Paul L. Furlong

The role of GABAergic modulation in motor function related neuronal network activity

At rest, the primary motor cortex (M1) exhibits spontaneous neuronal network oscillations in the beta (15-30 Hz) frequency range, mediated by inhibitory interneuron drive via GABA-A receptors. However, questions remain regarding the neuropharmacological basis of movement related oscillatory phenomena, such as movement related beta desynchronisation (MRBD), post-movement beta rebound (PMBR) and movement related gamma synchronisation (MRGS). To address this, we used magnetoencephalography (MEG) to study the movement related oscillatory changes in M1 cortex of eight healthy participants, following administration of the GABA-A modulator diazepam. Results demonstrate that, contrary to initial hypotheses, neither MRGS nor PMBR appear to be GABA-A dependent, whilst the MRBD is facilitated by increased GABAergic drive. These data demonstrate that while movement-related beta changes appear to be dependent upon spontaneous beta oscillations, they occur independently of one other. Crucially, MRBD is a GABA-A mediated process, offering a possible mechanism by which motor function may be modulated. However, in contrast, the transient increase in synchronous power observed in PMBR and MRGS appears to be generated by a non-GABA-A receptor mediated process; the elucidation of which may offer important insights into motor processes.

Neuronal network pharmacodynamics of GABAergic modulation in the human cortex determined using pharmaco-magnetoencephalography†

Neuronal network oscillations are a unifying phenomenon in neuroscience research, with comparable measurements across scales and species. Cortical oscillations are of central importance in the characterization of neuronal network function in health and disease and are influential in effective drug development. Whilst animal in vitro and in vivo electrophysiology is able to characterize pharmacologically induced modulations in neuronal activity, present human counterparts have spatial and temporal limitations. Consequently, the potential applications for a human equivalent are extensive. Here, we demonstrate a novel implementation of contemporary neuroimaging methods called pharmaco‐magnetoencephalography. This approach determines the spatial profile of neuronal network oscillatory power change across the cortex following drug administration and reconstructs the time course of these modulations at focal regions of interest. As a proof of concept, we characterize the nonspecific GABAergic modulator diazepam, which has a broad range of therapeutic applications. We demonstrate that diazepam variously modulates θ (4–7 Hz), α (7–14 Hz), β (15–25 Hz), and γ (30–80 Hz) frequency oscillations in specific regions of the cortex, with a pharmacodynamic profile consistent with that of drug uptake. We examine the relevance of these results with regard to the spatial and temporal observations from other modalities and the various therapeutic consequences of diazepam and discuss the potential applications of such an approach in terms of drug development and translational neuroscience. Hum Brain Mapp, 2010.

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.

Co-registration of magnetoencephalography with magnetic resonance imaging using bite-bar-based fiducials and surface-matching

OBJECTIVE To introduce a new technique for co-registration of Magnetoencephalography (MEG) with magnetic resonance imaging (MRI). We compare the accuracy of a new bite-bar with fixed fiducials to a previous technique whereby fiducial coils were attached proximal to landmarks on the skull. METHODS A bite-bar with fixed fiducial coils is used to determine the position of the head in the MEG co-ordinate system. Co-registration is performed by a surface-matching technique. The advantage of fixing the coils is that the co-ordinate system is not based upon arbitrary and operator dependent fiducial points that are attached to landmarks (e.g. nasion and the preauricular points), but rather on those that are permanently fixed in relation to the skull. RESULTS As a consequence of minimizing coil movement during digitization, errors in localization of the coils are significantly reduced, as shown by a randomization test. Displacement of the bite-bar caused by removal and repositioning between MEG recordings is minimal ( approximately 0.5 mm), and dipole localization accuracy of a somatosensory mapping paradigm shows a repeatability of approximately 5 mm. The overall accuracy of the new procedure is greatly improved compared to the previous technique. CONCLUSIONS The test-retest reliability and accuracy of target localization with the new design is superior to techniques that incorporate anatomical-based fiducial points or coils placed on the circumference of the head.

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.

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.

Evaluation of MRI-MEG/EEG co-registration strategies using Monte Carlo simulation

We present a Monte Carlo analysis method for evaluating MRI-MEG/EEG co-registration techniques. The method estimates the error in co-registration as a function of position within the brain. Using this analysis technique, we demonstrate the limitations of conventional head-based fiducial point methods, and propose a new strategy utilising a dental bite-bar incorporating accurately machined fiducial markers. Results presented demonstrate the improved accuracy of MEG/EEG to MRI co-registration using the bite-bar.

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.

Comparison of cortical potentials evoked by mechanical and electrical stimulation of the rectum

Patients with irritable bowel syndrome have heightened perception of gut sensation. The mechanisms responsible for this remain unknown, due to current poor knowledge of the central processing of gut sensation. Cortical evoked potentials (CEPs) have been recorded following both electrical rectal stimulation (ERS) and mechanical rectal stimulation (MRS). Because of the lack of a direct comparison of these two methods, their robustness for future clinical use remains unknown. The aim of our study was to compare the characteristics of CEPs following ERS and MRS. CEPs were recorded from the vertex in 14 healthy volunteers following ERS with bipolar ring electrodes, and MRS by repeated rectal distension. CEPs were recorded in all subjects following electrical stimulation, but only in 11 subjects following mechanical stimulation. In comparison with electrical stimulation, mechanical stimulation produced CEPs with a smaller amplitude and longer latency. However, the morphology of CEPs following electrical and mechanical rectal stimulation was similar, with no difference in the interpeak latencies. In conclusion, we have demonstrated that electrical rectal stimulation is a more reliable stimulus for recording CEPs. The similarity of the morphology and interpeak latencies of the CEPs suggests that both stimuli are activating a similar network of cortical neurones.

A general linear model for MEG beamformer imaging

A new general linear model (GLM) beamformer method is described for processing magnetoencephalography (MEG) data. A standard nonlinear beamformer is used to determine the time course of neuronal activation for each point in a predefined source space. A Hilbert transform gives the envelope of oscillatory activity at each location in any chosen frequency band (not necessary in the case of sustained (DC) fields), enabling the general linear model to be applied and a volumetric T statistic image to be determined. The new method is illustrated by a two-source simulation (sustained field and 20 Hz) and is shown to provide accurate localization. The method is also shown to locate accurately the increasing and decreasing gamma activities to the temporal and frontal lobes, respectively, in the case of a scintillating scotoma. The new method brings the advantages of the general linear model to the analysis of MEG data and should prove useful for the localization of changing patterns of activity across all frequency ranges including DC (sustained fields).