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1.  Mitochondrial abnormalities and low grade inflammation are present in the skeletal muscle of a minority of patients with amyotrophic lateral sclerosis; an observational myopathology study 
Amyotrophic lateral sclerosis (ALS) is a primary progressive neurodegenerative disease characterised by neuronal loss of lower motor neurons (in the spinal cord and brainstem) and/or upper motor neurons (in the motor cortex) and subsequent denervation atrophy of skeletal muscle.
A comprehensive examination of muscle pathology from a cohort of clinically confirmed ALS patients, including an investigation of inflammation, complement activation, and deposition of abnormal proteins in order to compare them with findings from an age-matched, control group.
Material and methods
31 muscle biopsies from clinically confirmed ALS patients and 20 normal controls underwent a comprehensive protocol of histochemical and immunohistochemical stains, including HLA-ABC, C5b-9, p62, and TDP-43.
Neurogenic changes were confirmed in 30/31 ALS cases. In one case, no neurogenic changes could be detected. Muscle fibre necrosis was seen in 5/31 cases and chronic mononuclear inflammatory cell infiltration in 5/31 (2 of them overlapped with those showing muscle necrosis). In four biopsies there was an increase in the proportion of cytochrome oxidase (COX) negative fibres (2-3%). p62 faintly stained cytoplasmic bodies in eight cases and none were immunoreactive to TDP-43.
This large series of muscle biopsies from patients with ALS demonstrates neurogenic atrophy is a nearly uniform finding and that mild mitochondrial abnormalities and low-grade inflammation can be seen and do not rule out the diagnosis of ALS. These findings could lend support to the notion that ALS is a complex and heterogeneous disorder.
PMCID: PMC4297389  PMID: 25510661
Amyotrophic lateral Sclerosis; Mitochondria; Inflammation; Pathology and Muscle
2.  Primary glioblastoma with oligodendroglial differentiation has better clinical outcome but no difference in common biological markers compared with other types of glioblastoma 
Neuro-Oncology  2013;15(12):1635-1643.
Glioblastoma multiforme with an oligodendroglial component (GBMO) has been recognized in the World Health Organization classification—however, the diagnostic criteria, molecular biology, and clinical outcome of primary GBMO remain unclear. Our aim was to investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation.
We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome.
GBMO comprised 21.5% of our GBM specimens and showed significantly longer survival compared with our other GBM (12 mo vs 5.8 mo, P = .006); there was also a strong correlation with younger age at diagnosis (56.4 y vs 60.6 y, P = .005). Singular LOH of 19q (P = .04) conferred a 1.9-fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (P = .8, P = 1.0, P = 1.0, respectively).
Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT, and IDH1 mutation compared with other primary GBM.
PMCID: PMC3829593  PMID: 24158110
glioblastoma with an oligodendroglial component; histopathology; 1p/19q; IDH1; MGMT
3.  Prosthetic Hip-Associated Cobalt Toxicity 
Journal of Medical Toxicology  2013;9(4):416-417.
Prosthetic hip-associated cobalt toxicity (PHACT) is gaining recognition due to the use of metal-on-metal total hip replacements. Identifying true toxicity from merely elevated cobalt levels can be extremely difficult due to the lack of available data. An extensive review of the medical literature was undertaken to characterize cobalt toxicity from prosthetic hips. As an objective approach to making the diagnosis of PHACT, we suggest the following criteria: (1) elevated serum or whole blood cobalt levels due to a prosthetic hip, (2) at least two test-confirmed findings consistent with cobalt toxicity, and (3) exclusion of other etiologies. Adhering to objective diagnostic data for PHACT is a realistic and prudent method by which to eliminate the subjectivity of vague or difficult to identify complaints. These diagnostic criteria are not meant to evaluate prosthetic hardware failure, but as a means to identify systemic cobalt toxicity. Finally, assessment of cobalt toxicity from prosthetic hips should be done in conjunction with a medical toxicologist.
