The influence of pain hypersensitivity and psychological factors on pain and disability in the transition from acute to chronic low back pain: a longitudinal exploratory investigation and cluster analysis.

Pain hypersensitivity is present in some people with acute low back pain (LBP) and thought to be involved in the development of chronic LBP. Early evidence suggests that pain hypersensitivity in acute LBP precedes poor long-term outcome. We aimed to examine whether the presence of pain hypersensitivity in acute LBP influenced recovery status at six months and differentiated how pain and disability changed over time. Participants with acute non-specific LBP (<6 weeks after pain onset, N=118) were included in this longitudinal study. Quantitative sensory testing including pressure and heat pain thresholds and conditioned pain modulation and questionnaires were compared at baseline and longitudinally (at three and six months) between recovered and unrecovered participants. Using k-means clustering, we identified subgroups based on baseline sensory measures alone, and in combination with psychological factors, and compared pain and disability outcomes between subgroups. Sensory measures did not differ at baseline or longitudinally between recovered (N=50) and unrecovered (N=68) participants. Subgrouping based on baseline sensory measures alone did not differentiate pain or disability outcomes at any timepoint. Participants with high psychological distress at baseline (N=19) had greater disability, but not pain, at all timepoints than those with low psychological distress, regardless of the degrees of pain sensitivity. Our findings suggest that pain hypersensitivity in acute LBP does not precede poor recovery at six months or differentiate how pain and disability change over time. High psychological distress during acute LBP is associated with unremitting and pronounced disability, while pain severity is unaffected. PERSPECTIVE: Pain hypersensitivity is thought to be involved in the transition to chronic LBP. Contradictory to prevailing hypothesis, our findings suggest pain hypersensitivity alone in acute LBP do not precede poor recovery. High psychological distress in acute LBP has stronger influence than pain hypersensitivity on long-term disability, but not pain outcomes.

Phosphene and motor transcranial magnetic stimulation thresholds are correlated: A meta-analytic investigation.

Transcranial magnetic stimulation (TMS) is commonly delivered at an intensity defined by the resting motor threshold (rMT), which is thought to represent cortical excitability, even if the TMS target area falls outside of the motor cortex. This approach rests on the assumption that cortical excitability, as measured through the motor cortex, represents a 'global' measure of excitability. Another common approach to measure cortical excitability relies on the phosphene threshold (PT), measured through the visual cortex of the brain. However, it remains unclear whether either estimate can serve as a singular measure to infer cortical excitability across different brain regions. If PT and rMT can indeed be used to infer cortical excitability across brain regions, they should be correlated. To test this, we systematically identified previous studies that measured PT and rMT to calculate an overall correlation between the two estimates. Our results, based on 16 effect sizes from eight studies, indicated that PT and rMT are correlated (ρ = 0.4), and thus one measure could potentially serve as a measure to infer cortical excitability across brain regions. Three exploratory meta-analyses revealed that the strength of the correlation is affected by different methodologies, and that PT intensities are higher than rMT. Evidence for a PT-rMT correlation remained robust across all analyses. Further research is necessary for an in-depth understanding of how cortical excitability is reflected through TMS.

Intramuscular injection of nerve growth factor as a model of temporomandibular disorder: nature, time-course, and sex differences characterising the pain experience.

Background: Temporomandibular disorder (TMD) is a common condition that frequently transitions to chronic symptoms. Experimental pain models that mimic the symptoms of clinical TMD may be useful in understanding the mechanisms, and sex differences, present in this disorder. Here we aimed to comprehensively characterise the nature and time-course of pain, functional impairment and hyperalgesia induced by repeated intramuscular injection of nerve growth factor (NGF) into the masseter muscle, and to investigate sex differences in the NGF-induced pain experience. Methods: 94 healthy individuals participated in a longitudinal study with 30-day follow-up. NGF was injected into the right masseter muscle on Day 0 and Day 2. Participants attended laboratory sessions to assess pain (Numerical Rating Scale; NRS), functional limitation (mouth opening distance, Jaw Functional Limitation Scale; JFLS) and mechanical sensitization (pressure pain thresholds; PPTs) on Days 0, 2 and 5 and completed twice daily electronic pain dairies from Day 0 to day 30. Results: Peak pain averaged 2.0/10 (95 % CI: 1.6-2.4) at rest and 4.3/10 (95 % CI: 3.9-4.8) on chewing. Pain-free mouth opening distance reduced from 5.0 cm (95 % CI: 4.8-5.1 cm) on Day 0 to 3.7 cm (95 % CI: 3.5-3.9 cm) on Day 5. The greatest reduction in PPTs was observed over the masseter muscle. Females experienced higher pain, greater functional impairment, and greater sensitivity to mechanical stimuli than males. Conclusion: Intramuscular injection of NGF is a useful model with which to explore the mechanisms, and sex differences, present in clinical TMD.

