Targeting neurotrophic factors for low back pain and sciatica: a systematic review and meta-analysis.

OBJECTIVES: This meta-analysis aims to investigate the efficacy and safety of medicines that target neurotrophic factors for low back pain (LBP) or sciatica. METHODS: We searched published and trial registry reports of randomized controlled trials evaluating the effect of medicines that target neurotrophic factors to LBP or sciatica in seven databases from inception to December 2020. Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty in the evidence. RESULTS: Nine studies (3370 participants) were included in the meta-analyses. Low certainty evidence showed that anti-nerve growth factor (NGF) may reduce pain at 4 weeks (mean difference [MD] -6.75, 95% CI: -8.61, -4.90) and 12 weeks (MD -6.16, 95% CI: -8.38, -3.94), and may increase adverse effects for chronic LBP (odds ratio [OR] 1.18, 95% CI: 1.01, 1.38). Higher doses of anti-NGF may offer a clinically important reduction in pain at the cost of increased adverse effects for chronic LBP. Very low certainty evidence showed that anti-NGF and glial cell line-derived neurotrophic factor (pro-GDNF) may not reduce pain for sciatica at 4 weeks (MD -1.40, 95% CI: -8.26, 5.46), at 12 weeks (MD -2.91, 95% CI: -13.69, 7.67) and may increase adverse effects for sciatica (OR 3.27, 95% CI: 1.78, 6.00). CONCLUSION: Anti-NGF may offer small reductions in pain intensity for chronic LBP. The effect may depend on the dose and types of medicines. For sciatica, anti-NGF or pro-GDNF may not reduce pain. Medicines that target neurotrophic factors for LBP or sciatica are associated with different adverse effects compared to those observed in commonly prescribed medicines for these conditions.

The analgesic effect of electroencephalographic neurofeedback for people with chronic pain: A systematic review and meta-analysis.

BACKGROUND: Electroencephalographic (EEG) neurofeedback has been utilized to regulate abnormal brain activity associated with chronic pain. METHODS: In this systematic review, we synthesized the evidence from randomized controlled trials (RCTs) to evaluate the effect of EEG neurofeedback on chronic pain using random effects meta-analyses. Additionally, we performed a narrative review to explore the results of non-randomized studies. The quality of included studies was assessed using Cochrane risk of bias tools, and the GRADE system was used to rate the certainty of evidence. RESULTS: Ten RCTs and 13 non-randomized studies were included. The primary meta-analysis on nine eligible RCTs indicated that although there is low confidence, EEG neurofeedback may have a clinically meaningful effect on pain intensity in short-term. Removing the studies with high risk of bias from the primary meta-analysis resulted in moderate confidence that there remained a clinically meaningful effect on pain intensity. We could not draw any conclusion from the findings of non-randomized studies, as they were mostly non-comparative trials or explorative case series. However, the extracted data indicated that the neurofeedback protocols in both RCTs and non-randomized studies mainly involved the conventional EEG neurofeedback approach, which targeted reinforcing either alpha or sensorimotor rhythms and suppressing theta and/or beta bands on one brain region at a time. A posthoc analysis of RCTs utilizing the conventional approach resulted in a clinically meaningful effect estimate for pain intensity. CONCLUSION: Although there is promising evidence on the analgesic effect of EEG neurofeedback, further studies with larger sample sizes and higher quality of evidence are required.

A Systematic Review of the Reporting Quality of Observational Studies That Use Mediation Analyses.