PMCID: PMC3846969  PMID: 24258006
Cobalt toxicity; Prosthetic hips; Metal-on-metal hip
4.  Adaptive Reweighting of Auditory Localization Cues in Response to Chronic Unilateral Ear-plugging in Humans 
Localizing a sound source involves the detection and integration of various spatial cues present in the sound waves at each ear. Previous studies indicate that the brain circuits underlying sound localization are calibrated by experience of the cues available to each individual. Plasticity in spatial hearing is most pronounced during development, but can also be demonstrated during adulthood under certain circumstances. Investigations into whether adult humans can adjust to reduced input in one ear and learn a new correspondence between interaural differences cues and directions in space have produced conflicting results. Here we show that humans of both sexes can relearn to localize broadband sounds with a “flat” spectrum in the horizontal plane after altering the spatial cues available by plugging one ear. In subjects who received daily training, localization accuracy progressively shifted back toward their pre-plug performance after one week of ear-plugging, whereas no improvement was seen if all trials were carried out on the same day. However, localization performance did not improve on a task that employed stimuli in which the source spectrum was randomized from trial to trial, indicating that monaural spectral cues are needed for plasticity. We also characterized the effects of the earplug on sensitivity to interaural time and level differences, and found no clear evidence for adaptation to these cues as the free-field localization performance improved. These findings suggest that the mature auditory system can accommodate abnormal inputs and maintain a stable spatial percept by reweighting different cues according to how informative they are.
PMCID: PMC4225134  PMID: 20371808
Auditory; Binaural; Plasticity; Human; Spatial perception; Hearing; Training
5.  Solving the shepherding problem: heuristics for herding autonomous, interacting agents 
Journal of the Royal Society Interface  2014;11(100):20140719.
Herding of sheep by dogs is a powerful example of one individual causing many unwilling individuals to move in the same direction. Similar phenomena are central to crowd control, cleaning the environment and other engineering problems. Despite single dogs solving this ‘shepherding problem’ every day, it remains unknown which algorithm they employ or whether a general algorithm exists for shepherding. Here, we demonstrate such an algorithm, based on adaptive switching between collecting the agents when they are too dispersed and driving them once they are aggregated. Our algorithm reproduces key features of empirical data collected from sheep–dog interactions and suggests new ways in which robots can be designed to influence movements of living and artificial agents.
PMCID: PMC4191104  PMID: 25165603
collective motion; agent-based model; sheep; sheepdog
6.  A transcriptome resource for the koala (Phascolarctos cinereus): insights into koala retrovirus transcription and sequence diversity 
BMC Genomics  2014;15(1):786.
The koala, Phascolarctos cinereus, is a biologically unique and evolutionarily distinct Australian arboreal marsupial. The goal of this study was to sequence the transcriptome from several tissues of two geographically separate koalas, and to create the first comprehensive catalog of annotated transcripts for this species, enabling detailed analysis of the unique attributes of this threatened native marsupial, including infection by the koala retrovirus.
RNA-Seq data was generated from a range of tissues from one male and one female koala and assembled de novo into transcripts using Velvet-Oases. Transcript abundance in each tissue was estimated. Transcripts were searched for likely protein-coding regions and a non-redundant set of 117,563 putative protein sequences was produced. In similarity searches there were 84,907 (72%) sequences that aligned to at least one sequence in the NCBI nr protein database. The best alignments were to sequences from other marsupials. After applying a reciprocal best hit requirement of koala sequences to those from tammar wallaby, Tasmanian devil and the gray short-tailed opossum, we estimate that our transcriptome dataset represents approximately 15,000 koala genes. The marsupial alignment information was used to look for potential gene duplications and we report evidence for copy number expansion of the alpha amylase gene, and of an aldehyde reductase gene.
Koala retrovirus (KoRV) transcripts were detected in the transcriptomes. These were analysed in detail and the structure of the spliced envelope gene transcript was determined. There was appreciable sequence diversity within KoRV, with 233 sites in the KoRV genome showing small insertions/deletions or single nucleotide polymorphisms. Both koalas had sequences from the KoRV-A subtype, but the male koala transcriptome has, in addition, sequences more closely related to the KoRV-B subtype. This is the first report of a KoRV-B-like sequence in a wild population.
This transcriptomic dataset is a useful resource for molecular genetic studies of the koala, for evolutionary genetic studies of marsupials, for validation and annotation of the koala genome sequence, and for investigation of koala retrovirus. Annotated transcripts can be browsed and queried at
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-786) contains supplementary material, which is available to authorized users.
PMCID: PMC4247155  PMID: 25214207
Transcriptome; Koala; Phascolarctos cinereus; Koala retrovirus; Alpha amylase; Aldehyde reductase
7.  The precedence effect and its buildup and breakdown in ferrets and humans 
Although many studies have examined the precedence effect (PE), few have tested whether it shows a buildup and breakdown in nonhuman animals comparable to that seen in humans. These processes are thought to reflect the ability of the auditory system to adjust to a listener’s acoustic environment, and their mechanisms are still poorly understood. In this study, ferrets were trained on a two-alternative forced-choice task to discriminate the azimuthal direction of brief sounds. In one experiment, pairs of noise bursts were presented from two loudspeakers at different interstimulus delays (ISDs). Results showed that localization performance changed as a function of ISD in a manner consistent with the PE being operative. A second experiment investigated buildup and breakdown of the PE by measuring the ability of ferrets to discriminate the direction of a click pair following presentation of a conditioning train. Human listeners were also tested using this paradigm. In both species, performance was better when the test clicks and conditioning train had the same ISD but deteriorated following a switch in the direction of the leading and lagging sounds between the conditioning train and test clicks. These results suggest that ferrets, like humans, experience a buildup and breakdown of the PE.
PMCID: PMC4153988  PMID: 24606278
8.  A New Approach to Quantify Semiochemical Effects on Insects Based on Energy Landscapes 
PLoS ONE  2014;9(8):e106276.
Our ability to document insect preference for semiochemicals is pivotal in pest control as these agents can improve monitoring and be deployed within integrated pest management programmes for more efficacious control of pest species. However, methods used to date have drawbacks that limit their utility. We present and test a new concept for determining insect motivation to move towards, or away from, semiochemicals by noting direction and speed of movement as animals work against a defined energy landscape (environmentally dependent variation in the cost of transport) requiring different powers to negotiate. We conducted trials with the pine weevils Hylobius abietis and peach-potato aphids Myzus persicae exposed to various attractants and repellents and placed so that they either moved up defined slopes against gravity or had to travel over variously rough surfaces.
Linear Mixed Models demonstrated clear reductions in travel speed by insects moving along increasingly energetically taxing energy landscapes but also that responses varied according to different semiochemicals, thus highlighting the value of energy landscapes as a new concept to help measure insect motivation to access or avoid different attractants or repellents across individuals.
New sensitive, detailed indicators of insect motivation derived from this approach should prove important in pest control across the world.
PMCID: PMC4149542  PMID: 25171062
9.  Multisensory Training Improves Auditory Spatial Processing following Bilateral Cochlear Implantation 
The Journal of Neuroscience  2014;34(33):11119-11130.
Cochlear implants (CIs) partially restore hearing to the deaf by directly stimulating the inner ear. In individuals fitted with CIs, lack of auditory experience due to loss of hearing before language acquisition can adversely impact outcomes. For example, adults with early-onset hearing loss generally do not integrate inputs from both ears effectively when fitted with bilateral CIs (BiCIs). Here, we used an animal model to investigate the effects of long-term deafness on auditory localization with BiCIs and approaches for promoting the use of binaural spatial cues. Ferrets were deafened either at the age of hearing onset or as adults. All animals were implanted in adulthood, either unilaterally or bilaterally, and were subsequently assessed for their ability to localize sound in the horizontal plane. The unilaterally implanted animals were unable to perform this task, regardless of the duration of deafness. Among animals with BiCIs, early-onset hearing loss was associated with poor auditory localization performance, compared with late-onset hearing loss. However, performance in the early-deafened group with BiCIs improved significantly after multisensory training with interleaved auditory and visual stimuli. We demonstrate a possible neural substrate for this by showing a training-induced improvement in the responsiveness of auditory cortical neurons and in their sensitivity to interaural level differences, the principal localization cue available to BiCI users. Importantly, our behavioral and physiological evidence demonstrates a facilitative role for vision in restoring auditory spatial processing following potential cross-modal reorganization. These findings support investigation of a similar training paradigm in human CI users.
