Non-invasive prehabilitation to foster widespread fMRI cortical reorganization before brain tumor surgery: lessons from a case series.

PURPOSE: The objective of this prospective, single-centre case series was to investigate feasibility, clinical outcomes, and neural correlates of non-invasive Neuromodulation-Induced Cortical Prehabilitation (NICP) before brain tumor surgery. Previous studies have shown that gross total resection is paramount to increase life expectancy but is counterbalanced by the need of preserving critical functional areas. NICP aims at expanding functional margins for extensive tumor resection without functional sequelae. Invasive NICP (intracranial neuromodulation) was effective but characterized by elevated costs and high rate of adverse events. Non-invasive NICP (transcranial neuromodulation) may represent a more feasible alternative. Nonetheless, up to this point, non-invasive NICP has been examined in only two case reports, yielding inconclusive findings. METHODS: Treatment sessions consisted of non-invasive neuromodulation, to transiently deactivate critical areas adjacent to the lesion, coupled with intensive functional training, to activate alternative nodes within the same functional network. Patients were evaluated pre-NICP, post-NICP, and at follow-up post-surgery. RESULTS: Ten patients performed the intervention. Feasibility criteria were met (retention, adherence, safety, and patient's satisfaction). Clinical outcomes showed overall stability and improvements in motor and executive function from pre- to post-NICP, and at follow-up. Relevant plasticity changes (increase in the distance between tumor and critical area) were observed when the neuromodulation target was guided by functional neuroimaging data. CONCLUSION: This is the first case series demonstrating feasibility of non-invasive NICP. Neural correlates indicate that neuroimaging-guided target selection may represent a valid strategy to leverage neuroplastic changes before neurosurgery. Further investigations are needed to confirm such preliminary findings.

Exploring the neural basis of non-invasive prehabilitation in brain tumour patients: An fMRI-based case report of language network plasticity.

Primary brain neoplasms are associated with elevated mortality and morbidity rates. Brain tumour surgery aims to achieve maximal tumour resection while minimizing damage to healthy brain tissue. Research on Neuromodulation Induced Cortical Prehabilitation (NICP) has highlighted the potential, before neurosurgery, of establishing new brain connections and transfer functional activity from one area of the brain to another. Nonetheless, the neural mechanisms underlying these processes, particularly in the context of space-occupying lesions, remain unclear. A patient with a left frontotemporoinsular tumour underwent a prehabilitation protocol providing 20 sessions of inhibitory non-invasive neuromodulation (rTMS and multichannel tDCS) over a language network coupled with intensive task training. Prehabilitation resulted in an increment of the distance between the tumour and the language network. Furthermore, enhanced functional connectivity within the language circuit was observed. The present innovative case-study exposed that inhibition of the functional network area surrounding the space-occupying lesion promotes a plastic change in the network's spatial organization, presumably through the establishment of novel functional pathways away from the lesion's site. While these outcomes are promising, prudence dictates the need for larger studies to confirm and generalize these findings.

Neuromodulation-induced prehabilitation to leverage neuroplasticity before brain tumor surgery: a single-cohort feasibility trial protocol.

Introduction: Neurosurgery for brain tumors needs to find a complex balance between the effective removal of targeted tissue and the preservation of surrounding brain areas. Neuromodulation-induced cortical prehabilitation (NICP) is a promising strategy that combines temporary inhibition of critical areas (virtual lesion) with intensive behavioral training to foster the activation of alternative brain resources. By progressively reducing the functional relevance of targeted areas, the goal is to facilitate resection with reduced risks of neurological sequelae. However, it is still unclear which modality (invasive vs. non-invasive neuromodulation) and volume of therapy (behavioral training) may be optimal in terms of feasibility and efficacy. Methods and analysis: Patients undertake between 10 and 20 daily sessions consisting of neuromodulation coupled with intensive task training, individualized based on the target site and neurological functions at risk of being compromised. The primary outcome of the proposed pilot, single-cohort trial is to investigate the feasibility and potential effectiveness of a non-invasive NICP protocol on neuroplasticity and post-surgical outcomes. Secondary outcomes investigating longitudinal changes (neuroimaging, neurophysiology, and clinical) are measured pre-NICP, post-NICP, and post-surgery. Ethics and dissemination: Ethics approval was obtained from the Research Ethical Committee of Fundació Unió Catalana d'Hospitals (approval number: CEI 21/65, version 1, 13/07/2021). The results of the study will be submitted to a peer-reviewed journal and presented at scientific congresses. Clinical trial registration: ClinicalTrials.gov, identifier NCT05844605.

Patient's assessment and prediction of recovery after stroke: a roadmap for clinicians.

BACKGROUND AND PURPOSE: In neurorehabilitation clinical practice, assessment is usually more oriented to evaluate patient's present status, than to plan interventions according to predicted outcomes. Therefore, we conducted an extensive review of current prognostic models available in the literature for recovery prediction of many functions and constructs, after stroke. We reported results in the form of a practical guide for clinicians, with the aim of promoting the culture of early clinical assessment for patient stratification, according to expected outcome. To define a roadmap for clinicians, a stepwise sequence of five actions has been developed, from collecting information of past medical history to the adoption of validated prediction tools. Furthermore, a clinically-oriented organization of available prediction tools for recovery after stroke have been proposed for motor, language, physiological and independency functions. Finally, biomarkers and online resources with prognostic value have been reviewed, to give the most updated state of the art on prediction tools after stroke. RECOMMENDATIONS FOR CLINICAL PRACTICE: Clinical assessment should be directed both towards the objective evaluation of the present health status, and to the prediction of expected recovery. The use of specific outcome measures with predictive value is recommended to help clinicians with the definition of sound therapeutic goals.

Shear wave elastography combined with electromyography to assess the effect of botulinum toxin on spastic dystonia following stroke: A pilot study.

Background: Shear wave elastography (SWE) is a method for carrying out a quantitative assessment of the mechanical properties of soft tissues in terms of stiffness. In stroke survivors, the paretic muscles may develop hypertonia due to both neural-mediated mechanisms and structural alterations with consequent muscular fibrous-fatty remodeling. Methods: Fourteen adult patients with spastic dystonia following stroke were recruited. Muscle hypertonia was assessed using the modified Ashworth scale (MAS). Muscle activation was measured by surface electromyography (sEMG) with the selected muscle in shortened (spastic dystonia) and stretched (dynamic stretch reflex) positions. SWE was performed on a selected paretic muscle and on the contralateral non-paretic one to calculate shear wave velocities (SWV) along and across muscular fibers. The modified Heckmatt scale (MHS) pattern was also determined. All evaluations were performed shortly before BoNT-A injections (T0) and one month later (T1). Results: All SWV on paretic muscles were higher than contralateral non-paretic ones (p < 0.01). After BoNT-A injection, a significant reduction in MAS (p = 0.0018), spastic dystonia (p = 0.0043), and longitudinal SWE measurements, both in shortened (p = 0.001) and in stretched muscular conditions (p = 0.0029), was observed. No significant changes in SWV on non-paretic muscles were observed. Higher SWV resulted along the direction of muscular fibers vs. across them (p = 0.001). No changes resulted from the MHS evaluations after BoNT-A. There was a positive correlation between MHS scores and SWV values while the muscle was in the shortened position, but not with spastic dystonia recorded by sEMG. Conclusions: This is the first study evaluating the effect of BoNT-A on muscle hypertonia following stroke, assessed by both SWE and sEMG. These findings support SWE as a useful method to disclose intrinsic muscular remodeling, independently of the effect of spastic dystonia, in particular, while muscles were assessed in a neutral position. SWE measurements of muscle stiffness cannot tell apart neural-mediated and intrinsic muscle hypertonia. Interestingly, when sEMG activity is very limited, as in spastic muscles kept in a shortened position, SWE can provide a measurement of stiffness due almost completely to intrinsic muscle changes. Alongside sEMG, SWE could aid clinicians in the assessment of responses to treatments.

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

The problem: 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. Proposed solutions: 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. Conclusions: 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.

Novel insights into the effects of levodopa on the up- and downstrokes of writing sequences.

Motor control of automatized and overlearned sequences, such as writing, is affected in Parkinson's disease (PD), impacting patients' daily life. Medication effects on motor performance are not only task-specific, but also variable within tasks. The nature of this variance is still unclear. This study aimed to investigate whether medication affects writing sequences differently when producing up- or downstrokes. Writing was assessed in healthy controls (HC) (N = 31) and PD (N = 32), when ON and OFF medication in a randomized order (interspersed by two months). Subjects wrote a sequential pattern with an increasing size on a digital tablet. Writing outcomes were movement vigor (amplitude and velocity), error and end-point variability, and sequence continuation, calculated separately for up- and downstrokes. Results showed that PD patients OFF-medication reduced movement vigor (amplitude) for up- and downstrokes compared to HC. Clear deficits were found for up- but not for downstroke error in PD patients in OFF, suggesting a directional bias. Dopaminergic medication improved motor vigor by increasing writing amplitude and upstroke continuation, but this occurred at the cost of the downstroke trajectory. Other writing outcomes did not improve with medication intake. In conclusion, we interpret these findings as that the impact of dopamine is complex, highly task-specific, supporting the most highly energy demanding components of a writing sequence. As medication did not regulate downstroke writing, we recommend supplementary training to address task demands that were less modulated by dopamine (registration: https://osf.io/gk5q8/ , 17 July 2018).

Premotor dorsal white matter integrity for the prediction of upper limb motor impairment after stroke.

Corticospinal tract integrity after stroke has been widely investigated through the evaluation of fibres descending from the primary motor cortex. However, about half of the corticospinal tract is composed by sub-pathways descending from premotor and parietal areas, to which damage may play a more specific role in motor impairment and recovery, particularly post-stroke. Therefore, the main aim of this study was to investigate lesion load within corticospinal tract sub-pathways as predictors of upper limb motor impairment after stroke. Motor impairment (Fugl-Meyer Upper Extremity score) was evaluated in 27 participants at one week and six months after stroke, together with other clinical and demographic data. Neuroimaging data were obtained within the first week after stroke. Univariate regression analysis indicated that among all neural correlates, lesion load within premotor fibres explained the most variance in motor impairment at six months (R2 = 0.44, p < 0.001). Multivariable regression analysis resulted in three independent, significant variables explaining motor impairment at six months; Fugl-Meyer Upper Extremity score at one week, premotor dorsal fibre lesion load at one week, and age below or above 70 years (total R2 = 0.81; p < 0.001). Early examination of premotor dorsal fibre integrity may be a promising biomarker of upper limb motor impairment after stroke.

Effectiveness of somatosensory interventions on somatosensory, motor and functional outcomes in the upper limb post-stroke: A systematic review and meta-analysis.

BACKGROUND: Research mainly focuses on motor recovery of the upper limb after stroke. Less attention has been paid to somatosensory recovery. OBJECTIVE: To review and summarize the effect of upper limb somatosensory interventions on somatosensory impairment, motor impairment, functional activity and participation after stroke. METHODS: Biomedical databases Ovid Medline, EMBASE, Web of Science, PEDro, and OTseeker were searched with an update in May 2018. Randomized controlled trials investigating the effect of somatosensory-specific interventions focusing on exteroceptive, proprioceptive or higher cortical somatosensory dysfunction, or any combination were eligible for inclusion. Quality of included studies were assessed using Physiotherapy Evidence Database (PEDro) scale. Standardized Mean Differences and Mean Differences and 95% confidence intervals were calculated and combined in meta-analyses. RESULTS: Active somatosensory interventions did not show a significant effect on somatosensation and activity, but demonstrated a significant improvement in motor impairment (SMD = 0.73, 95% CI = 0.14 to 1.32). No study evaluating active somatosensory intervention included participation. Passive somatosensory interventions significantly improved light touch sensation (SMD = 1.13, 95% CI = 0.20 to 2.05). Passive somatosensory interventions did not show significant effects on proprioception and higher cortical somatosensation, motor impairment, activity and participation. CONCLUSIONS: To date, there is low quality evidence suggesting active somatosensory interventions having a beneficial effect on upper limb impairment and very low quality evidence suggesting passive somatosensory interventions improving upper limb light touch sensation. There is a need for further well-designed trials of somatosensory rehabilitation post stroke.

