301
Restorative Neurology and Neuroscience 32 (2014) 301–312 DOI 10.3233/RNN-130349 IOS Press
After vs. priming effects of anodal transcranial direct current stimulation on upper extremity motor recovery in patients with subacute stroke Augusto Fuscoa,∗ , Marco Iosaa , Vincenzo Venturierob , Domenico De Angelisb , Giovanni Moronea , Luisa Maglionea , Maura Bragonib , Paola Coirob , Luca Pratesib and Stefano Paoluccia,b a Clinical b U.O.F
Laboratory of Experimental Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Rome Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Rome
Abstract. Purpose: Transcranial direct current stimulation (tDCS) of the motor cortex seems to be effective in improving motor performance in patients with chronic stroke, while some recent findings have reported conflicting results for the subacute phase. We aimed to verify whether upper extremity motor rehabilitation could be enhanced by treatment with tDCS administered before a rehabilitative session. Methods: Hand dexterity and force in 16 individuals with subacute stroke were assessed before (T0) and after anodal stimulation (T1) and after a successive session of motor rehabilitation (T2) in a double-blind, randomized, sham-controlled, crossover trial. To confirm the value of the device as a specific effector, behavioral tests were also administered. Results: Anodal and sham stimulation plus rehabilitation significantly improved manual dexterity (repeated-measure Anova: A-tDCS: p = 0.005; S-tDCS: p = 0.042). Post hoc analysis revealed a significant stimulation effect only for A-tDCS (p = 0.013 between T0 and T1) and not for S-tDCS, whereas the rehabilitation effect (between T1 and T2) was not significant in either group. Hand force and behavioral features were unchanged. Conclusions: Anodal brain stimulation improves hand dexterity but does not increase the effectiveness of the rehabilitation directly. These results suggest the presence of aftereffects, not priming effects, of A-tDCS superimposed onto motor learning phenomena. Keywords: Brain stimulation, stroke rehabilitation, motor learning, manual force, upper limb function
1. Introduction Nearly 1 million of people are affected annually by stroke in the European Union (Kwakkel et al., 2003). ∗ Corresponding
author: Augusto Fusco, M.D., Clinical Laboratory of Experimental Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Via Ardeatina, 306, 00179 Rome, Italy. Tel.: +39 06 51501077; Fax: +39 06 51501004; E-mail: [email protected].
More than 69% of all survivors experience incomplete motor recovery, particularly with regard to upper limb function. It forces them to require constant rehabilitation and long-term care (Jørgensen et al., 1999). These data are even more significant at the light that stroke is predicted to account for 6.2% of the total burden of illness in 2020, increasing demands on the health care systems (Menken et al., 2000; Sundberg et al., 2003).
0922-6028/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
302
A. Fusco et al. / After vs. priming effects of anodal transcranial direct current stimulation
Even if a certain degree of recovery occurs spontaneously, rehabilitation is essential to promote the motor improvement. It should be initiated as soon as possible to achieve the maximum potential recovery of motor skills and to avert the high likelihood of longterm functional disability. In fact, for the upper limb, a lack of recovery after 4 weeks is predictive of a poor outcome (Kwakkel et al., 2003). Conversely, gradual improvements in the first 2 months after the onset of stroke are crucial for regaining motor ability at 6 months (Kwakkel et al., 2003). Novel tools based on emerging technologies have been developed to improve motor and cognitive recovery after stroke (Iosa et al., 2012). Determining which techniques and the time for applying them and identifying which patients can benefit from them are paramount goals for clinicians to optimize treatments and properly inform patients about their prognosis. Among these new techniques, noninvasive brain stimulation has been studied widely in the past decade, but its potential role in stroke rehabilitation is still under investigation. Electrical cortical stimulation appears to enhance motor performance, constituting a novel approach to improving the effectiveness of rehabilitation as a stand-alone therapeutic intervention or as an add-on technique (Pomeroy et al., 2011). In this last case, it has been used as an adaptive or a restorative technique (Pomeroy et al., 2011). Some evidence has showed for improving patients’ abilities on complex tasks performed with the paretic hand (Kim et al., 2009) and manual force (Hummel et al., 2006) and for mitigating upper limb functional impairments and disability in the activities of daily living (Kim et al., 2010). Notwithstanding these encouraging results, the wide variability in inclusion criteria of existing studies (implying different impairments and severities among patients), the disparate parameters of stimulation (experimental setup, intensity, current density), and the presence or absence of rehabilitative integration have limited the strength of these preliminary findings, as recently highlighted in 2 meta-analyses on the effects of anodal transcranial direct current stimulation (tDCS) (Bastani and Jaberzadeh, 2011; Butler et al., 2012). Further, other studies have reported contrasting results, creating a heterogeneous clinical scenario that is difficult to interpret (Hesse et al., 2011; Rossi et al., 2012). This has also been confirmed by a Cochrane revision that is still on the way about the effects of tDCS on activities of daily living (ADL) and motor function in people with stroke.
