[Show abstract][Hide abstract] ABSTRACT: Data assimilation is a fundamental issue that arises across many scales in neuroscience - ranging from the study of single neurons using single electrode recordings to the interaction of thousands of neurons using fMRI. Data assimilation involves inverting a generative model that can not only explain observed data but also generate predictions. Typically, the model is inverted or fitted using conventional tools of (convex) optimization that invariably extremise some functional - norms, minimum descriptive length, variational free energy, etc. Generally, optimisation rests on evaluating the local gradients of the functional to be optimised. In this paper, we compare three different gradient estimation techniques that could be used for extremising any functional in time - (i) finite differences, (ii) forward sensitivities and a method based on (iii) the adjoint of the dynamical system. We demonstrate that the first-order gradients of a dynamical system, linear or non-linear, can be computed most efficiently using the adjoint method. This is particularly true for systems where the number of parameters is greater than the number of states. For such systems, integrating several sensitivity equations - as required with forward sensitivities - proves to be most expensive, while finite-difference approximations have an intermediate efficiency. In the context of neuroimaging, adjoint based inversion of dynamical causal models (DCMs) can, in principle, enable the study of models with large numbers of nodes and parameters.
[Show abstract][Hide abstract] ABSTRACT: Introduction
In order to define the pathophysiology underlying development of peripheral neuropathies, it is important to understand the excitability effects produced by alterations in membrane potential. Sensory and motor axons display different biophysical properties which are likely to affect their responsiveness to membrane potential changes.
To provide a template for the effects of membrane potential changes on sensory and motor axonal excitability.
Sensory and motor nerve excitability studies were recorded using threshold tracking techniques and QTracS software in six participants (mean age 31 ± 2 years). The median nerve was stimulated at the wrist, with both CMAPs and CSAPs recorded. A standard axonal excitability protocol was conducted, including assessment of strength–duration properties, threshold electrotonus, recovery cycle and current-threshold relationship. DC currents set to ±50% of the baseline rheobasic current were utilised to ensure comparability between motor and sensory axons.
As previously reported for motor axons, polarization had significant effects on axonal excitability. The overall pattern of excitability change was similar between motor and sensory axons – with depolarizing currents producing reduced threshold change in threshold electrotonus, upwards shift of the recovery cycle and reduced inward rectification in the current-threshold relationship. Effects on threshold electrotonus were more prominent in motor axons, with more significant reduction in threshold change to depolarizing and hyperpolarizing currents (TEd90ms; Depolarization: Motor: 46 ± 5%; Sensory: 23 ± 3%; P < .01; Hyperpolarization: Motor: −31 ± 2%; Sensory: −24 ± 2%; P < .05). By contrast, effects of hyperpolarization on measures associated with the hyperpolarization-activated cation conductance Ih were similar for motor and sensory axons (TEh70%peak: Motor: 18 ± 6%; Sensory 20 ± 4%; Hyperpolarizing IV drift – Motor: −4 ± 2%; Sensory: 7 ± 4%).
These findings provide a template for the differential interpretation of excitability changes associated with membrane potential change in sensory and motor neuropathies.
[Show abstract][Hide abstract] ABSTRACT: The prevailing view at present is that postsynaptic expression of the classical NMDA receptor-dependent long-term potentiation relies on an increase in the numbers of local AMPA receptors (AMPARs). This is thought to parallel an expansion of postsynaptic cell specializations, for instance dendritic spine heads, which accommodate synaptic receptor proteins. However, glutamate released into the synaptic cleft can normally activate only a hotspot of low-affinity AMPARs that occur in the vicinity of the release site. How the enlargement of the AMPAR pool is causally related to the potentiated AMPAR current remains therefore poorly understood. To understand possible scenarios of postsynaptic potentiation, here we explore a detailed Monte Carlo model of the typical small excitatory synapse. Simulations suggest that approximately 50% increase in the synaptic AMPAR current could be provided by expanding the existing AMPAR pool at the expense of 100-200% new AMPARs added at the same packing density. Alternatively, reducing the inter-receptor distances by only 30-35% could achieve a similar level of current potentiation without any changes in the receptor numbers. The NMDA receptor current also appears sensitive to the NMDA receptor crowding. Our observations provide a quantitative framework for understanding the 'resource-efficient' ways to enact use-dependent changes in the architecture of central synapses.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130167.
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[Show abstract][Hide abstract] ABSTRACT: In this manuscript we summarize the role of chronic stress as a potential trigger factor for Parkinson's disease. Underlying mechanisms and stress-induced changes to the neuronal networks have been highlighted. Examples of stress induced reversible symptoms that resemble parkinsonism in humans and in animal models raise the question whether emotional stress can cause striatal degeneration in susceptible patients. A Pubmed literature review searching for the terms 'Stress', 'Distress and Parkinson's disease', 'Emotional Distress and Parkinson's disease', 'Stress and Parkinson's disease', 'Prodromal Parkinson's disease', 'Non motor symptoms and Parkinson's disease', 'Paradoxical kinesia', 'Psychogenic parkinsonism', 'Functional somatic syndromes', 'Chronic fatigue syndrome', 'Irritable bowel syndrome', 'Fibromyalgia', 'Dopamine and fibromyalgia', 'Dopamine and chronic fatigue syndrome' and 'Dopamine and irritable bowel syndrome' was carried out until April 2013. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this viewpoint.
Journal of neurology, neurosurgery, and psychiatry 11/2013;
[Show abstract][Hide abstract] ABSTRACT: Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing.
To investigate the role of dopamine and serotonin in the interaction between action and valence during learning.
We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively.
We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition.
Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.
[Show abstract][Hide abstract] ABSTRACT: Action inhibition can globally prevent all motor output or selectively cancel specific actions during concurrent motor output. Here we examine the behavioral and neural basis of selective inhibition focusing on the role of preparation. In 18 healthy human participants we manipulated the extent to which they could prepare for selective inhibition by providing or withholding information on what actions might need to be stopped. We show that, on average, information improves both speed and selectivity of inhibition. Functional magnetic resonance imaging data show that preparation for selective inhibition engages the inferior frontal gyrus, supplementary motor area, and striatum. Examining interindividual differences, we find the benefit of proactive control to speed and selectivity of inhibition trade off against each other, such that an improvement in stopping speed leads to a deterioration of selectivity of inhibition, and vice versa. This trade-off is implemented through engagement of the dorsolateral prefrontal cortex and putamen. Our results suggest proactive selective inhibition is implemented within frontostriatal structures, and we provide evidence that a speed-selectivity trade-off might underlie a range of findings reported previously.
[Show abstract][Hide abstract] ABSTRACT: Amnesic patients with bilateral hippocampal damage sustained in adulthood are generally unable to construct scenes in their imagination. By contrast, patients with developmental amnesia (DA), where hippocampal damage was acquired early in life, have preserved performance on this task, although the reason for this sparing is unclear. One possibility is that residual function in remnant hippocampal tissue is sufficient to support basic scene construction in DA. Such a situation was found in the one amnesic patient with adult-acquired hippocampal damage (P01) who could also construct scenes. Alternatively, DA patients' scene construction might not depend on the hippocampus, perhaps being instead reliant on non-hippocampal regions and mediated by semantic knowledge. To adjudicate between these two possibilities, we examined scene construction during functional MRI (fMRI) in Jon, a well-characterised patient with DA who has previously been shown to have preserved scene construction. We found that when Jon constructed scenes he activated many of the regions known to be associated with imagining scenes in control participants including ventromedial prefrontal cortex, posterior cingulate, retrosplenial and posterior parietal cortices. Critically, however, activity was not increased in Jon's remnant hippocampal tissue. Direct comparisons with a group of control participants and patient P01, confirmed that they activated their right hippocampus more than Jon. Our results show that a type of non-hippocampal dependent scene construction is possible and occurs in DA, perhaps mediated by semantic memory, which does not appear to involve the vivid visualisation of imagined scenes.
[Show abstract][Hide abstract] ABSTRACT: To determine whether the association between multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) (known as "Harding disease") is a chance finding, or the 2 disorders are mechanistically linked.
We performed a United Kingdom-wide prospective cohort study of prevalent cases of MS with LHON mitochondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mutations to find evidence of a genetic association.
Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data.
Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded.
[Show abstract][Hide abstract] ABSTRACT: Multiple Sclerosis (MS) is the most common non-traumatic cause of acquired neurological disability in young people. Interferon-Beta (IFNβ) is a safe and well-tolerated first-line treatment for patients with MS (PwMS) in the relapsing-remitting phase of the disease (RRMS) and has been shown to reduce relapse rates by an average of 30% (Compston and Coles 2002). Neutralising antibodies (NAbs) are known to occur in approximately 25% of patients and in high titres reduce or eliminate the bioactivity of the drug [Pachner (Insight study) 2009, Farrell 2011]. Nabs are more likely to occur with high dose high frequency compounds-IFNβ 1a and IFNβ 1b (MS Study group 1996). Increased relapse rates and MRI activity have been described in patients with NAbs however effect on disability progression has been ambivalent [MS Study group 1996, Francis 2005, Kappos 2005, Farrell 2008]. Despite the existence of clinical guidelines recommending routine NAb testing with a view to switching therapy in those with persistent positive NAbs, uptake in the UK has been low [Polman 2010].
To assess the effect on disability in a UK cohort of patient attending the National Hospital for Neurology and Neurosurgery, London.
A historical sample library of sera from PwMS treated with IFNβ was utilised. Subjects were eligible if they had a diagnosis of RRMS (Poser/McDonald) and had been treated for a minimum of 3-6 years. Serial samples were tested using the luciferase NAb assay (Farrell 2011) for the presence of NAbs and medical records reviewed to determine the clinical disease state at each time point (RRMS vs SPMS).
112 subjects were identified, 53 remained RRMS up to at least the date of their last available sample and 59 patients had converted to secondary-progressive MS (SPMS) whilst on IFNβ or at a time point after the date of their last sample. Within the RRMS cohort (n=53), 4 were persistently positive at 2 years (7.5 %). Within the RRMS-SPMS cohort (n=59), 20 were persistently NAb positive at 2 years (34%). A positive NAb status at 24 months conferred a 4.25 fold increase in relative odds of progression to SPMS (95% CI: 1.53 to 11.84, p=0.006) using a logistic regression analysis. A sub-group analysis separating patients into high NAb titres (>400 neutralising units (NU)), low NAb titres (<100 NU) and negative titres (<20 NU) did not reveal a titre-dependent associated increase in risk of progression to SPMS (p>0.05).
This study demonstrates a significantly increased risk of progression from RRMS to SPMS in patients who become NAb positive. As no current disease modifying treatments are effective in this phase of the disease patients at risk should be detected early and routine NAb testing can help to inform this decision.
Journal of neurology, neurosurgery, and psychiatry 11/2013; 84(11):e2.
CA A Cancer Journal for Clinicians 11/2013; 63(6):419-37.
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