Mismatch between observed and perceived upper limb function: an eye-catching phenomenon after stroke.

PURPOSE: To investigate the relation between observed and perceived upper limb motor function in patients with chronic stroke. MATERIAL AND METHODS: We investigated 32 patients at six months after stroke with the Fugl-Meyer Assessment (observed function) and hand subscale of the Stroke Impact Scale (perceived function). Spearman correlation was calculated to relate observed and perceived function. Through cut-off scores, we divided our sample in low (Fugl-Meyer Assessment <31/66) and good observed function, and low (hand subscale of Stroke Impact Scale <61/100) and good perceived function. Scatterplot and hierarchical clustering analysis was conducted to detect distinct groups. RESULTS: A strong positive relation was found between observed and perceived function (r = 0.84). Three groups could be identified; a "low match group" of patients with low observed and low perceived function (n = 11, 34%), a "good match group" containing patients with good observed and good perceived function (n = 15, 47%), and a "mismatch group" comprising patients with good observed but low perceived function (n = 6, 19%). CONCLUSIONS: In our chronic sample, one in five patients showed good upper limb observed but low perceived function. Measuring both observed and perceived arm and hand function seems warranted together with considering a differential therapy approach for the distinct groups. Implications for rehabilitation A considerable group of patients in the chronic phase post-stroke have good motor function in their affected upper limb, but nevertheless perceive a restricted ability. In order to identify a mismatch in people with chronic stroke, both observed and perceived upper limb motor function should be assessed. Besides common measurement tools for observed function like the Fugl-Meyer Assessment, perceived function can be evaluated by means of the hand function section of the Stroke Impact Scale. For patients with good observed but low perceived function, an additional rehabilitation strategy should be considered, potentially including awareness of ability and a self-efficacy approach.

Is There Full or Proportional Somatosensory Recovery in the Upper Limb After Stroke? Investigating Behavioral Outcome and Neural Correlates.

BACKGROUND: Proportional motor recovery in the upper limb has been investigated, indicating about 70% of the potential for recovery of motor impairment within the first months poststroke. OBJECTIVE: To investigate whether the proportional recovery rule is applicable for upper-limb somatosensory impairment and to study underlying neural correlates of impairment and outcome at 6 months. METHODS: A total of 32 patients were evaluated at 4 to 7 days and 6 months using the Erasmus MC modification of the revised Nottingham Sensory Assessment (NSA) for impairment of (1) somatosensory perception (exteroception) and (2) passive somatosensory processing (sharp/blunt discrimination and proprioception); (3) active somatosensory processing was evaluated using the stereognosis component of the NSA. Magnetic resonance imaging scans were obtained within 1 week poststroke, from which lesion load (LL) was calculated for key somatosensory tracts. RESULTS: Somatosensory perception fully recovered within 6 months. Passive and active somatosensory processing showed proportional recovery of 86% (95% CI = 79%-93%) and 69% (95% CI = 49%-89%), respectively. Patients with somatosensory impairment at 4 to 7 days showed significantly greater thalamocortical and insulo-opercular tracts (TCT and IOT) LL ( P < .05) in comparison to patients without impairment. Sensorimotor tract disruption at 4 to 7 days did not provide significant contribution above somatosensory processing score at 4 to 7 days when predicting somatosensory processing outcome at 6 months. CONCLUSIONS: Our sample of stroke patients assessed early showed full somatosensory perception but proportional passive and active somatosensory processing recovery. Disruption of both the TCT and IOT early after stroke appears to be a factor associated with somatosensory impairment but not outcome.