Electrospun aligned tacrolimus-loaded polycaprolactone biomaterials for peripheral nerve repair

Background: Efficacious repair of peripheral nerve injury is an unmet clinical need. The implantation of biomaterials containing neurotrophic drugs at the injury site could promote nerve regeneration and improve outcomes for patients. Materials & methods: Random and aligned electrospun poly-ε-caprolactone scaffolds containing encapsulated tacrolimus were fabricated, and the gene expression profile of Schwann cells (SCs) cultured on the surface was elucidated. On aligned fibers, the morphology of SCs and primary rat neurons was investigated. Results: Both scaffold types exhibited sustained release of drug, and the gene expression of SCs was modulated by both nanofibrous topography and the presence of tacrolimus. Aligned fibers promoted the alignment of SCs and orientated outgrowth from neurons. Conclusion: Electrospun PCL scaffolds with tacrolimus hold promise for the repair of peripheral nerve injury

Hierarchical Organization of Frontotemporal Networks for the Prediction of Stimuli across Multiple Dimensions.

Brain function can be conceived as a hierarchy of generative models that optimizes predictions of sensory inputs and minimizes "surprise." Each level of the hierarchy makes predictions of neural events at a lower level in the hierarchy, which returns a prediction error when these expectations are violated. We tested the generalization of this hypothesis to multiple sequential deviations, and we identified the most likely organization of the network that accommodates deviations in temporal structure of stimuli. Magnetoencephalography of healthy human participants during an auditory paradigm identified prediction error responses in bilateral primary auditory cortex, superior temporal gyrus, and lateral prefrontal cortex for deviation by frequency, intensity, location, duration, and silent gap. We examined the connectivity between cortical sources using a set of 21 generative models that embedded alternate hypotheses of frontotemporal network dynamics. Bayesian model selection provided evidence for two new features of functional network organization. First, an expectancy signal provided input to the prefrontal cortex bilaterally, related to the temporal structure of stimuli. Second, there are functionally significant lateral connections between superior temporal and/or prefrontal cortex. The results support a predictive coding hypothesis but go beyond previous work in demonstrating the generalization to multiple concurrent stimulus dimensions and the evidence for a temporal expectancy input at the higher level of the frontotemporal hierarchy. We propose that this framework for studying the brain's response to unexpected events is not limited to simple sensory tasks but may also apply to the neurocognitive mechanisms of higher cognitive functions and their disorders.This work was supported by the Medical Research Council (Grant MC-A060-5PQ30 and a doctoral training award to H.N.P.), the Wellcome Trust (Grants 088324 and 103838 to J.B.R. and L.E.H., Biomedical Research Fellowship WT093811MA to T.A.B.), and the James F. McDonnell Foundation 21st Century Science Initiative: Understanding Human Cognition.This is the final version of the article. It first appeared from Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.5095-14.201

Local delivery of tacrolimus using electrospun poly-ε-caprolactone nanofibres suppresses the T-cell response to peripheral nerve allografts

OBJECTIVE: Repair of nerve gap injuries can be achieved through nerve autografting, but this approach is restricted by limited tissue supply and donor site morbidity. The use of living nerve allografts would provide an abundant tissue source, improving outcomes following peripheral nerve injury. Currently this approach is not used due to the requirement for systemic immunosuppression, to prevent donor-derived cells within the transplanted nerve causing an immune response, which is associated with severe adverse effects. The aim of this study was to develop a method for delivering immunosuppression locally, then to test its effectiveness in reducing the immune response to transplanted tissue in a rat model of nerve allograft repair. APPROACH: A coaxial electrospinning approach was used to produce poly-ε-caprolactone fibre sheets loaded with the immunosuppressant tacrolimus. The material was characterised in terms of structure and tacrolimus release, then tested in vivo through implantation in a rat sciatic nerve allograft model with immunologically mismatched host and donor tissue. MAIN RESULTS: Following successful drug encapsulation, the fibre sheets showed nanofibrous structure and controlled release of tacrolimus over several weeks. Materials containing tacrolimus (and blank material controls) were implanted around the nerve graft at the time of allograft or autograft repair. The fibre sheets were well tolerated by the animals and tacrolimus release resulted in a significant reduction in lymphocyte infiltration at three weeks post-transplantation. SIGNIFICANCE: These findings demonstrate proof of concept for a novel nanofibrous biomaterial-based targeted drug delivery strategy for immunosuppression in peripheral nerve allografting