This work has highlighted studies of tDCS that tend to have small sample sizes and high variability of data (Elsner et al., 2012). Nevertheless, tDCS might be the ideal tool to favor neuroplasticity and enhance the outcomes of rehabilitation (Nowak et al., 2010; Nitsche and Paulus, 2011). In fact, it may act on motor learning by modulating excitability in cortical primary motor areas (Nitsche et al., 2003; Tecchio et al., 2010). Anodal is a type of stimulation of tDCS that can influence synaptic plasticity of the affected hemisphere, facilitating neural excitability and hence enhancing the acquisition and consolidation of the motor skills. This facilitatory preconditioning of anodal tDCS (such as the inhibitory preconditioning of cathodal tDCS) seems to be based on the homeostatic plasticity of the human motor cortex (Siebner et al. 2004; Nitsche et al. 2007). This is a neural mechanism based on the fact that the ease with which a synaptic connection is facilitated/inhibited depends on the previous amount of network activity (Fricke et al. 2011). Based on homeostatic plasticity mechanisms, also after a single session of 10 minutes, it has been observed that tDCS aftereffects are sustained for over an hour (Nitsche and Paulus, 2000; Ardolino et al., 2005). tDCS can be used before rehabilitation (as a technique exploiting priming effects), during rehabilitation (aiming to augment the effects of physical training), or even postrehabilitation (for favoring the consolidation of motor learning) (Bolognini et al., 2009). The optimal time to deliver brain stimulation relative to motor training remains to be determined (Edwardson et al., 2013). Despite the studies reporting long-lasting aftereffects of tDCS and hence supporting the idea that it could be used as a priming technique applied before rehabilitation (Hummel et al., 2006; Boggio et al., 2007; Bolognini et al., 2009), most of the recent clinical studies have adopted an augmentative approach in which tDCS is used simultaneously with a rehabilitative session (Nair et al., 2011; Bolognini et al., 2011). This controversy limits the knowledge about the priming effects of anodal current stimulation performed immediately before a rehabilitative session. The principal aim of this study was to determine whether a motor rehabilitative session can benefit from previous anodal transcranial direct current stimulation with regard to motor performance in individuals with stroke in the subacute phase. Most of the clinical studies, in fact, have been focused on the chronic phase
A. Fusco et al. / After vs. priming effects of anodal transcranial direct current stimulation
of stroke (Hummel et al., 2005; Nair et al., 2011; Bolognini et al., 2011; Ochi et al., 2013). Despite most of the potential recovery occurring in subacute stroke, the enhancer effects of tDCS have received little attention in this phase. It is conceivable that if a tDCS session can prime the brain to be more responsive to a rehabilitative session enhancing motor recovery in chronic stroke (Hummel et al., 2006; Boggio et al., 2007; Bolognini et al., 2009), it could be even more effective in patients with subacute stroke. Patients were stimulated before a rehabilitative session and assessed before and after tDCS and at the end of the following therapy session. Hand dexterity and manual force were evaluated as outcome measures, comparing them between anodal and sham stimulation. To confirm the value of the device as a specific effector, behavioral testing was also performed: attention, fatigue, pain, and discomfort were assessed, similar to previous trials (Hummel et al., 2006; Gandiga et al., 2006; Tanaka et al., 2011).