Mediation analysis is a common statistical method used to investigate mechanisms of health exposure and interventions. The reporting quality of mediation studies used in randomised controlled trials has been considered heterogeneous and incomplete. The reporting quality of mediation analysis in observational studies is unknown. We conducted a systematic review to describe the reporting standards of recently published observational studies that used mediation analysis to understand the mechanism of health exposures. We searched for studies published between June 2017 and June 2019 indexed in EMBASE, MEDLINE and PsycINFO. Two reviewers screened articles and selected a random sample of 50 eligible studies for inclusion. We included studies across 13 healthcare fields and ten different health conditions. Most studies (74%) collected data on healthy individuals to assess their risk of developing a health disorder. Psychosocial and behavioural factors (self-control, self-esteem, alcohol consumption, pain) were the most prevalent exposures (n = 30, 60%), outcomes (n = 23, 46%) and mediators (n = 29, 58%). Most studies used a cross-sectional design (64%, n = 32), and a few studies reported sample size calculations (4%, n = 8). In 20% (n = 10) of the studies, adjustment for confounders was reported. Only 10% (n = 5) of studies reported the assumptions underlying the mediation analysis, and 14% (n = 7) of studies conducted some sensitivity analysis to assess the degree which unmeasured confounders would affect the estimate of the mediation effect. Mediation analysis is a common method used to investigate mechanisms in prevention research. The reporting of mediation analysis in observational studies is incomplete and may impact reproducibility, evidence synthesis and implementation.

A neuro-cardiac self-regulation therapy to improve autonomic and neural function after SCI: a randomized controlled trial protocol.

BACKGROUND: Spinal cord injury (SCI) is associated with autonomic imbalance and significant secondary conditions, including cardiac and brain dysfunction that adversely impact health and wellbeing. This study will investigate the effectiveness (intention-to-treat) of a neuro-cardiac self-regulation therapy to improve autonomic and neural/brain activity in adults with SCI living in the community. METHODS: A two-arm parallel, randomised controlled trial in which adults with SCI living in the community post-rehabilitation will be randomly assigned to a treatment or control group. The treatment group (N = 60) aged 18-70 years with a chronic traumatic or non-traumatic SCI, will receive intervention sessions once per week for 10 weeks, designed to regulate autonomic activity using computer-based feedback of heart rate variability and controlled breathing (called HRV-F). Comprehensive neurophysiological and psychological assessment will occur at baseline, immediate post-treatment, and 6 and 12-months post-treatment. Primary outcome measures include electrocardiography/heart rate variability (to assess autonomic nervous system function) and transcranial doppler sonography (to assess cerebral blood circulation in basal cerebral arteries). Secondary outcomes measures include continuous blood pressure, electroencephalography, functional near-infrared spectroscopy, respiration/breath rate, electrooculography, cognitive capacity, psychological status, pain, fatigue, sleep and quality of life. Controls (N = 60) will receive usual community care, reading material and a brief telephone call once per week for 10 weeks and be similarly assessed over the same time period as the HRV-F group. Linear mixed model analysis with repeated measures will determine effectiveness of HRV-F and latent class mixture modelling used to determine trajectories for primary and selected secondary outcomes of interest. DISCUSSION: Treatments for improving autonomic function after SCI are limited. It is therefore important to establish whether a neuro-cardiac self-regulation therapy can result in improved autonomic functioning post-SCI, as well as whether HRV-F is associated with better outcomes for secondary conditions such as cardiovascular health, cognitive capacity and mental health. TRIAL REGISTRATION: The study has been prospectively registered with the Australian and New Zealand Clinical Trial Registry ( ACTRN12621000870853 .aspx). Date of Registration: 6th July 2021. Trial Sponsor: The University of Sydney, NSW 2006. Protocol version: 22/07/2021.

Impact of acute stress on cortical electrical activity and cardiac autonomic coupling.

Assessment of heart rate variability (reflective of the cardiac autonomic nervous system) has shown some predictive power for stress. Further, the predictive power of the distinct patterns of cortical brain activity and - cardiac autonomic interactions are yet to be explored in the context of acute stress, as assessed by an electrocardiogram and electroencephalogram. The present study identified distinct patterns of neural-cardiac autonomic coupling during both resting and acute stress states. In particular, during the stress task, frontal delta waves activity was positively associated with low-frequency heart rate variability and negatively associated with high-frequency heart rate variability. Low high-frequency power is associated with stress and anxiety and reduced vagal control. A positive association between resting high-frequency heart rate variability and frontocentral gamma activity was found, with a direct inverse relationship of low-frequency heart rate variability and gamma wave coupling at rest. During the stress task, low-frequency heart rate variability was positively associated with frontal delta activity. That is, the parasympathetic nervous system is reduced during a stress task, whereas frontal delta wave activity is increased. Our findings suggest an association between cardiac parasympathetic nervous system activity and frontocentral gamma and delta activity at rest and during acute stress. This suggests that parasympathetic activity is decreased during acute stress, and this is coupled with neuronal cortical prefrontal activity. The distinct patterns of neural-cardiac coupling identified in this study provide a unique insight into the dynamic associations between brain and heart function during both resting and acute stress states.

New evidence for preserved somatosensory pathways in complete spinal cord injury: A fMRI study.

Trauma to the spinal cord rarely results in complete division of the cord with surviving nerves sometimes remaining silent or failing to function normally. The term motor or sensory discomplete has been used to describe this important but unclassified subgroup of complete SCI. Importantly, silent motor or sensory pathways may contribute to aversive symptoms (spasticity, pain) or improved treatment success. To demonstrate more objectively the presence of subclinical preserved somatosensory pathways in clinically complete SCI, a cross-sectional study using functional MRI (fMRI) was undertaken. The presence of brain activation following innocuous brushing of an insensate region below-injury (great toe) was analyzed in 23 people (19 males (83%), mean ± SD age 43 ± 13 years) with clinically complete (AIS A) SCI with (n = 13) and without (n = 10) below-level neuropathic pain and 21 people without SCI or pain (15 males (71%); mean ± SD age 41 ± 14 years). Location appropriate, significant fMRI brain activation was detected in 48% (n = 11/23) of subjects with clinically complete SCI from below-injury stimulation. No association was found between the presence of subclinical sensory pathways transmitting innocuous mechanical stimuli (dorsal column medical lemniscal) and below-level neuropathic pain (χ2  = 0.034, P = 0.9). The high prevalence of sensory discomplete injuries (∼50% complete SCI) strengthens the case to explore inclusion of this category into the international SCI taxonomy (ISNCSCI). This would ensure more widespread inclusion of discomplete SCI in ongoing pain and motor recovery research. Neurophysiological tests such as fMRI may play a role in this process. Hum Brain Mapp 39:588-598, 2018. © 2017 Wiley Periodicals, Inc.

The reliability of eyetracking to assess attentional bias to threatening words in healthy individuals.

Eyetracking is commonly used to investigate attentional bias. Although some studies have investigated the internal consistency of eyetracking, data are scarce on the test-retest reliability and agreement of eyetracking to investigate attentional bias. This study reports the test-retest reliability, measurement error, and internal consistency of 12 commonly used outcome measures thought to reflect the different components of attentional bias: overall attention, early attention, and late attention. Healthy participants completed a preferential-looking eyetracking task that involved the presentation of threatening (sensory words, general threat words, and affective words) and nonthreatening words. We used intraclass correlation coefficients (ICCs) to measure test-retest reliability (ICC > .70 indicates adequate reliability). The ICCs(2, 1) ranged from -.31 to .71. Reliability varied according to the outcome measure and threat word category. Sensory words had a lower mean ICC (.08) than either affective words (.32) or general threat words (.29). A longer exposure time was associated with higher test-retest reliability. All of the outcome measures, except second-run dwell time, demonstrated low measurement error (<6%). Most of the outcome measures reported high internal consistency (α > .93). Recommendations are discussed for improving the reliability of eyetracking tasks in future research.

Anatomical changes at the level of the primary synapse in neuropathic pain: evidence from the spinal trigeminal nucleus.