Effect of exercise on pain processing and motor output in people with knee osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: Guidelines recommend exercise as a core treatment for knee osteoarthritis. However, it is unclear how exercise affects measures of pain processing and motor function. The aim was to evaluate the effect of exercise on measures of pain processing and motor function in people with knee osteoarthritis. METHODS: We searched five electronic databases (MEDLINE, EMBASE, CINAHL, SCOPUS and Cochrane Central Register of Controlled Trials) for studies on knee osteoarthritis, of any design, evaluating pain processing and motor function before and after exercise. Data were pooled with random-effects meta-analysis. Study quality was assessed using the Downs and Black and quality of evidence was assessed using the GRADE. RESULTS: Eighteen studies were eligible and 16 were included. Following acute exercise, pressure pain threshold increased local to the study limb (standardised mean difference [95% confidence interval (CI)] 0.26, [0.02, 0.51], n = 159 from 5 studies), but there was no statistically significant change remote from the study limb (0.09, [-0.11, 0.29], n = 90 from 4 studies). Following an exercise program (range 5-12 weeks) there were no statistically significant changes in pressure pain threshold (local 0.23, [-0.01, 0.47], n = 218 from 8 studies; remote 0.33 [-0.13, 0.79], n = 76 from 4 studies), temporal pain summation (0.38 [-0.08, 0.85], n = 122 from 3 studies) or voluntary quadriceps muscle activation (4.23% [-1.84 to 10.30], n = 139 from 4 studies). CONCLUSION: Very-low quality evidence suggests that pressure pain threshold increases following acute exercise. Very-low quality evidence suggests that pressure pain threshold, temporal pain summation or voluntary quadriceps activation do not change statistically significantly following exercise programs.

Primary sensory and motor cortex function in response to acute muscle pain: A systematic review and meta-analysis.

Acute muscle pain has both motor and sensory consequences, yet the effect of muscle pain on the primary sensory (S1) and motor (M1) cortices has yet to be systematically evaluated. Here we aimed to determine the strength of the evidence for (1) altered activation of S1/M1 during and after pain, (2) the temporal profile of any change in activation and (3) the relationship between S1/M1 activity and the symptoms of pain. In September 2015, five electronic databases were systematically searched for neuroimaging and electrophysiological studies investigating the effect of acute experimental muscle pain on S1/M1 in healthy volunteers. Demographic data, methodological characteristics and primary outcomes for each study were extracted for critical appraisal. Meta-analyses were performed where appropriate. Twenty-five studies satisfied the inclusion criteria. There was consistent evidence from fMRI for increased S1 activation in the contralateral hemisphere during pain, but insufficient evidence to determine the effect at M1. Meta-analyses of TMS and EEG data revealed moderate to strong evidence of reduced S1 and corticomotor excitability during and following the resolution of muscle pain. A comprehensive understanding of the temporal profile of altered activity in S1/M1, and the relationship to symptoms of pain, is hampered by differences in methodological design, pain modality and pain severity between studies. Overall, the findings of this review indicate reduced S1 and corticomotor activity during and after resolution of acute muscle pain, mechanisms that could plausibly underpin altered sensorimotor function in pain. WHAT DOES THIS REVIEW ADD?: We provide the first systematic evaluation of the primary sensory (S1) and motor (M1) cortex response to acute experimental muscle pain in healthy volunteers. We present evidence from a range of methodologies to provide a comprehensive understanding of the effect of pain on S1/M1. Through meta-analyses we evaluate the strength of evidence concerning the direction and temporal profile of the S1/M1 response to acute muscle pain.

Altered function of intracortical networks in chronic lateral epicondylalgia.

BACKGROUND: Lateral epicondylalgia (LE) is a musculotendinous condition characterized by persistent pain, sensorimotor dysfunction and motor cortex reorganization. Although there is evidence linking cortical reorganization with clinical symptoms in LE, the mechanisms underpinning these changes are unknown. Here we investigated activity in motor cortical (M1) intracortical inhibitory and facilitatory networks in individuals with chronic LE and healthy controls. METHODS: Surface electromyography was recorded bilaterally from the extensor carpi radialis brevis (ECRB) muscle of 14 LE (4 men, 41.5 ± 9.9 years) and 14 control participants (4 men, 42.1 ± 11.1 years). Transcranial magnetic stimulation of M1 was used to evaluate resting and active motor threshold, corticomotor output, short- (SICI) and long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) of both hemispheres. RESULTS: In individuals with LE, SICI (p = 0.005), ICF (p = 0.026) and LICI (p = 0.046) were less in the M1 contralateral to the affected ECRB muscle compared with healthy controls. Motor cortical threshold (rest: p = 0.57, active: p = 0.97) and corticomotor output (p = 0.15) were similar between groups. No differences were observed between individuals with LE and healthy controls for the M1 contralateral to the unaffected ECRB muscle. CONCLUSIONS: These data provide evidence of less intracortical inhibition mediated by both GABAA and GABAB receptors, and less intracortical facilitation in the M1 contralateral to the affected ECRB in individuals with LE compared with healthy controls. Similar changes were not present in the M1 contralateral to the unaffected ECRB. These changes may provide the substrate for M1 reorganization in chronic LE and could provide a target for future therapy. WHAT DOES THIS STUDY ADD: Lateral epicondylalgia (LE) is a common musculoskeletal condition characterized by elbow pain and sensorimotor dysfunction. The excitability and organization of the motor cortical representation of the wrist extensor muscles is altered in LE, but the mechanisms that underpin these changes are unknown. evidence of less intracortical inhibition mediated by both GABAA and GABAB receptors, and less intracortical facilitation mediated by NMDA receptors, in the M1 contralateral to the affected extensor carpi radialis brevis muscle in chronic LE compared with healthy controls. Altered activity in intracortical networks may contribute to altered motor cortex organization in LE and could provide a potential target for future treatments.

Motor Cortex Reorganization and Impaired Function in the Transition to Sustained Muscle Pain.

Primary motor cortical (M1) adaptation has not been investigated in the transition to sustained muscle pain. Daily injection of nerve growth factor (NGF) induces hyperalgesia reminiscent of musculoskeletal pain and provides a novel model to study M1 in response to progressively developing muscle soreness. Twelve healthy individuals were injected with NGF into right extensor carpi radialis brevis (ECRB) on Days 0 and 2 and with hypertonic saline on Day 4. Quantitative sensory and motor testing and assessment of M1 organization and function using transcranial magnetic stimulation were performed prior to injection on Days 0, 2, and 4 and again on Day 14. Pain and disability increased at Day 2 and increased further at Day 4. Reorganization of M1 was evident at Day 4 and was characterized by increased map excitability. These changes were accompanied by reduced intracortical inhibition and increased intracortical facilitation. Interhemispheric inhibition was reduced from the "affected" to the "unaffected" hemisphere on Day 4, and this was associated with increased pressure sensitivity in left ECRB. These data provide the first evidence of M1 adaptation in the transition to sustained muscle pain and have relevance for the development of therapies that seek to target M1 in musculoskeletal pain.

A new temporal window for inducing depressant associative plasticity in human primary motor cortex.

