rTMS and tDCS treatments
Site of Action of Non-invasive Brain Stimulation Applied in the Rehabilitation of Parkinson’s Disease and Stroke
Judit Málly MD, PhD, habil.
Head of the Institute of Neurorehabilitation
There are two non-invasive brain stimulation techniques in common use around the world:
repetitive trasncranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). TMS induces a current with a changing electromagnetic field in the nervous system (Di Lazzaro 1998), whereas tDCS changes the polarity of cell membranes (Nitsche and Paulus 2000). During the last twenty years the interest has shifted to the therapy of central nervous diseases (CND) with non-invasive brain stimulation. Lately, evidence based guidelines have been published (Lefaucheur at al. 2014) which summarizes different mental and motor symptoms of CND influenced by rTMS. Both the Parkinson’s disease and the post-stroke state have similar cognitive and motor symptoms in the different stages of the disease (Goetz and Pal 2014). The non-motor and motor symptoms of PD can be influenced by rT
MS and tDCS. The rTMS and tDCS can improve the memory, attention in neurodegenerative diseases (Miniussi at al 2008, Elder and Taylor 2014,) and in the learning process (Reis at al 2008). Even early studies with rTMS indicated that the motor symptoms of Parkinson’s disease could be influenced by both low and high frequency stimulations (Málly and Stone 1998, Khedr 2003).
According to PubMed, nearly three hundred publications dealt with the non-invasive brain stimulation as a therapy for different symptoms of post-stroke state. Overwhelmingly the paresis was studied in different protocols (Málly 2008, 2013) but the life threatening swallow problem, non-fluent and fluent aphasia, post-stroke depression significantly improved after the treatment period. Protocols lasted from 5 to 10 days; intensity was around the motor threshold and the frequency with low (1 Hz) or high (5 to 10 Hz) was applied over the interested (appropriate) part of the cortex. Mainly the primary motor cortex was stimulated, because of its well defined response, the motor evoked potential (MEP). After the paired pulse stimulation, the change in the amplitude of MEP and the length of the silent-period provide information about intracortical excitability. It reflects the brain plasticity assessed by electrophysiological method. The analyzing the brain plasticity preceded the therapeutic applications this might lead to explain every therapeutic change with facilitation or inhibition in the intracortical connections. There is no question that non-invasive brain stimulations like rTMS and tDCS can modify the intracortical excitability but it is not yet clear whether it can be responsible for all of the therapeutic effect. Although, we know that stimulating different parts of cortex can influence different symptoms, mainly the dorsolateral prefrontal area (DLPF) and primary motor cortex were involved in the studies with PD and post-stroke state. The second problem with the explanation of the therapeutic effect with brain plasticity in PD and post-stroke is that the significant effect is delayed and develops after weeks or months after treatment period while the intracortical excitability can be changed immediately after the stimulation. The experimental studies revealed other mechanisms than brain plasticity in the effect of non-invasive brain stimulations like increased production of progenitor cells, enhanced production of BDNF, decreased apoptosis.
The goal of this short paper is to review the different site of actions of non-invasive brain stimulation in the post-stroke state and Parkinson’s disease.
Change in the intracortical excitability (brain plasticity)
Change in the intracortical excitability was the first phenomenon which was detected after the rTMS or tDCS. The possibility came from the introduction of paired –pulse stimulation into the studies with non-invasive brain stimulation.
General Aspects of TMS and tDCS
TMS is widely used in medical practice and research.
It was introduced as a diagnostic tool approximately thirty years ago to test the functioning of motor pathways (Barker1986). The motor evoked potential (MEP) and the measurement of the central motor conduction time (CMCT) have been adopted in daily practice.
TMS is also used to assess other parameters in research (Chen 2008). TMS aids the diagnosis of multiple sclerosis and also predicts the prognosis of stroke (D’Olhaberriague 1997). Different paired pulse stimulations with TMS have provided new insight into the functions of the brain. In recent years, sophisticated brain plasticity can be detected by the measurement of intracortical excitability (Kujirai 1993, Ridding 2001). These studies have revealed how different conditions can modify brain plasticity, which can be changed by different diseases, altered by drugs (Ziemann 1996) and strongly influenced by non-invasive stimulations (Pascual Leone 1994, Nitsche and Paulus 2000). Treatment with a single TMS and one session of repetitive stimulation has a short after-effect. However, the effect of repeated stimulation for days persists well beyond the stimulation period and often lasts for months. This effect of rTMS has made it useful for therapy for the last 20 years. This therapy is based on the assumption that we must change the intracortical excitability to induce facilitation or inhibition. It is done by low and high frequency stimulation, continuous theta burst stimulation (cTBS), intermittent theta burst stimulation (iTBS), anodal or cathodal stimulation. The intensity of rTMS was around the motor threshold and the duration of stimulation was 7-10 days. This paper briefly reviews the most frequently studied symptoms of Parkinson’s diseases and stroke and how they can be changed by rTMS.
Parkinson’s Disease (PD)
The first protocol was low frequency, low intensity monophasic stimulation for 7 days which improved the Parkinsonian symptoms. The results were maintained for several months after the stimulation (Málly 1998, 1999). The authors performed a “dose (intensity) response” curve with 1 Hz stimulation which indicated that there is an optimal intensity using 1 Hz (Málly 1999). These studies demonstrated that the therapeutic effect of rTMS develops after a delay of a few weeks. The improvement continues for several months after the treatment. The later studies confirmed these observations not only in PD but also in other diseases. In contrast, the high frequency stimulations over the primary motor cortex (Khedr 2006, 2003) had the same effect on the Parkinsonian scores but the after-effects lasted for a shorter time. iTBS over the dorsolateral prefrontal area improved the depression without effecting bradykinesia (Benninger 2011). The studies concentrated on varying the frequency that was applied but did not try to find the optimal intensity of high frequency stimulation. Using the optimal intensity will produce longer lasting therapeutic effects. At present, levodopa- induced dyskinesia cannot be effectively treated, although this dyskinesia can be decreased by low frequency rTMS over the primary motor cortex or cTBS over the cerebellum (Koch 2009, 2010). rTMS over the motor cortex induced the release of dopamine in the ipsilateral putamen assessed by a [11C] raclopide PET study. The dopamine release also contributes to the effect of rTMS in PD (Strafella 2005). The regularly repeated rTMS periods may slow the development of PD (Málly 2004). This observation needs further confirmation. The motor deficit of Parkinson’s disease can be influenced by tDCS applied over the motor or the prefrontal areas (Benninger 2010). According to animal studies, one of the supposed sites of action of tDCS is the dopamine release in the striatum (Tanaka 2013) similarly to the rTMS. These promising results urge the use of non-invasive brain stimulation in the treatment of Parkinson’s disease because the response for dopaminergic therapy decreases over years and severe side effects develop.
Stroke is most frequently observed to occur in the brain regions fed by the cerebral media artery. Stroke produces different symptoms such as paresis, spasticity, aphasia, neglect. dysphagia and cognitive decline. Stroke has been shown to destroy the mutual inhibition between two hemispheres. Therefore, the goal of non-invasive brain stimulations is to restore the decreased excitability of the lesioned hemisphere and decrease the overactivity of the non-lesioned hemisphere (Murase 2004). Low frequency stimulation and cTBS stimulation are applied over the non-lesioned hemisphere to decrease the excitability and the high frequency and iTBS stimulation are applied over the lesioned hemisphere to enhance the excitability. In slight cases of stroke, both treatments led to faster movement in the paretic hand and decreased the reaction time (Talelli 2007, Fregni 2006, Kakuda 2011, Chang 2010). As far as the stimulation frequency is concerned, the 3 Hz stimulation showed a more pronounced effect than the 10 Hz stimulation, as assessed by NIHSS, after one year (Khedr 2010). In fact the best results were achieved after 1 Hz stimulation (Khedr 2009), which induced new movement in the paretic hand years after the onset of stroke (Málly 2008).Ameta-analysis confirmed that 1 Hz rTMS over the unaffected hemisphere may be more beneficial for the motor outcome than the high frequency rTMS over the affected hemisphere (Hsu 2012). It has been shown anodal and cathodal stimulations for 6 days were superior to sham stimulation over the primary motor cortex in a three-month follow up study (Khedr 2013). The usefulness of tDCS in chronic stroke was summarized by Stagg (Stagg 2013). Both fluent an non-fluent aphasia can be improved by rTMS (Naeser 2005, Barwood 2011, Szaflarski 2011, Weiduschat 2011) and tDCS (Baker 2010, Marangolo 2011). There is a reversion of the imbalance of the interhemispheric inhibition. Speech-induced activity shifts from the left side to both sides or to the right side. The best outcome for aphasia would be if the activity returns to the left side.
This dynamic change may responsible for the better outcome of aphasia several weeks after stimulation.
In addition, both neglect and dysphagia can be improved by non-invasion brain stimulation.
Neglect makes the improvement of paretic extremities more difficult. It can be ameliorated by one Hz stimulation over the right parietal cortex (Brighina 2003).
Dysphagia is a life threatening symptom of a brain injury. It may be caused by pseudobulbar paralysis or a lesion in the brain stem that can be improved by rTMS (Khedr 2009, 2010). Different aetiology can cause spasticity, which can be reduced by rTMS with low and high frequency stimulation (Kakuda 2011, Kumru 2010).
