RESTORATION OF BRAIN FUNCTION
IN MULTIPLE SCLEROSIS
Responsabile scientifico del progetto
V
ALENTINATOMASSINI
Università di Cardiff (Gran Bretagna) – Fondazione Santa Lucia
SUMMARY
In MS, neuroimaging methods have provided significant insights into the characteristics and mechanisms of spontaneous recovery. They have also started to demonstrate a pharmacological modulation of brain function in MS. However, so far their potential in understanding mechanisms for improving recovery of function in MS has not been exploited.
Rehabilitation relies on multiple mechanisms of brain plasticity, some of which are shared with motor adaptation and learning in the healthy brain. I have, therefore, used motor learning to probe mechanisms of brain plasticity
mediating clinical recovery in MS[1]. I developed a motor skill learning task[2]
to test behavioral improvements and underpinning functional changes in MS patients associated with spontaneous and driven recovery.
My work has also focused on understanding the structural and functional neuroscientific framework in which my clinical results could be interpreted. As the premotor cortex plays an important causal role in recovery, I investigated the functional anatomy of human premotor cortex and its prefrontal-parietal circuits. These basic neuroscience studies provide target regions for the imaging analysis of this proposal and ways to interpret remote functional consequences of localized pathology.
My imaging studies generate hypotheses about specific changes in brain function associated with rehabilitation in MS and the relevance of specific brain regions and pathways for rehabilitation to be successful. This proposal represents therefore the next step of my research plan in restorative neurology of MS.
COLLABORATIONS
The proposed Institution (Santa Lucia Foundation, Rome) has research facilities for studying brain structure and function, as well as clinical expertise in neurorehabilitation that will support the rehabilitation plan of this proposal. Over the past 10 years, I established scientific collaborations with basic and clinical scientists both in Italy and in the UK. This proposal will benefit from these collaborations that include:
Heidi Johansen-Berg, University Professor (Oxford), Head of the Plasticity and Connectivity groups at FMRIB Centre, my former PhD supervisor, who has expertise in imaging studies on functional and structural plasticity both in the healthy volunteers and in the stroke patients. She will collaborate on the basic neuroscience aspects of the project.
I have also established collaborations with theAnalysis Group at FMRIB,
University of Oxford, which produces the imaging analysis software used in
this proposal (http://www.fmrib.ox.ac.uk/fsl/fsl/list.html). I will benefit from
this expert support during the period of the proposed grant.
Paul M Matthews, Head, GSK Clinical Imaging Centre and Professor of Clinical Neurosciences, at Imperial College (London), former Head of FMRIB
Centre and my PhD supervisor, who has wide expertise in imaging studies on recovery of function after brain damage. He has also contributed widely to the research field of recovery in MS. He leads a clinical imaging centre in London dedicated to drug discovery using advanced imaging methods. He will provide mentorship and will be a valuable advisor in the intellectual direction of this proposal and my work beyond.
Richard G Wise, Head of FMRI, Cardiff University Brain Research Imaging Centre (CUBRIC), and University Professor, former senior post-doc physicist at the FMRIB Centre, who has expertise in FMRI signal modeling and pharma-cological FMRI. This collaboration will be useful for the biomarker qualification phase of this proposal as well as for the pharmacological FMRI study.
Carlo Pozzilli, Head of MS Clinical Services, La Sapienza University (Rome) and Professor of Clinical Neurology, my former clinical supervisor, who has wide clinical expertise in MS. His scientific contribution has led to improve management of MS patients. He will support the patients’ recruitment and provide valuable mentorship and intellectual contribution.
RATIONALE, PURPOSES AND SPECIFIC IMPACTS Background
MS affects young people, causing progressive disability. Over recent years there have been several advances in its pharmacological management. Disease modifying treatments, however, have little or no impact on existing impairments. Consequently, much of the management of the person with MS is focused on optimizing function and symptom control.
Rehabilitation (rehab) is a non-pharmacological approach that improves disability and quality of life in MS[3-6]. Mechanisms underlying its clinical benefits
or their exhaustion after cessation of therapy (i.e., loss of initial gain after rehab) remain largely unknown, hindering the development of novel recovery-oriented strategies. While the neuroscientific foundation for rehab after stroke is well
established[7,8], our current approaches to drive recovery in MS would benefit from
a better understanding of mechanisms underlying rehab-mediated improvements and identification of markers to measure them in the specific context of such a peculiarly dynamic and diffuse pathology. This could help in the development of new strategies to enhance effects of rehab and in the design of ancillary interventions to promote plasticity in MS.