PMCID: PMC4131019  PMID: 25122908
auditory cortex; cochlear implant; cross-modal plasticity; hearing loss; multisensory; sound localization
10.  Acute Testicular Ischemia following Endovascular Abdominal Aortic Aneurysm Repair Identified in the Emergency Department 
Endovascular aneurysm repair (EVAR) is perhaps the most widely utilized surgical procedure for patients with large abdominal aortic aneurysms. This procedure is minimally invasive and reduces inpatient hospitalization requirements. The case involves a 72-year-old male who presented to the emergency department with right testicular ischemia two days following EVAR. Given the minimal inpatient hospitalization associated with this procedure, emergency physicians are likely to encounter associated complications. Ischemic and thromboembolic events following EVAR are extremely rare but require prompt vascular surgery intervention to minimize morbidity and mortality.
PMCID: PMC4119903  PMID: 25114810
11.  Visual sensitivity is a stronger determinant of illusory processes than auditory cue parameters in the sound-induced flash illusion 
Journal of Vision  2014;14(7):12.
The sound-induced flash illusion (SIFI) is a multisensory perceptual phenomenon in which the number of brief visual stimuli perceived by an observer is influenced by the number of concurrently presented sounds. While the strength of this illusion has been shown to be modulated by the temporal congruence of the stimuli from each modality, there is conflicting evidence regarding its dependence upon their spatial congruence. We addressed this question by examining SIFIs under conditions in which the spatial reliability of the visual stimuli was degraded and different sound localization cues were presented using either free-field or closed-field stimulation. The likelihood of reporting a SIFI varied with the spatial cue composition of the auditory stimulus and was highest when binaural cues were presented over headphones. SIFIs were more common for small flashes than for large flashes, and for small flashes at peripheral locations, subjects experienced a greater number of illusory fusion events than fission events. However, the SIFI was not dependent on the spatial proximity of the audiovisual stimuli, but was instead determined primarily by differences in subjects' underlying sensitivity across the visual field to the number of flashes presented. Our findings indicate that the influence of auditory stimulation on visual numerosity judgments can occur independently of the spatial relationship between the stimuli.
PMCID: PMC4070624  PMID: 24961249
auditory-visual interactions; sound-induced flash illusion; sound localization; visual sensitivity; signal detection theory
12.  Articles You Might Have Missed 
Journal of Medical Toxicology  2013;9(2):212-214.
PMCID: PMC3657030
Verapamil; Cyclodextrin; N-acetylcysteine; Pediatric acute liver failure; Azithromycin; Sudden cardiac death; Dexmedetomidine; Withdrawal syndrome; Clonidine
13.  The Effect of Calcium Phosphate Particle Shape and Size on their Antibacterial and Osteogenic Activity in the Delivery of Antibiotics in vitro 
ACS applied materials & interfaces  2013;5(7):2422-2431.
Powders composed of four morphologically different calcium phosphate particles were prepared by precipitation from aqueous solutions: flaky, brick-like, elongated orthogonal, and spherical. The particles were then loaded with either clindamycin phosphate as the antibiotic of choice, or fluorescein, a model molecule used to assess the drug release properties. A comparison was carried out of the comparative effect of such antibiotic-releasing materials on: sustained drug release profiles; Staphylococcus aureus growth inhibition; and osteogenic propensities in vitro. Raman spectroscopic analysis indicated the presence of various calcium phosphate phases, including monetite (flaky and elongated orthogonal particles), octacalcium phosphate (brick-shaped particles) and hydroxyapatite (spherical particles). Testing the antibiotic-loaded calcium phosphate powders for bacterial growth inhibition demonstrated satisfying antibacterial properties both in broths and on agar plates. All four calcium-phosphate-fluorescein powders exhibited sustained drug release over 21 days. The calcium phosphate sample with the highest specific surface area and the smallest, spherical particle size was the most effective in both drug loading and release, consequently having the highest antibacterial efficiency. Moreover, the highest cell viability, the largest gene expression upregulation of three different osteogenic markers – osteocalcin, osteopontin and Runx2 - as well as the least disrupted cell cytoskeleton and cell morphologies were also noticed for the calcium phosphate powder composed of smallest, spherical nanosized particles. Still, all four powders exerted a viable effect on osteoblastic MC3T3-E1 cells in vitro, as evidenced by both morphological assessments on fluorescently stained cells and measurements of their mitochondrial activity. The obtained results suggest that the nanoscale particle size and the corresponding coarseness of the surface of particle conglomerates as the cell attachment points may present a favorable starting point for the development of calcium-phosphate-based osteogenic drug delivery devices.
