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1.  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.
doi:10.1021/am4000694
PMCID: PMC3647690  PMID: 23484624
Calcium Phosphate; Controlled Drug Delivery; Morphology; Osteomyelitis; Raman Spectroscopy; Staphylococcus aureus
2.  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.
doi:10.1055/s-0033-1333617
PMCID: PMC3699212  PMID: 24436892
trigeminal neuralgia; microvascular decompression; percutaneous glycerol injection; neurovascular contact; multiple sclerosis
3.  What happens to your hearing if you are born blind? 
Brain  2014;137(1):6-8.
doi:10.1093/brain/awt346
PMCID: PMC3891451  PMID: 24424914
4.  The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1742-2094-11-1
PMCID: PMC3892121  PMID: 24383930
5.  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; http://arpcard.mcmaster.ca). 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.
doi:10.1128/AAC.00419-13
PMCID: PMC3697360  PMID: 23650175
6.  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.
Objectives
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.
Design
Retrospective cohort study.
Setting
14 acute and specialist hospitals served by the neurosurgical unit at Salford Royal NHS Foundation Trust, Salford, UK.
Participants
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.
Results
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).
Conclusions
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.
doi:10.1136/bmjopen-2013-003684
PMCID: PMC3884585  PMID: 24345898
Neurosurgery
7.  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.
doi:10.1371/journal.pone.0081116
PMCID: PMC3852232  PMID: 24324664
8.  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.
doi:10.1371/journal.pbio.1001710
PMCID: PMC3825667  PMID: 24265596
9.  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.
doi:10.1523/JNEUROSCI.5039-12.2013
PMCID: PMC3682393  PMID: 23575862
auditory cortex; nucleus basalis; acetylcholine; sound localization; adult plasticity; learning; ferret
10.  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.
doi:10.1121/1.4768798
PMCID: PMC3783993  PMID: 23297909
11.  4-Aminopyridine Toxicity: a Case Report and Review of the Literature 
Journal of Medical Toxicology  2012;8(3):314-321.
Introduction
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.
Discussion
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.
doi:10.1007/s13181-012-0248-9
PMCID: PMC3550165  PMID: 22782458
4-Aminopyridine; Case report; Overdose; Toxicity
12.  Erratum: Cooccurrence patterns of plants and soil bacteria in the high-alpine subnival zone track environmental harshness 
doi:10.3389/fmicb.2013.00239
PMCID: PMC3748318  PMID: 23970882
erratum; community assembly; co-occurrence networks; niwot ridge; plant-microbe interactions
13.  Simulated surgical-type cerebral biopsies from post-mortem brains allows accurate neuropathological diagnoses in the majority of neurodegenerative disease groups 
Background
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.
Results
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.
Conclusions
The study shows that with certain caveats the cerebral biopsy in life should be a viable method of accurately diagnosing many neurodegenerative diseases.
doi:10.1186/2051-5960-1-53
PMCID: PMC3893367  PMID: 24252649
Neurodegeneration; Biopsy; Dementia
14.  Plasticity of spatial hearing: behavioural effects of cortical inactivation 
The Journal of Physiology  2012;590(Pt 16):3965-3986.
The contribution of auditory cortex to spatial information processing was explored behaviourally in adult ferrets by reversibly deactivating different cortical areas by subdural placement of a polymer that released the GABAA agonist muscimol over a period of weeks. The spatial extent and time course of cortical inactivation were determined electrophysiologically. Muscimol-Elvax was placed bilaterally over the anterior (AEG), middle (MEG) or posterior ectosylvian gyrus (PEG), so that different regions of the auditory cortex could be deactivated in different cases. Sound localization accuracy in the horizontal plane was assessed by measuring both the initial head orienting and approach-to-target responses made by the animals. Head orienting behaviour was unaffected by silencing any region of the auditory cortex, whereas the accuracy of approach-to-target responses to brief sounds (40 ms noise bursts) was reduced by muscimol-Elvax but not by drug-free implants. Modest but significant localization impairments were observed after deactivating the MEG, AEG or PEG, although the largest deficits were produced in animals in which the MEG, where the primary auditory fields are located, was silenced. We also examined experience-induced spatial plasticity by reversibly plugging one ear. In control animals, localization accuracy for both approach-to-target and head orienting responses was initially impaired by monaural occlusion, but recovered with training over the next few days. Deactivating any part of the auditory cortex resulted in less complete recovery than in controls, with the largest deficits observed after silencing the higher-level cortical areas in the AEG and PEG. Although suggesting that each region of auditory cortex contributes to spatial learning, differences in the localization deficits and degree of adaptation between groups imply a regional specialization in the processing of spatial information across the auditory cortex.