Here I propose to identify imaging markers of rehab-mediated changes (H1) and develop a novel strategy to pharmacologically enhance effects of rehab in MS (H2).
Non-conventional Magnetic Resonance Imaging (MRI) is a non-invasive tool to study brain function and structure with the potential to steer the optimization of restorative interventions promoting brain plasticity in neurological conditions. In stroke, imaging methods have contributed substantially to our improved
understanding of mechanisms underlying rehab-driven recovery[9]and to the
identification of target regions responsible for clinical effects of intervention[10].
They have driven efficiently the optimization of recovery-oriented strategies by opening up the possibility of developing new approaches to directly interfering
behaviorally [11], electrophysiologically [12] or pharmacologically [13] with the
function of specific areas and related networks. They have also offered ways
to measure intervention effects [14]and to optimize experimental designs for
restorative trials[15].
In MS, neuroimaging methods have provided significant insights into the
characteristics[16-17]and mechanisms of spontaneous recovery [18-20]. They have
also demonstrated a pharmacological modulation of brain function in MS[21-23].
However, so far their potential in understanding mechanisms, identifying targets and offering markers of intervention for improving recovery of function in MS has not been exploited.
Brain plasticity is the ability of the brain to adapt to environmental changes
or injury through changes in its function and structure[8]. As rehab is mediated
by multiple mechanisms of brain plasticity and some of these mechanisms also
mediate motor adaptation and learning in the healthy brain[8,24], learning has
been used to probe mechanisms of rehab-mediated recovery after damage. Imaging of motor learning has therefore provided insights into the mechanisms underlying restoration of brain function in MS.
1. Functional MRI (FMRI), during learning of new movements, images
dynamic brain changes associated with behavioral improvements [25-27]. In
collaboration with neuroscientists in Oxford, I developed a motor learning task
to study mechanisms of brain plasticity in neurological patients[2]. Using this task
I demonstrated that the ability to learn is preserved at increasing levels of MS
disability[1]. I showed that different mechanisms for motor skill learning, however,
may exist in MS patients compared with healthy controls[28]. I also demonstrated
that altered structural architecture of the sub-cortical regions is associated with impaired motor learning in MS patients and local structural impairment may
propagate functionally throughout cortical-subcortical networks[29].
2.Diffusion Weighted Imaging (DWI) allows the integrity of white matter
tracts to be characterized in MS [30] and correlated with relevant clinical
measures. Tract mapping using Diffusion Tensor Imaging (DTI) may localize
these correlations within specific tracts [31], which carry information between
brain regions. In collaboration with neuroscientists in Oxford, I developed DTI
methods forin vivoparcellation of complex cortical regions[32]and characterized
the functional anatomy of cortical areas relevant for motor control and learning
[33], providing an anatomical framework for interpreting rehab-related changes
in the present proposal. Also, as the premotor cortex plays an important causal role in recovery after brain damage, I investigated the functional anatomy of the human premotor cortex and its prefrontal-parietal circuits. I identified distinct prefrontal-parietal networks and tested the functional specialization of these circuits.
3. High-resolution T1-weighted images (T1-WI)are used to define grey matter
structures and measure their changes in volume with MS pathology[34]. Such
volume changes have clinically relevant motor and cognitive consequences[35].
Changes in GM volume also occur with learning in normal brains[36]and are
reflected in brain regions relevant for individual differences in skill learning[2].
Indeed my previous work has contributed to the understanding of the structural and functional neuroscientific framework in which clinical results can be interpreted. By combining FMRI with structural imaging, I identified higher motor control areas responsible for individual differences in normal skill
learning [2]and then mapped their functional connectivity using resting state
FMRI[37]. As clinical recovery relies on re-learning of lost functions, these regions
inform more anatomically targeted investigations in the present proposal and ways to interpret remote functional consequences of intervention.
Aims
This proposal has two main aims:
1. To investigate mechanisms underlying rehab effects in MS and identify imaging markers of improvements.
2. To develop a novel recovery-oriented strategy by enhancing pharmaco-logically brain plasticity and thus the effect of rehab.