2. Materials and methods
303
This protocol was approved by the independent ethics committee of our hospital, and all participants provided written informed consent. 2.2. Procedure Patients underwent 2 consecutive days of stimulation: 1 day with anodal stimulation (A-tDCS) and 1 day with sham stimulation (S-tDCS). Patients were randomized into 2 groups based on the sequence of stimulation (anodal-sham and sham-anodal), in accordance to a binary sequence previously generated using MATLAB R2007b Software (® , The Matworks Inc., U.S.A.). Subjects were stimulated immediately prior to the motor rehabilitative session to determine possible enhancing effects on rehabilitation. As a blind condition, the device was hidden from the patient’s view during stimulation, whereas an unblinded investigator administered the stimulation. Another blinded investigator performed the evaluations before (T0) and after (T1) tDCS and after the rehabilitative session (T2).
2.1. Study design
2.3. Transcranial direct current stimulation
This study was a double-blind, randomized, shamcontrolled, crossover trial. Every patient who was admitted to our unit was screened per the diagnosis and evaluated with regard to the inclusion/exclusion criteria. The inclusion criteria were: first-ever stroke due to ischemia; subacute phase (onset from the cerebrovascular accident between 2 and 12 weeks); cortical or cortical-subcortical lesion, as confirmed by computed tomography or magnetic resonance imaging; presence of mild upper limb hemiparesis with the possibility of performing manual hand movements (as demonstrated by pinch and grip test); age between 18 and 80 years; absence of severe cognitive impairments (as confirmed by a Mini-Mental State Examination score ≥ 25); and/or hemispatial neglect (patients evaluated routinely by a neuropsychologist). Exclusion criteria were the following: presence of chronic disabling pathologies or severe spasticity that can interfere with the upper limb function; presence of pacemaker, severe cardiovascular disease, tumor, or a history of tumor or epilepsy (for safety reasons due to the use of electric stimulation); major psychiatric disorders that could impede correct performance of the required tasks; and prior neurosurgical brain intervention.
tDCS was delivered for 15 minutes for the anodal and sham stimulation. The Eldith DC Stimulator® tDCS model [NeuroConn, Ilmenau, Germany] was supplied by 2 gel-sponge electrodes with a surface area of 35 cm2 (5 cm × 7 cm), embedded in a saline-soaked solution. The active electrode (anode) was positioned on C3 or C4 of the 10–20 International EEG system of the affected primary motor cortex, and the reference electrode (cathode) was placed on the skin over the contralateral supraorbital region, in accordance with previous studies (Gandiga et al., 2006; Kim et al., 2010; Tanaka et al., 2011). We delivered to the patient a current density of 0.043 mA/cm2 (intensity of 1.5 mA, electrode area 35 cm2 ), with a session duration of 15 minutes. Stimulation was also preceded by 60 seconds (fade in) during which the current increased gradually to the selected intensity (1.5 mA), eliciting transient sensations that disappeared in several seconds and followed by 60 seconds (fade out) during which current was progressively reduced. Duration of tDCS session and intensity and density of delivered current are variable parameters in the literature. Most of the studies reported sessions
304
A. Fusco et al. / After vs. priming effects of anodal transcranial direct current stimulation
between 10 and 30 minutes with a current intensity between 1 and 2 mA (Holland and Crinion, 2012; Ochi et al., 2013; Lefebvre et al., 2013). Short applications (
Restorative Neurology and Neuroscience 32 (2014) 301–312 DOI 10.3233/RNN-130349 IOS Press
After vs. priming effects of anodal transcranial direct current stimulation on upper extremity motor recovery in patients with subacute stroke Augusto Fuscoa,∗ , Marco Iosaa , Vincenzo Venturierob , Domenico De Angelisb , Giovanni Moronea , Luisa Maglionea , Maura Bragonib , Paola Coirob , Luca Pratesib and Stefano Paoluccia,b a Clinical b U.O.F
Laboratory of Experimental Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Rome Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Rome