Questionnaire study to gain an insight into the manufacturing and fitting process of artificial eyes in children: an ocularist perspective

Purpose To gain an insight into the manufacturing and fitting of artificial eyes in children and potential improvements to the process. Method An online qualitative survey was distributed to 39 ocularists/prosthetists in Europe and Canada. Participants were recruited through purposive sampling, specifically maximum variation sampling from the researcher’s contacts and an online search. Results The findings highlighted the current impression technique as being the most difficult yet most important part of the current process for both the ocularist and child patient. Negatively affecting obtaining a good impression, the child patients distress can be reduced by their parents by providing encouragement, reassurance, practicing the insertion and removal of the artificial eye and being matter of fact. Whilst improvements to the current process provided mixed views, the incorporation of current technology was perceived as not being able to meet the requirements to produce aesthetically pleasing artificial eyes. Conclusion The current artificial eye process can be seen as an interaction with its success being dependent on the child patient’s acceptance and adjustment which is dependent on the factors associated to the process. Investigation into the needs of the patient and whether technology can improve the process are the next steps in its advancement

GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENT Understanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain

Convergent evidence for hierarchical prediction networks from human electrocorticography and magnetoencephalography.

We propose that sensory inputs are processed in terms of optimised predictions and prediction error signals within hierarchical neurocognitive models. The combination of non-invasive brain imaging and generative network models has provided support for hierarchical frontotemporal interactions in oddball tasks, including recent identification of a temporal expectancy signal acting on prefrontal cortex. However, these studies are limited by the need to invert magnetoencephalographic or electroencephalographic sensor signals to localise activity from cortical 'nodes' in the network, or to infer neural responses from indirect measures such as the fMRI BOLD signal. To overcome this limitation, we examined frontotemporal interactions estimated from direct cortical recordings from two human participants with cortical electrode grids (electrocorticography - ECoG). Their frontotemporal network dynamics were compared to those identified by magnetoencephalography (MEG) in forty healthy adults. All participants performed the same auditory oddball task with standard tones interspersed with five deviant tone types. We normalised post-operative electrode locations to standardised anatomic space, to compare across modalities, and inverted the MEG to cortical sources using the estimated lead field from subject-specific head models. A mismatch negativity signal in frontal and temporal cortex was identified in all subjects. Generative models of the electrocorticographic and magnetoencephalographic data were separately compared using the free-energy estimate of the model evidence. Model comparison confirmed the same critical features of hierarchical frontotemporal networks in each patient as in the group-wise MEG analysis. These features included bilateral, feedforward and feedback frontotemporal modulated connectivity, in addition to an asymmetric expectancy driving input on left frontal cortex. The invasive ECoG provides an important step in construct validation of the use of neural generative models of MEG, which in turn enables generalisation to larger populations. Together, they give convergent evidence for the hierarchical interactions in frontotemporal networks for expectation and processing of sensory inputs.Medical Research Council (MC-A060-5PQ30 and a Doctoral Training award to HNP), Wellcome Trust (103838 Senior Research Fellowship to JBR, LEH, Biomedical Research Fellowship WT093811MA to TAB), the James F. McDonnell Foundation 21st Century Science Initiative: Understanding Human Cognition. The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) research was supported by the Biotechnology and Biological Sciences Research Council (grant number BB/H008217/1). PIDC 53/2012, PICT 0775/2012 and UNAJ investiga 2014 to AB and SK.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.cortex.2016.05.00

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials