Bachelor thesis Jasper van der Zwaag
June 2014
The Role of Transcranial Direct Current Stimulation in Motor
Revalidation after Stroke
Jasper van der Zwaag
University of Amsterdam
Student:
Jasper van der Zwaag
10189556
Mentor:
L.J. Talsma(Ph. D)
Co-corrector:
5297 words
Department of Brain and Cognition
University of Amsterdam
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Abstract
Literature is reviewed considering the positive effects of the non-invasive neurostimulation technique of transcranial direct current stimulation (tDCS) on motor revalidation after stroke and the
mechanisms underlying these effects. It is observed that TDCS has a positive effect on behavioural functioning after stroke by enhancing motor functioning. The applied methods of tDCS can be
combined or modulated with other neurostimulation methods for maximizing its effects. The effects of tDCS result from increased neuroplasticity in brain areas, caused by increased neuronal excitability in which biochemical change and the neurotransmitter GABA possibly plays a significant role. Small heterogeneous samples and spatial imprecision limit observed validity in experiments. Future research should be aimed at validating the theoretical framework underlying tDCS.
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Content
Abstract 2
Content 3
1. General Introduction
1.1 Transcranial direct current stimulation in motor revalidation after stroke 4
1.2 Methods of tDCS 4
1.3 Goals 5
2. TDCS in stroke revalidation
2.1 The role of tDCS in behavioural improvement 6
2.2 Modulation of methods of tDCS 8
3. Mechanisms of tDCS
3.1 Basic mechanisms of tDCS 11
3.2 Biochemical changes resulting from tDCS 12
3.3 Homeostatic plasticity 14
4. Conclusions & Discussion
4.1 Conclusions 15
4.2 Discussion 16
4.3 Recommendations 17
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1
General Introduction
1.1 Transcranial direct current stimulation in motor revalidation after stroke
Transcranial Direct Current Stimulation (tDCS) is a non-invasive neurostimulation technique which has received considerable experimental attention since the discovery of the utility of this method in stroke revalidation (for a review see Nitsche & Paulus, 2011). Clinical use was established and confirmed when the neuroplasticity generating effects of tDCS were discovered in patients with physical disabilities resulting from stroke. Neuroplasticity can be described as the ability of the brain to functionally reorganize itself by forming new neural connections allowing it to adapt the brain to situations or requests from the environment, and also in response to internal damage (Fusco et al., 2014). This reorganization can restore or save functions associated with the damaged brain area and can therefore lead to improvement in behavioural functioning (Cramer & Riley, 2008). Consequently, this naturally occurring neuroplasticity plays a valuable role in the decreasing loss of function. While this is a valuable process, this cell-saving natural neuroplasticity is often not able to fully compensate for neural loss and stroke patients are often left with severe motor function loss (Clark, 1991).Neuroplasticity can also be generated by a form of tDCS in which an electrical current is applied through the scalp to the brain area affected by stroke. The neuroplasticity generating effects of this non-invasive stimulation might be a promising method for stroke revalidation because tDCS might lead to a stronger and more fully restoration of damaged brain areas affected by stroke, compared to only naturally induced neuroplasticity (Webster, Celnik & Cohen, 2006).
1.2 Methods of tDCS
The relatively simple method of tDCS is based on the application of a low electric current through the scalp onto the damaged brain area. This is done by using two electrodes in which one electrode is placed over the region of interest and the second electrode is placed elsewhere on the body to complete the electrical circuit. For the electrical stimulation a device is needed which can deliver a constant electrical current (e.g. a battery). In active application of tDCS there are two main forms of tDCS, anodal and cathodal. Anodal tDCS is the application of a positive current through the scalp,
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leading to increased activity of the brain area. Conversely, cathodal tDCS is a negative current, leading to decreased activity in the stimulated brain area. Also, applying cathodal tDCS to the unaffected hemisphere leads to increased activity in the affected hemisphere by limiting hemispheric inhibition between the two hemispheres (Nowak, Grefkes, Ameli & Fink, 2009). Sham tDCS is also used for controlling the effects of the application of tDCS without the electrical current. In practice, mostly anodal tDCS is used to generate neuroplasticity in the affected hemisphere. Less often single cathodal tDCS is used and combinations of anodal tDCS and cathodal tDCS are used even less frequently because of the uncertain effect of these method.
While it is known that these methods induce neuroplasticity, the effects of tDCS on a practical behavioural level remain unspecified. The consequences of tDCS for behavioural improvement are highly relevant considering the high rate of disability seen in patients who are recovering from stroke. Today, the known empirical results considering the effects of tDCS on behavioural improvement are not yet unified in a theoretical framework which can be used to support the use of tDCS in clinical practice and the question of how tDCS can be of practical use in daily life for stroke patients is a question still highly in need of an answer.
Another mainly undiscovered field in tDCS is the field of the underlying mechanisms of the neuroplasticity induced by tDCS. For example, little is known about the possible changes in
biochemical processes associated with neuroplasticity induced by tDCS or the modulation of neurons caused by the electrical current. For optimal safety and maximizing clinical effects it is necessary to understand the mechanisms responsible for changes in behaviour such as behavioural improvement after stroke. If these responsible mechanisms are known, stroke treatment and revalidation can be optimized for stroke patients in safe way. This can possibly be done by enhancing the mechanisms responsible for the observed recovery, making recovery more absolute.
1.3 Goals
Because of the lack of theoretical and practical framework for tDCS, the main goals of this review are integrating empirical knowledge about the effect of tDCS on behavioural improvement and clarifying the mechanisms underlying the effects of tDCS. The integrated knowledge of the effects and
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mechanisms underlying of tDCS will hopefully lead to a firm theoretical basis for using tDCS in motor revalidation after stroke.
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TDCS in Stroke Revalidation
2.1 The role of tDCS in behavioural improvement
A well-known neurological process after acute stroke is the induction of natural
neuroplasticity in the brain (Nudo, 2003). This neuronal plasticity is also an effect of the application of anodal tDCS to the damaged brain area. This neuroplasticity induced by tDCS might contribute to a positive outcome in motor revalidation by enhancing the function of motor neurons in the damaged brain areas after stroke (Boros et al., 2008). Enhanced motor function is highly valuable in clinical and daily practice because stroke patients are often unable to perform activities that are important for normal daily functioning because of the motor dysfunction resulting from stroke. So the
neuroplasticity inducing effects of tDCS might play a valuable role in motor functioning and thus behavioural improvement.
Earlier research argued that substantial effects of anodal tDCS on activities of daily living were lacking, while neuroplasticity is proved to be enhanced (Elsner, Kugles, Pohl & Mehrholz, 2013). After the reviewing of 11 studies, Elsner observed only a slight positive effect of the
application of tDCS for improving activities of daily living and motor functioning. These results were based on the pooling of participants of the included studies and the authors conclude that
methodological and population quality was sometimes lacking and might have negatively influenced the outcome effects. Other research also focused on daily functioning, but started with the principles underlying motor revalidation. Underlying principles of motor revalidation are for example the motor functioning of negatively affected limbs and learning of specific movements after stroke (Levin, Klein & Wolf, 2009). A positive effect of tDCS on this motor learning was found by Nitsche (Nitsche et al., 2003). In this experiment by Nitsche, 80 healthy subjects were compared on the improvement of reaction time to stimuli visually presented after tDCS. Subjects undergoing tDCS to the primary motor
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cortex (PMC) were compared with subjects undergoing sham tDCS. Results indicated that subjects who received anodal tDCS to the PMC performed better with less time needed to respond to the presented stimuli, compared to the subjects in the sham tDCS group. The PMC is essential for the acquisition of motor learning in motor functioning and the authors suggest that this increased performance might result from the positive influence of tDCS on the excitability of neurons in the PMC and that this increased excitability can lead to behavioural improvement. This positive effect of DCS on motor functioning was also noticed by Prichard et al. (Prichard, Fritsch, Reis & Weiller, 2014), who concluded that anodal stimulation of the PMC resulted in an enhanced performance of motor skill learning and thus can have a positive effect on behavioural functioning. Also Prichard further implies that the gains of using tDCS for motor skill might be used in a neurorehabilitation setting. Prichard argues that the positive effects of tDCS on healthy subjects could be generalized to a group of patients suffering from motoric loss after stroke. This generalization would be used to enhance the motor learning of the patients after the loss of these motor skills. In this way tDCS could be used to help stroke patients recover from motoric loss.