PMCID: PMC3647690  PMID: 23484624
Calcium Phosphate; Controlled Drug Delivery; Morphology; Osteomyelitis; Raman Spectroscopy; Staphylococcus aureus
14.  Factors Influencing Decision-making and Outcome in the Surgical Management of Trigeminal Neuralgia 
Objectives The aim was to optimize the algorithm of operative intervention for trigeminal neuralgia (TN).
Design A multivariate analysis was undertaken to determine factors that had influenced both the initial choice of surgical intervention and the subsequent outcomes.
Setting The study was undertaken with patients who underwent microvascular decompression (MVD) or percutaneous glycerol injection (PGI) for TN between 2007 and 2009.
Participants Seventy-one consecutive patients (43 female) were selected.
Main Outcome Measures Data were prospectively recorded and included demographics, etiology, and presentation of TN, duration of symptoms, neurovascular contact, and the outcomes of surgery.
Results The response rates for MVD and PGI were 96.2% and 87.5%, respectively. The recurrence rates were 9.8% following MVD and 33.3% following PGI. Multivariate analyses confirmed multiple sclerosis and the identification of neurovascular contact as the only factors predictive of the choice of surgical intervention and the risk of recurrence following MVD.
Conclusions Our approach to choosing an operative intervention has been validated. The presence of neurovascular contact and the diagnosis of multiple sclerosis influenced the choice of surgery and were predictive of subsequent outcome. Both MVD and PGI offer effective treatment options for TN. Surgery should be offered early when medical management fails.
PMCID: PMC3699212  PMID: 24436892
trigeminal neuralgia; microvascular decompression; percutaneous glycerol injection; neurovascular contact; multiple sclerosis
15.  What happens to your hearing if you are born blind? 
Brain  2014;137(1):6-8.
PMCID: PMC3891451  PMID: 24424914
16.  The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial 
Interleukin-1 (IL-1) is a key mediator of ischaemic brain injury induced by stroke and subarachnoid haemorrhage (SAH). IL-1 receptor antagonist (IL-1Ra) limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome in ischaemic stroke patients. Intravenous (IV) IL-1Ra crosses the blood–brain barrier (BBB) in patients with SAH, to achieve cerebrospinal fluid (CSF) concentrations that are neuroprotective in rats.
A small phase II, double-blind, randomised controlled study was carried out across two UK neurosurgical centres with the aim of recruiting 32 patients. Adult patients with aneurysmal SAH, requiring external ventricular drainage (EVD) within 72 hours of ictus, were eligible. Patients were randomised to receive IL-1Ra (500 mg bolus, then a 10 mg/kg/hr infusion for 24 hours) or placebo. Serial samples of CSF and plasma were taken and analysed for inflammatory mediators, with change in CSF IL-6 between 6 and 24 hours as the primary outcome measure.
Six patients received IL-1Ra and seven received placebo. Concentrations of IL-6 in CSF and plasma were reduced by one standard deviation in the IL-1Ra group compared to the placebo group, between 6 and 24 hours, as predicted by the power calculation. This did not reach statistical significance (P = 0.08 and P = 0.06, respectively), since recruitment did not reach the target figure of 32. No adverse or serious adverse events reported were attributable to IL-1Ra.
IL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra.
PMCID: PMC3892121  PMID: 24383930
17.  The Comprehensive Antibiotic Resistance Database 
The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.
PMCID: PMC3697360  PMID: 23650175
18.  Which factors influence decisions to transfer and treat patients with acute intracerebral haemorrhage and which are associated with prognosis? A retrospective cohort study 
BMJ Open  2013;3(12):e003684.
