Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Different patterns of cortical excitability in major depression and vascular depression: a transcranial magnetic stimulation study

BACKGROUND: Clinical and functional studies consider major depression (MD) and vascular depression (VD) as different neurobiological processes. Hypoexcitability of the left frontal cortex to transcranial magnetic stimulation (TMS) is frequently reported in MD, whereas little is known about the effects of TMS in VD. Thus, we aimed to assess and compare motor cortex excitability in patients with VD and MD. METHODS: Eleven VD patients, 11 recurrent drug-resistant MD patients, and 11 healthy controls underwent clinical, neuropsychological and neuroimaging evaluations in addition to bilateral resting motor threshold, cortical silent period, and paired-pulse TMS curves of intracortical excitability. All patients continued on psychotropic drugs, which were unchanged throughout the study. RESULTS: Scores on one of the tests evaluating frontal lobe abilities (Stroop Color-Word interference test) were worse in patients compared with controls. The resting motor threshold in patients with MD was significantly higher in the left hemisphere compared with the right (p < 0.05), and compared with the VD patients and controls. The cortical silent period was bilaterally prolonged in MD patients compared with VD patients and controls, with a statistically significant difference in the left hemisphere (p < 0.01). No differences were observed in the paired-pulse curves between patients and controls. CONCLUSIONS: This study showed distinctive patterns of motor cortex excitability between late-onset depression with subcortical vascular disease and early-onset recurrent drug resistant MD. The data provide a TMS model of the different processes underlying VD and MD. Additionally, our results support the “Vascular depression hypothesis” at the neurophysiological level, and confirm the inter-hemispheric asymmetry to TMS in patients with MD. We were unable to support previous findings of impaired intracortical inhibitory mechanisms to TMS in patients with MD, although a drug-induced effect on our results cannot be excluded. This study may aid the understanding of the pathogenetic differences underlying the clinical spectrum of depressive disorders

Combined action observation and motor imagery therapy: a novel method for post-stroke motor rehabilitation

Cerebral vascular accidents (strokes) are a leading cause of motor deficiency in millions of people worldwide. While a complex range of biological systems is affected following a stroke, in this paper we focus primarily on impairments of the motor system and the recovery of motor skills. We briefly review research that has assessed two types of mental practice, which are currently recommended in stroke rehabilitation. Namely, action observation (AO) therapy and motor imagery (MI) training. We highlight the strengths and limitations in both techniques, before making the case for combined action observation and motor imagery (AO + MI) therapy as a potentially more effective method. This is based on a growing body of multimodal brain imaging research showing advantages for combined AO + MI instructions over the two separate methods of AO and MI. Finally, we offer a series of suggestions and considerations for how combined AO + MI therapy could be employed in neurorehabilitation

Multisite Repetitive Transcranial Magnetic Stimulation: Safety, Feasibility, Tolerability, and Electro-Neurophysiology

The thesis investigated the potential clinical application and measurement of multisite priming repetitive transcranial magnetic stimulation (rTMS) protocols. The findings showed that multisite rTMS protocols are safe and tolerable. Furthermore, the neuro-modulatory effects of rTMS are highly variable but can be characterised using multi-modal techniques

Optimising the Application of Transcranial Direct Current Stimulation

The ability of transcranial direct current stimulation (tDCS) to modulate brain activity has vast scientific and therapeutic potential, however, its effects are often variable which limit its utility. Both current flow direction and variance in electric field intensities reaching a cortical target may be vital sources of the variable tDCS effects on neuroplastic change. Controlling for these and exploring the subsequent effects on corticospinal excitability is the aim of this thesis. I here attempted to optimise the delivery of tDCS application by investigating the controlled application of current flow direction and whether through the use of current flow models, we can deliver comparable electric fields with reduced variability across differential montages. To assess whether current flow models are useful, I further investigated if dose-control translates to more consistent physiological outcomes. I demonstrate, firstly, that different current flow directions did not differentially affect the two banks of the central sulcus. Secondly, with the use of dose-control, high-definition tDCS (HD-tDCS) remains focally more advantageous, even with the delivery of comparable electric field intensity and variability as posterior-anterior tDCS (PA-tDCS) to a cortical region. Thirdly, dose-controlled tDCS does not translate to reduced physiological variability. Together, the work presented here suggests that current flow models are useful for informing dose-controlled protocols and montage comparisons for improved tDCS delivery, however, controlling for anatomical differences in the delivery of electric fields to a target is not sufficient to reduce the variability of tDCS effects in physiology. Thus, the methodology for optimised tDCS delivery remains a subject for further improvement and investigation. Advancements in this field may lead to a trusted methodology assisting stroke survivors with a more effective and efficient motor recovery journey

Plasticity of the cortical representation of finger extensors induced by paired associative stimulation

This dissertation first explored associative plasticity of the human motor cortical representation with the use of noninvasive transcranial magnetic stimulation (TMS) paired with peripheral electrical stimulation. Paired Associative Stimulation (PAS) has grown in popularity because of its potential clinical applications. PAS techniques are used in combination with electromyography (EMG) measurements to study cortical excitability and features of hand movement. This work focuses on a cohesive approach to answer central questions about: the ideal mechanism to facilitate cortical plasticity via PAS, the interaction between the behavior performed and type of stimulation delivered to the targeted cortical network and the effects of PAS, the interaction between interstimulus timing, stimulus timing during movement and the translation of these effects into measurable changes starting from neurophysiological changes and ending up with the behavioral modulation of hand movement. First the role of interstimulus timing and intracortical facilitation on modulation of cortical excitability is explored in the extrinsic hand muscles by showing that PAS can be conditioned by these facilitatory intracortical networks. Using standard indirect approaches utilizing peripheral EMG measures and novel virtual reality (VR) environments, a graded excitability response is shown for the PAS technique and illustrates that interactions of PAS with voluntary movements impacts the degree as well as the state of cortical excitability. Rules governing the interactions of brain stimulation techniques and motor learning are important because brain stimulation techniques can be used to modify and improve neuro motor adaptation and skill learning with great potential for clinical applications such as facilitation of recovery after stroke. PAS provides us with a unique opportunity to study the rules of plasticity at a systems level, which is a combination of synaptic and non-synaptic (metaplastic) changes. Finally, it is shown that changes in cortical excitability may help modulate certain neurophysiological and clinical features of hand function in a pair of patients with chronic stroke in a pilot study. As expected, stroke patients exhibited a smaller degree of excitability increase. It is demonstrated that sessions of intense training with PAS in a VR environment induces significant neuroplastic changes in the sensorimotor cortex. Explicitly, VR based PAS facilitates corticospinal excitability in the ipsilesional sensorimotor cortex. As a result, this dissertation provides a new methodological and technical framework to condition the standard PAS paradigm to engage other intracortical networks. It also shows how PAS can be used to affect motor learning and the role of state of cortical excitation in induction of homeostatic or non-homeostatic plasticity for patients with neurological and neuromuscular impairments for example stroke plus the potential behavioral consequences of PAS in human motor cortex to facilitate functional recovery of hand function

Time to reconcile research findings and clinical practice on upper limb neurorehabilitation

In the field of upper limb neurorehabilitation, the translation from research findings to clinical practice remains troublesome. Patients are not receiving treatments based on the best available evidence. There are certainly multiple reasons to account for this issue, including the power of habit over innovation, subjective beliefs over objective results. We need to take a step forward, by looking at most important results from randomized controlled trials, and then identify key active ingredients that determined the success of interventions. On the other hand, we need to recognize those specific categories of patients having the greatest benefit from each intervention, and why. The aim is to reach the ability to design a neurorehabilitation program based on motor learning principles with established clinical efficacy and tailored for specific patient's needs. The objective of the present manuscript is to facilitate the translation of research findings to clinical practice. Starting from a literature review of selected neurorehabilitation approaches, for each intervention the following elements were highlighted: definition of active ingredients; identification of underlying motor learning principles and neural mechanisms of recovery; inferences from research findings; and recommendations for clinical practice. Furthermore, we included a dedicated chapter on the importance of a comprehensive assessment (objective impairments and patient's perspective) to design personalized and effective neurorehabilitation interventions. It's time to reconcile research findings with clinical practice. Evidence from literature is consistently showing that neurological patients improve upper limb function, when core strategies based on motor learning principles are applied. To this end, practical take-home messages in the concluding section are provided, focusing on the importance of graded task practice, high number of repetitions, interventions tailored to patient's goals and expectations, solutions to increase and distribute therapy beyond the formal patient-therapist session, and how to integrate different interventions to maximize upper limb motor outcomes. We hope that this manuscript will serve as starting point to fill the gap between theory and practice in upper limb neurorehabilitation, and as a practical tool to leverage the positive impact of clinicians on patients' recovery

FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders

Non-invasive treatment of neurodegenerative diseases is particularly challenging in Western countries, where the population age is increasing. In this work, magnetic propagation in human head is modelled by Finite-Difference Time-Domain (FDTD) method, taking into account specific characteristics of Transcranial Magnetic Stimulation (TMS) in neurodegenerative diseases. It uses a realistic high-resolution three-dimensional human head mesh. The numerical method is applied to the analysis of magnetic radiation distribution in the brain using two realistic magnetic source models: a circular coil and a figure-8 coil commonly employed in TMS. The complete model was applied to the study of magnetic stimulation in Alzheimer and Parkinson Diseases (AD, PD). The results show the electrical field distribution when magnetic stimulation is supplied to those brain areas of specific interest for each particular disease. Thereby the current approach entails a high potential for the establishment of the current underdeveloped TMS dosimetry in its emerging application to AD and PD

Time to reconcile research findings and clinical practice on upper limb neurorehabilitation

The problemIn the field of upper limb neurorehabilitation, the translation from research findings to clinical practice remains troublesome. Patients are not receiving treatments based on the best available evidence. There are certainly multiple reasons to account for this issue, including the power of habit over innovation, subjective beliefs over objective results. We need to take a step forward, by looking at most important results from randomized controlled trials, and then identify key active ingredients that determined the success of interventions. On the other hand, we need to recognize those specific categories of patients having the greatest benefit from each intervention, and why. The aim is to reach the ability to design a neurorehabilitation program based on motor learning principles with established clinical efficacy and tailored for specific patient's needs. Proposed solutionsThe objective of the present manuscript is to facilitate the translation of research findings to clinical practice. Starting from a literature review of selected neurorehabilitation approaches, for each intervention the following elements were highlighted: definition of active ingredients; identification of underlying motor learning principles and neural mechanisms of recovery; inferences from research findings; and recommendations for clinical practice. Furthermore, we included a dedicated chapter on the importance of a comprehensive assessment (objective impairments and patient's perspective) to design personalized and effective neurorehabilitation interventions. ConclusionsIt's time to reconcile research findings with clinical practice. Evidence from literature is consistently showing that neurological patients improve upper limb function, when core strategies based on motor learning principles are applied. To this end, practical take-home messages in the concluding section are provided, focusing on the importance of graded task practice, high number of repetitions, interventions tailored to patient's goals and expectations, solutions to increase and distribute therapy beyond the formal patient-therapist session, and how to integrate different interventions to maximize upper limb motor outcomes. We hope that this manuscript will serve as starting point to fill the gap between theory and practice in upper limb neurorehabilitation, and as a practical tool to leverage the positive impact of clinicians on patients' recovery