The hypothesis that anodal tDCS can lead to enhanced motor functioning in daily life activities was tested by Hummel et al. (2005) who conducted a sham-controlled experiment in which they compared the effects of anodal tDCS to sham tDCS on the Jebsen-Taylor Hand Function Test (JTT). The JTT is a measure for activities in daily life because this test measures hand movements required to perform daily activities. In this experiment six chronic stroke patients participated, who suffered from motoric loss, making them unable to function adequately in daily life. Anodal tDCS and sham tDCS was applied, and results indicated a higher score on the JTT in the anodal tDCS group compared to sham tDCS. These results suggest a positive influence of anodal tDCS in behavioural outcome measures. Complementary, Fusco et al (2013) recently also reported a positive effect of anodal tDCS compared to sham tDCS on subparts of motor functioning in daily activities. These results argue in favour of the positive effects of anodal tDCS on behavioural improvement.
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2.2
Modulation of methods of tDCS
The positive effects of anodal tDCS on motor functioning are valuable in daily practice, but can be optimized by specifying the conditions of application of tDCS (Boggio et al, 2007.) These specifying conditions are modifications in the method of applying tDCS by for example changing the duration of tDCS or the sort of tasks performed while receiving tDCS. A modification commonly combined with the method of using tDCS is the application of tDCS with another neurostimulation technique, such as a form of mental or physical training. Physical or mental training can activate motor neurons, induce excitation and can therefore enhance motor functioning. These modifications or additions in the application of tDCS can lead to enhancement of behavioural effects when these techniques both have a positive influence on neuronal excitability or positively influence each other. Contrastingly, these modifications might also have a negative influence on behaviour when, for example, the combination of anodal tDCS with training leads to less excitability of neurons, decreased motor functioning and decreased behavioural improvement. Summarized, the modulation of tDCS can lead to a reduced or enhanced effect of tDCS on behavioural improvement.
To test the possibility of increased enhancement of motor functioning by cumulative application of anodal tDCS an experiment was conducted including nine chronic stroke patients as subjects (Boggio et al., 2007). In the first experiment, anodal tDCS was applied to the affected hemisphere and cathodal tDCS was applied to the unaffected hemisphere in the first condition and the second condition received sham tDCS. The motor improvement measured by JTT in the active tDCS groups was compared to improvement with sham tDCS. Both forms of tDCS resulted in behavioural improvement in contrast to a lacking effect of sham tDCS on motor- and behavioural improvement. In the following experiment only cathodal tDCS was used on the unaffected hemisphere, now applied in a five day consecutive session. Behavioural improvement was measured at baseline, during daily sessions and after the intervention with the JJT. The results indicated a positive effect of the five day consecutive application of tDCS over time as measured by the JJT. Also, the enhanced excitability of neurons was a relative long lasting effect compared to single application of cathodal tDCS. These results suggest a positive effect of cumulative cathodal tDCS on a behavioural outcome. Research
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done by Khedr (Khedr et al., 2013) compared both anodal and cathodal tDCS to sham tDCS in stroke patients for a consecutive period of six days and also reported positive effects of this trial on long term motor recovery, suggesting positive effects of the consecutive application of tDCS on behavioural improvement.
This cumulative positive effect of multiple sessions of tDCS with a daily interval could be explained by the effects of anodal tDCS on increased excitability; tDCS leads to increased excitability by neural modulation, which declines over time. Because of the short interval of the application of tDCS on a daily interval, excitability is not decreased before renewed stimulation is applied. Therefore the already increased excitability is even more increased. It is also known that tDCS can produce widespread changes in regional neural activity, even after single application (Lang et al., 2005). Rapid repeated modification of this neural excitability by cumulative tDCS might lead to the even longer sustained effects as seen in the research conducted.
