Modulation of brain plasticity in stroke: a novel model for neurorehabilitation

 Yes we know neuroplasticity works but not how.

Why does a neuron give up its current job and take on a neighboring function? If we don't know that, neuroplasticity will never be repeatable on demand. This tells us nothing useful.

 Modulation of brain plasticity in stroke: a novel model for neurorehabilitation

 
 

 
Correspondence to: V.D.L. V.DiLazzaro@unicampus.it
Modulation of brain plasticity in stroke: a novel model for neurorehabilitation
Giovanni Di Pino, Giovanni Pellegrino, Giovanni Assenza, Fioravante Capone, Florinda Ferreri, Domenico Formica, Federico Ranieri, Mario Tombini, Ulf Ziemann, John C. Rothwell and Vincenzo Di Lazzaro

Abstract

 | Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

Introduction

Stroke is among the principal causes of death worldwide, and although most stroke survivors achieve at least some spontaneous recovery after the ictus, it remains the main cause of permanent disability in Europe and the USA.^1–3The only existing treatment for stroke is tissue plasmino-gen activator, which can salvage tissue at risk in the penumbra of a brain infarct and reduce future disability if administered within a few hours after stroke onset.⁴No treatments specifically designed to restore function through repair of damaged tissue have been developed to date. Current best practice in stroke management is to reduce initial impact, take precautions to avoid the further burden of complications, and maximize f unctional ability through extensive physiotherapy.Although early rehabilitative interventions can improve arm function above what would be achieved by natural recovery alone,⁵the majority of patients are still unable to use the affected hand and/or arm for simple activities of daily living 6 months after the stroke.⁶Robot-assisted therapy has been proposed as an excellent low-cost way to increase the amount of therapy that an individual patient receives, because a robot can deliver a higher amount of exercise in the same time than can a human physio-therapist,⁷but in controlled trials robot-assisted therapy has shown disappointingly little additional benefit over conventional regimes of intensive physiotherapy.^8,9The lack of effective neurorepair after stroke and the limitations of functional recovery attained by physio-therapy have led researchers to consider alternative approaches that improve the scope for recovery by enhancing the natural plasticity of the sensorimotor system. If recovery depends on ‘relearning’ new patterns of activity to maximize the use of remaining undamaged brain, interventions that increase plasticity, and thereby the ability to learn, should improve recovery. Two approaches are of great current interest: pharmaco logical interventions and noninvasive brain stimulation (NIBS). In this Review, we focus on NIBS. Although NIBS has been used to improve gait, neglect symptoms and lan-guage after stroke, we will concentrate here on its application to recovery of arm and hand function, because most studies have assessed the efficacy of NIBS on upper limb function.More than 350 articles have been published on trans-cranial stimulation in stroke since 2012. These include more than 50 small clinical trials that evaluated the potential for NIBS to enhance recovery of hand and arm function. Recent meta-analyses disagree on the effectiveness of these techniques: two Cochrane reviews do not support the use of repetitive transcranial magnetic stimu-lation (rTMS)¹⁰or transcranial direct current stimu lation (tDCS)¹¹in stroke rehabilitation, whereas two other sys-tematic reviews conclude that NIBS can have a moder-ate benefit in terms of stroke recovery, with few major adverse effects.^12,13Here, we discuss the factors that have contributed to the slow progress of accepting NIBS as a part of routine clinical practice, and suggest ways to develop the use of NIBS in stroke rehabilitation. Synaptic dysfunction in stroke Noninvasive neuromodulatory strategies are thought to alter synaptic efficacy in glutamatergic and γ-aminobutyric acid-mediated (GABAergic) circuits,¹⁴which are essential for motor learning. Knowing how stroke alters these circuits, and determining the time course over which the stroke-related changes occur, might aid the development of more-effective neuromodulatory strategies.Brain infarcts lead to an imbalance in energy demand and blood supply. The majority of energy consumed by the brain is devoted to synaptic transmission and the postsynaptic effects of glutamate,¹⁵and interruption of synaptic transmission accounts for the electrical silence in the penumbra after stroke.^16,17At the level of
the gluta matergic synapse, hypoxic failure leads to focal post synap tic hyperpolarization^18,19 followed by a massive hypoxic depolarization of the postsynaptic terminal.²⁰ Even though inhibitory synapses are more resistant to hypoxia than are excitatory synapses,²¹ synaptic disinhib-ition fails before synaptic excitation because of reduced excitatory input to inhibitory interneurons,²²potentially contributing to excitotoxicity that causes delayed cell death.During days and weeks following stroke, slower syn-aptic changes can emerge. A critical period of approxi-mately 90 days of increased synaptic plasticity is thought to parallel the initial period of rapid behavioural recov-ery.^5,23Two factors exert opposing effects during this period. First, in mouse models of stroke, a sustained increase in tonic GABAergic signalling lasting over a month can reduce plasticity; during this period behavioural recovery can be enhanced by blocking extrasynaptic GABA receptors.²⁴ Simultaneously, a sustained increase in glutamatergic excitability mediated by AMPA receptors promotes plasticity and the release of brain-derived neurotropic factor.²⁵ Data from rodent studies have shown that stroke-related changes can also involve brain regions in the hemisphere unaffected by stroke. These changes include bihemispheric reductions in phasic (synaptic) GABAergic inhibition,²⁶in parallel with downregulation of GABA A receptor binding and GABA A receptor subunit expression.²⁷Changes in calcium currents have also been demonstrated in the noninfarcted tissue of the unaffected hemisphere.²⁸Excitability and connectivity in stroke Several methods and protocols are available for assess-ing the altered excitability and connectivity after stroke, both in acute and chronic phases. (Box 1, Figure 1). In this article, we have adopted the following classification of the phases of stroke: hyperacute: the first 6 h post-ictus; acute: 6–24 h post-ictus; subacute: 24 h to 6 weeks post-ictus; chronic: greater than 6 weeks post-ictus.
12,29
During the acute phase after stroke, TMS of the affected hemisphere is often unable to elicit motor evoked potentials (MEPs), even at maximum deliverable stimulation intensity. In patients with preserved MEPs, the motor thresholds are generally higher and MEPs are smaller compared with those recorded from the unaffec-ted hemisphere or from healthy individuals. Within the first few months, MEPs may reappear and gradually increase in amplitude,^30–33while the motor threshold tends to decrease.^34–38Many authors have reported that TMS measures of corticospinal tract integrity evaluated early after stroke,^35,39–41and the improvement of TMS measures of corticospinal integrity during the first few months^33,39of recovery, both correlate with the long-term functional outcome. Absence of MEPs in the first few hours or days following stroke is associated with poor clinical recovery,
42
 although exceptions have been reported.^36,44–46Presence or absence of MEPs in arm muscles within the first week after stroke is an important component of the ‘PREP algorithm’ proposed by 

