Biomedical subjects

Graeme M Clark

Publications and source records attributed to Graeme M Clark.

14 recordsLinked to original sources

PubMed2006

Optimising the incorporation and release of a neurotrophic factor using conducting polypyrrole.

In this study, a neurotrophin delivery system based on an inherently conducting polymer (ICP) has been developed. Direct incorporation of neurotrophin-3 (NT-3) was investigated and controlled release was tested under various electrochemical conditions. The loading capacity and amount of NT-3 released from the polymer was determined using (125)I-labelled NT-3. Electrochemical stimulation of polypyrrole by pulsed voltage, pulsed current or cyclic voltammetry promoted the release of NT-3 at a greater rate than natural diffusion of NT-3. NT-3 was released from polypyrrole as an initial burst in the first 24 h followed by prolonged release over a subsequent 6 days of sampling. The amount of NT-3 incorporated into the polymer could be controlled by varying the polymerisation time, with longer growth periods incorporating more NT-3. The NT-3 release results indicated that the polymers grown for longer released a lower percentage of the incorporated NT-3 compared to the polymers grown for shorter times. Polymer-based neurotrophin delivery systems have the potential to be incorporated into future treatments for nerve injuries to prevent nerve degradation and promote nerve protection.

Delayed-Action Preparations↗

PubMed2006

The multiple-channel cochlear implant: the interface between sound and the central nervous system for hearing, speech, and language in deaf people-a personal perspective.

The multiple-channel cochlear implant is the first sensori-neural prosthesis to effectively and safely bring electronic technology into a direct physiological relation with the central nervous system and human consciousness, and to give speech perception to severely-profoundly deaf people and spoken language to children. Research showed that the place and temporal coding of sound frequencies could be partly replicated by multiple-channel stimulation of the auditory nerve. This required safety studies on how to prevent the effects to the cochlea of trauma, electrical stimuli, biomaterials and middle ear infection. The mechanical properties of an array and mode of stimulation for the place coding of speech frequencies were determined. A fully implantable receiver-stimulator was developed, as well as the procedures for the clinical assessment of deaf people, and the surgical placement of the device. The perception of electrically coded sounds was determined, and a speech processing strategy discovered that enabled late-deafened adults to comprehend running speech. The brain processing systems for patterns of electrical stimuli reproducing speech were elucidated. The research was developed industrially, and improvements in speech processing made through presenting additional speech frequencies by place coding. Finally, the importance of the multiple-channel cochlear implant for early deafened children was established.

Cochlear Implants↗

PubMed2006

Pneumococcal meningitis threshold model: A potential tool to assess infectious risk of new or existing inner ear surgical interventions.

HYPOTHESIS: A minimal threshold of Streptococcus pneumoniae is required to induce meningitis in healthy animals for intraperitoneal (hematogenous), middle ear, and inner ear inoculations, and this threshold may be altered via recent inner ear surgery. BACKGROUND: There has been an increase in the number of reported cases of cochlear implant-related pneumococcal meningitis since 2002. The pathogenesis of pneumococcal meningitis is complex and not completely understood. The bacteria can reach the central nervous system (CNS) from the upper respiratory tract mucosa via either hematogenous route or via the inner ear. The establishment of a threshold model for all potential routes of infection to the CNS in animals without cochlear implantation is an important first step to help us understand the pathogenesis of the disease in animals with cochlear implantation. METHODS: Fifty-four otologically normal adult Hooded Wistar rats (27 receiving cochleostomy and 27 controls) were inoculated with different amounts of bacterial counts via three different routes (intraperitoneal, middle ear, and inner ear). Rats were monitored during 5 days for signs of meningitis. Blood, cerebrospinal fluid, and middle ear swabs were taken for bacterial culture, and brains and cochleae were examined for signs of infection. RESULTS: The threshold of bacterial counts required to induce meningitis is lowest in rats receiving direct inner ear inoculation compared with both intraperitoneal and middle ear inoculation. There is no change in threshold between the group of rats with cochleostomy and the control (Fisher's exact test, p < 0.05). CONCLUSION: A minimal threshold of bacteria is required to induce meningitis in healthy animals and is different for three different routes of infection (intraperitoneal, middle ear, and inner ear). Cochleostomy performed 4 weeks before the inoculation did not reduce the threshold of bacteria required for meningitis in all three infectious routes. This threshold model will also serve as a valuable tool, assisting clinicians to quantitatively analyze if the presence of a cochlear implant or other CNS prostheses alter the risk of meningitis.

Animals↗

PubMed2006

Pneumococcal meningitis: development of a new animal model.