Besides cumulative application of tDCS, a method conducted by Lefebvre is different from the standard procedure of applying tDCS, and might be a valuable modification to improve behavioural functioning after stroke. Lefebvre et al (2012) used the concept of online learning combined with tDCS. In this experiment, 18 stroke patients received anodal tDCS or sham tDCS while performing, and simultaneously learning, a motor skill task. Results indicated that performance of the motor skill while receiving tDCS was better than the performance in the sham condition. After a one week interval the tDCS group performed better on the motor skill task compared to the sham group. This positive effect of online learning combined with anodal was later combined with a three day
consecutive application of tDCS, which also led to increased motor skill learning compared to sham tDCS (Prichard et al., 2014). These results confirm the possible implications for tDCS in online motor learning and show that specifications of tDCS methods (e.g. repeated tDCS, online learning or
combined) might even further enhance the usability of tDCS in motoric revalidation for stroke. Another factor that has been included in tDCS research is the combination of tDCS
application with mental or physical training. Forms of physical training and mental training can lead to enhanced neuroplasticity and strengthened neural connections (Liepert et al. (1999), cited in
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Sunderland & Tuke, 2005; Asanuma & Keller, 1991; Butefisch et al., 1995). Both these effects might interact with the positive effects of tDCS. To assess these possible interactions, Lindenberg
(Lindenberg et al., 2010) recruited 20 chronic stroke patients and used combined tDCS, anodal over the affected and cathodal over the unaffected hemisphere, with physical training. The group of physical training with combined tDCS was compared to a condition in which subjects received solely physical training. Changes in motor impairment and motor activity were measured at baseline and after the treatment .Thecombined tDCS and physical training led to greater improvement in motor function than in the sham tDCS group. Also, the combination of physical training with the combined tDCS led to better motor improvement than one of the methods, physical training or combined tDCS, alone. Cha et al. (Cha, Chang & Kim, 2014), also found a beneficial effect of physical training combined with tDCS compared with only physical training in stroke patients on motor functioning, suggesting a positive interaction between physical training and anodal tDCS. The results suggest that combined tDCS in combination with physical training might be a promising process in motor
behavioural improvement after stroke.
Not only physical training can have a complementary effect on the efficacy of tDCS, but also mental motor practice is commonly cited as an influential therapy for stroke patients (Braun et al., 2006). In mental motor training, a mental representation of a movement is formed and mentally repeated, without conducting the movement physically. This mental representation of the movement can enhance motor performance (Malouin et al, 2004). The combination of this effective method for regaining motor function after stroke with tDCS might form a valuable contribution in the field of maximizing effects of stroke treatment. To test the hypothesis of a synergetic effect of tDCS with mental motor training an experiment was conducted in which 18 subjects participated (Foerster et al., 2013).The application of anodal tDCS to the PMC combined with mental training was compared to sham tDCS with mental training. Motor functioning was tested with the handwriting test. The combination of active anodal tDCS in the PMC combined with mental training resulted in higher positive effects on the handwriting test compared to sham tDCS combined with mental motor practice. This positive effect argues in favour of the combination of anodal tDCS with mental motor practice for
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behavioural improvement after stroke. Cha et al. (Cha, Chang & Kim, 2014), also found a beneficial effect of physical training combined with tDCS compared with only physical training in stroke patients on motor improvement.
Currently available research argues in favour of the behavioural improving effects of tDCS. While tDCS leads to neuronal changes, for example neuronal plasticity, these changes mostly directly reflect on motor functioning improving behavioural functioning in patients affected by motor loss after stroke. While single tDCS might have been on the basis of this positive influence, recent experimental research points out that modulation of the methods of tDCS might be usable for enhancing or even maximizing these positive effects. Examples of these modulations are the repeated application of tDCS or combining tDCS with physical or mental training. The explorations of these alterations are a valuable introduction towards the enhancement of the treatment of motor loss after stroke.
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Mechanisms of tDCS
3.1 Basic mechanisms of tDCS
While the effects of tDCS on behavioural improvement are visible, there is yet little known about the specific underlying mechanisms responsible for these effects of tDCS. Quite basic mechanisms of tDCS such as the previously stated neuroplasticity induced by cortical excitability were earlier described by Nitsche and Paulus (Nitsche & Paulus, 2000), for a review see Nitsche & Stagg, 2011 (Nitsche & Stagg, 2011) and these form an important basis for understanding these functional mechanisms of tDCS. Yet, not all the mechanisms are clarified and to fully understand the role of tDCS in motor revalidation in stroke it is necessary to be familiar with all the processes underlying tDCS. If these are clarified, stroke treatment can be optimized and specialized for individual cases or specific functional loss.