Accumulated evidence from experimental animal models suggests that neuronal loss within the dorsal horn is involved in the development and/or maintenance of peripheral neuropathic pain. However, to date, no study has specifically investigated whether such neuroanatomical changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the spinal trigeminal nucleus in subjects with chronic orofacial neuropathic pain. In 22 subjects with painful trigeminal neuropathy and 44 pain-free controls, voxel-based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional gray matter volume and microstructural changes within the brainstem. In addition, deterministic tractography was used to assess the integrity of ascending pain pathways. Orofacial neuropathic pain was associated with significant regional gray matter volume decreases, fractional anisotropy increases, and mean diffusivity decreases within the spinal trigeminal nucleus, specifically the subnucleus oralis. In addition, tractography revealed no significant differences in diffusivity properties in the root entry zone of the trigeminal nerve, the spinal trigeminal tract, or the ventral trigeminothalamic tracts in painful trigeminal neuropathy subjects compared with controls. These data reveal that chronic neuropathic pain in humans is associated with discrete alterations in the anatomy of the primary synapse. These neuroanatomical changes may be critical for the generation and/or maintenance of pathological pain.

Pain and Personality: Do Individuals with Different Forms of Chronic Pain Exhibit a Mutual Personality?

The role of personality in the experience of chronic pain is a growing field, with endless debate regarding the existence of a "pain personality". This study aims to compare different chronic pain types and consolidate the existence of a common personality. Thirty-two females with chronic orofacial pain and 37 age-matched healthy females were assessed with the Temperament and Character Inventory-Revised. Chronic pain subjects had either trigeminal neuropathy (neuropathic pain) or temporomandibular disorders (nociceptive pain). This study revealed that individuals with different chronic pain types exhibit a mutual personality profile encompassing significantly higher scores in Harm Avoidance and significantly lower scores in Self-Directedness when compared to healthy subjects. In fact, this combination is associated with Cluster C personality disorders. In conclusion, our study reveals that irrespective of type, chronic pain may be associated with Cluster C personality disorders. Indeed, there has never been empirical evidence in the past to suggest that chronic pain as an overall concept is associated with any particular personality disorders. Therefore, a potential future avenue of chronic pain treatment may lie in targeting particular personality aspects and shift the target of pain-relieving treatments from sensory and psychologically state focused to psychologically trait focused.

Chronic pain: lost inhibition?

Human brain imaging has revealed that acute pain results from activation of a network of brain regions, including the somatosensory, insular, prefrontal, and cingulate cortices. In contrast, many investigations report little or no alteration in brain activity associated with chronic pain, particularly neuropathic pain. It has been hypothesized that neuropathic pain results from misinterpretation of thalamocortical activity, and recent evidence has revealed altered thalamocortical rhythm in individuals with neuropathic pain. Indeed, it was suggested nearly four decades ago that neuropathic pain may be maintained by a discrete central generator, possibly within the thalamus. In this investigation, we used multiple brain imaging techniques to explore central changes in subjects with neuropathic pain of the trigeminal nerve resulting in most cases (20 of 23) from a surgical event. Individuals with chronic neuropathic pain displayed significant somatosensory thalamus volume loss (voxel-based morphometry) which was associated with decreased thalamic reticular nucleus and primary somatosensory cortex activity (quantitative arterial spin labeling). Furthermore, thalamic inhibitory neurotransmitter content was significantly reduced (magnetic resonance spectroscopy), which was significantly correlated to the degree of functional connectivity between the somatosensory thalamus and cortical regions including the primary and secondary somatosensory cortices, anterior insula, and cerebellar cortex. These data suggest that chronic neuropathic pain is associated with altered thalamic anatomy and activity, which may result in disturbed thalamocortical circuits. This disturbed thalamocortical activity may result in the constant perception of pain.

Emotion regulation skills-focused interventions for chronic pain: A systematic review and meta-analysis.

