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Delineation of neural mechanisms involved in reflex cough is essential for understanding its many physiological and clinical complexities, and the development of more desirable antitussive agents. Brainstem networks that generate and modulate the breathing pattern are also involved in producing the motor patterns during reflex cough. Neurones of the ventrolateral medulla respiratory pattern generator mutually interact with neural networks in the pons, medulla and cerebellum to form a larger dynamic network. This paper discusses evidence from our laboratory and others supporting the involvement of the nucleus tractus solitarii, midline raphe nuclei and lateral tegmental field in the medulla, and the pontine respiratory group and cerebellum in the production of reflex cough. Gaps in our knowledge are identified to stimulate further research on this complicated issue.

1. This study addressed the hypothesis that ventrolateral medullary respiratory neurones participate in the control of laryngeal motoneurones during both eupnoea and coughing. 2. Data were obtained from 28 mid-collicular decerebrated, artificially ventilated cats. Cough-like motor patterns (fictive cough) in phrenic, lumbar and recurrent laryngeal nerves were elicited by mechanical stimulation of the intrathoracic trachea. Microelectrode arrays were used to monitor simultaneously several neurones in the ventral respiratory group, including the Bötzinger and pre-Bötzinger complexes. Spike trains were evaluated for responses during fictive cough and evidence of functional connectivity with spike-triggered averages of efferent recurrent laryngeal nerve activity. 3. Primary features were observed in averages triggered by 94 of 332 (28 %) neurones. An offset biphasic wave with a positive time lag was present in the unrectified average for 10 inspiratory and 13 expiratory neurones. These trigger neurones were respectively identified as inspiratory laryngeal motoneurones with augmenting, decrementing, plateau and "other" discharge patterns, and expiratory laryngeal motoneurones with decrementing firing patterns. 4. Rectified averages triggered by inspiratory neurones included 37 offset peaks, 11 central peaks and one offset trough. Averages triggered by expiratory neurones had 12 offset peaks, six central peaks and four offset troughs. Relationships inferred from these features included premotor actions of inspiratory neurones with augmenting, decrementing, plateau and "other" patterns on inspiratory laryngeal motoneurones, and premotor actions of decrementing and "other" expiratory neurones on expiratory laryngeal motoneurones. Corresponding changes in neuronal firing patterns during fictive cough supported these inferences. 5. The data confirm and extend previous results on the control of laryngeal motoneurones during eupnoea and support the hypothesis that the same premotor neurones help to shape motoneurone firing patterns during both eupnoea and coughing.

The use of the computer program CONTIN to analyze pulsed-field gradient NMR (PFG-NMR) data for several standard humic and fulvic acids is described. An advantage of PFG-NMR analysis is that integration of different spectral regions provides a picture of how the diffusion coefficients vary with functional group composition for a given sample. Using prior knowledge of the sample and the principle of parsimony, CONTIN approximates a solution to the inverse Laplace transform applied to the decay of peak intensity with gradient area in the PFG-NMR experiment. Thus, a continuous distribution of diffusion coefficients is resolved for the polydisperse humic and fulvic acids. The results of the CONTIN analyses are in the form of a distribution function and a two-dimensional DOSY plot. The 2D DOSY spectrum displays chemical shifts along one axis and diffusion coefficients along the other, while a number-average diffusion coefficient, D(N), a weight-average diffusion coefficient, D(W), and a most probable diffusion coefficient, D(P), are realized from the diffusion coefficient distribution. For all spectral regions of each humic sample, D(W) was greater than D(N), which in turn was greater than or equal to the D(P), suggesting that the diffusion coefficient distribution is weighted toward smaller, more rapidly diffusing molecules. Polydispersities, estimated from the ratio D(W)/D(N), were less than the reported M(W)/M(N) values for similar humic substances. Thus, the D(W)/D(N) ratio obtained by CONTIN analysis of PFG-NMR data can be at least a qualitative, and at best a semiquantitative, indication of the polydispersity of the humic sample, but should not be used as a quantitative measure of polydispersity.

This study addresses the hypothesis that multiple sensory systems, each capable of reflexly altering breathing, jointly influence neurons of the brain stem respiratory network. Carotid chemoreceptors, baroreceptors, and foot pad nociceptors were stimulated sequentially in 33 Dial-urethan-anesthetized or decerebrate vagotomized adult cats. Neuronal impulses were monitored with microelectrode arrays in the rostral and caudal ventral respiratory group (VRG), nucleus tractus solitarius (NTS), and n. raphe obscurus. Efferent phrenic nerve activity was recorded. Spike trains of 889 neurons were analyzed with cycle-triggered histograms and tested for respiratory-modulated firing rates. Responses to stimulus protocols were assessed with peristimulus time and cumulative sum histograms. Cross-correlation analysis was used to test for nonrandom temporal relationships between spike trains. Spike-triggered averages of efferent phrenic activity and antidromic stimulation methods provided evidence for functional associations of bulbar neurons with phrenic motoneurons. Spike train cross-correlograms were calculated for 6,471 pairs of neurons. Significant correlogram features were detected for 425 pairs, including 189 primary central peaks or troughs, 156 offset peaks or troughs, and 80 pairs with multiple peaks and troughs. The results provide evidence that correlational medullary assemblies include neurons with overlapping memberships in groups responsive to different sets of sensory modalities. The data suggest and support several hypotheses concerning cooperative relationships that modulate the respiratory motor pattern. 1) Neurons responsive to a single tested modality promote or limit changes in firing rate of multimodal target neurons. 2) Multimodal neurons contribute to changes in firing rate of neurons responsive to a single tested modality. 3) Multimodal neurons may promote responses during stimulation of one modality and "limit" changes in firing rates during stimulation of another sensory modality. 4) Caudal VRG inspiratory neurons have inhibitory connections that provide negative feedback regulation of inspiratory drive and phase duration.

This study addresses the hypothesis that multiple afferent systems share elements of a distributed brain stem network that modulates the respiratory motor pattern. Data were collected from 18 decerebrate, bilaterally vagotomized, paralyzed, artificially ventilated cats. Up to 28 neurons distributed in the rostral and caudal ventral respiratory group, nucleus tractus solitarius, and raphe obscurus were recorded simultaneously with microelectrode arrays. Phases of the respiratory cycle and inspiratory drive were assessed from integrated efferent phrenic nerve activity. Carotid chemoreceptors were stimulated by injection of CO2-saturated saline solution via the external carotid artery. Baroreceptors were stimulated by increased blood pressure secondary to inflation of an embolectomy catheter in the descending aorta. Cutaneous nociceptors were stimulated by pinching a footpad. Four hundred seventy-four neurons were tested for respiratory modulated firing rates and responses; 403 neurons were tested with stimulation of all 3 modalities. Chemoreceptor stimulation and pinch, perturbations that tend to increase respiratory drive, caused similar responses in 52 neurons; 28 responded oppositely. Chemoreceptor and baroreceptor stimulation resulted in similar primary responses in 45 neurons; 48 responded oppositely. Similar responses to baroreceptor stimulation and pinch were recorded for 38 neurons; opposite effects were measured in 26 neurons. Among simultaneously recorded neurons, distinct combinations of firing rate changes were evoked in response to stimulation of the different modalities. The results show a functional convergence of information from carotid chemoreceptors, baroreceptors, and cutaneous nociceptors on respiratory-modulated neurons distributed in the medulla. The data are consistent with the hypothesis that brain stem neurons have overlapping memberships in multifunctional groups that influence the respiratory motor pattern.

The primary hypothesis of this study was that the cough motor pattern is produced, at least in part, by the medullary respiratory neuronal network in response to inputs from "cough" and pulmonary stretch receptor relay neurons in the nucleus tractus solitarii. Computer simulations of a distributed network model with proposed connections from the nucleus tractus solitarii to ventrolateral medullary respiratory neurons produced coughlike inspiratory and expiratory motor patterns. Predicted responses of various "types" of neurons (I-DRIVER, I-AUG, I-DEC, E-AUG, and E-DEC) derived from the simulations were tested in vivo. Parallel and sequential responses of functionally characterized respiratory-modulated neurons were monitored during fictive cough in decerebrate, paralyzed, ventilated cats. Coughlike patterns in phrenic and lumbar nerves were elicited by mechanical stimulation of the intrathoracic trachea. Altered discharge patterns were measured in most types of respiratory neurons during fictive cough. The results supported many of the specific predictions of our cough generation model and suggested several revisions. The two main conclusions were as follows: 1) The Bötzinger/rostral ventral respiratory group neurons implicated in the generation of the eupneic pattern of breathing also participate in the configuration of the cough motor pattern. 2) This altered activity of Bötzinger/rostral ventral respiratory group neurons is transmitted to phrenic, intercostal, and abdominal motoneurons via the same bulbospinal neurons that provide descending drive during eupnea.

Purpose: In adult studies, MRI volumetrics is a proven technique in presurgical assessment of epilepsy. Hippocampal volume loss is maximal in the syndrome of mesial temporal lobe epilepsy. We aimed (a) to validate this methodology in a pediatric outpatient epilepsy population (b) to determine the relationship of hippocampal asymmetry (HA) to epileptic syndromes and risk factors., Methods: Two neurologists classified the epileptic syndrome in 79 pediatric outpatients, according to the International Classification of Epilepsies and Epileptic Syndromes (ILAE). Hippocampal volumetrics were performed in all patients. HA was defined according to adult control values., Results: Inter-rater variability on measurement of HA was very small (Correlation of test retest of 0.97 on 17 children <3 years old). The rate of HA was 44/79 (57%). In 21 patients, (27%) potentially epileptogenic lesions (other than HA) were identified (cerebral dysgenesis n = 11). HA was present in 9/15 (60%) of temporal lobe epilepsy and in 15/28 (54%) extratemporal onset epilepsy and 5/11 (46%) of generalized symptomatic epilepsy. Analysis confined to <13 years also showed HA was not specific for epileptic syndrome. There was no significant association of febrile convulsions (13%) with HA or temporal lobe epilepsy., Conclusions: There is a high incidence of HA in childhood epilepsy. HA was not confined to clinically defined temporal lobe epilepsy. The poor correlation of epileptic syndrome to quantitative MRI findings may be due to the inadequacies of epilepsy classification in the younger child, with the clinical semiology providing misleading localizing information. Normative childhood data for hippocampal volumes and symmetry is needed.

The focus of this review is work that supports a model of the medullary neuronal network that is involved in producing the cough motor pattern of inspiratory and expiratory pump muscles. Evidence is presented that supports the following hypotheses: (1) Bulbospinal drive to respiratory motoneurons during cough arises, at least in part, from the same medullary neurons involved in providing drive during eupnoea. (2) Medullary Bötzinger/ rostral ventral respiratory group neurons implicated in generating and shaping the eupnoeic pattern of breathing are also involved in producing the central cough motor pattern. The results were not consistent with a "cough centre" separate from the BOT/VRG. Observed neurons (in cats) included most of all previously identified respiratory modulated "types". The results showed that there were alterations in discharge patterns of all respiratory neurons during fictive cough. Many "types" responded as predicted by cough model network simulations. Based on neuron behaviours in our studies and inferred synaptic actions among BOT/VRG neurons, we propose a preliminary model for cough generation by the BOT/rVRG network.