doi:10.1113/jphysiol.2011.222828
PMCID: PMC3464400  PMID: 22547635
15.  Context-Specific Reweighting of Auditory Spatial Cues following Altered Experience during Development 
Current Biology  2013;23(14):1291-1299.
Summary
Background
Neural systems must weight and integrate different sensory cues in order to make decisions. However, environmental conditions often change over time, altering the reliability of different cues and therefore the optimal way for combining them. To explore how cue integration develops in dynamic environments, we examined the effects on auditory spatial processing of rearing ferrets with localization cues that were modified via a unilateral earplug, interspersed with brief periods of normal hearing.
Results
In contrast with control animals, which rely primarily on timing and intensity differences between their two ears to localize sound sources, the juvenile-plugged ferrets developed the ability to localize sounds accurately by relying more on the unchanged spectral localization cues provided by the single normal ear. This adaptive process was paralleled by changes in neuronal responses in the primary auditory cortex, which became relatively more sensitive to these monaural spatial cues. Our behavioral and physiological data demonstrated, however, that the reweighting of different spatial cues disappeared as soon as normal hearing was experienced, showing for the first time that this type of plasticity can be context specific.
Conclusions
These results show that developmental changes can be selectively expressed in response to specific acoustic conditions. In this way, the auditory system can develop and simultaneously maintain two distinct models of auditory space and switch between these models depending on the prevailing sensory context. This ability is likely to be critical for maintaining accurate perception in dynamic environments and may point toward novel therapeutic strategies for individuals who experience sensory deficits during development.
Graphical Abstract
Highlights
•Ferrets reared with a unilateral hearing loss are able to localize sounds accurately•Adaptation relies on cue reweighting that reverses when normal hearing is available•Auditory cortical neurons show corresponding context-specific plasticity•Contextual cue reweighting maintains perceptual stability in dynamic environments
doi:10.1016/j.cub.2013.05.045
PMCID: PMC3722484  PMID: 23810532
16.  Unraveling the principles of auditory cortical processing: can we learn from the visual system? 
Nature neuroscience  2009;12(6):698-701.
Studies of auditory cortex are often driven by the assumption, derived from our better understanding of visual cortex, that basic physical properties of sounds are represented there before being used by higher-level areas for determining sound-source identity and location. However, we only have a limited appreciation of what the cortex adds to the extensive subcortical processing of auditory information, which can account for many perceptual abilities. This is partly because of the approaches that have dominated the study of auditory cortical processing to date, and future progress will unquestionably profit from the adoption of methods that have provided valuable insights into the neural basis of visual perception. At the same time, we propose that there are unique operating principles employed by the auditory cortex that relate largely to the simultaneous and sequential processing of previously derived features and that therefore need to be studied and understood in their own right.
doi:10.1038/nn.2308
PMCID: PMC3657701  PMID: 19471268
17.  Behavioral Sensitivity to Broadband Binaural Localization Cues in the Ferret 
Although the ferret has become an important model species for studying both fundamental and clinical aspects of spatial hearing, previous behavioral work has focused on studies of sound localization and spatial release from masking in the free field. This makes it difficult to tease apart the role played by different spatial cues. In humans and other species, interaural time differences (ITDs) and interaural level differences (ILDs) play a critical role in sound localization in the azimuthal plane and also facilitate sound source separation in noisy environments. In this study, we used a range of broadband noise stimuli presented via customized earphones to measure ITD and ILD sensitivity in the ferret. Our behavioral data show that ferrets are extremely sensitive to changes in either binaural cue, with levels of performance approximating that found in humans. The measured thresholds were relatively stable despite extensive and prolonged (>16 weeks) testing on ITD and ILD tasks with broadband stimuli. For both cues, sensitivity was reduced at shorter durations. In addition, subtle effects of changing the stimulus envelope were observed on ITD, but not ILD, thresholds. Sensitivity to these cues also differed in other ways. Whereas ILD sensitivity was unaffected by changes in average binaural level or interaural correlation, the same manipulations produced much larger effects on ITD sensitivity, with thresholds declining when either of these parameters was reduced. The binaural sensitivity measured in this study can largely account for the ability of ferrets to localize broadband stimuli in the azimuthal plane. Our results are also broadly consistent with data from humans and confirm the ferret as an excellent experimental model for studying spatial hearing.
doi:10.1007/s10162-013-0390-3
PMCID: PMC3705081  PMID: 23615803
sound localization; spatial hearing; psychometric function; interaural time difference; interaural level difference; azimuth
18.  The descending corticocollicular pathway mediates learning-induced auditory plasticity 
Nature neuroscience  2009;13(2):253-260.
Descending projections from sensory areas of the cerebral cortex are among the largest pathways in the brain, suggesting that they are important for subcortical processing. Although corticofugal inputs have been shown to modulate neuronal responses in the thalamus and midbrain, the behavioral importance of these changes remains unknown. In the auditory system, one of the major descending pathways is from cortical layer V pyramidal cells to the inferior colliculus in the midbrain. We examined the role of these neurons in experience-dependent recalibration of sound localization in adult ferrets by selectively killing the neurons using chromophore-targeted laser photolysis. When provided with appropriate training, animals normally relearn to localize sound accurately after altering the spatial cues available by reversibly occluding one ear. However, this ability was lost after eliminating corticocollicular neurons, whereas normal sound-localization accuracy was unaffected. The integrity of this descending pathway is therefore critical for learning-induced localization plasticity.
doi:10.1038/nn.2466
PMCID: PMC3634157  PMID: 20037578
Auditory cortex; corticofugal projection; inferior colliculus; chromophore-targeted neuronal degeneration; apoptosis; adult plasticity; sound localization; binaural cues; ferret
19.  Is the true ‘wisdom of the crowd’ to copy successful individuals? 
Biology Letters  2011;8(2):197-200.
Diversity of expertise at an individual level can increase intelligence at a collective level—a type of swarm intelligence (SI) popularly known as the ‘wisdom of the crowd’. However, this requires independent estimates (rare in the real world owing to the availability of public information) and contradicts people's bias for copying successful individuals. To explain these inconsistencies, 429 people took part in a ‘guess the number of sweets’ exercise. Guesses made with no public information were diverse, resulting in highly accurate SI. Individuals with access to the previous guess, mean guess or a randomly chosen guess, tended to over-estimate the number of sweets and this undermined SI. However, when people were provided with the current best guess, this prevented very large (inaccurate) guesses, resulting in convergence of guesses towards the true value and accurate SI across a range of group sizes. Thus, contrary to previous work, we show that social influence need not undermine SI, especially where individual decisions are made sequentially and then aggregated. Furthermore, we offer an explanation for why people have a bias to recruit and follow experts in team settings: copying successful individuals can enable accuracy at both the individual and group level, even at small group sizes.
doi:10.1098/rsbl.2011.0795
PMCID: PMC3297389  PMID: 21920956
swarm intelligence; averaging; collective cognition; copying behaviour; cognitive problem; leadership
20.  Auditory Cortex Represents Both Pitch Judgments and the Corresponding Acoustic Cues 
Current Biology  2013;23(7):620-625.
