Anthony Hobson

Contribution of central sensitisation to the development of noncardiac chest pain

BACKGROUND Non-cardiac chest pain mimics angina pectoris but generally originates from the oesophagus. Visceral hypersensitivity may contribute, but its neurophysiological basis is unclear. We investigated whether central sensitisation, an activity-dependent amplification of sensory transfer in the central nervous system, underlies visceral pain hypersensitivity and non-cardiac chest pain. METHODS We studied 19 healthy volunteers and seven patients with non-cardiac chest pain. Acid was infused into the lower oesophagus. Sensory responses to electrical stimulation were monitored within the acid-exposed lower oesophagus, the non-exposed upper oesophagus, and the cutaneous area of pain referral, before and after the infusion. FINDINGS In healthy volunteers, acid infusion into the lower oesophagus lowered the pain threshold in the upper oesophagus (mean decrease 18.2% [95% CI 10.4 to 26.0]; p=0.01) and on the chest wall (24.5% [10.2 to 38.7]; p=0.01). Patients with non-cardiac chest pain had a lower resting oesophageal pain threshold than healthy controls (45 [30 to 58] vs 64 [49 to 81] mA; p=0.04). In response to acid infusion, their pain threshold in the upper oesophagus fell further and for longer (mean fall in area under threshold/time curve 26.7 [11.0 to 42.3] vs 5.8 [2.8 to 8.8] units; p=0.04). INTERPRETATION The finding of secondary viscerovisceral and viscerosomatic pain hypersensitivity suggests that central sensitisation may contribute to visceral pain disorders. The prolonged visceral pain hypersensitivity in patients with non-cardiac chest pain suggests a central enhancement of sensory transfer. New therapeutic opportunities are therefore possible.

Driving Plasticity in Human Adult Motor Cortex Is Associated with Improved Motor Function after Brain Injury

Changes in somatosensory input can remodel human cortical motor organization, yet the input characteristics that promote reorganization and their functional significance have not been explored. Here we show with transcranial magnetic stimulation that sensory-driven reorganization of human motor cortex is highly dependent upon the frequency, intensity, and duration of stimulus applied. Those patterns of input associated with enhanced excitability (5 Hz, 75% maximal tolerated intensity for 10 min) induce stronger cortical activation to fMRI. When applied to acutely dysphagic stroke patients, swallowing corticobulbar excitability is increased mainly in the undamaged hemisphere, being strongly correlated with an improvement in swallowing function. Thus, input to the human adult brain can be programmed to promote beneficial changes in neuroplasticity and function after cerebral injury.

Induction of long-term plasticity in human swallowing motor cortex following repetitive cortical stimulation

OBJECTIVE The excitability of corticobulbar projections to swallowing musculature undergoes remarkable long-term increases after short periods of pharyngeal stimulation. The aim of this study was to investigate the excitability of swallowing motor cortex following repetitive transcranial magnetic stimulation (rTMS). METHODS Twelve healthy subjects were given 100 rTMS pulses over motor cortex at frequencies of 1, 5 and 10 Hz at an intensity of 80% threshold for corticobulbar activation. The excitability of the corticobulbar projection was assessed before and after rTMS and compared both to sham stimulation and to the corticospinal projection. RESULTS Stimulation at 5 Hz, but not 1 Hz, 10 Hz or sham stimulation increased the excitability of the corticobulbar projection to the pharynx, reaching a peak 60 min after rTMS (Delta increase: 65%, P=0.016). Excitability in the projection from the opposite hemisphere also increased, suggesting the presence of inter-hemispheric interactions, whereas excitability in the projection to thenar muscles was unchanged. CONCLUSIONS Corticobulbar and corticospinal projections may differ in response to rTMS, implying differences in relative thresholds of inhibitory and excitatory elements in hand versus swallowing cortex. SIGNIFICANCE This might be a useful approach in the motor rehabilitation of dysphagic stroke patients who have damage to sensory projections to the swallowing cortex.

Sensorimotor modulation of human cortical swallowing pathways.

1 Transcranial magnetic stimulation over motor areas of cerebral cortex in man can activate short latency bilateral cortical projections to the pharynx and oesophagus. In the present paper we investigate the interaction between pathways from each hemisphere and explore how activity in these pathways is modulated by afferent feedback from the face, pharynx and oesophagus. 2 Comparison of unilateral and bilateral stimulation (using interstimulus intervals (ISIs) of 1, 5 or 10 ms between shocks) showed spatial summation of responses from each hemisphere at an ISI of 1 ms, indicating that cortical efferents project onto a shared population of target neurones. Such summation was not evident at ISIs of 5 or 10 ms. There was little evidence for transcallosal inhibition of responses from each hemisphere, as described for limb muscles. 3 Single stimuli applied to the vagus nerve in the neck or the supraorbital nerve, which alone produce intermediate (onset 20‐30 ms) and long (50‐70 ms) latency reflex responses in the pharynx and oesophagus, were used to condition the cortical responses. Compared with rest, responses evoked by cortical stimulation were facilitated when they were timed to coincide with the late part of the reflex. The onset latency was reduced during both parts of the reflex response. No facilitation was observed with subthreshold reflex stimuli. 4 Single electrical stimuli applied to the pharynx or oesophagus had no effect on the response to cortical stimulation. However, trains of stimuli at frequencies varying from 0.2 to 10 Hz decreased the latency of the cortically evoked responses without consistently influencing their amplitudes. The effect was site specific: pharyngeal stimulation shortened both pharyngeal and oesophageal response latencies, whereas oesophageal stimulation shortened only the oesophageal response latencies. 5 Cortical swallowing motor pathways from each hemisphere interact and their excitability is modulated in a site‐specific manner by sensory input. The latter may produce a mixture of excitation and inhibition at both brainstem and cortical levels.

Dissociating the spatio-temporal characteristics of cortical neuronal activity associated with human volitional swallowing in the healthy adult brain

Human swallowing represents a complex highly coordinated sensorimotor function whose functional neuroanatomy remains incompletely understood. Specifically, previous studies have failed to delineate the temporo-spatial sequence of those cerebral loci active during the differing phases of swallowing. We therefore sought to define the temporal characteristics of cortical activity associated with human swallowing behaviour using a novel application of magnetoencephalography (MEG). In healthy volunteers (n = 8, aged 28-45), 151-channel whole cortex MEG was recorded during the conditions of oral water infusion, volitional wet swallowing (5 ml bolus), tongue thrust or rest. Each condition lasted for 5 s and was repeated 20 times. Synthetic aperture magnetometry (SAM) analysis was performed on each active epoch and compared to rest. Temporal sequencing of brain activations utilised time-frequency wavelet plots of regions selected using virtual electrodes. Following SAM analysis, water infusion preferentially activated the caudolateral sensorimotor cortex, whereas during volitional swallowing and tongue movement, the superior sensorimotor cortex was more strongly active. Time-frequency wavelet analysis indicated that sensory input from the tongue simultaneously activated caudolateral sensorimotor and primary gustatory cortex, which appeared to prime the superior sensory and motor cortical areas, involved in the volitional phase of swallowing. Our data support the existence of a temporal synchrony across the whole cortical swallowing network, with sensory input from the tongue being critical. Thus, the ability to non-invasively image this network, with intra-individual and high temporal resolution, provides new insights into the brain processing of human swallowing.

Topographic mapping of cortical potentials evoked by distension of the human proximal and distal oesophagus

We describe cortical potentials evoked by balloon distension of the proximal and distal oesophagus in 8 healthy right handed volunteers. Oesophageal stimulation was performed using a pump which rapidly inflated a 2 cm silicone balloon positioned either 3 cm distal to the upper oesophageal sphincter or 5 cm proximal to the lower oesophageal sphincter, at a frequency of 0.2 Hz, using inflation volumes which produced a definite but not painful sensation. Oesophageal evoked cortical potentials were recorded in all subjects with an initial negative and positive component (N1 and P1), followed by a second negative and positive component (N2 and P2) in 6 subjects. The morphology and the scalp topography of the N1 component elicited by proximal and distal oesophageal stimulation suggests activation of the primary somatosensory cortex and/or the insular. There was also evidence for hemispheric dominance for the N1 potential which was independent of handedness. The frontal emphasis of the proximal oesophageal N1 component, in contrast to the central emphasis of the distal oesophageal N1 component, suggests that different neuronal populations were activated by stimulation of the two sites. The frontal emphasis of the ensuing P1 component from both oesophageal sites suggests that it originates in a separate precentral source. The topography of the N2 components obtained by stimulation of either oesophageal site was similar to that of the N1 component, suggesting that they originate in similar areas of the cortex. The P2 component evoked by stimulation of both oesophageal sites was localised at the vertex. The inter- and intra-subject variation in the morphology of the N2 and P2 components suggests that secondary cortical processes related to cognition may be involved in their generation.

Patients with chest pain and occult gastroesophageal reflux demonstrate visceral pain hypersensitivity which may be partially responsive to acid suppression.

OBJECTIVES:Mechanisms of chest pain in gastroesophageal reflux disease (GERD) are poorly understood. The recent demonstration in healthy subjects that lower esophageal acid exposure induces pain hypersensitivity within the nonacid-exposed upper esophagus (secondary allodynia) raises the possibility that an increase in spinal neuronal excitability (i.e., central sensitization) contributes to chest pain in GERD. The aim of this study was to determine whether in patients with unexplained chest pain, acid reflux contributes to esophageal pain hypersensitivity.METHODS:In 14 patients with chest pain and GERD and 8 healthy volunteers, electrical pain thresholds (PT) were recorded from the upper esophagus before, and then repeatedly for 90 min after either hydrochloric acid (0.15 M) or saline (0.15 M) infusion into the lower esophagus. Six patients underwent a repeat study after 6 wk of high-dose proton pump inhibitor (PPI) therapy.RESULTS:GERD patients had lower resting upper esophageal PT than in healthy subjects (40.8 ± 9 mA and 70.4 ± 11 mA, respectively; P = 0.018). Acid infusion reduced PT in the non-acid-exposed upper esophagus in healthy subjects, but not in the patients (area under curve [AUC] − 304 ± 333 and 786 ± 464; P = 0.03, respectively). Following PPI therapy, resting PT increased (34.65 ± 13.4 to 40.5 ± 12.5 mA; P = 0.03), and a reduction in PT now occurred in acid infusion (AUC − 369 ± 321; P = 0.03).CONCLUSIONS:Patients with unexplained chest pain and occult GERD have esophageal pain hypersensitivity that is PPI responsive. The increase in resting PT and secondary allodynia only following PPI therapy suggests that pain hypersensitivity in these GERD patients may partially be the result of central sensitization.

Evaluating Oral Stimulation as a Treatment for Dysphagia after Stroke

Deglutitive aspiration is common after stroke and can have devastating consequences. While the application of oral sensory stimulation as a treatment for dysphagia remains controversial, data from our laboratory have suggested that it may increase corticobulbar excitability, which in previous work was correlated with swallowing recovery after stroke. Our study assessed the effects of oral stimulation at the faucial pillar on measures of swallowing and aspiration in patients with dysphagic stroke. Swallowing was assessed before and 60 min after 0.2-Hz electrical or sham stimulation in 16 stroke patients (12 male, mean age = 73 ± 12 years). Swallowing measures included laryngeal closure (initiation and duration) and pharyngeal transit time, taken from digitally acquired videofluoroscopy. Aspiration severity was assessed using a validated penetration-aspiration scale. Preintervention, the initiation of laryngeal closure, was delayed in both groups, occurring 0.66 ± 0.17 s after the bolus arrived at the hypopharynx. The larynx was closed for 0.79 ± 0.07 s and pharyngeal transit time was 0.94 ± 0.06 s. Baseline swallowing measures and aspiration severity were similar between groups (stimulation: 24.9 ± 3.01; sham: 24.9 ± 3.3, p = 0.2). Compared with baseline, no change was observed in the speed of laryngeal elevation, pharyngeal transit time, or aspiration severity within subjects or between groups for either active or sham stimulation. Our study found no evidence for functional change in swallow physiology after faucial pillar stimulation in dysphagic stroke. Therefore, with the parameters used in this study, oral stimulation does not offer an effective treatment for poststroke patients.

Characterising the central mechanisms of sensory modulation in human swallowing motor cortex

OBJECTIVE Pharyngeal stimulation can induce remarkable increases in the excitability of swallowing motor cortex, which is associated with short-term improvements in swallowing behaviour in dysphagic stroke patients. However, the mechanism by which this input induces cortical change remains unclear. Our aims were to explore the stimulus-induced facilitation of the cortico-bulbar projections to swallowing musculature and examine how input from the pharynx interacts with swallowing motor cortex. METHODS In 8 healthy subjects, a transcranial magnetic stimulation (TMS) paired-pulse investigation was performed comprising a single conditioning electrical pharyngeal stimulus (pulse width 0.2 ms, 240 V) followed by cortical TMS at inter-stimulus intervals (ISI) of 10-100 ms. Pharyngeal sensory evoked potentials (PSEP) were also measured over the vertex. In 6 subjects whole-brain magnetoencephalography (MEG) was further acquired following pharyngeal stimulation. RESULTS TMS evoked pharyngeal motor evoked potentials were facilitated by the pharyngeal stimulus at ISI between 50 and 80 ms (Delta mean increase: 47+/-6%, P < 0.05). This correlated with the peak latency of the P1 component of the PSEP (mean 79.6+/-8.5 ms). MEG confirmed that the equivalent P1 peak activities were localised to caudolateral sensory and motor cortices (BA 4, 1, 2). CONCLUSIONS Facilitation of the cortico-bulbar pathway to pharyngeal stimulation relates to coincident afferent input to sensorimotor cortex. SIGNIFICANCE These findings have mechanistic importance on how pharyngeal stimulation may increase motor excitability and provide guidance on temporal windows for future manipulations of swallowing motor cortex.

Development of esophageal hypersensitivity following experimental duodenal acidification.

OBJECTIVE:As visceral afferents from different regions of the gastrointestinal tract converge at the level of the spinal cord, we hypothesized that sensitization of one gut organ would induce visceral hypersensitivity in another gut organ, remote to the sensitizing stimulus.METHODS:Protocol 1: Eight healthy male volunteers, age 30 ± 8.2 yr, underwent three studies on different days. Esophageal pain thresholds (PT) were recorded at 10-min intervals prior to and for 2 h following a 30-min duodenal infusion of either 0.15 M hydrochloric acid (HCl), saline, or no infusion. Five subjects repeated the study to demonstrate reproducibility. Protocol 2: Esophageal evoked potentials (EEP) were studied in six subjects on two occasions prior to and 1 h after a 30-min duodenal infusion of 0.15 M HCl or saline.RESULTS:Protocol 1: After acid infusion, there were reproducible reductions in esophageal PT (ICC = 0.88), which were maximal at 110 min (15.05 ± 2.25 mA) (p < 0.002). Following saline infusion there was an increase in esophageal PT (ICC = 0.71), which was similar to the no-infusion condition (6.21 ± 1.54 mA vs 8.5 + 7.6 mA; p > 0.05). Protocol 2: Esophageal sensation scores increased (p= 0.02) after acid, but not after saline infusion (p= 0.1). A comparison of the latencies of EEP components prior to and following acid and saline infusion revealed a reduction in the N1 (p= 0.02) and P2 components (p= 0.04).CONCLUSION:This study provides the first objective evidence that duodenal acidification can induce esophageal hypersensitivity associated with changes in sensitivity of the central visceral pain pathway. As the esophagus was remote from the sensitizing stimulus, central sensitization of spinal dorsal horn neurons is likely to have contributed to these changes.