HYPOTHESIS: The rat is a suitable animal to establish a model for the study of pneumococcal meningitis postcochlear implantation. BACKGROUND: There has been an increase in the number of cases of cochlear implant-related meningitis. The most common organism identified was Streptococcus pneumoniae. Whether cochlear implantation increases the risk of pneumococcal meningitis in healthy subjects without other risk factors remains to be determined. Previous animal studies do not focus on the pathogenesis and risk of pneumococcal meningitis postimplantation and are based on relatively small animal numbers, making it difficult to assess the cause-and-effect relationship. There is, therefore, a need to develop a new animal model allowing direct examination of the pathogenesis of meningitis in the presence of a cochlear implant. METHODS: Eighteen nonimplanted rats were infected with 1 x 10 and 1 x 10 colony-forming units (CFU) of a clinical isolate of S. pneumoniae via three different inoculation routes (middle ear, inner ear, and i.p.) to examine for evidence of meningitis during 24 hours. Six implanted rats were infected with the highest amount of bacteria possible for each route of inoculation (4 x 10 CFU i.p., 3 x 10 CFU middle ear, and 1 x 10 CFU inner ear) to examine for evidence of meningitis with the presence of an implant. The histological pattern of cochlear infections for each of the three different inoculating routes were examined. RESULTS: Pneumococcal meningitis was evident in all 6 implanted animals for each of the three different routes of inoculation. Once in the inner ear, bacteria were found to enter the central nervous system via either the cochlear aqueduct or canaliculi perforantes of the osseous spiral lamina, reaching the perineural and perivascular space then the internal acoustic meatus. The rate, extent, and pattern of infection within the cochleae depended on the route of inoculation. Finally, there was no evidence of pneumococcal meningitis observed in 18 nonimplanted rats inoculated at a lower concentration of S. pneumoniae when observed for 24 hours postinoculation. CONCLUSION: Meningitis in implanted rats after inoculation with a clinical isolate of S. pneumoniae is possible via all three potential routes of infection via the upper respiratory tract. The lack of meningitis observed in the 18 nonimplanted rats suggests that longer postinoculation monitoring periods are required to ensure whether or not meningitis will develop. Based on this work, we have developed a new animal model that will allow quantitative risk assessment of meningitis postcochlear implantation, and the assessment of the efficacy of potential interventional strategies in future studies.

Animals↗

PubMed2006

Protective effects of local administration of ciprofloxacin on the risk of pneumococcal meningitis after cochlear implantation.

OBJECTIVES: To determine whether ciprofloxacin retains its antimicrobial activity after storage with Healon at ambient temperature and at 37 degrees C over 5 weeks and then to establish whether the application of ciprofloxacin/Healon onto scala tympani electrode arrays reduces the risk of meningitis in implanted rats inoculated with S. pneumoniae. STUDY DESIGN: In vitro laboratory and in vivo animal studies METHODS: The antibacterial activity of three concentrations of ciprofloxacin/Healon (7.5, 75, and 750 microg/mL) was examined over 5 weeks at both ambient temperature (23 degrees C) and body temperature (37 degrees C). Thirty-six rats (18 implanted with ciprofloxacin [750 mg/mL]/Healon-coated electrode array and 18 without the coating) were infected with S. pneumoniae 4 weeks after implantation by way of three different routes of infection (hematogenous, middle ear, and inner ear) and observed for the development of meningitis. RESULTS: The antibacterial activity of ciprofloxacin/Healon was maintained over 5 weeks at both 23 degrees C and 37 degrees C. The implanted rats with the ciprofloxacin/Healon-coated electrode array were protected from meningitis when the bacteria were given by way of the hematogenous route (Fisher's exact test, P = .008) but not when the bacteria were inoculated directly into the middle or inner ear. However, the time to develop meningitis was significantly longer in rats implanted with a coated array, irrespective of the route of inoculation (P < .05, log rank test). CONCLUSION: Our animal model demonstrated that a ciprofloxacin-coated electrode array can protect healthy implanted rats from meningitis when the route of infection is hematogenous and can delay the onset of meningitis when bacteria are inoculated directly into the middle or inner ear.

Adjuvants, Immunologic↗

PubMed2005

Netrin-1 as a guidance molecule in the postnatal rat cochlea.

During synaptogenesis a number of growth factors and peptides control the guidance of auditory neuron (spiral ganglion neuron, SGN) axons to their target cells. Furthermore, evidence suggests that these factors exert their actions at discrete times and sites during development. This study demonstrates that the guidance molecule netrin-1 is expressed in the early postnatal rat cochlea, but shows decreasing expression with increasing age. These results suggest that netrin-1 may be involved in guiding axonal growth from SGNs for the onset of innervation, but is not required for maintenance of synaptic connections.

Aging↗

PubMed2005

Balanced inhibition and excitation underlies spike firing regularity in ventral cochlear nucleus chopper neurons.

Ventral cochlear nucleus stellate cells respond to characteristic frequency (CF) tones with sustained (C(S)), transient (C(T)) or onset chopping (O(C)) activity. The mechanisms underlying these different response patterns are not fully understood, and the present study used in vivo intracellular recordings (n = 42) in urethane-anaesthetized rats to examine the possible influence of inhibition on action potential regularity. Hyperpolarization following the offset of a CF tone burst was used as a measure of on-CF inhibition. A cluster analysis based on several membrane potential features, including on-CF inhibition, discriminated three groups in addition to the C(S) response type - two types of C(T) responses and the O(C) type. The different patterns of firing regularity exhibited by C(S/T) neurons reflected different thresholds or degrees of overlap between these cells' narrowly tuned excitatory and inhibitory inputs. C(T) cells with closely matched inhibitory and excitatory response areas showed substantial on-CF inhibition and the greatest decline in firing regularity during a CF tone, whereas those with a mismatch between their response areas showed lateral inhibition and a less marked decline in firing regularity. The presence of inhibition in C(S) neurons did not alter their firing regularity, possibly because of the lower threshold for excitation compared with inhibition. The latency, duration and frequency extent of sustained hyperpolarization in C(S/T) cells is inconsistent with the response properties of O(C) neurons, suggesting that another source(s) of inhibition influences firing regularity, and presumably response magnitude, in these neurons.

Acoustic Stimulation↗

PubMed2004

Delayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs.

As key factors in the development and maintenance of the auditory system, neurotrophins can prevent auditory neuron degeneration when applied within three to five days of deafening. We tested each of the neurotrophins BDNF, NT-3, NT-4/5 and NGF for their ability to support auditory neuron survival following a two-week period of deafness in guinea pigs, when approximately 15% auditory neuron degeneration has already occurred. Although delayed, the treatment with each neurotrophin prevented further degeneration with similar efficacy.

Animals↗

PubMed2004

Fast inhibition alters first spike timing in auditory brainstem neurons.

Within the first processing site of the central auditory pathway, inhibitory neurons (D stellate cells) broadly tuned to tonal frequency project on narrowly tuned, excitatory output neurons (T stellate cells). The latter is thought to provide a topographic representation of sound spectrum, whereas the former is thought to provide lateral inhibition that improves spectral contrast, particularly in noise. In response to pure tones, the overall discharge rate in T stellate cells is unlikely to be suppressed dramatically by D stellate cells because they respond primarily to stimulus onset and provide fast, short-duration inhibition. In vivo intracellular recordings from the ventral cochlear nucleus (VCN) showed that, when tones were presented above or below the characteristic frequency (CF) of a T stellate neuron, they were inhibited during depolarization. This resulted in a delay in the initial action potential produced by T stellate cells. This ability of fast inhibition to alter the first spike timing of a T stellate neuron was confirmed by electrically activating the D stellate cell pathway that arises in the contralateral cochlear nucleus. Delay was also induced when two tones were presented: one at CF and one outside the frequency response area of the T stellate neuron. These findings suggest that the traditional view of lateral inhibition within the VCN should incorporate delay as one of its principle outcomes.

Acoustic Stimulation↗

PubMed2004

Ventral cochlear nucleus coding of voice onset time in naturally spoken syllables.

These experiments examined the coding of the voice onset time (VOT) of six naturally spoken syllables, presented at a number of intensities, by ventral cochlear nucleus (VCN) neurons in rats anesthetized with urethane. VOT is one of the cues for the identification of a stop consonant, and is defined by the interval between stop release and the first glottal pulse that marks the onset of voicing associated with a vowel. The syllables presented (/bot/, /dot/, /got/, /pot/, /tot/, /kot/) each had a different VOT, ranging between 10 and 108 ms. Extracellular recordings were made from single neurons (N=202) with a wide range of best frequencies (BFs; 0.66-10 kHz) that represented the major VCN response types - primary-like (67.8% of sample), chopper (19.8%), and onset (12.4%) neurons. The different VOTs of the syllables were accurately reflected in sharp, precisely timed, and statistically significant changes in average discharge rate in all cell types, as well as the entire VCN sample. The prominence of the response to stop release and voice onset, and the level of activity prior to the VOT, were influenced by syllable intensity and the spectrum of stop release, as well as cell BF and type. Our results suggest that the responses of VCN cells with BFs above the first formant frequency are dominated by their sensitivity to the onsets of broadband events in speech, and allows them to convey accurate information about a syllable's VOT.