To identify factors associated with the decision to transfer and/or operate on patients with intracerebral haemorrhage (ICH) at a UK regional neurosurgical centre and test whether these decisions were associated with patient survival.
Retrospective cohort study.
14 acute and specialist hospitals served by the neurosurgical unit at Salford Royal NHS Foundation Trust, Salford, UK.
All patients referred acutely to neurosurgery from January 2008 to October 2010.
Outcome measures
Primary outcome was survival and secondary outcomes were transfer to the neurosurgical centre and acute neurosurgery.
We obtained clinical data from 1364 consecutive spontaneous patients with ICH and 1175 cases were included in the final analysis. 140 (12%) patients were transferred and 75 (6%) had surgery. In a multifactorial analysis, the decision to transfer was more likely with younger age, women, brainstem and cerebellar location and larger haematomas. Risk of death in the following year was higher with advancing age, lower Glasgow Coma Scale, larger haematomas, brainstem ICH and intraventricular haemorrhage. The transferred patients had a lower risk of death relative to those remaining at the referring centre whether they had surgery (HR 0.46, 95% CI 0.32 to 0.67) or not (HR 0.41, 95% CI 0.22 to 0.73). Acute management decisions were included in the regression model for the 227 patients under either stroke medicine or neurosurgery at the neurosurgical centre and early do-not-resuscitate orders accounted for much of the observed difference, independently associated with an increased risk of death (HR 4.8, 95% CI 2.7 to 8.6).
The clear association between transfer to a specialist centre and survival, independent of established prognostic factors, suggests aggressive supportive care at a specialist centre may improve survival in ICH and warrants further investigation in prospective studies.
PMCID: PMC3884585  PMID: 24345898
19.  Sex-Differences and Temporal Consistency in Stickleback Fish Boldness 
PLoS ONE  2013;8(12):e81116.
Behavioural traits that co-vary across contexts or situations often reflect fundamental trade-offs which individuals experience in different contexts (e.g. fitness trade-offs between exploration and predation risk). Since males tend to experience greater variance in reproductive success than females, there may be considerable fitness benefits associated with “bolder” behavioural types, but only recently have researchers begun to consider sex-specific and life-history strategies associated with these. Here we test the hypothesis that male three-spined sticklebacks (Gasterosteus aculeatus) show high risk but potentially high return behaviours compared to females. According to this hypothesis we predicted that male fish would show greater exploration of their environment in a foraging context, and be caught sooner by an experimenter than females. We found that the time fish spent out of cover exploring their environment was correlated over two days, and males spent significantly more time out of cover than females. Also, the order in which fish were net-caught from their holding aquarium by an experimenter prior to experiments was negatively correlated with the time spent out of cover during tests, and males tended to be caught sooner than females. Moreover, we found a positive correlation between the catch number prior to our experiments and nine months after, pointing towards consistent, long-term individual differences in behaviour.
PMCID: PMC3852232  PMID: 24324664
20.  Constructing Noise-Invariant Representations of Sound in the Auditory Pathway 
PLoS Biology  2013;11(11):e1001710.
Along the auditory pathway from auditory nerve to midbrain to cortex, individual neurons adapt progressively to sound statistics, enabling the discernment of foreground sounds, such as speech, over background noise.
Identifying behaviorally relevant sounds in the presence of background noise is one of the most important and poorly understood challenges faced by the auditory system. An elegant solution to this problem would be for the auditory system to represent sounds in a noise-invariant fashion. Since a major effect of background noise is to alter the statistics of the sounds reaching the ear, noise-invariant representations could be promoted by neurons adapting to stimulus statistics. Here we investigated the extent of neuronal adaptation to the mean and contrast of auditory stimulation as one ascends the auditory pathway. We measured these forms of adaptation by presenting complex synthetic and natural sounds, recording neuronal responses in the inferior colliculus and primary fields of the auditory cortex of anaesthetized ferrets, and comparing these responses with a sophisticated model of the auditory nerve. We find that the strength of both forms of adaptation increases as one ascends the auditory pathway. To investigate whether this adaptation to stimulus statistics contributes to the construction of noise-invariant sound representations, we also presented complex, natural sounds embedded in stationary noise, and used a decoding approach to assess the noise tolerance of the neuronal population code. We find that the code for complex sounds in the periphery is affected more by the addition of noise than the cortical code. We also find that noise tolerance is correlated with adaptation to stimulus statistics, so that populations that show the strongest adaptation to stimulus statistics are also the most noise-tolerant. This suggests that the increase in adaptation to sound statistics from auditory nerve to midbrain to cortex is an important stage in the construction of noise-invariant sound representations in the higher auditory brain.
Author Summary
We rarely hear sounds (such as someone talking) in isolation, but rather against a background of noise. When mixtures of sounds and background noise reach the ears, peripheral auditory neurons represent the whole sound mixture. Previous evidence suggests, however, that the higher auditory brain represents just the sounds of interest, and is less affected by the presence of background noise. The neural mechanisms underlying this transformation are poorly understood. Here, we investigate these mechanisms by studying the representation of sound by populations of neurons at three stages along the auditory pathway; we simulate the auditory nerve and record from neurons in the midbrain and primary auditory cortex of anesthetized ferrets. We find that the transformation from noise-sensitive representations of sound to noise-tolerant processing takes place gradually along the pathway from auditory nerve to midbrain to cortex. Our results suggest that this results from neurons adapting to the statistics of heard sounds.
PMCID: PMC3825667  PMID: 24265596
21.  Cortical cholinergic input is required for normal auditory perception and experience-dependent plasticity in adult ferrets 
The nucleus basalis (NB) in the basal forebrain provides most of the cholinergic input to the neocortex, and has been implicated in a variety of cognitive functions related to the processing of sensory stimuli. However, the role that cortical acetylcholine release plays in perception remains unclear. Here we show that selective loss of cholinergic NB neurons that project to the cortex reduces the accuracy with which ferrets localize brief sounds, and prevents them from adaptively reweighting auditory localization cues in response to chronic occlusion of one ear. Cholinergic input to the cortex was disrupted by making bilateral injections of the immunotoxin ME20.4-SAP into the NB. This produced a substantial loss of both p75NTR and choline acetyltransferase-positive cells in this region and of acetylcholinesterase-positive fibers throughout the auditory cortex. These animals were significantly impaired in their ability to localize short broadband sounds (40-500 ms in duration) in the horizontal plane, with larger cholinergic cell lesions producing greater performance impairments. Although they localized longer sounds with normal accuracy, their response times were significantly longer than controls. Ferrets with cholinergic forebrain lesions were also less able to relearn to localize sound after plugging one ear. In contrast to controls, they exhibited little recovery of localization performance following behavioral training. Together, these results show that cortical cholinergic inputs contribute to the perception of sound source location under normal hearing conditions, and play a critical role in allowing the auditory system to adapt to changes in the spatial cues available.
PMCID: PMC3682393  PMID: 23575862
auditory cortex; nucleus basalis; acetylcholine; sound localization; adult plasticity; learning; ferret
22.  Spectral timbre perception in ferrets; discrimination of artificial vowels under different listening conditions 
Spectral timbre is an acoustic feature that enables human listeners to determine the identity of a spoken vowel. Despite its importance to sound perception, little is known about the neural representation of sound timbre and few psychophysical studies have investigated timbre discrimination in non-human species. In this study, ferrets were positively conditioned to discriminate artificial vowel sounds in a two-alternative-forced-choice paradigm. Animals quickly learned to discriminate the vowel sound /u/ from /ε/, and were immediately able to generalize across a range of voice pitches. They were further tested in a series of experiments designed to assess how well they could discriminate these vowel sounds under different listening conditions. First, a series of morphed vowels was created by systematically shifting the location of the first and second formant frequencies. Second, the ferrets were tested with single formant stimuli designed to assess which spectral cues they could be using to make their decisions. Finally, vowel discrimination thresholds were derived in the presence of noise maskers presented from either the same or a different spatial location. These data indicate that ferrets show robust vowel discrimination behavior across a range of listening conditions and that this ability shares many similarities with human listeners.
PMCID: PMC3783993  PMID: 23297909
23.  4-Aminopyridine Toxicity: a Case Report and Review of the Literature 
Journal of Medical Toxicology  2012;8(3):314-321.
4-Aminopyridine (4-AP) selectively blocks voltage-gated potassium channels, prolongs the action potential, increases calcium influx, and subsequently, enhances interneuronal and neuromuscular synaptic transmission. This medication has been studied and used in many disease processes hallmarked by poor neuronal transmission in both the central and peripheral nervous systems including: multiple sclerosis (MS), spinal cord injuries (SCI), botulism, Lambert-Eaton syndrome, and myasthenia gravis. It has also been postulated as a potential treatment of verapamil toxicity and reversal agent for anesthesia-induced neuromuscular blockade. To date, there have been limited reports of either intentional or accidental 4-AP toxicity in humans. Both a case of a patient with 4-AP toxicity and review of the literature are discussed, highlighting commonalities observed in overdose.
Case Report
A 37-year-old man with progressive MS presented with diaphoresis, delirium, agitation, and choreathetoid movements after a presumed 4-AP overdose. 4-AP concentration at 6 h was 140 ng/mL. With aggressive benzodiazepine administration and intubation, he recovered uneventfully.
The commonalities associated with 4-AP toxicity conforms to what is known about its mechanism of action combining cholinergic features including diaphoresis, altered mental status, and seizures with dopamine-related movement abnormalities including tremor, choreoathetosis, and dystonia. Management of patients poisoned by 4-AP centers around good supportive care with definitive airway management and controlling CNS hyperexcitability aggressively with gamma-aminobutyric acid agonist agents. Adjunctive use of dopamine antagonists for extrapyramidal effects after sedation is a treatment possibility. As 4-aminopyridine recently received Federal Drug Administration approval for the treatment of ambulation in patients with MS, physicians should be keenly aware of its presentation, mechanism of action, and management in overdose.
PMCID: PMC3550165  PMID: 22782458
4-Aminopyridine; Case report; Overdose; Toxicity
24.  Erratum: Cooccurrence patterns of plants and soil bacteria in the high-alpine subnival zone track environmental harshness 
PMCID: PMC3748318  PMID: 23970882
erratum; community assembly; co-occurrence networks; niwot ridge; plant-microbe interactions
25.  Simulated surgical-type cerebral biopsies from post-mortem brains allows accurate neuropathological diagnoses in the majority of neurodegenerative disease groups 
In theory, cerebral biopsies could provide the diagnosis in a significant proportion of patients with neurodegenerative diseases, however, there are considerable ethical barriers. Previous series of cerebral biopsies have shown variable diagnostic accuracy but have understandably suffered because of lack of post-mortem tissue with which to compare the diagnosis. To determine the accuracy of such biopsies in neurodegenerative disease we took small biopsy-sized samples of predominantly fresh post-mortem brain tissue from frontal and temporal lobes in 62 cases. These were processed as for a biopsy and stained for H&E, p62, tau, Aβ, α-synuclein, and TDP-43. The sections were assessed blind by 3 neuropathologists and the results compared with the final post-mortem diagnosis.
The agreement and sensitivity in most cases was good especially: controls; Alzheimer’s disease (AD); multiple system atrophy (MSA); frontotemporal lobar degeneration with TDP-43 positive inclusions and/or motor neurone disease (FTLD-TDP/MND); Huntington’s disease (HD); corticobasal degeneration (CBD) / microtubular associated protein tau mutation cases with CBD-like features (CBD/MAPT); and combined AD- Dementia with Lewy Bodies (AD-DLB) where the sensitivity on assessing both brain regions varied between 75-100%. There was poor sensitivity for progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) (both 0%), but moderate sensitivity for pure DLB (60%). The temporal lobe assessment was marginally more accurate than the frontal lobe but these were only slightly worse than both combined.
The study shows that with certain caveats the cerebral biopsy in life should be a viable method of accurately diagnosing many neurodegenerative diseases.
PMCID: PMC3893367  PMID: 24252649
Neurodegeneration; Biopsy; Dementia

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