Rationale
Aim1. Remodeling the brain after injury with rehab. Brain plasticity is the dynamic reorganization of brain function in response to experience (e.g., skill
learning), as well as to damage[38]. Brain plasticity allows for spontaneous recovery
to occur in MS[16,18,39]and may be adaptively driven by rehab. Rehab and injury can
act as modulators of cortical function in different ways. Injury can act as a trigger for plastic changes; rehab can alter pathological patterns of activation. Rehab and injury can interact in such a way that brain function can be remodeled during
recovery, shaped by the sensorimotor experiences of the individual after injury[40].
My hypothesis (H1) is that mechanisms contributing to recovery of function in MS can be adaptively driven by rehab, i.e., rehab may promote desired patterns of movement control despite ongoing pathology. I suggest that rehab-mediated improvements (as well as exhaustion of effects) may be associated with measurable functional changes in sensorimotor regions and interact with
tissue damage in relevant brain pathways [41]. Previous work from my Oxford
collaborators as well as my own work on brain plasticity in MS (in Background) support these hypotheses and suggest that changes can be measured using
imaging methods[10].
Aim2. Pharmacological modulation of brain plasticity. I propose to enhance effects of rehab in MS by pharmacologically predisposing relevant cortical nodes
to therapeutic changes [22,23]. Rapid modulation of neurotransmitter systems
motor learning[42-43]. Rehab, driving recovery of function through re-learning of
lost abilities, could benefit from modulatory effects of interventions enhancing brain plasticity[44].
My hypothesis (H2) is that pharmacologically modulated brain plasticity predisposes sensorimotor systems to rehab effects, enhancing and prolonging the effects of rehab in MS. I will test this hypothesis in a proof-of-concept study using 4-aminopyridine (4-AP), a K+ channel blocker prolonging action potentials. 4-AP
is expected to improve signal transmission[45], enhance neuronal excitability[22]
and local brain plasticity[46], improve signal summation[47], and overall favor the
efficiency of neuronal processing and plastic reorganization[48]underlying rehab
effects[8].
Impact of this proposal on clinical and research practice
Clinical practice:
– By proposing a novel approach to pharmacologically enhance rehab effects on functional recovery, this proposal directly develops new approaches to improve MS patients’ overall management.
– By characterizing brain networks associated with rehab-mediated improvements, this proposal will generate hypotheses for targeting regions and developing more biologically informed recovery strategies.
Research practice:
– By identifying rehab markers, this proposal will quantify effects of rehab and open up the possibility of standardizing new recovery-oriented markers to evaluate and compare interventions promoting recovery in clinical trial settings.
– By testing the functional relevance of imaging measures to provide clinically meaningful information, this proposal offers the possibility of translating advanced non-conventional MRI methods from scientific to more clinically oriented settings.
ORIGINALITY
This proposal in the context of research into recovery. In the last 5 years research in the field of recovery from neurological conditions has grown hugely. The high social costs of chronic neurological diseases, often affecting young individuals, and their impact on the allocation of resources have been major contributors towards this evolution. Research on recovery in MS, therefore, has
followed two main parallel paths:(a) a research-oriented path to characterize
the patterns of spontaneous recovery;(b)a clinically-oriented path to identify
effective rehab approaches.
While providing an important background for research on recovery to build
on, there remain gaps in our knowledge on: (a) how MS brains respond to
therapeutic intervention; (b)how we can reliably and reproducibly measure
results from single studies. Indeed the novelty of this proposal lies in bridging these gaps in knowledge and in proposing novel approaches to enhance recovery in MS.
Why this proposal is timely. There has been remarkable progress in our understanding of the extent to which functional recovery is possible following neural damage and how it may be promoted. This recent progress comprises: – appreciation of the role of activity and environmental input in driving plasticity in healthy and injured brains;
– better understanding of brain-behavior relationships through cognitive neuroscience and the role of factors such as attention and motivation in rehab; – new methodologies in clinical trial design and measurement of outcome; – new investigations such as neuroimaging, electro- and magneto-encephalo graphy (EEG/MEG), and transcranial magnetic stimulation (TMS), singly or in combination, to investigate brain pathophysiology and to monitor treatment;
– new treatment modalities such as TMS, deep brain stimulation and neuroprotective agents that are in different stages of development.
Specifically, the recent advances in imaging methods include:
– FMRI has recently allowed non-invasive mapping of brain functions. The widespread availability, relatively low cost and informativeness of FMRI has made
it the most popular of the techniques available to study repair mechanisms[49].
The combination of functional and perfusion imaging approaches has improved the interpretability of the results and has contributed to the development of FMRI as a tool for drug development[50].
– The possibility to characterize and quantify brain connectivity with diffusion imaging, as well as to model the brain architecture as interconnected and efficient networks has offered ways to study neurodegeneration in pathological conditions affecting multiple brain systems diffusely[51].
– New MRI acquisitions at high-field and with greater pathological specificity (e.g., MR spectroscopy, myelin water imaging) have offered ways to
investigate mechanisms of tissue regeneration[52].
This proposal will combine these new functional and structural imaging methods to address the research questions. My expertise on clinical application of imaging methods learned at the FMRIB Centre, University of Oxford, along with the proposed collaborations with scientists and methods developers based in UK and in Italy will be beneficial for this proposal.
The novelty of the proposed drug approach. This program proposes a new model of recovery-oriented intervention in MS by pharmacologically pre-disposing the brain to the effect of rehab.
Previous studies in healthy volunteers have shown the
behaviorally-relevant potential of drug-modulation of brain neurotransmitters [53]. The
search for pharmacological therapies that affect the recovery process after injury has been intensified during the last decade. Studies in stroke have suggested that adjuvant pharmacological therapies (e.g., amphetamine) may
strategies in combination with training are currently one of the most promising approaches for recovery after stroke.
At this stage of knowledge in the field of recovery in MS, the advantage of using a pharmacological systems-level approach (rather than an electro-physiological target-oriented approach, also attempted in stroke) to enhance rehab-driven recovery stems from the diffuse and heterogeneous nature of MS damage. More targeted approaches may be attempted when an improved understanding of mechanisms of rehab-driven recovery has been gained in MS.
A new field of restorative neurology. Neuroimaging techniques have begun to reveal the substantial ability of the adult brain to reorganize itself in health and in disease. This evolving branch of neuroscience examining brain plasticity has offered the opportunity to improve our understanding of the functional basis by which therapeutic interventions adaptively modify brain activity, as well as reliable identification of markers of improvements.
In stroke this basic neuroscientific knowledge has been successfully translated into clinical application of therapeutic intervention promoting recovery of function. Imaging methods have driven efficiently the optimization of recovery-oriented strategies by opening up the possibility of developing new approaches to directly interfere with the function of specific networks. This successful translational research has led to the definition of a new clinical science called restorative neurology, at the interface of neuroscience and clinical neurology, whose interdisciplinary principles have been formalized in recommendations from the UK Academy of Medical Sciences in 2004 (Restoring Neurological Function: Putting the neurosciences to work in
neurorehabilitation,http://www.acmedsci.ac.uk/p99puid19.html).
This proposal aims to develop this exciting field of translational research in MS. This program will provide tools to measure the effects of novel treatments promoting recovery and inform new therapeutic strategies for MS, with important consequences for the social burden of the disease and for clinical resource allocation.
My long-term vision for restorative neurology in MS. The long-term strategy of my research in recovery is the development of new scientifically-informed approaches to improve patients’ management. Building on my previous studies on motor learning in healthy volunteers and MS patients (basic neuroscience phase), this proposal, aiming at understanding the ways the brain responds to intervention and at quantifying this response, represents the next step in my research path (translational phase). It also lays the foundation for a further stage with a short-term proof-of-concept recovery study (clinical phase). I anticipate, therefore, that this proposal will contribute to improve our current restorative approaches to MS patients and provide tools to encourage further translational research in this field.
Over the next 10 years I expect to see further advances in recovery research with a greater emphasis on:
affect plasticity in MS. Their investigation may provide a basis for new pharmacological phase-dependant targets for MS recovery.
– The exploitation of combined pharmacological and non-pharmacological approaches (e.g., rehab+drugs, electrophysiology+rehab) for enhancing recovery in MS.
– Multicenter studies validating markers of recovery and testing novel recovery-oriented therapeutic approaches. With new ways of assessing interventions, new treatment targets should become practical, helping to translate advances in immunology and regenerative medicine (e.g., stem cells) into novel therapies for MS patients.
DEVELOPMENT AND STRATEGY OF THE PROJECT, METHODOLOGY AND PRELIMINARY DATA
Research plan and methods
The two aims of this proposal will be addressed together in an experiment including a placebo arm and an enhancement (drug) arm.