Acoustic Stimulation↗

PubMed2003

BDNF-induced survival of auditory neurons in vivo: Cessation of treatment leads to accelerated loss of survival effects.

Neurotrophic factors are important for the development and maintenance of the auditory system. They have also been shown to act as survival factors for auditory neurons in animal deafness models. Studies have demonstrated recently that these neurotrophic factors not only maintain survival of auditory neurons, but that these surviving neurons retain functionality. It remains to be determined, however, if a single administration of a neurotrophic factor is sufficient to maintain auditory neuron survival after loss of hair cells, or if sustained delivery is required. This study investigated the longevity of the survival effects of BDNF on auditory neurons in deafened guinea pigs. Briefly, the left cochleae of deafened guinea pigs were infused with BDNF for 28 days via a mini-osmotic pump, and neuronal survival was analyzed at various stages after the completion of treatment. BDNF treatment prevented the degeneration of auditory neurons that normally is seen after a loss of hair cells, supporting previous studies. Our results indicate, however, that cessation of BDNF treatment leads to an accelerated decline in auditory neuron survival as compared to that observed in deafened, untreated cochleae. These findings indicate that much work remains to be done to establish a technique for the long-term survival of auditory neurons in the deaf ear.

Animals↗

PubMed2002

Speech perception outcomes in older children who use multichannel cochlear implants: older is not always poorer.

Speech perception outcomes for early-deafened children who undergo implantation as teenagers or young adults are generally reported to be poorer than results for young children. It is important to provide appropriate expectations when counseling adolescents and their families to help them make an informed choice regarding cochlear implant surgery. The considerable variation of results in this group makes this process more difficult. This study considered a number of factors in a group of 25 children who underwent implantation in Melbourne between the ages of 8 and 18 years. Each subject completed open-set speech perception testing with Bamford-Kowal-Bench sentences before and after implantation and preoperative language testing with the Peabody Picture Vocabulary Test. Data were collected regarding the type of hearing loss, age at implantation, age at hearing aid fitting, audiometric details, and preoperative and postoperative communication mode. Results were submitted to a stepwise multiple linear regression analysis with postoperative open-set sentence scores as the dependent variables. The analysis suggested that 3 factors have a significant predictive value for speech perception after implantation: preoperative open-set sentence score, duration of profound hearing loss, and equivalent language age. These 3 factors accounted for 66% of the variance in this group. The results of this study suggest that children who have useful speech perception before implantation, and higher age-equivalent scores on language measures, would be expected to do well with a cochlear implant. Consistent with other studies, a shorter duration of profound hearing loss is also advantageous. The mean sentence score for this group, 47%, was not significantly different from the mean result across all children in the Melbourne program.

Adolescent↗

PubMed2002

Cognitive processing in children using cochlear implants: the relationship between visual memory, attention, and executive functions and developing language skills.

We performed this study to determine whether children using a cochlear implant performed differently from age- and gender-matched hearing aid users on 8 neuropsychological measures of visual memory, attention, and executive functioning. The study also examined whether differences in cognitive skills could account for some of the observed variance in speech perception, vocabulary, and language abilities of hearing-impaired children. In contrast to previous studies, our results revealed no significant cognitive differences between children who use a cochlear implant and children who use hearing aids. Partial correlation analysis indicated that the children's visual memory skills, ie, their recognition memory, delayed recall, and paired associative learning memory skills, correlated significantly with their language skills. When examined at a significance level of .01, attention and executive functioning skills did not relate to the children's developing speech perception, vocabulary, or language skills. The results suggested that differences in visual memory skills may account for some of the variance seen in the language abilities of children using implants and children using hearing aids.

Adolescent↗

PubMedDate not supplied

Summation of spatiotemporal input patterns in leaky integrate-and-fire neurons: application to neurons in the cochlear nucleus receiving converging auditory nerve fiber input.

The response of leaky integrate-and-fire neurons is analyzed for periodic inputs whose phases vary with their spatial location. The model gives the relationship between the spatial summation distance and the degree of phase locking of the output spikes (i.e., locking to the periodic stochastic inputs, measured by the synchronization index). The synaptic inputs are modeled as an inhomogeneous Poisson process, and the analysis is carried out in the Gaussian approximation. The model has been applied to globular bushy cells of the cochlear nucleus, which receive converging inputs from auditory nerve fibers that originate at neighboring sites in the cochlea. The model elucidates the roles played by spatial summation and coincidence detection, showing how synchronization decreases with an increase in both frequency and spatial spread of inputs. It also shows under what conditions an enhancement of synchronization of the output relative to the input takes place.

Action Potentials↗