Cognitive impairment appears not only in Alzheimer’s disease, but also in many other diseases. The most prominent examples are brain injuries, stroke and different neurodegenerative diseases. Working memory and executive function can be improved by low and high frequency stimulation over the dorsolateral prefrontal cortex but not over the primary motor cortex in stroke patients (Rektorova 2005). The working memory and visuo-motor learning were facilitated by tDCS (Fregni 2005, Antal 2004). The effect of non-invasive stimulation depends on the tasks performed in the study, which may contribute to the great variability of the results, as summarized by Miniussi (Miniussi 2008).
Depression is an independent entity, but it often accompanies other chronic diseases. No unified protocol for the treatment of depression has been identified. The U.S. Food and Drug Administration accepted treatment with high frequency stimulation of drug resistant cases. Similarly to the previous symptoms, depression can be improved by low and high frequency stimulation of rTMS (Stern 2007, Eranti 2007). The right dorsolateral prefrontal cortex (DLPFC) was stimulated with low frequency while the left DLPFC was treated with high frequency stimulation. Both were equally effective according a meta-analysis (Chen 2013). The affective and motor symptoms, aphasia and cognitive function can all be influenced by non-invasive stimulations. These benefits prove the great advantage of these therapies.
Site of action
Whether the change in intracortical excitability is responsible for the therapeutic effect of the brain stimulation remains unknown. At the beginning, its therapeutic use was based on influencing brain plasticity but there is a time delay in the two effects of rTMS. The effect on brain plasticity develops immediately and ceases at the end of the stimulation but the therapeutic effect develops over a period of weeks or months. This discrepancy in time frames led to the conclusion that TMS and tDCS are able to influence both effects but that these two effects are partially independent from each another (Hoogendam 2010).
An interesting observation in animal studies is that the production of stem cells under the subventicular zone and their migration to the lesioned area increase in response to rTMS. (Arias-Carrion 2008, Yamashita 2006) If this is also true in humans, rTMS will not only be a symptomatic treatment but could also be used to influence the aetiology of the disease. BDNF is the regenerating hormone for the nervous system, and rTMS and tDCS increases its production (Fritsch 2010,Gersner 2011, Müller 2000, Clarkson 2011).
The effects of rTMS and tDCS are not localized, but the activity of the central nervous system can be increased or decreased far from the area that was stimulated. We cannot exclude the possibility that non-synpatic transmission via extrasynaptic receptors (Vizi 2013) contributes to the effect of non-invasive stimulation because the non-stimulated parts of the brain are also activated by non-invasive stimulations (Vizi 2000). GABA has been shown to be increased in the cortex after low frequency stimulation(Stagg 2009 Yue 2009).After high frequency stimulation, the glutamate is also increased (Michael 2003). In addition, a new balance between the inhibitory and excitatory neurotransmitter systems can be achieved by the rTMS and tDCS (Stagg 2011).
Therefore the mode of action of rTMS and tDCS may be similar in restoring impaired neuronal activity, thereby resulting in better functional activity.
Difficulties in therapies using non-invasive brain stimulation
It is almost impossible to compare the results of different publications because of the great variations of protocols and equipment. Two modes of TMS stimulation, monophasic and biphasic, can be applied, and they differ from each other at a basic level. Consequently, the same intensity and frequency do not translate into the same electric current being induced by the stimulation. Furthermore, intracortical excitability can be facilitated by high frequency stimulation and inhibited by low frequency stimulation, but the individual values present a great variability which may lead to different therapeutic effects. The variability depends on which interneuron networks are affected by TMS in the subject (Hamada 2013). The heterogeneity of a group of patients may lead to divergent results.
Both non-invasive brain stimulations improve different symptoms of central nervous diseases. The effect develops slowly and can be maintained for months after the stimulation. Both the low and high frequency stimulations appear to be effective but the intensity and duration of stimulations are different. They influence both neuroplasticity and disease symptoms, but these effects may be partially independent from each other. The therapeutic effect may be attributed to the elevated production of brain stem cells, increased levels of BDNF, and a new balance in the inhibitory and excitatory neurotransmitters. In addition, non-synaptic transmission may play a role in the healing effect of non-invasive stimulation.
Although the stimulation of motor pathways had quickly spread throughout the world, the therapeutic use of repetitive stimulation has remained restricted to electrophysiologists and remains rarely used in the daily practice of neurology and rehabilitation. During the last twenty years, more than one thousand patients with different diseases have been involved in the electrostimulation studies, and the results of these studies have shown significant improvements in most cases. These methods are safe (following the existing guidelines) and should be uses to benefit our patients.
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