Study design
26 patients will be assessed at week -6 and baseline for reproducibility of measures. At baseline, patients will be randomly assigned to either the placebo (Arm1) or the enhancement (Arm2) arm. 26 newly recruited patients will also be randomized into the arms at baseline. Both Arm1 (n=26) and Arm2 (n=26) will undergo a 6-week rehab program. At the end of the rehab period both arms will stop drug or placebo intake. Longitudinal changes in the placebo arm will address Aim1. Comparison between the placebo and the enhancement arms will address Aim2. Patients will be tested at week -6, baseline, week +6 and week +12. The overall study duration for each patient will be 18 weeks.
Participants – 52 right-handed patients with clinically stable secondary progressive (SP) MS [Expanded Disability Status Scale (EDSS): 3.0-6.5] and right upper limb dysfunction will be recruited. Right upper limb dysfunction will be quantified by impaired performance in dexterity test [average time>30 seconds in 2 trials of 9-Hole Peg (9HP) test with the right hand]. Major exclusion criteria: significant cognitive impairment; relapse in the prior year; rehab in the prior 6 months; history of seizures. Pharmacological treatments will be allowed if at stable regimen for the preceding 3 months and not contra-indicated in association with the experimental drug. Recruiting clinically stable SPMS patients will reduce the chance of detecting longitudinal changes in imaging measures due to new lesion occurrence, and include patients with diffuse and therefore more homogenous brain damage. Patients will be asked to keep their own medication stable during the study. Withdrawal criteria: one point increase in EDSS; relapse or steroid course during the study; new T2WI lesion occurrence.
Rehabilitation– Patients will receive a 6-week individually tailored rehab program focused on improving right limb strength and coordination to produce a re-training on goal directed tasks. Patients will receive 3 sessions of rehab/week and will be trained to perform progressive exercises at home. A treating assessor (collaborating consultant in neurological rehab) will be responsible for the rehab program. An evaluating assessor (research assistant) will record clinical data and perform blind neurological evaluations.
Drug –Patients of the enhancement arm will take 20 mg/day of 4-amino
pyridine (4-AP)[55], a K+ channel blocker prolonging action potentials, with a
known pharmacokinetics and tolerability profile in MS[56].
Clinical measures– They will be assessed as baseline descriptors and measures of changes to test for the clinical relevance of the intervention. They will include a multidimensional evaluation of impairment and disability [EDSS; Functional Independence Measures (FIM); MS Impact Scale (MSIS) 29-items; MS Functional Composite (MSFC)], quality of life [MS Quality of Life (MSQoL) 54-items] depression (Beck Depression Inventory), fatigue [Fatigue Impact Scale (FIS)]. Continuous, quantitative measurements of upper limb function (9HP-test) will
quantify rehab-related clinical improvements to be related to functional changes[57].
Imaging measures –MRI data will be acquired using a state-of-the-art 3T Philips Achieva scanner. MRI data analysis will be carried out using tools from
the FSL toolbox (http://www.fmrib.ox.ac.uk/fsl/).
Brain FMRI will use a right hand motor active task (finger movement). Percent blood-oxygen-level-dependant (BOLD) signal change (%SC) associated with motor task will quantify the functional responses associated with the study interventions in the whole brain, as well as in predefined sensorimotor regions of interest (ROIs). Within-group changes in %SC will quantify the reproducibility of imaging measures in the pre-intervention phase and the rehab effects in Arm1. Between-group difference in %SC changes will quantify the pharmacological enhancement of rehab (Arm1 vs. Arm2). A breath-holding task will quantify vascular reactivity to account for a significant component of inter-session variability[58]. Drug effects on cerebral blood flow will be measured by arterial spin
labeling and will be used to account for the influence of baseline flow changes on the task-related BOLD FMRI contrast. Resting state FMRI provides information on spontaneous activity of spatially defined networks exhibiting organized
fluctuations in neuronal activity[59]. Motor learning can modulate this resting
activity[25]. Here resting state FMRI will quantify the strength of the functional
expression of the sensorimotor network and its changes with interventions.
Brain DTIwill be used to identify specific white matter tracts sub-serving task relevant sensorimotor regions. The contribution of damage along these tracts to baseline patterns of reorganization and functional changes following intervention will be quantified. I will also carry out multi-subject tract-based statistics to investigate the relationship between tissue integrity and behavioral measures of successful rehab.
