The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia

The computational neurology of movement under active inference

We propose a computational neurology of movement based on the convergence of theoretical neurobiology and clinical neurology. A significant development in the former is the idea that we can frame brain function as a process of (active) inference, in which the nervous system makes predictions about its sensory data. These predictions depend upon an implicit predictive (generative) model used by the brain. This means neural dynamics can be framed as generating actions to ensure sensations are consistent with these predictions-and adjusting predictions when they are not. We illustrate the significance of this formulation for clinical neurology through simulating a clinical examination of the motor system; i.e. an upper limb coordination task. Specifically, we show how tendon reflexes emerge naturally under the right kind of generative model. Through simulated perturbations, pertaining to prior probabilities of this model's variables, we illustrate the emergence of hyperreflexia and pendular reflexes, reminiscent of neurological lesions in the corticospinal tract and cerebellum. We then turn to the computational lesions causing hypokinesia and deficits of coordination. This in silico lesion-deficit analysis provides an opportunity to revisit classic neurological dichotomies (e.g. pyramidal versus extrapyramidal systems) from the perspective of modern approaches to theoretical neurobiology-and our understanding of the neurocomputational architecture of movement control based on first principles

Impulsivity in Parkinson’s disease and Tourette syndrome, and human motor decision making

Motor response inhibition pertains to the ability to inhibit motor actions. It is hypothesised that a breakdown in motor response inhibition might underlie impulsivity in Parkinson’s disease and tics in Tourette syndrome. This thesis outlines how motor response inhibition is modulated in these clinical disorders by first characterising them in healthy subjects. We use TMS to show that one set of inputs to the motor cortex are inhibited during motor preparation whilst the other inputs reflect uncertainty about potential stopping. In the next chapter, we challenged an assumption that movement preparation during proactive inhibition always preceded movement execution and found that movement preparation and execution are two independent processes. With this in mind, we investigated features of motor response inhibition and movement preparation and execution in patients with Tourette syndrome, finding that these were remarkably similar to healthy controls, suggesting that volitional features of movement and inhibition are normal in Tourette syndrome. However, we did find a specific impairment of automatic inhibition in Tourette syndrome, which correlated with motor tic severity. As dopamine agonists are implicated as triggers for impulsivity in Parkinson’s disease, we first investigated the influence of ropinirole on motor response inhibition in healthy control subjects, finding that motor response inhibition was globally impaired. This was accompanied by analyses suggesting that ropinirole impaired the ability to adjust the decision threshold when stopping might be required. However, investigation of motor inhibition in Parkinson’s disease patients on dopamine agonists showed unremarkable effects compared to patients without dopamine agonist use. Our data provide a novel insight into the basic mechanisms of voluntary movement and propose a new theory for tic generation in Tourette syndrome

Comparison between surface electrodes and ultrasound monitoring to measure TMS evoked muscle contraction

INTRODUCTION: Transcranial magnetic stimulation (TMS) is widely employed to explore cortical physiology in health and disease. Surface electromyography (sEMG) is appropriate for superficial muscles, but cannot be applied easily to less accessible muscles. Muscle ultrasound (mUS) may provide an elegant solution to this problem, but fundamental questions remain. We explore the relationship between TMS evoked muscle potentials and TMS evoked muscle contractions measured with mUS. METHODS: In 10 participants we performed a TMS recruitment curve, simultaneously measuring motor evoked potentials (MEPs) and mUS in biceps (BI), first dorsal interosseous (FDI), tibialis anterior (TA) and the tongue (TO). RESULTS: Resting motor threshold (RMT) measurements and recruitment curves were found to be consistent across sEMG and mUS. DISCUSSION: This work supports the use of TMS-US to study less accessible muscles. The implications are broad but could include the study of a new range of muscles in disorders such as amyotrophic lateral sclerosis

Ropinirole, a dopamine agonist with high D3 affinity, reduces proactive inhibition: A double-blind, placebo-controlled study in healthy adults

Response inhibition describes the cognitive processes mediating the suppression of unwanted actions. A network involving the basal ganglia mediates two forms of response inhibition: reactive and proactive inhibition. Reactive inhibition serves to abruptly stop motor activity, whereas proactive inhibition is goal-orientated and results in slowing of motor activity in anticipation of stopping. Due to its impairment in several psychiatric disorders, the neurochemistry of response inhibition has become of recent interest. Dopamine has been posed as a candidate mediator of response inhibition due to its role in functioning of the basal ganglia and the observation that patients with Parkinson's disease on dopamine agonists develop impulse control disorders. Although the effects of dopamine on reactive inhibition have been studied, substantial literature on the role of dopamine on proactive inhibition is lacking. To fill this gap, we devised a double-blind, placebo-controlled study of 1 mg ropinirole (a dopamine agonist) on response inhibition in healthy volunteers. We found that whilst reactive inhibition was unchanged, proactive inhibition was impaired when participants were on ropinirole relative to when on placebo. To investigate how ropinirole mediated this effect on proactive inhibition, we used hierarchical drift-diffusion modelling. We found that ropinirole impaired the ability to raise the decision threshold when proactive inhibition was called upon. Our results provide novel evidence that an acute dose of ropinirole selectively reduces proactive inhibition in healthy participants. These results may help explain how ropinirole induces impulse control disorders in susceptible patients with Parkinson's disease

On the Use of TMS to Investigate the Pathophysiology of Neurodegenerative Diseases

Neurodegenerative diseases are a collection of disorders that result in the progressive degeneration and death of neurons. They are clinically heterogenous and can present as deficits in movement, cognition, executive function, memory, visuospatial awareness and language. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool that allows for the assessment of cortical function in vivo. We review how TMS has been used for the investigation of three neurodegenerative diseases that differ in their neuroanatomical axes: (1) Motor cortex—corticospinal tract (motor neuron diseases), (2) Non-motor cortical areas (dementias), and (3) Subcortical structures (parkinsonisms). We also make four recommendations that we hope will benefit the use of TMS in neurodegenerative diseases. Firstly, TMS has traditionally been limited by the lack of an objective output and so has been confined to stimulation of the motor cortex; this limitation can be overcome by the use of concurrent neuroimaging methods such as EEG. Given that neurodegenerative diseases progress over time, TMS measures should aim to track longitudinal changes, especially when the aim of the study is to look at disease progression and symptomatology. The lack of gold-standard diagnostic confirmation undermines the validity of findings in clinical populations. Consequently, diagnostic certainty should be maximized through a variety of methods including multiple, independent clinical assessments, imaging and fluids biomarkers, and post-mortem pathological confirmation where possible. There is great interest in understanding the mechanisms by which symptoms arise in neurodegenerative disorders. However, TMS assessments in patients are usually carried out during resting conditions, when the brain network engaged during these symptoms is not expressed. Rather, a context-appropriate form of TMS would be more suitable in probing the physiology driving clinical symptoms. In all, we hope that the recommendations made here will help to further understand the pathophysiology of neurodegenerative diseases

Ropinirole, a dopamine agonist with high D3 affinity, reduces proactive inhibition: A double-blind, placebo-controlled study in healthy adults

Response inhibition describes the cognitive processes mediating the suppression of unwanted actions. A network involving the basal ganglia mediates two forms of response inhibition: reactive and proactive inhibition. Reactive inhibition serves to abruptly stop motor activity, whereas proactive inhibition is goal-orientated and results in slowing of motor activity in anticipation of stopping. Due to its impairment in several psychiatric disorders, the neurochemistry of response inhibition has become of recent interest. Dopamine has been posed as a candidate mediator of response inhibition due to its role in functioning of the basal ganglia and the observation that patients with Parkinson's disease on dopamine agonists develop impulse control disorders. Although the effects of dopamine on reactive inhibition have been studied, substantial literature on the role of dopamine on proactive inhibition is lacking. To fill this gap, we devised a double-blind, placebo-controlled study of 1 mg ropinirole (a dopamine agonist) on response inhibition in healthy volunteers. We found that whilst reactive inhibition was unchanged, proactive inhibition was impaired when participants were on ropinirole relative to when on placebo. To investigate how ropinirole mediated this effect on proactive inhibition, we used hierarchical drift-diffusion modelling. We found that ropinirole impaired the ability to raise the decision threshold when proactive inhibition was called upon. Our results provide novel evidence that an acute dose of ropinirole selectively reduces proactive inhibition in healthy participants. These results may help explain how ropinirole induces impulse control disorders in susceptible patients with Parkinson's disease

The Role of Astrocytes in Remyelination.

Remyelination is the regeneration of myelin sheaths following demyelination. This regenerative process is critical for the re-establishment of axonal conduction velocity and metabolic support to the axons. Successful remyelination in the CNS generally depends on the activation, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs). However, other cell types play critical roles in establishing where a lesion is conducive for regeneration. In the last few years, several studies have described beneficial and detrimental roles played by astrocytes in remyelination. This review will discuss recent developments in the concept of astrocyte reactivity, what is known about the astrocytic contribution to remyelination, and highlight future avenues of investigation.The authors’ laboratory is supported by funding from the UK Multiple Sclerosis Society (MS50), The Adelson Medical Research Foundation, and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). KSR is supported by a postdoctoral fellowship from the Multiple Sclerosis Society of Canad

Preconditioning stimulus intensity alters paired‐pulse tms evoked potentials

Motor cortex (M1) paired‐pulse TMS (ppTMS) probes excitatory and inhibitory intracor-tical dynamics by measurement of motor‐evoked potentials (MEPs). However, MEPs reflect cortical and spinal excitabilities and therefore cannot isolate cortical function. Concurrent TMS‐EEG has the ability to measure cortical function, while limiting peripheral confounds; TMS stimulates M1, whilst EEG acts as the readout: the TMS‐evoked potential (TEP). Whilst varying preconditioning stimulus intensity influences intracortical inhibition measured by MEPs, the effects on TEPs is undefined. TMS was delivered to the left M1 using single‐pulse and three, ppTMS paradigms, each using a different preconditioning stimulus: 70%, 80% or 90% of resting motor threshold. Corticospinal inhibition was present in all three ppTMS conditions. ppTMS TEP peaks were reduced predominantly under the ppTMS 70 protocol but less so for ppTMS 80 and not at all for ppTMS 90. There was a significant negative correlation between MEPs and N45 TEP peak for ppTMS 70 reaching statistical trends for ppTMS 80 and 90. Whilst ppTMS MEPs show inhibition across a range of preconditioning stimulus intensities, ppTMS TEPs do not. TEPs after M1 ppTMS vary as a function of preconditioning stimulus intensity: smaller preconditioning stimulus intensities result in better discriminability between conditioned and unconditioned TEPs. We recommend that preconditioning stimulus intensity should be minimized when using ppTMS to probe intracortical inhibition

Variability and predictors of response to continuous theta burst stimulation: a TMS-EEG study

Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG