Do nociceptive stimulation intensity and temporal predictability influence pain-induced corticospinal excitability modulation?

Temporal predictability and intensity of an impending nociceptive input both shape pain experience and modulate laser-evoked potentials (LEPs) amplitude. However, it remains unclear whether and how these two factors could influence pain-induced corticospinal excitability modulation. The current study investigated the influence of nociceptive stimulation intensity and temporal predictability on motor-evoked potentials (MEPs) modulation, in parallel to their effect on pain perception and LEPs amplitude. Twenty participants completed electroencephalographic and transcranial magnetic stimulation experiments during which two laser nociceptive stimulation intensities (high and low) were either unpredictably delivered (random delay) or preceded by a fixed-timing cue (fixed delay). The amplitude of the conditioned MEPs was significantly reduced only for the high nociceptive stimulation and was not affected by the temporal predictability of pain (despite the fact that temporal predictability modulated the amplitude of P2 LEP component amplitude). However, a posteriori analyses based on patterns of pain-induced MEPs modulation revealed that participants in which nociceptive stimulation resulted in an increase in corticospinal excitability were more affected by the predictability of pain (i.e. increasing corticospinal excitability even more when pain occurrence was predictable), regardless of the nociceptive stimulation intensity; whereas participants in which nociceptive stimulation resulted in a decrease in corticospinal excitability were sensitive to the intensity of the stimulation but not its predictability. These results suggest a potential influence of cognitive factors such as temporal predictability on the response of the motor system in the presence of pain for some participants, contributing to explain, at least in part, the high variability highlighted in a number of previous studies.

Design and Characterization of Protein E-PilA, a Candidate Fusion Antigen for Nontypeable Haemophilus influenzae Vaccine.

Nontypeable Haemophilus influenzae (NTHi) is a pathogen known for being a frequent cause of acute otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. In the present study, a vaccine antigen based on the fusion of two known NTHi adhesive proteins, protein E (PE) and a pilin subunit (PilA), was developed. The quality of the combined antigen was investigated through functional, biophysical, and structural analyses. It was shown that the PE and PilA individual structures are not modified in the PE-PilA fusion and that PE-PilA assembles as a dimer in solution, reflecting PE dimerization. PE-PilA was found to bind vitronectin by enzyme-linked immunosorbent assay, as isolated PE does. Disulfide bridges were conserved and homogeneous, which was determined by peptide mapping and top-down analysis of PE, PilA, and PE-PilA molecules. Finally, the PE-PilA crystal showed a PE entity with a three-dimensional (3D) structure similar to that of the recently published isolated PE, while the structure of the PilA entity was similar to that of a 3D model elaborated from two other type 4 pilin subunits. Taken together, our observations suggest that the two tethered proteins behave independently within the chimeric molecule and display structures similar to those of the respective isolated antigens, which are important characteristics for eliciting optimal antibody-mediated immunity. PE and PilA can thus be further developed as a single fusion protein in a vaccine perspective, in the knowledge that tethering the two antigens does not perceptibly compromise the structural attributes offered by the individual antigens.

Effect of movement-related pain on behaviour and corticospinal excitability changes associated with arm movement preparation.

KEY POINTS: Experimental pain or its anticipation influence motor preparation processes as well as upcoming movement execution, but the underlying physiological mechanisms remain unknown. Our results showed that movement-related pain modulates corticospinal excitability during motor preparation. In accordance with the pain adaptation theory, corticospinal excitability was higher when the muscle has an antagonist (vs. an agonist) role for the upcoming movement associated with pain. Anticipation of movement-related pain also affects motor initiation and execution, with slower movement initiation (longer reaction times) and faster movement execution compared to movements that do not evoke pain. These results confirm the implementation of protective strategies during motor preparation known to be relevant for acute pain, but which may potentially have detrimental long-term consequences and lead to the development of chronic pain. ABSTRACT: When a movement repeatedly generates pain, we anticipate movement-related pain and establish self-protective strategies during motor preparation, but the underlying mechanisms remains poorly understood. The current study investigated the effect of movement-related pain anticipation on the modulation of behaviour and corticospinal excitability during the preparation of arm movements. Participants completed an instructed-delay reaction-time (RT) task consisting of elbow flexions and extensions instructed by visual cues. Nociceptive laser stimulations (unconditioned stimuli) were applied to the lateral epicondyle during movement execution in a specific direction (CS+) but not in the other (CS-), depending on experimental group. During motor preparation, transcranial magnetic stimulation was used to measure corticospinal excitability in the biceps brachii (BB). RT and peak end-point velocity were also measured. Neurophysiological results revealed an opposite modulation of corticospinal excitability in BB depending on whether it plays an agonist (i.e. flexion) or antagonist (i.e. extension) role for the CS+ movements (P < 0.001). Moreover, behavioural results showed that for the CS+ movements RT did not change relative to baseline, whereas the CS- movements were initiated more quickly (P = 0.023) and the CS+ flexion movements were faster relative to the CS- flexion movements (P < 0.001). This is consistent with the pain adaptation theory which proposes that in order to protect the body from further pain, agonist muscle activity is reduced and antagonist muscle activity is increased. If these strategies are initially relevant and lead to short-term pain alleviation, they may potentially have detrimental long-term consequences and lead to the development of chronic pain.

Characterization of Pre-F-GCN4t, a Modified Human Respiratory Syncytial Virus Fusion Protein Stabilized in a Noncleaved Prefusion Conformation.

The human respiratory syncytial virus (hRSV) fusion (F) protein is considered a major target of the neutralizing antibody response to hRSV. This glycoprotein undergoes a major structural shift from the prefusion (pre-F) to the postfusion (post-F) state at the time of virus-host cell membrane fusion. Recent evidences suggest that the pre-F state is a superior target for neutralizing antibodies compared to the post-F state. Therefore, for vaccine purposes, we have designed and characterized a recombinant hRSV F protein, called Pre-F-GCN4t, stabilized in a pre-F conformation. To show that Pre-F-GCN4t does not switch to a post-F conformation, it was compared with a recombinant post-F molecule, called Post-F-XC. Pre-F-GCN4t was glycosylated and trimeric and displayed a conformational stability different from that of Post-F-XC, as shown by chemical denaturation. Electron microscopy analysis suggested that Pre-F-GCN4t adopts a lollipop-like structure. In contrast, Post-F-XC had a typical elongated conical shape. Hydrogen/deuterium exchange mass spectrometry demonstrated that the two molecules had common rigid folding core and dynamic regions and provided structural insight for their biophysical and biochemical properties and reactivity. Pre-F-GCN4t was shown to deplete hRSV-neutralizing antibodies from human serum more efficiently than Post-F-XC. Importantly, Pre-F-GCN4t was also shown to bind D25, a highly potent monoclonal antibody specific for the pre-F conformation. In conclusion, this construct presents several pre-F characteristics, does not switch to the post-F conformation, and presents antigenic features required for a protective neutralizing antibody response. Therefore, Pre-F-GCN4t can be considered a promising candidate vaccine antigen.IMPORTANCE Human respiratory syncytial virus (RSV) is a global leading cause of infant mortality and adult morbidity. The development of a safe and efficacious RSV vaccine remains an important goal. The RSV class I fusion (F) glycoprotein is considered one of the most promising vaccine candidates, and recent evidences suggest that the prefusion (pre-F) state is a superior target for neutralizing antibodies. Our study presents the physicochemical characterization of Pre-F-GCN4t, a molecule designed to be stabilized in the pre-F conformation. To confirm its pre-F conformation, Pre-F-GCN4t was analyzed in parallel with Post-F-XC, a molecule in the post-F conformation. Our results show that Pre-F-GCN4t presents characteristics of a stabilized pre-F conformation and support its use as an RSV vaccine antigen. Such an antigen may represent a significant advance in the development of an RSV vaccine.

Effect of Cutaneous Heat Pain on Corticospinal Excitability of the Tibialis Anterior at Rest and during Submaximal Contraction.

Previous studies have shown that pain can interfere with motor control. The neural mechanisms underlying these effects remain largely unknown. At the upper limb, mounting evidence suggests that pain-induced reduction in corticospinal excitability is involved. No equivalent data is currently available at the lower limb. The present study therefore examined the effect of thermal pain on the corticospinal drive to tibialis anterior (TA) at rest and during an isometric submaximal dorsiflexion. Transcranial magnetic stimulation was used to induce motor-evoked potentials (MEPs) in the TA at rest and during contraction in the presence or absence of cutaneous heat pain induced by a thermode positioned above the TA (51°C during 1 s). With similar pain ratings between conditions (3.9/10 at rest and 3.6/10 during contraction), results indicate significant decreases in MEP amplitude during both rest (-9%) and active conditions (-13%) (main effect of pain, p = 0.02). These results therefore suggest that cutaneous heat pain can reduce corticospinal excitability in the TA muscle and that such reduction in corticospinal excitability could contribute to the interference of pain on motor control/motor learning.

Intranasal immunization with a proteosome-adjuvanted SARS-CoV-2 spike protein-based vaccine is immunogenic and efficacious in mice and hamsters.

With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.

The map is not the territory: motor system reorganization in upper limb amputees.

It is generally considered that hand amputation changes primary motor cortex (M1) stump muscle representations. Transcranial magnetic stimulation (TMS) studies show that the corticospinal excitability of a stump muscle and its homologous muscle on the intact side is not equivalent, and that the resting level of excitability is higher in the stump muscle. Since changes in M1 stump muscle map characteristics (e.g., size and location) are identified by comparing stump and intact muscle maps, such changes might reflect between-side differences in corticospinal excitability rather than a true reorganization of the stump muscle's map. In eight above-elbow amputees we used TMS to map the M1 representation of a stump muscle and its homologous muscle on the intact side during rest and contraction. Importantly, the same relative stimulation intensity was used to construct each map; stimulation was performed at 120% of the motor threshold of each muscle (intact/amputated limb) measured in each condition (rest/active contraction). Resting motor threshold was lower in the stump muscle, but active motor thresholds did not differ. Motor-evoked potential amplitudes increased between the rest and muscle contraction conditions, but this increase was smaller for the stump muscle because its at-rest corticospinal excitability was higher than that of the intact muscle. When the between-side difference in excitability was considered no interhemispheric difference was found for map areas or for their medio-lateral locations. The present results challenge the view that after an upper limb amputation the stump representation moves laterally and occupies a larger M1 territory.

Conditioned Pain Modulation Decreases Over Time in Patients With Neuropathic Pain Following a Spinal Cord Injury.

BACKGROUND: Neuropathic pain is a major problem following spinal cord injury (SCI). Central mechanisms involved in the modulation of nociceptive signals have been shown to be altered at the chronic stage, and it has been hypothesized that they might play a role in the development of chronic pain. OBJECTIVE: This prospective longitudinal study aimed to describe the evolution of pain modulation mechanisms over time after SCI, and to explore the relationships with the presence of clinical (neuropathic and musculoskeletal) pain. METHODS: Patients with an SCI were assessed on admission (n = 35; average of 38 days postinjury) and discharge (n = 25; average of 131 days postinjury) using the International Spinal Cord Injury Pain Basic Data Set. Conditioned pain modulation was assessed using the cold pressor test (10 °C; 120 s) as the conditioning stimulus and tonic heat pain, applied above the level of injury, as the test stimulus (120 s). Heat pain threshold was also assessed. RESULTS: A marked decrease in the efficacy of conditioned pain modulation was observed over time, with 30.2% of inhibition at admission and only 12.9% at discharge on average (P = .010). This decrease was observed only in patients already suffering from neuropathic pain at admission and was not explained by a general increase in sensitivity to thermal nociceptive stimuli. CONCLUSION: These results suggest that the presence of neuropathic pain leads to a decrease in conditioned pain modulation over time, rather than supporting the hypothesis that inefficient conditioned pain modulation mechanisms are leading to the development of neuropathic pain.

Exploring the Relationships Between Altered Body Perception, Limb Position Sense, and Limb Movement Sense in Complex Regional Pain Syndrome.

Chronic pain is often accompanied by patient-reported distorted body perception and an altered kinesthesia (referring to the senses of limb position and limb movement), but the association between these deficits is unknown. The objectives of this study were to assess body perception and the senses of limb position and limb movement in complex regional pain syndrome (CRPS) and to test whether these variables are related to each other and to pain intensity. Thirteen patients with upper limb CRPS (mean pain intensity, 4.2 ± 2.4 out of 10) and 13 controls were recruited. Body perception was self-reported with a questionnaire, and the senses of limb position (task 1) and of limb movement (task 2) were assessed with a robotic system combined with a 2D virtual reality display. The results showed altered kinesthesia in the patients with CRPS compared with controls (all P < .05). Moreover, in the CRPS group, greater pain intensity was associated with lower performance on task 2 (r = -.60; P < .05). Although alterations in participants' sense of limb position and limb movement were associated with each other (r = -.70, P < .01), they were not related to the altered body perception (all P > .26). Therefore, the results suggest that kinesthesia and body perception should be considered and evaluated separately in patients with CRPS. PERSPECTIVE: Senses of limb position and movement rely on sensorimotor integration. Both are altered in complex regional pain syndrome. However, they are not related to the subjective perception of the painful limb, and thus they should be assessed separately in rehabilitation.

Tracking Changes in Neuropathic Pain After Acute Spinal Cord Injury.

Neuropathic pain represents a primary detrimental outcome of spinal cord injury. A major challenge facing effective management is a lack of surrogate measures to examine the physiology and anatomy of neuropathic pain. To this end, we investigated the relationship between psychophysical responses to tonic heat stimulation and neuropathic pain rating after traumatic spinal cord injury. Subjects provided a continuous rating to 2 min of tonic heat at admission to rehabilitation and again at discharge. Adaptation, temporal summation of pain, and modulation profile (i.e., the relationship between adaptation and temporal summation of pain) were extracted from tonic heat curves for each subject. There was no association between any of the tonic heat outcomes and neuropathic pain severity at admission. The degree of adaptation, the degree of temporal summation of pain, and the modulation profile did not change significantly from admission to discharge. However, changes in modulation profiles between admission and discharge were significantly correlated with changes in neuropathic pain severity (p = 0.027; R 2 = 0.323). The modulation profile may represent an effective measure to track changes in neuropathic pain severity from early to later stages of spinal cord injury.

Dynamic influence of wrist flexion and extension on the intracortical inhibition of the first dorsal interosseus muscle during precision grip.

This work questioned further the influence of wrist movements on the control of precision grip. Seated subjects wearing a full-arm orthosis with the wrist and hand free were instructed to maintain a thumb/index finger opposition corresponding to 15% of maximal voluntary contraction for the first dorsal interosseus (FDI). Paired-pulse transcranial magnetic stimulation eliciting conditioned MEPs of FDI was used to determine the modulation of short intracortical inhibition (SICI) during cyclic active and passive wrist flexion and extension and during a static condition (no wrist movement, hand in the neutral position). The FDI active motor threshold (AMT) and the conditioning stimulus (0.8 AMT) were assessed in each series of FDI SICI measurements and the test stimulus (TS) was adjusted to match the amplitudes of test FDI MEPs across conditions. An increase of FDI background EMG during active wrist flexion compared to extension in some subjects did not influence FDI SICI as tested at matched EMG levels in the static condition. FDI SICI was reduced during wrist flexion (whether active or passive) compared to wrist extension, the latter being of equivalent FDI SICI as in the static condition. We suggest that wrist flexion and precision grip could be linked in a functional proximo-distal synergy. Indeed, coupling the activity between M1 sites of wrist flexors and FDI muscle via cortico-cortical disinhibition of FDI site may help recruit the interjoint synergy. Also, the salience of afferent information from wrist muscles may contribute to the phase-dependent modulation of SICI in the preactivated FDI muscle.

Motor and sensory disturbances induced by sensorimotor conflicts during passive and active movements in healthy participants.

Sensorimotor conflict induces both sensory and motor disturbances, but the specific factors playing a role in conflict-induced disturbances are still misunderstood. For example, we still do not know the role played by motor intention (vs. a purely visuo-proprioceptive conflict) or the influence of specific types of incongruent visual feedback. The objective of this study was threefold: 1- to compare the effect of passive and active movement during sensorimotor conflict on sensory disturbances measured with a questionnaire; 2- to compare the effect of three incongruent visual feedback conditions on sensory and motor (mediolateral drift and movement amplitude) disturbances; 3- to test whether conflict-induced sensory and motor disturbances were stable over time. 20 healthy participants realized active or passive cyclic upper limb movements while viewing either congruent or incongruent visual feedback about their movement using a robotized exoskeleton combined with 2D virtual reality interface. First, results showed that in condition of conflict, participants reported higher sensory disturbances during active movements compared to passive movements (p = 0.034), suggesting that the efference copy reinforces the conflict between vision and proprioception. Second, the three conditions of incongruence in the active condition induced similar sensory (all p>0.45) and motor disturbances (medio-lateral drift: all p>0.59 and amplitude: all p>0.25), suggesting that conflict induced motor disturbances could be related more to the observation of another movement rather than to a detection of conflict between motor intention and sensory feedback. Finally, both sensory and motor disturbances were stable over time (all ICCs between 0.76 and 0.87), demonstrating low variability within participants. Overall, our results suggest that the efference copy is more involved in sensory disturbances than in motor disturbances, suggesting that they might rely on independent processes.

Double Trouble: Massive Unruptured Aortic Aneurysms.

We describe a patient who presented to the emergency department complaining of generalized weakness, dark stools, and urinary retention who was found to have two large abdominal aortic aneurysms (AAA) compressing his bilateral ureters with associated hydronephrosis and renal insufficiency. In elderly male patients presenting with signs of obstructive uropathy, AAA should be considered as a potential cause.

Dynamic changes in corticospinal control of precision grip during wrist movements.

This work tested the physiological basis underlying the control of a proximo-distal muscle coordination. Using transcranial magnetic stimulation (TMS) of the hand territory within the primary motor cortex (M1), we examined whether the corticospinal excitability of the first dorsal interosseus muscle (FDI, index abductor), engaged in a precision grip, was altered during wrist movements. To this end, 12 seated subjects maintained a pinch between the right index finger and the thumb and FDI motor evoked potentials (MEPs) were elicited under four conditions: (1) during active and (2) passive cyclic wrist flexion/extension, (3) in three positions of static wrist flexion and extension, respectively, and (4) at three levels of isometric force of wrist flexors (FCR) and extensors (ECR) respectively. FDI MEPs were normalized relative to the MEP/EMG linear relationship. They were facilitated during wrist flexion in the active and the passive conditions and this did not depend on FDI background EMG. Interestingly, the occurrence of the most facilitated FDI MEPs was correlated only with the peak of FCR activity. Also, the duration of the post-MEP silent periods normalized to FDI MEP amplitudes was shorter during wrist flexion compared to extension. We discussed the extent to which the dynamic influence of wrist flexion on FDI corticospinal excitability reflects the existence of a proximo-distal synergy between wrist flexion and precision grip and whether this synergy relies on the phase-dependent recruitment of common M1 networks between FCR and FDI muscles and on the salience of proprioceptive afferents from wrist muscles.

Sensory Disturbances, but Not Motor Disturbances, Induced by Sensorimotor Conflicts Are Increased in the Presence of Acute Pain.

Incongruence between our motor intention and the sensory feedback of the action (sensorimotor conflict) induces abnormalities in sensory perception in various chronic pain populations, and to a lesser extent in pain-free individuals. The aim of this study was to simultaneously investigate sensory and motor disturbances evoked by sensorimotor conflicts, as well as to assess how they are influenced by the presence of acute pain. It was hypothesized that both sensory and motor disturbances would be increased in presence of pain, which would suggest that pain makes body representations less robust. Thirty healthy participants realized cyclic asymmetric movements of flexion-extension with both upper limbs in a robotized system combined to a 2D virtual environment. The virtual environment provided a visual feedback (VF) about movements that was either congruent or incongruent, while the robotized system precisely measured motor performance (characterized by bilateral amplitude asymmetry and medio-lateral drift). Changes in sensory perception were assessed with a questionnaire after each trial. The effect of pain (induced with capsaicin) was compared to three control conditions (no somatosensory stimulation, tactile distraction and proprioceptive masking). Results showed that while both sensory and motor disturbances were induced by sensorimotor conflicts, only sensory disturbances were enhanced during pain condition comparatively to the three control conditions. This increase did not statistically differ across VF conditions (congruent or incongruent). Interestingly however, the types of sensations evoked by the conflict in the presence of pain (changes in intensity of pain or discomfort, changes in temperature or impression of a missing limb) were different than those evoked by the conflict alone (loss of control, peculiarity and the perception of having an extra limb). Finally, results showed no relationship between the amount of motor and sensory disturbances evoked in a given individual. Contrary to what was hypothesized, acute pain does not appear to make people more sensitive to the conflict itself, but rather impacts on the type and amount of sensory disturbances that they experienced in response to that conflict. Moreover, the results suggest that some sensorimotor integration processes remain intact in presence of acute pain, allowing us to maintain adaptive motor behavior.

Effect of Experimental Hand Pain on Training-Induced Changes in Motor Performance and Corticospinal Excitability.

Pain influences plasticity within the sensorimotor system and the aim of this study was to assess the effect of pain on changes in motor performance and corticospinal excitability during training for a novel motor task. A total of 30 subjects were allocated to one of two groups (Pain, NoPain) and performed ten training blocks of a visually-guided isometric pinch task. Each block consisted of 15 force sequences, and subjects modulated the force applied to a transducer in order to reach one of five target forces. Pain was induced by applying capsaicin cream to the thumb. Motor performance was assessed by a skill index that measured shifts in the speed-accuracy trade-off function. Neurophysiological measures were taken from the first dorsal interosseous using transcranial magnetic stimulation. Overall, the Pain group performed better throughout the training (p = 0.03), but both groups showed similar improvements across training blocks (p < 0.001), and there was no significant interaction. Corticospinal excitability in the NoPain group increased halfway through the training, but this was not observed in the Pain group (Time × Group interaction; p = 0.01). These results suggest that, even when pain does not negatively impact on the acquisition of a novel motor task, it can affect training-related changes in corticospinal excitability.

Modulation of corticospinal output in agonist and antagonist proximal arm muscles during motor preparation.

Previous studies have shown modulation of corticospinal output of the agonist muscle when a known-movement is prepared but withheld until a response signal appearance, reflecting motor preparation processes. However, modulation in the antagonist muscles has not been described, despite the fact that reaching movements require precise coordination between the activation of agonist and antagonist muscles. In this study, participants performed an instructed-delay reaction time (RT) task, with randomized elbow flexion and extension movements. The aim was to assess the time course modulation of corticospinal output in two antagonist muscles, by simultaneously quantified the amplitude of motor evoked potentials (MEPs) in biceps brachii and triceps brachii, and the amplitude and direction of elbow movements evoked by transcranial magnetic stimulation (TMS). Depending on the prepared movement direction, a specific modulation of corticospinal output was observed, MEPs and TMS-evoked movements amplitude being relatively greater for extension compared to flexion. At the end of motor preparation, a decrease in MEPs amplitude was observed for both biceps brachii and triceps brachii, regardless of the prepared movement direction. In contrast, the probability of evoking movement in the flexion direction and the amplitude of TMS-evoked movement decreased at the end of preparation for flexion, but not for extension. Together, these results confirm the existence of inhibitory processes at the end of the motor preparation, probably to avoid a premature motor response. Moreover, they provide evidence of differences in the corticospinal control of elbow flexor and extensor muscles with patterns of modulation that are not necessarily reciprocal during motor preparation.

Effect of Experimental Cutaneous Hand Pain on Corticospinal Excitability and Short Afferent Inhibition.

Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition (SAI) paradigm was used to assess sensorimotor integration in the presence and absence of experimental cutaneous heat pain applied to the hand. Ulnar nerve stimulation was combined with transcranial magnetic stimulation to condition motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Four interstimulus intervals (ISI) were tested, based on the latency of the N20 component of the afferent sensory volley (N20-5 ms, N20+2 ms, N20+4 ms, N20+10 ms). In the PAIN condition, MEPs were smaller compared to the NEUTRAL condition (p = 0.005), and were modulated as a function of the ISI (p = 0.012). Post-hoc planned comparisons revealed that MEPs at N20+2 and N20+4 were inhibited compared to unconditioned MEPs. However, the level of inhibition (SAI) was similar in the PAIN and NEUTRAL conditions. This suggests that the interplay between pain and sensorimotor integration is not mediated through direct and rapid pathways as assessed by SAI, but rather might involve higher-order integrative areas.

Osteopathic manipulative treatment as a useful adjunctive tool for pneumonia.

Pneumonia, the inflammatory state of lung tissue primarily due to microbial infection, claimed 52,306 lives in the United States in 2007 (1) and resulted in the hospitalization of 1.1 million patients (2). With an average length of in-patient hospital stay of five days (2), pneumonia and influenza comprise significant financial burden costing the United States $40.2 billion in 2005 (3). Under the current Infectious Disease Society of America/American Thoracic Society guidelines, standard-of-care recommendations include the rapid administration of an appropriate antibiotic regiment, fluid replacement, and ventilation (if necessary). Non-standard therapies include the use of corticosteroids and statins; however, these therapies lack conclusive supporting evidence (4). (Figure 1) Osteopathic Manipulative Treatment (OMT) is a cost-effective adjunctive treatment of pneumonia that has been shown to reduce patients' length of hospital stay, duration of intravenous antibiotics, and incidence of respiratory failure or death when compared to subjects who received conventional care alone (5). The use of manual manipulation techniques for pneumonia was first recorded as early as the Spanish influenza pandemic of 1918, when patients treated with standard medical care had an estimated mortality rate of 33%, compared to a 10% mortality rate in patients treated by osteopathic physicians (6). When applied to the management of pneumonia, manual manipulation techniques bolster lymphatic flow, respiratory function, and immunological defense by targeting anatomical structures involved in the these systems(7,8, 9, 10). The objective of this review video-article is three-fold: a) summarize the findings of randomized controlled studies on the efficacy of OMT in adult patients with diagnosed pneumonia, b) demonstrate established protocols utilized by osteopathic physicians treating pneumonia, c) elucidate the physiological mechanisms behind manual manipulation of the respiratory and lymphatic systems. Specifically, we will discuss and demonstrate four routine techniques that address autonomics, lymph drainage, and rib cage mobility: (1) Rib Raising, (2) Thoracic Pump, (3) Doming of the Thoracic Diaphragm, and (4) Muscle Energy for Rib 1.

Effect of tonic pain on motor acquisition and retention while learning to reach in a force field.

Most patients receiving intensive rehabilitation to improve their upper limb function experience pain. Despite this, the impact of pain on the ability to learn a specific motor task is still unknown. The aim of this study was to determine whether the presence of experimental tonic pain interferes with the acquisition and retention stages of motor learning associated with training in a reaching task. Twenty-nine healthy subjects were randomized to either a Control or Pain Group (receiving topical capsaicin cream on the upper arm during training on Day 1). On two consecutive days, subjects made ballistic movements towards two targets (NEAR/FAR) using a robotized exoskeleton. On Day 1, the task was performed without (baseline) and with a force field (adaptation). The adaptation task was repeated on Day 2. Task performance was assessed using index distance from the target at the end of the reaching movement. Motor planning was assessed using initial angle of deviation of index trajectory from a straight line to the target. Results show that tonic pain did not affect baseline reaching. Both groups improved task performance across time (p<0.001), but the Pain group showed a larger final error (under-compensation) than the Control group for the FAR target (p = 0.030) during both acquisition and retention. Moreover, a Group x Time interaction (p = 0.028) was observed on initial angle of deviation, suggesting that subjects with Pain made larger adjustments in the feedforward component of the movement over time. Interestingly, behaviour of the Pain group was very stable from the end of Day 1 (with pain) to the beginning of Day 2 (pain-free), indicating that the differences observed could not solely be explained by the impact of pain on immediate performance. This suggests that if people learn to move differently in the presence of pain, they might maintain this altered strategy over time.