High-resolution T1-WIwill quantify the contribution of brain atrophy to the baseline pattern of reorganization and functional changes associated with rehab. Using a voxel-based morphometry approach, it will also assess grey matter regions whose structural integrity is relevant for successful rehab. T2-WI will control for lesion occurrence during the study. A similar analysis approach will guide comparison of clinical and imaging changes after rehab cessation and will assess whether beneficial effects of enhanced rehab continue into the follow-up period.
Healthy controls
26 age – and sex-matched controls will be examined at week -6 and baseline to establish the normal networks engaged in tasks and resting state. This is important for subsequent comparison with hypothesized abnormal networks in patients under the alternative hypotheses that the networks normalize following rehab or modified networks are established that are associated with rehab-mediated improvements.
Two time-points are imaged to also model the session effect for characterizing the reproducibility of imaging markers between sessions and comparing this with the patient group, hypothesized to show poorer reproducibility. This would provide data to develop image analysis strategies for improving the reproducibility of imaging markers and choosing the most stable imaging markers in patient groups.
Sample size
To underpin Aim1 it is necessary to establish a clinical effect of rehab. Clinical studies on rehab in MS suggest recruiting 20 patients to detect a 20% clinical change in FIM motor domain (80% power, p<0.05, two-tailed) over a
period of rehab comparable to that proposed here (i.e., 6 weeks)[4,5]. Considering
30% dropouts on the basis of previous pharmacological imaging studies in MS[21],
I propose to recruit a total of 26 patients.
For Aim2, as the size of drug effect is unknown, the sample size calculation is based on rehab outcomes and includes 26 patients/ group, allowing for 30% dropouts.
The pre-rehab reproducibility phase to characterize imaging markers will include 26 matched healthy volunteers as well as the 26 MS patients.
Study timeline
The study design has been optimized to address multiple questions. It will answer the initial research questions efficiently as well as optimizing patient recruitment.
Potential experimental issues
Patients will be recruited from both Santa Lucia Hospital and the MS Centre at La Sapienza University (proposed collaborating University), where
out of 3000 patients in the MS database, we expect that about 30% of them will fulfill the eligibility criteria.
I will work on the clinical (recruitment only) as well as on the research (imaging acquisition and analysis) side of the proposal to keep up the rate of recruitment and increase the patients’ compliance. As the experiment includes a rehab intervention, I would expect high compliance to the experimental protocol. The number of scans for the experiment can be accommodated within the scanning time available at the MRI Unit in Santa Lucia.
A 30% dropout rate is taken into account on the consideration that patients may withdraw from the study for disease-related issues (i.e., relapses/new lesion occurrence during the study, new treatments required), lack of active intervention during the first 6 weeks of the study, side effects from the drug used in Arm2 or discomfort from the MRI acquisitions.
Preliminary results
My work in Oxford has focused on mechanisms of brain plasticity in the healthy brain and in MS probed by a newly developed visuomotor skill learning task. These studies led to the hypotheses of this proposal.
MS patients showed a preserved ability to learn new motor skills even at higher levels of disability. After one week of training patients performed as well as the controls had done at baseline[1]. Despite a preserved ability to learn, behavioral
improvements in patients were paralleled by learning-related functional changes
in brain regions significantly different from controls[2]. While controls showed
higher activation of dorsal parietal regions implicated in retrieval of learned visuomotor representations, patients showed no significant relationship with these regions. Altered structural architecture of the putamen anatomically connected with these areas and relevant for motor learning suggested that local structural impairment in patients may propagate functionally throughout the striatal-cortical
network[29]. The behavioral evidence for preserved motor learning in patients along
with the activation of a widespread network of sensorimotor regions suggested that in MS patients learning may occur by establishing sensorimotor networks,
which mediate key aspects of learning[28].
Overall these imaging studies generated hypotheses about specific changes in brain function associated with rehab in MS and the relevance of specific brain regions and pathways for rehab to be successful. I wish to test these hypotheses by inducing and measuring rehab-mediated changes in brain function, and enhancing them pharmacologically. This proposal represents therefore the next step of my research plan in restorative neurology of MS.
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RELEVANCE OF THE PROJECT FOR THE NATIONAL HEALTH SERVICE
Chronic disability in young adulthood is a major social and health-care economic burden for western countries. Currently, MS is the major cause of acquired chronic neurological disability in young adults, second only to sequelae of CNS trauma. Its disabling consequences present a great challenge for health system organization. Indeed the rehab of patients with chronic neurological diseases has a high impact on health system costs, as it goes beyond medical care narrowly constructed and requires the integration of different expertise within the health care system.