Summary
The neural processing of sensory stimuli involves a transformation of physical stimulus parameters into perceptual features, and elucidating where and how this transformation occurs is one of the ultimate aims of sensory neurophysiology. Recent studies have shown that the firing of neurons in early sensory cortex can be modulated by multisensory interactions [1–5], motor behavior [1, 3, 6, 7], and reward feedback [1, 8, 9], but it remains unclear whether neural activity is more closely tied to perception, as indicated by behavioral choice, or to the physical properties of the stimulus. We investigated which of these properties are predominantly represented in auditory cortex by recording local field potentials (LFPs) and multiunit spiking activity in ferrets while they discriminated the pitch of artificial vowels. We found that auditory cortical activity is informative both about the fundamental frequency (F0) of a target sound and also about the pitch that the animals appear to perceive given their behavioral responses. Surprisingly, although the stimulus F0 was well represented at the onset of the target sound, neural activity throughout auditory cortex frequently predicted the reported pitch better than the target F0.
Highlights
► Auditory cortical responses were recorded while ferrets discriminated pitch shifts ► LFP and multiunit activity are sensitive to the sound’s fundamental frequency (F0) ► Neural activity related to animals’ reported pitch increases throughout the trial ► Cortical responses were more informative about behavioral choices than the sound F0
doi:10.1016/j.cub.2013.03.003
PMCID: PMC3696731  PMID: 23523247
21.  Spectrotemporal Contrast Kernels for Neurons in Primary Auditory Cortex 
Auditory neurons are often described in terms of their spectrotemporal receptive fields (STRFs). These map the relationship between features of the sound spectrogram and neurons’ firing rates. Recently we showed that neurons in the primary fields of the ferret auditory cortex are also subject to gain control: when sounds undergo smaller fluctuations in their level over time, the neurons become more sensitive to small level changes (Rabinowitz et al., 2011). Just as STRFs measure the spectrotemporal features of a sound that lead to changes in neurons’ firing rates, in this study we sought to estimate the spectrotemporal regions in which sound statistics lead to changes in neurons’ gain. We designed a set of stimuli with complex contrast profiles to characterize these regions. This allowed us to estimate cortical neurons’ STRFs alongside a set of spectrotemporal contrast kernels. We find that these two sets of integration windows match up: the extent to which a stimulus feature causes a neuron’s firing rate to change is strongly correlated with the extent to which that feature’s contrast modulates the neuron’s gain. Adding contrast kernels to STRF models also yields considerable improvements in the ability to capture and predict how auditory cortical neurons respond to statistically complex sounds.
doi:10.1523/JNEUROSCI.1715-12.2012
PMCID: PMC3542625  PMID: 22895711
22.  Developmental plasticity of spatial hearing following asymmetric hearing loss: context-dependent cue integration and its clinical implications 
Under normal hearing conditions, comparisons of the sounds reaching each ear are critical for accurate sound localization. Asymmetric hearing loss should therefore degrade spatial hearing and has become an important experimental tool for probing the plasticity of the auditory system, both during development and adulthood. In clinical populations, hearing loss affecting one ear more than the other is commonly associated with otitis media with effusion, a disorder experienced by approximately 80% of children before the age of two. Asymmetric hearing may also arise in other clinical situations, such as after unilateral cochlear implantation. Here, we consider the role played by spatial cue integration in sound localization under normal acoustical conditions. We then review evidence for adaptive changes in spatial hearing following a developmental hearing loss in one ear, and show that adaptation may be achieved either by learning a new relationship between the altered cues and directions in space or by changing the way different cues are integrated in the brain. We next consider developmental plasticity as a source of vulnerability, describing maladaptive effects of asymmetric hearing loss that persist even when normal hearing is provided. We also examine the extent to which the consequences of asymmetric hearing loss depend upon its timing and duration. Although much of the experimental literature has focused on the effects of a stable unilateral hearing loss, some of the most common hearing impairments experienced by children tend to fluctuate over time. We therefore propose that there is a need to bridge this gap by investigating the effects of recurring hearing loss during development, and outline recent steps in this direction. We conclude by arguing that this work points toward a more nuanced view of developmental plasticity, in which plasticity may be selectively expressed in response to specific sensory contexts, and consider the clinical implications of this.
doi:10.3389/fnsys.2013.00123
PMCID: PMC3873525  PMID: 24409125
auditory localization; binaural; monaural; conductive hearing loss; adaptation; learning; cortex; midbrain
23.  Characterizing microbial communities through space and time 
Current opinion in biotechnology  2011;23(3):431-436.