OBJECTIVES: To investigate the effect of emotion regulation skills-focused (ERSF) interventions to reduce pain intensity and improve psychological outcomes for people with chronic pain and to narratively report on safety and intervention compliance. METHODS: Six databases and four registries were searched for randomized controlled trials (RCTs) up to 29 April 2022. Risk of bias was evaluated using the Cochrane RoB 2.0 tool, and certainty of evidence was assessed according to the Grading, Assessment, Development and Evaluation (GRADE). Meta-analyses for eight studies (902 participants) assessed pain intensity (primary outcome), emotion regulation, affect, symptoms of depression and anxiety, and pain interference (secondary outcomes), at two time points when available, post-intervention (closest to intervention end) and follow-up (the first measurement after the post-intervention assessment). RESULTS: Compared to TAU, pain intensity improved post-intervention (weighted mean difference [WMD] = -10.86; 95% confidence interval [CI] [-17.55, -2.56]) and at follow-up (WMD = -11.38; 95% CI [-13.55, -9.21]). Emotion regulation improved post-intervention (standard mean difference [SMD] = 0.57; 95% CI [0.14, 1.01]), and depressive symptoms improved at follow-up (SMD = -0.45; 95% CI [-0.66, -0.24]). Compared to active comparators, anxiety symptoms improved favouring the comparator post-intervention (SMD = 0.10; 95% CI [0.03, 0.18]), and compared to CBT, pain interference improved post-intervention (SMD = -0.37; 95% CI [-0.69, -0.04]). Certainty of evidence ranged from very low to moderate. SIGNIFICANCE: The findings provide evidence that ERSF interventions reduce pain intensity for people with chronic pain compared to usual treatment. These interventions are at least as beneficial to reduce pain intensity as the current gold standard psychological intervention, CBT. However, the limited number of studies and certainty of evidence mean further high-quality RCTs are warranted. Additionally, further research is needed to identify whether ERSF interventions may be more beneficial for specific chronic pain conditions.

Pain and plasticity: is chronic pain always associated with somatosensory cortex activity and reorganization?

The somatosensory cortex remodels in response to sensory deprivation, with regions deprived of input invaded by neighboring representations. The degree of cortical reorganization is correlated with ongoing pain intensity, which has led to the assumption that chronic pain conditions are invariably associated with somatosensory cortex reorganization. Because the presentation and etiology of chronic pain vary, we determined whether cortical changes in human subjects are similar for differing pain types. Using functional and anatomical magnetic resonance imaging, we found that, while human patients with neuropathic pain displayed cortical reorganization and changes in somatosensory cortex activity, patients with non-neuropathic chronic pain did not. Furthermore, cortical reorganization in neuropathic pain patients was associated with changes in regional anatomy. These data, by showing that pain per se is not associated with cortical plasticity, suggest that treatments aimed at reversing cortical reorganization should only be considered for use in patients with certain types of chronic pain.

Depressive symptoms moderate functional connectivity within the emotional brain in chronic pain.

BACKGROUND: Depressive symptoms are often comorbid with chronic pain. These conditions share aberrant emotion processing and regulation, as well as having common brain networks. However, the relationship between depressive symptoms and chronic pain and the effects on emotional brain function are unclear. AIMS: The present study aimed to disentangle the effects of chronic pain and depressive symptoms on functional connectivity between regions implicated in both these conditions. METHOD: Twenty-six individuals with chronic pain (referred to as the pain group) and 32 healthy controls underwent resting-state functional magnetic resonance imaging and completed the Beck Depression Inventory. Main effects of group, depressive symptoms (total severity score) and their interaction on the functional connectivity of three seed regions (the left and right amygdalae and the medial prefrontal cortex; mPFC) with the rest of the brain were evaluated. In cases of significant interaction, moderation analyses were conducted. RESULTS: The group × depressive symptoms interaction was significantly associated with changes in connectivity between the right amygdala and the mPFC (family-wise error-corrected P-threshold (pFWEc = 0.008). In the moderation analysis, the pain group showed weaker connectivity between these regions at lower levels of depressive symptoms (P = 0.020), and stronger connectivity at higher levels of depressive symptoms (P = 0.003), compared with the healthy controls. In addition, the strength of connectivity decreased in the healthy controls (P = 0.005) and increased in the pain group (P = 0.014) as the severity of depressive symptoms increased. CONCLUSIONS: Depressive symptoms moderate the impact of chronic pain on emotional brain function, with potential implications for the choice of treatment for chronic pain.

Internet-Delivered Dialectical Behavioral Therapy Skills Training for Chronic Pain: Protocol for a Randomized Controlled Trial.

BACKGROUND: Emotion dysregulation is key to the development and maintenance of chronic pain, feeding into a cycle of worsening pain and disability. Dialectical behavioral therapy (DBT), an evidence-based treatment for complex transdiagnostic conditions presenting with high emotion dysregulation, may be beneficial to manage and mitigate the emotional and sensory aspects of chronic pain. Increasingly, DBT skills training as a key component of standard DBT is being delivered as a stand-alone intervention without concurrent therapy to help develop skills for effective emotion regulation. A previous repeated-measure single-case trial investigating a novel technologically driven DBT skills training, internet-delivered DBT skills training for chronic pain (iDBT-Pain), revealed promising findings to improve both emotion dysregulation and pain intensity. OBJECTIVE: This randomized controlled trial aims to examine the efficacy of iDBT-Pain in comparison with treatment as usual to reduce emotion dysregulation (primary outcome) for individuals with chronic pain after 9 weeks and at the 21-week follow-up. The secondary outcomes include pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, posttraumatic stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. The trial also examines the acceptability of the iDBT-Pain intervention for future development and testing. METHODS: A total of 48 people with chronic pain will be randomly assigned to 1 of 2 conditions: treatment and treatment as usual. Participants in the treatment condition will receive iDBT-Pain, consisting of 6 live web-based group sessions led by a DBT skills trainer and supervised by a registered psychologist and the iDBT-Pain app. Participants in the treatment-as-usual condition will not receive iDBT-Pain but will still access their usual medication and health interventions. We predict that iDBT-Pain will improve the primary outcome of emotion dysregulation and the secondary outcomes of pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. A linear mixed model with random effects of individuals will be conducted to investigate the differences between the baseline, 9-week (primary end point), and 21-week (follow-up) assessments as a function of experimental condition. RESULTS: Recruitment started in February 2023, and the clinical trial started in March 2023. Data collection for the final assessment is planned to be completed by July 2024. CONCLUSIONS: If our hypothesis is confirmed, our findings will contribute to the evidence for the efficacy and acceptability of a viable intervention that may be used by health care professionals for people with chronic pain. The results will add to the chronic pain literature to inform about the potential benefits of DBT skills training for chronic pain and will contribute evidence about technologically driven interventions. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12622000113752; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383208&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/41890.

Central neuropathic pain.

Central neuropathic pain arises from a lesion or disease of the central somatosensory nervous system such as brain injury, spinal cord injury, stroke, multiple sclerosis or related neuroinflammatory conditions. The incidence of central neuropathic pain differs based on its underlying cause. Individuals with spinal cord injury are at the highest risk; however, central post-stroke pain is the most prevalent form of central neuropathic pain worldwide. The mechanisms that underlie central neuropathic pain are not fully understood, but the pathophysiology likely involves intricate interactions and maladaptive plasticity within spinal circuits and brain circuits associated with nociception and antinociception coupled with neuronal hyperexcitability. Modulation of neuronal activity, neuron-glia and neuro-immune interactions and targeting pain-related alterations in brain connectivity, represent potential therapeutic approaches. Current evidence-based pharmacological treatments include antidepressants and gabapentinoids as first-line options. Non-pharmacological pain management options include self-management strategies, exercise and neuromodulation. A comprehensive pain history and clinical examination form the foundation of central neuropathic pain classification, identification of potential risk factors and stratification of patients for clinical trials. Advanced neurophysiological and neuroimaging techniques hold promise to improve the understanding of mechanisms that underlie central neuropathic pain and as predictive biomarkers of treatment outcome.

"My Back is Fit for Movement": A Qualitative Study Alongside a Randomized Controlled Trial for Chronic Low Back Pain.

A new wave of treatments has emerged to target nervous system alterations and maladaptive conceptualizations about pain for chronic low back pain. The acceptability of these treatments is still uncertain. We conducted a qualitative study alongside a randomized controlled trial to identify perceptions of facilitators or barriers to participation in a non-pharmacological intervention that resulted in clinically meaningful reductions across 12 months for disability compared to a sham intervention. We conducted semi-structured interviews with participants from the trial's active arm after they completed the 12-week program. We included a purposeful sample (baseline and clinical characteristics) (n = 20). We used reflexive thematic analysis informed by the Theoretical Framework of Acceptability for health care interventions. We identified positive and negative emotional/cognitive responses associated with treatment acceptability and potential efficacy, including emotional support, cognitive empowerment, readiness for self-management, and acceptance of face-to-face and online components designed to target the brain. These findings suggest the importance of psychoeducation and behavior change techniques to create a positive attitude towards movement and increase the perception of pain control; systematic approaches to monitor and target misconceptions about the interventions during treatment; and psychoeducation and behavior change techniques to maintain the improvements after the cessation of formal care. PERSPECTIVE: This article presents the experiences of people with chronic low back pain participating in a new non-pharmacological brain-targeted treatment that includes face-to-face and self-directed approaches. The facilitators and barriers of the interventions could potentially inform adaptations and optimization of treatments designed to target the brain to treat chronic low back pain.

Cortical Mechanisms Underlying Immersive Interactive Virtual Walking Treatment for Amelioration of Neuropathic Pain after Spinal Cord Injury: Findings from a Preliminary Investigation of Thalamic Inhibitory Function.

BACKGROUND: Neuropathic pain following spinal cord injury (SCI) affects approximately 60% of individuals with SCI. Effective pharmacological and non-pharmacological treatments remain elusive. We recently demonstrated that our immersive virtual reality walking intervention (VRWalk) may be effective for SCI NP. Additionally, we found that SCI NP may result from a decrease in thalamic γ-aminobutyric-acid (GABA), which disturbs central sensorimotor processing. OBJECTIVE: While we identified GABAergic changes associated with SCI NP, a critical outstanding question is whether a decrease in SCI NP generated by our VRWalk intervention causes GABA content to rise. METHOD: A subset of participants (n = 7) of our VRWalk trial underwent magnetic resonance spectroscopy pre- and post-VRWalk intervention to determine if the decrease in SCI NP is associated with an increase in thalamic GABA. RESULTS: The findings revealed a significant increase in thalamic GABA content from pre- to post-VRWalk treatment. CONCLUSION: While the current findings are preliminary and should be interpreted with caution, pre- to post-VRWalk reductions in SCI NP may be mediated by pre- to post-treatment increases in thalamic GABA by targeting and normalizing maladaptive sensorimotor cortex reorganization. Understanding the underlying mechanisms of pain recovery can serve to validate the efficacy of home-based VR walking treatment as a means of managing pain following SCI. Neuromodulatory interventions aimed at increasing thalamic inhibitory function may provide more effective pain relief than currently available treatments.

Comparative effectiveness and safety of analgesic medicines for adults with acute non-specific low back pain: systematic review and network meta-analysis.

OBJECTIVE: To evaluate the comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, PubMed, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and World Health Organization's International Clinical Trials Registry Platform from database inception to 20 February 2022. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials of analgesic medicines (eg, non-steroidal anti-inflammatory drugs, paracetamol, opioids, anti-convulsant drugs, skeletal muscle relaxants, or corticosteroids) compared with another analgesic medicine, placebo, or no treatment. Adults (≥18 years) who reported acute non-specific low back pain (for less than six weeks). DATA EXTRACTION AND SYNTHESIS: Primary outcomes were low back pain intensity (0-100 scale) at end of treatment and safety (number of participants who reported any adverse event during treatment). Secondary outcomes were low back specific function, serious adverse events, and discontinuation from treatment. Two reviewers independently identified studies, extracted data, and assessed risk of bias. A random effects network meta-analysis was done and confidence was evaluated by the Confidence in Network Meta-Analysis method. RESULTS: 98 randomised controlled trials (15 134 participants, 49% women) included 69 different medicines or combinations. Low or very low confidence was noted in evidence for reduced pain intensity after treatment with tolperisone (mean difference -26.1 (95% confidence intervals -34.0 to -18.2)), aceclofenac plus tizanidine (-26.1 (-38.5 to -13.6)), pregabalin (-24.7 (-34.6 to -14.7)), and 14 other medicines compared with placebo. Low or very low confidence was noted for no difference between the effects of several of these medicines. Increased adverse events had moderate to very low confidence with tramadol (risk ratio 2.6 (95% confidence interval 1.5 to 4.5)), paracetamol plus sustained release tramadol (2.4 (1.5 to 3.8)), baclofen (2.3 (1.5 to 3.4)), and paracetamol plus tramadol (2.1 (1.3 to 3.4)) compared with placebo. These medicines could increase the risk of adverse events compared with other medicines with moderate to low confidence. Moderate to low confidence was also noted for secondary outcomes and secondary analysis of medicine classes. CONCLUSIONS: The comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain are uncertain. Until higher quality randomised controlled trials of head-to-head comparisons are published, clinicians and patients are recommended to take a cautious approach to manage acute non-specific low back pain with analgesic medicines. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019145257.

Functional reorganization of the brain in humans following spinal cord injury: evidence for underlying changes in cortical anatomy.

Loss of somatosensory drive results in functional reorganization of the primary somatosensory cortex (SI). While the phenomenon of functional cortical reorganization is well established, it remains unknown whether in humans, functional reorganization results from changes in brain anatomy, or simply reflects an unmasking of already existing dormant synapses. In 20 subjects with complete thoracic spinal cord injuries (SCIs) and 23 controls, we used functional and structural magnetic resonance imaging to determine whether SI reorganization was associated with changes in SI anatomy. SCI resulted in a significant SI reorganization, with the little finger representation moving medially toward the lower body representation (i.e., area of sensory loss). Furthermore, although SCI was associated with gray matter volume loss in the lower body representation, this loss was minimized as reorganization increased. That is, the greater the medial shift in little finger representation, the greater the gray matter preservation in the lower body representation. In addition, in the region of greatest SI reorganization (little finger), fractional anisotropy was correlated with SI reorganization. That is, as SI reorganization increased, the extent of aligned structures decreased. Finally, although thalamocortical fibers remained unchanged, the ease and direction of water movement within the little finger representation was altered, being directed more toward the midline in SCI subjects. These data show that SI reorganization following SCI is associated with changes in SI anatomy and provide compelling evidence that SI reorganization in humans results from the growth of new lateral connections, and not simply from the unmasking of already existing lateral connections.

Different pain, different brain: thalamic anatomy in neuropathic and non-neuropathic chronic pain syndromes.

Trigeminal neuropathic pain (TNP) and temporomandibular disorders (TMD) are thought to have fundamentally different etiologies. It has been proposed that TNP arises through damage to, or pressure on, somatosensory afferents in the trigeminal nerve, whereas TMD results primarily from peripheral nociceptor activation. Because some reports suggest that neuropathic pain is associated with changes in brain anatomy, it is possible that TNP is maintained by changes in higher brain structures, whereas TMD is not. The aim of this investigation is to determine whether changes in regional brain anatomy and biochemistry occur in both conditions. Twenty-one TNP subjects, 20 TMD subjects, and 36 healthy controls were recruited. Voxel-based morphometry of T1-weighted anatomical images revealed no significant regional gray matter volume change in TMD patients. In contrast, gray matter volume of TNP patients was reduced in the primary somatosensory cortex, anterior insula, putamen, nucleus accumbens, and the thalamus, whereas gray matter volume was increased in the posterior insula. The thalamic volume decrease was only seen in the TNP patients classified as having trigeminal neuropathy but not those with trigeminal neuralgia. Furthermore, in trigeminal neuropathy patients, magnetic resonance spectroscopy revealed a significant reduction in the N-acetylaspartate/creatine ratio, a biochemical marker of neural viability, in the region of thalamic volume loss. The data suggest that the pathogenesis underlying neuropathic and non-neuropathic pain conditions are fundamentally different and that neuropathic pain conditions that result from peripheral injuries may be generated and/or maintained by structural changes in regions such as the thalamus.