short stature SD patients and associated with poor physical function. Further study is required to clarify the temporal relationship among pain, function and treatments.     

Flexed lumbar spine postures are associated with greater strength and efficiency than lordotic postures during a maximal lift in pain-free individuals

BackgroundInspite of common lifting advice to maintain a lordotic posture, there is debate regarding optimal lumbar spine posture during lifting. To date, the influence of lumbar posture on trunk muscle recruitment, strength and efficiency during high intensity lifting has not been fully explored.Research questionHow do differences in lumbar posture influence trunk extensor strength (moment), trunk muscle activity, and neuromuscular efficiency during maximal lifting?MethodsTwenty-six healthy participants adopted three lumbar postures (maximal extension (lordotic), mid-range (flat-back), and fully flexed) in a free lifting position. Motion analysis and force measurements were used to determine the back extensor, hip and knee moments. Surface electromyography (EMG) of three trunk extensors and the internal obliques were recorded. Neuromuscular efficiency (NME) was expressed as a ratio of normalised extensor moment to normalised EMG.ResultsSignificantly higher back extensor moments were exerted when moving from an extended to mid-range, and from a mid-range to fully flexed lumbar posture. This was accompanied by a decrease in activity across all three back extensor muscles (P < 0.001) resulting in a higher NME of these muscles in more flexed postures. Change in lumbar posture did not influence hip or knee moments or internal oblique activation.SignificanceA flexed-back posture is associated with increased strength and efficiency of the back muscles compared to a lordotic posture. These findings further question the manual handling advice to lift with a lordotic lumbar spine.     

The standing knee lift test is not a useful screening tool for time loss from low back pain in youth basketball and floorball players

ObjectivesThe aim of this study was to investigate the association between pelvic kinematics during the standing knee lift (SKL) test and low back pain (LBP) in youth floorball and basketball players.DesignA prospective cohort study.SettingFinnish elite youth floorball and basketball players.ParticipantsFinnish elite youth female and male floorball and basketball players (n = 258, mean age 15.7 ± 1.8).Main outcome measuresLBP resulting in time loss from practice and games was recorded over a 12-month period and verified by a study physician. Associations between LBP and sagittal plane pelvic tilt and frontal plane pelvic obliquity during the SKL test as measured at baseline were investigated. Individual training and game hours were recorded, and Cox’s proportional hazard models with mixed effects were used for the analysis.ResultsCox analyses revealed that sagittal plane pelvic tilt and frontal plane pelvic obliquity were not associated with LBP in floorball and basketball players during the follow-up. The hazard ratios for pelvic tilt and pelvic obliquity ranged between 0.93 and 1.08 (95% CIs between 0.91 and 1.07 and 0.83 and 1.29), respectively.ConclusionsPelvic movement during the SKL test is not associated with future LBP in youth floorball and basketball players.     

Immediate functional progression program in adolescent athletes with a spondylolysis

ObjectiveTo assess the preliminary evidence for the efficacy and safety of an immediate functional progression program to treat adolescent athletes with an active spondylolysis.DesignProspective single-arm trial.SettingHospital-based sports medicine and physical therapy clinic.ParticipantsTwelve adolescent athletes (14.2 ± 2 years, 25% female) with an active spondylolysis.Main outcome measuresClinical outcomes included time out of sport, Micheli Functional Scale (Function and Pain) and adverse reactions. Clinical outcomes were assessed at baseline, 1 month, 3 months and 6 months. Magnetic resonance imaging was performed at baseline and 3 months to confirm diagnosis and assess healing of lesion.ResultsEleven participants (92%) fully returned to sport in a median time of 2.5 months (75 days; interquartile range 55 days, 85 days). All participants demonstrated marked improvements in pain and function by the end of the program. One participant (8%) had an adverse reaction during care with a significant recurrence of LBP and had not returned to sport by 6 months. Magnetic resonance imaging demonstrated improvement of the spondylolytic lesion in all but one participant.ConclusionThe immediate functional progression program appears a viable method for treating active spondylolysis and warrants future research.     

Kv4.3 Channel Dysfunction Contributes to Trigeminal Neuropathic Pain Manifested with Orofacial Cold Hypersensitivity in Rats

Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K⁺ currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K⁺ channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain.SIGNIFICANCE STATEMENT Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K⁺ channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.     

Temporal Contribution of Myeloid-Lineage TLR4 to the Transition to Chronic Pain: A Focus on Sex Differences

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sex-dependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigorously characterize a novel spatiotemporal transgenic mouse line, Cx3CR1-Cre^ERT2-eYFP;TLR4^fl/fl (TLR4 cKO) to specifically knock out TLR4 only in microglia and no other myeloid-lineage cells. Using this transgenic mouse, we find that early TLR4 cKO results in profound improvement in chronic, but not acute, allodynia in males, with a significant but less robust effect in females. In contrast, late TLR4 cKO results in partial improvement in allodynia in both sexes, suggesting that downstream cellular or molecular TLR4-independent events may have already been triggered. Overall, we find that the contribution of TLR4 is time- and microglia-dependent in both sexes; however, females also rely on peripheral myeloid-lineage (or other TLR4 expressing) cells to trigger chronic pain.SIGNIFICANCE STATEMENT The contribution of myeloid cell TLR4 to sex-specific pain progression remains controversial. We used complementary pharmacologic and transgenic approaches to specifically manipulate TLR4 based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We discovered that microglial TLR4 contributes to early pain progression in males, and to a lesser extent in females. We further found that maintenance of chronic pain likely occurs through myeloid TLR4-independent mechanisms in both sexes. Together, we define a more nuanced contribution of this receptor to the acute-to-chronic pain transition in a mouse model of complex regional pain syndrome.     

Conservative and Surgical Treatment Improves Pain and Ankle-Brachial Index in Patients with Lumbar Spinal Stenosis

Purpose

The pathological mechanism of lumbar spinal stenosis is reduced blood flow in nerve roots and degeneration of nerve roots. Exercise and prostaglandin E1 is used for patients with peripheral arterial disease to increase capillary flow around the main artery and improve symptoms; however, the ankle-brachial index (ABI), an estimation of blood flow in the main artery in the leg, does not change after treatment. Lumbar spinal nerve roots contain somatosensory, somatomotor, and unmyelinated autonomic nerves. Improved blood flow by medication with prostaglandin E1 and decompression surgery in these spinal nerve roots may improve the function of nerve fibers innervating muscle, capillary, and main vessels in the lower leg, resulting in an increased ABI. The purpose of the study was to examine whether these treatments can improve ABI.

Materials and Methods

One hundred and seven patients who received conservative treatment such as exercise and medication (n=56) or surgical treatment (n=51) were included. Low back pain and leg pain scores, walking distance, and ABI were measured before treatment and after 3 months of conservative treatment alone or surgical treatment followed by conservative treatment.

Results

Low back pain, leg pain, and walking distance significantly improved after both treatments (p<0.05). ABI significantly increased in each group (p<0.05).

Conclusion

This is the first investigation of changes in ABI after treatment in patients with lumbar spinal stenosis. Improvement of the spinal nerve roots by medication and decompression surgery may improve the supply of blood flow to the lower leg in patients with lumbar spinal stenosis.     

Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice

The reactivity of microglia within the spinal cord in response to nerve injury, has been associated with the development and maintenance of neuropathic pain. However, the temporal changes in microglial reactivity following nerve injury remains to be defined. Importantly, the magnitude of behavioural allodynia displayed and the relationship to the phenotypic microglial changes is also unexplored. Using a heterozygous CX₃CR₁ ^gfp+ transgenic mouse strain, we monitored microglial activity as measured by cell density, morphology, process movement and process length over 14 days following chronic constriction of the sciatic nerve via in vivo confocal microscopy. Uniquely this relationship was explored in groups of male mice which had graded nerve injury and associated graded behavioural mechanical nociceptive sensitivity. Significant mechanical allodynia was quantified from the ipsilateral hind paw and this interacted with the extent of nerve injury from day 5 to day 14 (p < 0.009). The extent of this ipsilateral allodynia was proportional to the nerve injury from day 5 to 14 (Spearman rho = −0.58 to −0.77; p < 0.002). This approach allowed for the assessment of the association of spinal microglial changes with the magnitude of the mechanical sensitivity quantified behaviourally. Additionally, the haemodynamic response in the somatosensory cortex was quantified as a surrogate measure of neuronal activity. We found that spinal dorsal horn microglia underwent changes unilateral to the injury in density (Spearman rho = 0.47; p = 0.01), velocity (Spearman rho = −0.68; p = 0.00009), and circularity (Spearman rho = 0.55; p = 0.01) proportional to the degree of the neuronal injury. Importantly, these data demonstrate for the first time that the mechanical allodynia behaviour is not a binary all or nothing state, and that microglial reactivity change proportional to this behavioural measurement. Increased total haemoglobin levels in the somatosensory cortex of higher-grade injured animals was observed when compared to sham controls suggesting increased neuronal activity in this brain region. The degree of phenotypic microglial changes quantified here, may explain how microglia can induce both rapid onset and sustained functional changes in the spinal cord dorsal horn, following peripheral injury.