Abstract. Purpose: Transcranial direct current stimulation (tDCS) of the motor cortex seems to be effective in improving motor performance in patients with chronic stroke, while some recent findings have reported conflicting results for the subacute phase. We aimed to verify whether upper extremity motor rehabilitation could be enhanced by treatment with tDCS administered before a rehabilitative session. Methods: Hand dexterity and force in 16 individuals with subacute stroke were assessed before (T0) and after anodal stimulation (T1) and after a successive session of motor rehabilitation (T2) in a double-blind, randomized, sham-controlled, crossover trial. To confirm the value of the device as a specific effector, behavioral tests were also administered. Results: Anodal and sham stimulation plus rehabilitation significantly improved manual dexterity (repeated-measure Anova: A-tDCS: p = 0.005; S-tDCS: p = 0.042). Post hoc analysis revealed a significant stimulation effect only for A-tDCS (p = 0.013 between T0 and T1) and not for S-tDCS, whereas the rehabilitation effect (between T1 and T2) was not significant in either group. Hand force and behavioral features were unchanged. Conclusions: Anodal brain stimulation improves hand dexterity but does not increase the effectiveness of the rehabilitation directly. These results suggest the presence of aftereffects, not priming effects, of A-tDCS superimposed onto motor learning phenomena. Keywords: Brain stimulation, stroke rehabilitation, motor learning, manual force, upper limb function
1. Introduction Nearly 1 million of people are affected annually by stroke in the European Union (Kwakkel et al., 2003). ∗ Corresponding
author: Augusto Fusco, M.D., Clinical Laboratory of Experimental Neurorehabilitation, I.R.C.C.S. Santa Lucia Foundation, Via Ardeatina, 306, 00179 Rome, Italy. Tel.: +39 06 51501077; Fax: +39 06 51501004; E-mail: [email protected].
More than 69% of all survivors experience incomplete motor recovery, particularly with regard to upper limb function. It forces them to require constant rehabilitation and long-term care (Jørgensen et al., 1999). These data are even more significant at the light that stroke is predicted to account for 6.2% of the total burden of illness in 2020, increasing demands on the health care systems (Menken et al., 2000; Sundberg et al., 2003).
0922-6028/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
302
A. Fusco et al. / After vs. priming effects of anodal transcranial direct current stimulation
Even if a certain degree of recovery occurs spontaneously, rehabilitation is essential to promote the motor improvement. It should be initiated as soon as possible to achieve the maximum potential recovery of motor skills and to avert the high likelihood of longterm functional disability. In fact, for the upper limb, a lack of recovery after 4 weeks is predictive of a poor outcome (Kwakkel et al., 2003). Conversely, gradual improvements in the first 2 months after the onset of stroke are crucial for regaining motor ability at 6 months (Kwakkel et al., 2003). Novel tools based on emerging technologies have been developed to improve motor and cognitive recovery after stroke (Iosa et al., 2012). Determining which techniques and the time for applying them and identifying which patients can benefit from them are paramount goals for clinicians to optimize treatments and properly inform patients about their prognosis. Among these new techniques, noninvasive brain stimulation has been studied widely in the past decade, but its potential role in stroke rehabilitation is still under investigation. Electrical cortical stimulation appears to enhance motor performance, constituting a novel approach to improving the effectiveness of rehabilitation as a stand-alone therapeutic intervention or as an add-on technique (Pomeroy et al., 2011). In this last case, it has been used as an adaptive or a restorative technique (Pomeroy et al., 2011). Some evidence has showed for improving patients’ abilities on complex tasks performed with the paretic hand (Kim et al., 2009) and manual force (Hummel et al., 2006) and for mitigating upper limb functional impairments and disability in the activities of daily living (Kim et al., 2010). Notwithstanding these encouraging results, the wide variability in inclusion criteria of existing studies (implying different impairments and severities among patients), the disparate parameters of stimulation (experimental setup, intensity, current density), and the presence or absence of rehabilitative integration have limited the strength of these preliminary findings, as recently highlighted in 2 meta-analyses on the effects of anodal transcranial direct current stimulation (tDCS) (Bastani and Jaberzadeh, 2011; Butler et al., 2012). Further, other studies have reported contrasting results, creating a heterogeneous clinical scenario that is difficult to interpret (Hesse et al., 2011; Rossi et al., 2012). This has also been confirmed by a Cochrane revision that is still on the way about the effects of tDCS on activities of daily living (ADL) and motor function in people with stroke.