 Box 1
| TMS protocols for assessment of brain excitability and connectivity
TMS has been widely used to investigate excitability and connectivity in M1 after stroke. Single-pulse, paired-pulse and repetitive TMS protocols probe different aspects of excitatory and inhibitory function (Figure 1).A single pulse of TMS applied over M1 can produce a peripheral muscular response, or MEP. TMS that triggers MEPs is called suprathreshold TMS, whereas TMS that is not of sufficient intensity to trigger MEPs is called subthreshold TMS. The threshold and recruitment of MEPs at different intensities of stimulation provide information about the level of corticospinal excitability.The effect of GABA receptor type A-modulated inhibitory circuits on corticospinal neurons can be probed by short-interval intracortical inhibition paradigm (Figure 1a).^146,147The role of GABA receptor type B-expressing interneurons can be probed by the controlateral cortical silent period protocol, in which a single TMS pulse is delivered during tonic contralateral hand/arm contraction,¹⁴⁸or by the long-interval intracortical inhibition protocol.
149
 Other inhibitory mechanisms can be evaluated with short-latency afferent inhibition, which depends on GABAergic and cholinergic circuits.¹⁵⁰Studies using these protocols have elucidated the involvement of GABAergic circuits in intracortical inhibition,^148,151,152whereas the origin and nature of the increased excitability of the intracortical facilitation (Figure 1b) is still poorly defined.TMS can also be paired with neuroimaging or electrophysiological techniques.^153,154TMS–EEG could aid probing of the functional impact of a stroke lesion on the connectivity of the whole brain, even when the lesion is not located at the site of stimulation.¹⁵⁵In TMS–EEG, a TMS pulse evokes an initial activation of the target area, followed by later effects that are attributable to activity triggered by axonally and synaptically propagated signals.¹⁴⁵ 

Abbreviations: GABA,
γ
-aminobutyric acid; M1, primary motor cortext; MEP, motor evoked potential; TMS, transcranial magnetic stimulation.

Key points

■ Noninvasive brain stimulation (NIBS) is a promising approach to enhance recovery after stroke, but its beneficial effect is limited and the technique is not yet ready for broad clinical use 

■ We suggest that the disappointments in NIBS trials are related to over-reliance on the interhemispheric competition and vicariation models of recovery, which are oversimplified and do not apply to all patients with stroke

■ The concept of ’structural reserve’ integrates the effects that interhemispheric inhibition and vicariation exert on the unlesioned residual network 

■ We propose a unified ‘bimodal balance–recovery model’ that takes into account this individual residual network 

■ The model could be used to tailor treatment for individual patients and increase the efficacy of NIBS in stroke rehabilitation