In fundamental research exploring mechanisms of tDCS (Nitsche & Paulus, 2000) the effects of anodal tDCS and cathodal tDCS on neural excitability were compared. In these experiments subjects received cathodal or anodal tDCS to the motor cortex and change in cortical excitability was
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measured by recording the evoked potentials. The results showed that anodal tDCS leads to enhanced excitability and cathodal tDCS leads to decreased excitability. The authors suggest that this modulated excitability is a result of change in the neuronal polarisation; anodal tDCS leads to depolarization of neuronal membrane current and cathodal tDCS leads to hyperpolarisation of this neuronal membrane current. These results were later repeated and confirmed (Nair, Renga & Schlaug, 2008). This change in polarization can lead to long lasting neuronal and synaptic change (Lang et al., 2005). The
modulation of neuronal excitability and polarization change led to increased experimental research on this subject with the goal of illustrating the mechanisms underlying this change in polarization and excitability induced by tDCS. One of the underlying mechanisms of this polarization change excitability proposed is the modulation of cortical neurotransmitters such as GABA (Stagg et al., 2009). GABA is an inhibitory neurotransmitter in the mammalian central nervous system and plays a significant role in the neural excitability in the nervous system (Dutar & Nicoll, 1988). GABA neurotransmitters are also reduced in human brain areas involved in motor functioning, especially when a learning task is carried out (Floyer-Lea, Wylezinska, Kincses & Matthews, 2005). The positive effects of tDCS on excitability might be associated with the modulation of the presence of this
inhibitory neurotransmitter.
3.2 Biochemical changes resulting from tDCS
To clarify the possibility of involvement of GABA in polarization change induced by tDCS Stagg (Stagg et al., 2009) conducted three experiments. In the first experiment, 11 healthy subjects received sham tDCS, anodal tDCS and cathodal tDCS to the Primary Motor Cortex. The application of the different forms of tDCS was at least separated by a 48-hour time interval, to reduce interfering effects. The second and third experiment were methodological comparable, but conducted with only anodal tDCS and cathodal tDCS. After the application, neurotransmitter change was measured by magnetic resonance spectroscopy which is a method of measuring specific neurotransmitters and their quantitative change in the brain. Results from the experiment showed that anodal tDCS induced a reduction of GABA neurotransmitters in the primary motor cortex and cathodal tDCS induced a raise
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in the amount of GABA available in the Primary Motor Cortex. Because of the inhibiting and enhancing effects of GABA the authors suggest that the decrease of GABA plays a role in the neuroplasticity inducing effects of anodal tDCS.
This finding exposes one of the possible underlying mechanisms of tDCS. The reduction of inhibitory GABA neurotransmitter caused by tDCS might lead to the excitation observed by tDCS; when the inhibitory effects of GABA neurotransmitters are inhibited by anodal tDCS, logically the inhibitory effects of GABA can be undone and excitation might follow upon this change of
neurotransmitter activity. This explanation was tested by Nitsche et al. (Nitsche et al., 2004) who combined the effects of anodal tDCS with Lorazepam. Lorazepam is a drug which acts on
neurotransmitters and enhances the function of GABA, resulting in a stronger inhibitory function of this neurotransmitter. In their experiment 12 healthy subject received Lorazepam with anodal tDCS, Lorazepam with placebo or Lorazepam with no additional treatment. After this procedure, subjects were tested on their changes of global cortical excitability. The results showed no direct effect of Lorazepam on the cortical excitability during tDCS, but a trend towards reduced excitability was observed in the first phase. Several minutes later in the experimental procedure, a stronger effect of tDCS was found. This effect shows that anodal tDCS is significantly involved in the modulation of GABA neurotransmitters; it was suggested that the GABA inducing effects of Lorazepam are possibly diminished by the effects of anodal tDCS.
Biochemical and neuronal change induced by tDCS can lead to more excitability which can induce plasticity. The interaction between these three levels, neuronal, cortical and plasticity was also convincingly stated by Stagg (Stagg et al, 2014), who conducted a sequence of experiments in which they demonstrated an inverse correlation between functional connectivity in the motor areas and the presence of GABA neurotransmitters in the primary motor cortex. Functional connectivity can be described as neural networks with correlated activity in functionally linked regions. While the exact functions and neurochemical basis of these functional networks remain unclear, they are heavily associated with excitability changes and Stagg showed that the GABA modulating properties of anodal tDCS can lead to the GABA reduction and to an increased functional connectivity of these
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neural networks. This functional connectivity might then again be relevant for the improved motor function in stroke patients suffering from loss of motor functions. Earlier, Stagg, Bachtiar and Johanson-Berg (Stagg, Bachtiar & Johanson-Berg, 2011) also explicated the functional role of the particular responsiveness of GABA in motor learning capacity by comparing the learning possibilities of subjects with high responsiveness towards GABA modulating anodal tDCS and subjects with a low responsiveness towards anodal tDCS. Conclusions suggested a positive correlational relationship between responsiveness to GABA and motor learning. This relationship could therefore be established by the effects of GABA modulation in functional networks, eventually leading to higher excitability.
3.3 Homeostatic plasticity
As shown, functional connectivity in neural circuits form a connection between the basic neural processes and the overarching neural networks who are mainly associated with neuroplasticity. The resulting neuroplasticity of tDCS is not fully independent of factors influencing this process. One of these processes influencing neuroplasticity aims at stabilizing the synaptic strength in neural networks with the goal to keep them functionally intact and preventing for example overexcitation (Turrigiano & Nelson, 2004). This mechanism of stabilizing the neural networks is guided by a process called homeostatic plasticity which can be defined as a mechanism that makes the ease with which a synaptic connection is enforced or depressed dependent of the amount of neural activity in the past of this neuron (Turrigiano & Nelson, 2004). This process might also be relevant for cortical plasticity induced by tDCS. Fricke et al (Fricke et al., 2011) conducted research in which they applied anodal tDCS multiple times, with different time intervals between the tDCS application. The possible induction of cortical excitability in the second application of tDCS showed to be dependent of the time interval and the nature of the primary stimulation.
These results show homeostatic control of synaptic activity by regulating activity en therefore regulating cortical plasticity. Kuo et al. (Kuo et al., 2008) underscored the theory that synaptic
modulation has to be controlled in a useful range to maintain their functionality and tested the hypothesis of homeostatic plasticity in actual learning on a reaction time task. Homeostatic plasticity
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only occurred in the learning process when anodal tDCS was combined with a pharmalogical intervention that magnified the small effects. These results suggest that homeostatic plasticity is also dependent on the amount of previous stimulation and not only on the direction, negative or positive, of previous stimulation. In this experiment, it was suggested that the induced neuronal activity did not reach the point of the activation of homeostatic plasticity.
Current available result show that neuroplasticity is a fundamental process induced by tDCS. This neurological plasticity is a complex process and bases on the change in neuronal membrane polarization. A process underlying this polarization is the alteration of neurotransmitters and mainly the neurotransmitter GABA has a fundamental role in the induction of this plasticity. Specifically, recent literature shows that anodal tDCS has a now firmly established association with the reduction of GABA neurotransmitters, leading to a diminishing of the inhibitory effects of GABA. This diminished GABA availability leads to an increased excitation, leading to increased excitability and induced plasticity. For this plasticity to remain functional, it is dependent on yet uncertain mechanisms. One of the mechanisms that might be relevant is the mechanisms of homeostatic plasticity; a mechanism which makes the activity of neurons via a negative relation dependent on the previous amount and direction of activity in the neuron. In this way homeostatic plasticity might influence the activity in the higher levels networks (e.g. functional network, neuroplasticity) by allowing increased or reduced activity. The specific mechanisms regulating cortical plasticity remain undisclosed and are therefore interesting subjects for future research.
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Conclusions & Discussion
4.1 Conclusions
Empirical research has established firm grounds for concluding that tDCS can play a valuable role in motor revalidation after stroke by improving neuroplasticity in the damaged brain areas. The application of tDCS improves behavioural functioning as measured by several outcome scales. TDCS can be functionally combined with mental or physical training, or applied consecutive to enhance its positive effects. The underlying mechanisms for the positive effect are the induction or neuroplasticity
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by decreasing the resting membrane current of neuronal cells and biochemical changes in the form of the reduced presence of the inhibitory neurotransmitter GABA. A decreased neuronal membrane current leads to easier depolarization leading to more frequent excitability. The reduced presence of GABA leads to less inhibitory influence of this neurotransmitter on neuronal excitability, making neuroplasticity possible. This neuroplasticity is not fully dependent of factors regulating the generated cortical plasticity. A proposed homeostatic-like rule influences the excitation of neuronal cells, by making the excitability dependent of earlier excitation of this cell. There was found that a negative relationship between previous activity and future activity modulates the possible future excitability. In the practice of tDCS this means that an excited neuron cannot be excited again by tDCS. The possible functionality of this process is preventing damaging overexcitability of the neuron. This negative correlation might be important for the effects of future methods tDCS because the effects of, for example, repeated tDCS are based on repeated stimulation of neuronal cells.
4.2 Discussion
While there is now a fundamental base of research about tDCS and its effects, there is still a lack of theoretical foundation for several methods of tDCS, leading to possible concerns about safety. While there are no reports of aversive effects of the application of tDCS, this is an inverted way of thinking. Experimental research should be focussing more on discovering potential harming
(side)effects of tDCS instead of ‘waiting’ until damage might occur. Specifically the intensity of the applied current is a concept which should receive considerable attention. The consecutive application of a 2 mA current for 20 minutes a day for the duration of a week might establish effects on neuronal level which cannot be seen directly, but might lead towards fundamental change in the neuronal functioning. Before more experimental research with differencing, high intensity methods is
conducted, safety issues are important to incorporate in the theory on which tDCS research is based. Also, future research might explore the effects of the lack of spatial precision of tDCS application. In research now conducted currents are passed through the scalp with electrodes with varying size, mostly between 25 to 35 square centimetres. Causality or even correlation of the effects established by tDCS and selected brain areas might be invalid when spatial precision is lacking. The
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usability of tDCS in clinical practice is not reduced in the way tDCS is currently applied, but more focused application might lead to more beneficial effects and more valid scientific conclusions.
Lastly, the heterogeneity of the subjects used in research can be a point which deserves some attention. The relatively and heterogeneous research populations combined with the often small samples included in the experiments make the establishing of an effect of tDCS for a specific group rather methodological difficult. Different sorts of strokes, with different consequences and times of onset are used in an experimental condition, making the correlation between tDCS application and the positive outcomes effects only more theoretical.
4.3 Recommendations
Implications for future research concern this methodological adjustment in the sense of the use of more controlled subjects. This problem of high inter-subject variability can be undermined when imaging techniques are used before inclusion in experimental conditions. Practically, this may a lay burden on the shoulders of future researchers because the use of imaging techniques is often a time and financial resource consuming process. Nevertheless, when this methodological adjustment is made in practice, it will lead to higher correlations between the effects found and the subjects used. This will consequently lead to more valid conclusions about the effects of tDCS of the selected population.
For future research it seems interesting to focus on the long lasting effects of tDCS by modulation the methods now used. The consecutive application of tDCS has already shown to lead to more positive effect on behavioural improvement and this sort of modulation might form a valuable basis of enhancing the already present effects. Also, the combination of tDCS with mental or physical training has shown to improve effects and is another example of the enhancement of effects by modulating applied methods. This line of research should be continued to determine theoretical foundations and possibly establish effects that concern improved functioning over longer periods. These long lasting effects might provide opportunities for patients who are left with chronic deficits as a result of stroke.
For now, tDCS has proven to be a valuable method in the clinical field of motor recovery after stroke. The method has proven clinical utility and the effects established are relevant on behavioural
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level as well on neuronal level. Transcranial direct current stimulation can be used in daily practice with the knowledge now available, but further empirical research is needed to establish a more robust theoretical framework before any experimental and methodological expansions are made.
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