Until recently, the study of microbial diversity has mainly been limited to descriptive approaches, rather than predictive model-based analyses. The development of advanced analytical tools and decreasing cost of high-throughput multi-omics technologies has made the later approach more feasible. However, consensus is lacking as to which spatial and temporal scales best facilitate understanding of the role of microbial diversity in determining both public and environmental health. Here, we review the potential for combining these new technologies with both traditional and nascent spatio-temporal analysis methods. The fusion of proper spatio-temporal sampling, combined with modern multi-omics and computational tools, will provide insight into the tracking, development and manipulation of microbial communities.
doi:10.1016/j.copbio.2011.11.017
PMCID: PMC3311466  PMID: 22154467
24.  Cerebrospinal fluid and plasma cytokines after subarachnoid haemorrhage: CSF interleukin-6 may be an early marker of infection 
Background
Cytokines and cytokine receptor concentrations increase in plasma and cerebrospinal fluid (CSF) of patients following subarachnoid haemorrhage (SAH). The relationship between plasma and CSF cytokines, and factors affecting this, are not clear.
Methods
To help define the relationship, paired plasma and cerebrospinal fluid (CSF) samples were collected from patients subject to ventriculostomy. Concentrations of key inflammatory cytokines, interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1Ra), IL-1 receptor 2, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and TNF receptors (TNF-R) 1 and 2 were determined by immunoassay of CSF and plasma from 21 patients, where samples were available at three or more time points.
Results
Plasma concentrations of IL-1ß, IL-1Ra, IL-10, TNF-α and TNF-R1 were similar to those in CSF. Plasma TNF-R2 and IL-1R2 concentrations were higher than in CSF. Concentrations of IL-8 and IL-6 in CSF were approximately10 to 1,000-fold higher than in plasma. There was a weak correlation between CSF and plasma IL-8 concentrations (r = 0.26), but no correlation for IL-6. Differences between the central and peripheral pattern of IL-6 were associated with episodes of ventriculostomy-related infection (VRI). A VRI was associated with CSF IL-6 >10,000 pg/mL (P = 0.0002), although peripheral infection was not significantly associated with plasma IL-6.
Conclusions
These data suggest that plasma cytokine concentrations cannot be used to identify relative changes in the CSF, but that measurement of CSF IL-6 could provide a useful marker of VRI.
doi:10.1186/1742-2094-9-255
PMCID: PMC3526412  PMID: 23176037
Cerebrospinal fluid; Cytokines; Infection; Interleukin-6; Markers; Plasma; Subarachnoid haemorrhage; Ventriculostomy
25.  Co-Occurrence Patterns of Plants and Soil Bacteria in the High-Alpine Subnival Zone Track Environmental Harshness 
Plants and soil microorganisms interact to play a central role in ecosystem functioning. To determine the potential importance of biotic interactions in shaping the distributions of these organisms in a high-alpine subnival landscape, we examine co-occurrence patterns between plant species and bulk soil bacteria abundances. In this context, a co-occurrence relationship reflects a combination of several assembly processes: that both parties can disperse to the site, that they can survive the abiotic environmental conditions, and that interactions between the biota either facilitate survival or allow for coexistence. Across the entire landscape, 31% of the bacterial sequences in this dataset were significantly correlated to the abundance distribution of one or more plant species. These sequences fell into 14 clades, 6 of which are related to bacteria that are known to form symbioses with plants in other systems. Abundant plant species were more likely to have significant as well as stronger correlations with bacteria and these patterns were more prevalent in lower altitude sites. Conversely, correlations between plant species abundances and bacterial relative abundances were less frequent in sites near the snowline. Thus, plant-bacteria associations became more common as environmental conditions became less harsh and plants became more abundant. This pattern in co-occurrence strength and frequency across the subnival landscape suggests that plant-bacteria interactions are important for the success of life, both below- and above-ground, in an extreme environment.
doi:10.3389/fmicb.2012.00347
PMCID: PMC3469205  PMID: 23087675
community assembly; co-occurrence networks; facilitation; mutualism; Niwot Ridge; plant-microbe interactions; soil microbial communities; symbiosis

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