My program aiming to facilitate functional recovery of chronically disabled MS patients will directly benefit health system organization by reducing the direct costs associated with the disease and by identifying predictors of responses to rehab. This should help to rationalize the allocation of clinical and financial resources.
Its translational intent will be also relevant in the longer-term to direct studies on recovery taking advantage of the qualified imaging measures. Further investigations on new interventions may be optimized on the basis of this proposal’s results.
Predictors of response to recovery intervention and the development of tailored approaches. By improving our understanding of the neural bases of rehab effects in MS patients this proposal will identify brain regions associated with clinical improvements, which could predict the functional potential for upper limb recovery and be targets of rehab intervention in future studies. An algorithm to guide individualized rehab programs could be built from here, which could identify patients who would benefit from specific rehab approaches. This would be the first step towards individually tailored therapeutic strategies for upper limb dysfunction and the more methodologically challenging investigations on lower limb disability.
Testing current intervention and developing novel recovery-oriented approaches. Currently, it is not clear precisely which elements of a rehab package are effective because many hands-on techniques have not been properly evaluated. Many such treatments are based on custom, practice and experience rather than being rooted in neuroscience. Consequently, their cost effectiveness for the health system remains to be established and the best approach for the patient has still to be determined. Developing ways to measure and compare the effect of rehab strategies in future studies is crucial to this purpose. Further, while our current clinical approaches to rehab are focused on people with disabilities, recovery oriented strategies may be used to produce an enrichment of functional resources and allow patients in the early phase to withstand more disease-related damage before disability becomes apparent. This would have a direct impact on long-term costs. Finally, testing novel approaches to enhance patient’s recovery will have a great impact on the rationalization of the demand for rehab and thus on the optimization of clinical resources.
The indirect effect on caregivers.Enablement of people with chronic diseases has consequences on daily activity and the ability of individuals to participate in the worlds of work and leisure beyond pathology and the bodily impairments that it brings. Limitations imposed on an individual by a disabling disease are not simply proportional to the quantity of biological impairment but also reflect material and social circumstances that individuals contend with. In this respect, the consequences of disabling diseases go beyond the individual and involve his caregivers, both emotionally and socially. Lessening patients’ disability and improving their quality of life through an optimization of functional recovery has therefore important wider consequences, as it is reflected in the health status of their caregivers. Previous evidence has identified the health status of caregivers as associated with the health status of patients and therefore as an independent targets of therapeutic strategies. By aiming at facilitating functional recovery this proposal will have an impact on this category of secondary patients.
Encouraging a rehab network.While physiotherapy approaches are established rehab interventions, current restorative approaches go beyond that and may include new treatment modalities (electrophysiology and drugs). This multidisciplinary vocation of restorative neurology requires collaborations between dedicated rehab centers (such as Santa Lucia Foundation, the proposed Institution), hospitals and universities. These may take the form of clinical (between rehab and MS centers) as well as scientific (between rehab centers and Universities) collaborations to facilitate patient recruitment for clinical trials, to use an integrated modern scientific approach to rehab research and to encourage dissemination of a research culture through the clinical community. Therefore this proposal may have consequences on the allocation of resources within different areas of the health system and encourage review of research portfolios.
Understanding recovery and new treatment modalities. This proposal will optimize and increase informativeness of future trials. By directly translating advanced imaging methods to measure recovery, this program will offer methodological and scientific contribution for future studies. It will qualify functional measures of recovery that can be used to power clinical studies more efficiently. This proposal will suggest targets of intervention, which may be used in future recovery studies using new treatment modalities (e.g., electrophysiology or drugs). Finally, this proposal will provide data for powering studies on rehab treatment of upper limb dysfunction using similar experimental design.
Beyond MS.Results from this proposal promise to become useful for other progressive disabling neurological conditions of high social and economic burden. With its diffuse effect on brain tissue and the presence of a neuro-degenerative component along with the inflammatory damage, MS constitutes an example for progressive disabling conditions providing an improved understanding of how the brain responds to progressive damage. Qualifying imaging markers of intervention-driven recovery may also help to design future studies testing new therapeutic options for neuroprotection and repair in other neurological conditions.