This work has highlighted studies of tDCS that tend to have small sample sizes and high variability of data (Elsner et al., 2012). Nevertheless, tDCS might be the ideal tool to favor neuroplasticity and enhance the outcomes of rehabilitation (Nowak et al., 2010; Nitsche and Paulus, 2011). In fact, it may act on motor learning by modulating excitability in cortical primary motor areas (Nitsche et al., 2003; Tecchio et al., 2010). Anodal is a type of stimulation of tDCS that can influence synaptic plasticity of the affected hemisphere, facilitating neural excitability and hence enhancing the acquisition and consolidation of the motor skills. This facilitatory preconditioning of anodal tDCS (such as the inhibitory preconditioning of cathodal tDCS) seems to be based on the homeostatic plasticity of the human motor cortex (Siebner et al. 2004; Nitsche et al. 2007). This is a neural mechanism based on the fact that the ease with which a synaptic connection is facilitated/inhibited depends on the previous amount of network activity (Fricke et al. 2011). Based on homeostatic plasticity mechanisms, also after a single session of 10 minutes, it has been observed that tDCS aftereffects are sustained for over an hour (Nitsche and Paulus, 2000; Ardolino et al., 2005). tDCS can be used before rehabilitation (as a technique exploiting priming effects), during rehabilitation (aiming to augment the effects of physical training), or even postrehabilitation (for favoring the consolidation of motor learning) (Bolognini et al., 2009). The optimal time to deliver brain stimulation relative to motor training remains to be determined (Edwardson et al., 2013). Despite the studies reporting long-lasting aftereffects of tDCS and hence supporting the idea that it could be used as a priming technique applied before rehabilitation (Hummel et al., 2006; Boggio et al., 2007; Bolognini et al., 2009), most of the recent clinical studies have adopted an augmentative approach in which tDCS is used simultaneously with a rehabilitative session (Nair et al., 2011; Bolognini et al., 2011). This controversy limits the knowledge about the priming effects of anodal current stimulation performed immediately before a rehabilitative session. The principal aim of this study was to determine whether a motor rehabilitative session can benefit from previous anodal transcranial direct current stimulation with regard to motor performance in individuals with stroke in the subacute phase. Most of the clinical studies, in fact, have been focused on the chronic phase
A. Fusco et al. / After vs. priming effects of anodal transcranial direct current stimulation
of stroke (Hummel et al., 2005; Nair et al., 2011; Bolognini et al., 2011; Ochi et al., 2013). Despite most of the potential recovery occurring in subacute stroke, the enhancer effects of tDCS have received little attention in this phase. It is conceivable that if a tDCS session can prime the brain to be more responsive to a rehabilitative session enhancing motor recovery in chronic stroke (Hummel et al., 2006; Boggio et al., 2007; Bolognini et al., 2009), it could be even more effective in patients with subacute stroke. Patients were stimulated before a rehabilitative session and assessed before and after tDCS and at the end of the following therapy session. Hand dexterity and manual force were evaluated as outcome measures, comparing them between anodal and sham stimulation. To confirm the value of the device as a specific effector, behavioral testing was also performed: attention, fatigue, pain, and discomfort were assessed, similar to previous trials (Hummel et al., 2006; Gandiga et al., 2006; Tanaka et al., 2011).
2. Materials and methods
303
This protocol was approved by the independent ethics committee of our hospital, and all participants provided written informed consent. 2.2. Procedure Patients underwent 2 consecutive days of stimulation: 1 day with anodal stimulation (A-tDCS) and 1 day with sham stimulation (S-tDCS). Patients were randomized into 2 groups based on the sequence of stimulation (anodal-sham and sham-anodal), in accordance to a binary sequence previously generated using MATLAB R2007b Software (® , The Matworks Inc., U.S.A.). Subjects were stimulated immediately prior to the motor rehabilitative session to determine possible enhancing effects on rehabilitation. As a blind condition, the device was hidden from the patient’s view during stimulation, whereas an unblinded investigator administered the stimulation. Another blinded investigator performed the evaluations before (T0) and after (T1) tDCS and after the rehabilitative session (T2).
2.1. Study design
2.3. Transcranial direct current stimulation
This study was a double-blind, randomized, shamcontrolled, crossover trial. Every patient who was admitted to our unit was screened per the diagnosis and evaluated with regard to the inclusion/exclusion criteria. The inclusion criteria were: first-ever stroke due to ischemia; subacute phase (onset from the cerebrovascular accident between 2 and 12 weeks); cortical or cortical-subcortical lesion, as confirmed by computed tomography or magnetic resonance imaging; presence of mild upper limb hemiparesis with the possibility of performing manual hand movements (as demonstrated by pinch and grip test); age between 18 and 80 years; absence of severe cognitive impairments (as confirmed by a Mini-Mental State Examination score ≥ 25); and/or hemispatial neglect (patients evaluated routinely by a neuropsychologist). Exclusion criteria were the following: presence of chronic disabling pathologies or severe spasticity that can interfere with the upper limb function; presence of pacemaker, severe cardiovascular disease, tumor, or a history of tumor or epilepsy (for safety reasons due to the use of electric stimulation); major psychiatric disorders that could impede correct performance of the required tasks; and prior neurosurgical brain intervention.
tDCS was delivered for 15 minutes for the anodal and sham stimulation. The Eldith DC Stimulator® tDCS model [NeuroConn, Ilmenau, Germany] was supplied by 2 gel-sponge electrodes with a surface area of 35 cm2 (5 cm × 7 cm), embedded in a saline-soaked solution. The active electrode (anode) was positioned on C3 or C4 of the 10–20 International EEG system of the affected primary motor cortex, and the reference electrode (cathode) was placed on the skin over the contralateral supraorbital region, in accordance with previous studies (Gandiga et al., 2006; Kim et al., 2010; Tanaka et al., 2011). We delivered to the patient a current density of 0.043 mA/cm2 (intensity of 1.5 mA, electrode area 35 cm2 ), with a session duration of 15 minutes. Stimulation was also preceded by 60 seconds (fade in) during which the current increased gradually to the selected intensity (1.5 mA), eliciting transient sensations that disappeared in several seconds and followed by 60 seconds (fade out) during which current was progressively reduced. Duration of tDCS session and intensity and density of delivered current are variable parameters in the literature. Most of the studies reported sessions
304
A. Fusco et al. / After vs. priming effects of anodal transcranial direct current stimulation
between 10 and 30 minutes with a current intensity between 1 and 2 mA (Holland and Crinion, 2012; Ochi et al., 2013; Lefebvre et al., 2013). Short applications (