OBJECTIVE: Spike-timing dependent plasticity (STDP) usually refers to synaptic plasticity induced by near-synchronous activation of neuronal input and neuronal firing. However, some models of STDP predict effects that deviate from this tight temporal synchrony. We aimed to characterise the induction of STDP using paired associative stimulation (PAS) when the pre-synaptic input arrives in primary motor cortex (M1) at (i) intermediate intervals (50-80 ms; PAS(50),..PAS(80)) before the post-synaptic neuron is activated and (ii) long intervals (100-450 ms; PAS(-100),..PAS(-450)) after the post-synaptic neuron is activated. PAS at near-synchronicity (PAS(25)) was applied for comparison. METHODS: To characterise the physiological effects of the different PAS protocols, we examined short- and long-interval intra-cortical inhibition; intra-cortical facilitation and short- and long-latency afferent inhibition, in addition to recording MEPs in 45 healthy individuals. RESULTS: MEP amplitude was reduced at PAS intervals between -250 and -450 ms, increased with PAS(25), and unaltered at the remaining intervals. There was no change in intra-cortical inhibitory or facilitatory circuits following any PAS protocol. CONCLUSIONS: These findings provide evidence of a previously unreported temporal window in which PAS induces a depression of corticospinal excitability in human M1. SIGNIFICANCE: Establishing new temporal rules for STDP broadens its applicability for therapeutic usage in future.

Temporal association between changes in primary sensory cortex and corticomotor output during muscle pain.

BACKGROUND: Integration of information between multiple cortical regions is thought to underpin the experience of pain. Yet studies tend to focus on pain related changes in discrete cortical regions. Although altered processing in the primary motor (M1) and sensory cortex (S1) is implicated in pain, the temporal relationship between these regions is unknown and may provide insight into the interaction between them. METHODS: We used recordings of somatosensory-evoked potentials (SEPs) and transcranial magnetic stimulation to investigate the temporal relationship between altered excitability of the primary sensory cortex and corticomotor output during and after muscle pain induced by hypertonic saline infusion into the right first dorsal interosseous. SEPs and motor-evoked potentials (MEPs) were recorded in 12 healthy individuals. RESULTS: Participants reported an average pain intensity of 5.4 (0.5) on a 10-cm visual analogue scale. The area of the N20-P25-N33 complex of the SEP was reduced during and after pain, but MEP amplitudes were suppressed only after pain had resolved. CONCLUSIONS: Our data show that pain reduces sensory processing before motor output is altered. This temporal dispersion, coupled with the lack of correlation between pain-induced changes in S1 and M1 excitability, imply either that independent processes are involved, or that reduced excitability of S1 during acute experimental muscle pain mediates latent reductions in motor output via processes that are non-linear and potentially involve activation of a wider brain network.

Peripheral electrical stimulation to induce cortical plasticity: a systematic review of stimulus parameters.

Peripheral electrical stimulation (ES) is commonly used as an intervention to facilitate movement and relieve pain in a variety of conditions. It is widely accepted that ES induces rapid plastic change in the motor cortex. This leads to the exciting possibility that ES could be used to drive cortical plasticity in movement disorders, such as stroke, and conditions where pain affects motor control. This paper aimed to critically review the literature to determine which parameters induced cortical plasticity in healthy individuals using ES. A literature search located papers that assessed plasticity in the primary motor cortex of adult humans. Studies that evaluated plasticity using change in the amplitude of potentials evoked by transcranial magnetic stimulation of the motor cortex were included. Details from each study including sample size, ES parameters and reported findings were extracted and compared. Where data were available, Cohen's standardised mean differences (SMD) were calculated. Nineteen studies were located. Of the parameters evaluated, variation of the intensity of peripheral ES appeared to have the most consistent effect on modulation of excitability of corticomotor pathway to stimulated muscles. There was a trend for stimulation above motor threshold to increase excitability (SMD 0.79 mV, CI -0.10 to 1.64). Stimulation below motor threshold, but sufficient to induce sensory perception, produced conflicting results. Further studies with consistent methodology and larger subject numbers are needed before definitive conclusions can be drawn. There also appeared to be a time effect. That is, longer periods of ES induced more sustained changes in cortical excitability. There is insufficient evidence to determine the effect of other stimulation parameters such as frequency and waveform. Further research is needed to confirm whether modulation of these parameters affects plastic change.

Evidence for the retraining of sensation after stroke: a systematic review.

OBJECTIVE: Retraining of sensory function following stroke is frequently overlooked in rehabilitation protocols despite more than 60% of patients presenting with sensory deficits. Methods to train sensory function include both passive and active training protocols. Here we examined the volume and quality of the evidence available for both passive and active sensory training following stroke. In addition, we aimed to quantify the effect of sensory training on impairment and function. DATA SOURCES: Databases searched included MEDLINE, AMED, CINAHL, Academic search elite, Scopus and the Cochrane library. Unpublished articles were identified using a search engine. REVIEW METHODS: Studies utilizing passive or active sensory training paradigms post stroke were identified. Methodological quality was examined using the National Health and Medical Research Council hierarchy of evidence and the McMaster University critical appraisal tool. RESULTS: Fourteen studies met the inclusion criteria; 8 examined passive and 6 active sensory training. Methodological quality scores ranged from 11 to 18.5 (maximum 20). Meta-analysis was performed using three studies examining hand function, demonstrating a moderate effect in favour of passive sensory training. Other studies were unable to be pooled due to heterogeneity of measures or insufficient data. CONCLUSION: Meta-analyses and single studies offer some support for the effectiveness of passive sensory training in relation to sensory impairment and motor function. However, empirical evidence for active sensory training is limited. Further high-quality studies with greater statistical power and meaningful clinical measures are required in order to accurately determine the effectiveness of sensory retraining following stroke.

Role of the primary motor and sensory cortex in precision grasping: a transcranial magnetic stimulation study.

Human precision grip requires precise scaling of the grip force to match the weight and frictional conditions of the object. The ability to produce an accurately scaled grip force prior to lifting an object is thought to be the result of an internal feedforward model. However, relatively little is known about the roles of various brain regions in the control of such precision grip-lift synergies. Here we investigate the role of the primary motor (M1) and sensory (S1) cortices during a grip-lift task using inhibitory transcranial magnetic theta-burst stimulation (TBS). Fifteen healthy individuals received 40 s of either (i) M1 TBS, (ii) S1 TBS or (iii) sham stimulation. Following a 5-min rest, subjects lifted a manipulandum five times using a precision grip or completed a simple reaction time task. Following S1 stimulation, the duration of the pre-load phase was significantly longer than following sham stimulation. Following M1 stimulation, the temporal relationship between changes in grip and load force was altered, with changes in grip force coming to lag behind changes in load force. This result contrasts with that seen in the sham condition where changes in grip force preceded changes in load force. No significant difference was observed in the simple reaction task following either M1 or S1 stimulation. These results further quantify the contribution of the M1 to anticipatory grip-force scaling. In addition, they provide the first evidence for the contribution of S1 to object manipulation, suggesting that sensory information is not necessary for optimal functioning of anticipatory control.

The influence of correlated afferent input on motor cortical representations in humans.

Animal models reveal that correlated afferent inputs are a powerful driver of sensorimotor cortex reorganisation. Recently we developed a stimulation paradigm, which evokes convergent afferent input from two hand muscles and induces reorganisation within human motor cortex. Here we investigated whether this reorganisation is characterised by expansion and greater overlap of muscle representation zones, as reported in animal models. Using transcranial magnetic stimulation, we mapped the motor representation of the right first dorsal interosseous (FDI), abductor digiti minimi (ADM) and abductor pollicis brevis (APB) in 24 healthy subjects before and after 1 h of (1) associative stimulation to FDI and ADM motor points, (2) associative stimulation to digits II and V (3) a control condition employing non-correlated stimulation of FDI and ADM motor points. Motor point associative stimulation induced a significant increase in the number of active sites in all three muscles and volume in FDI and ADM. Additionally, the centre of gravity of the FDI and ADM maps shifted closer together. Similar changes were not observed following digital associative stimulation or motor point non-associative stimulation. These novel findings provide evidence that convergent input induces reorganisation of the human motor cortex characterised by expansion and greater overlap of representational zones.