By Priyanka Basu, Neurobiology, Physiology & Behavior ‘22

Author’s Note: I wrote this review article during my time in UWP102B this past quarter, though my inspiration in digging deeper into this topic came from my personal experience with my uncle who had recently incurred a stroke to his brain leading him to face its detrimental effects. I realized I wanted to investigate the possible solutions there were for him and others, allowing me to consequently further my knowledge about this field of study. I’d love for readers to understand the complexity and dynamics that non-invasive brain stimulation therapies have on post-stroke patients, and its beneficial effects when used in conjunction with other therapies. Though studies are in their preliminary phases and there are quite a bit of unknowns, it is still important to keep in mind the innumerable therapeutics being created that target patient populations experiencing a certain extent of brain damage- their results are absolutely phenomenal.

Abstract: 

Non-invasive brain stimulation therapies have become an overwhelmingly dominant innovation of biotechnology that has proven to be greatly effective for treating post-cerebral damage. Stimulation therapies use magnetic fields that can induce electric fields in the brain by administering intense electric currents that pulse through neural circuits. Although several stimulation therapies exist, the therapies discussed in this review include the most widely used therapeutic technologies: transcranial magnetic stimulation (TMS), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and theta-burst stimulation (TBS). Post-stroke patients often experience significant impairments to their sensorimotor systems that may include the inability to make arm or hand movements, while other impairments include memory or behavioral incapacities. Stimulatory therapies have been shown to allow for certain neuronal excitability that can improve the impairments seen in these patients unlike alternative standardized procedures. Although the individual efficacies of stimulation therapies have shown viable outcomes, current research dives into how the use of stimulation therapies in conjunction with secondary therapeutics can have synergistic effects.

Introduction:

Basic stimulation therapies were first put to clinical use in 1985 to investigate the workings of the human corticospinal system [1]. The magnetic field that is produced by stimulation is capable of penetrating through the scalp and neural tissue, easily activating neurons in the cortex and strengthening the electrical field of the brain [1]. By inducing depolarizing currents and action potentials in certain regions of the brain, patients with damaged areas of the cerebral cortex found great relief as they regained a degree of normal functionality in their motor, behavioral, or cognitive abilities [1]. 

In recent years, stroke has become the second leading cause of death in the United States [2]. Neurologically speaking, stroke can interrupt blood flow in regions of the brain, such as the motor cortex, weakening overall neurological function throughout the body [2]. Stimulatory therapies are used in these cases to successfully activate neurons which jumpstarts their firing capabilities and rewires the body’s normal functionality [1]. Although certain reperfusion therapies using thrombolysis have been seen to treat certain ischemic (i.e. hemorrhaged) tissue in stroke patients by removing deadly clots in blood vessels, these therapeutics are often starkly inaccessible to the general population because of their price tag and scarcity [2]. Oftentimes, even standard pharmacological drugs prove ineffective [2]. By way of heavy experimentation, scientists have discovered that the brain can simply reconstruct itself through a method called, “cortical plasticity,” allowing for neural connections to be modified back to their normal firing pattern [3]. By understanding this innate and adaptive tool that the brain possesses, researchers invented the method of stimulatory therapies to essentially boost our own neural hardware [2].

Over the years, by investigating how these therapies and their mechanisms can work in conjunction with other therapeutics on post-stroke patients, an in-depth understanding of further possible advantageous therapies can be made. 

Mechanism of Non-Invasive Neural Stimulation

Most current noninvasive brain stimulation therapies use similar methodologies involving the induction of magnetic fields or electrical currents along cerebral cortical regions of the skull and brain to induce rapid excitation of neurons [4]. Some of the most common noninvasive brain stimulation (NIBS) techniques currently used are transcranial magnetic stimulation (TMS), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and theta-burst stimulation (TBS) [4]. Our brains reorganize innately after stroke or cerebral damage through mechanisms of cortical plasticity [3]. However, non-invasive stimulation therapies can stimulate cortical plasticity by quickly modulating neural connections through electrical activation for efficient neuronal and/or motor recovery after the incident [3]. According to Takeuchi et al., TMS and other similar therapies stimulate the cortex through the scalp and the skull. This method positions a coiled wire over the scalp to generate a local magnetic field [4]. As these magnetic fields are pulsed and begin to enter the brain, they establish an electrical current that stimulates cortical neurons which induces a neuronal depolarization (i.e. excitation) [4]. rTMS involves a similar mechanism as TMS, but it has a greater rate of repetition of the ejected magnetic stimulation inducing a higher frequency current [5]. Meanwhile, TBS therapy is a modification of rTMS. While TBS has a similar degree of frequency to rTMS, TBS involves larger bursts of magnetic stimulation rather than small, frequent action [6]. 

When understanding the degree that noninvasive brain stimulation works on cortical neural plasticity, it is best to see its functionality in the motor cortex—one of the most easily damaged regions of the brain in stroke patients [4]. Neuronally, NIBS can excite the damaged hemisphere allowing for an increase in activity of the opposite or ‘ipsilesional’ motor cortex [4]. This excitement is highly inducible and is required for proper motor learning and functioning in normal human behavior [7,8]. In addition, these therapeutics may also induce certain metabolic changes that stimulate our innate neural plastic network for successful post-stroke motor recovery [4]. Over time, and with continuous electric stimulation therapy, long-term potentiation of our neural hardware can lead to swift recovery of the affected hemisphere [3]. By this method of magnetic stimulation on damaged cortical regions of the brain, post-stroke patients can recover faster than ever before. 

Excitability of Motor and Behavioral Neural Networks 

Ultimately, NIBS treatments induce excitability of motor and behavioral neural networks that allow for the atrophy of affected cerebral regions and increase neural plasticity in the region [5]. In a study led by Delvaux et al., TMS therapies were used to excite changes in the reorganization of motor cortical areas of post-stroke patients [9]. Scientists investigated a group of 31 patients that experienced an ischemic stroke in their middle cerebral artery which led to severe hand palsy [9]. The patients were clinically assessed with the Medical Research Council, the National Institutes of Health stroke scales, and Barthel Index on certain dates of experimentation after stroke [9]. From the data collected, when damaged regions were measured by electrical motor-evoked potential (MEP) amplitudes, the areas were initially statistically smaller than the unaffected areas, thus indicating a lesser degree of motor activation resulting from the effects of certain damaged regions of the brain [9]. After the affected regions were treated with focal transcranial magnetic stimulation (fTMS), a specific type of TMS therapy, the stimulation ultimately induced excitability of affected motor regions as well as unaffected motor regions due to the inducible nature of connected regions in the brain [9]. This study evaluates a TMS technique involving MEP amplitude measurements and FDI motor maps unique to most other stimulatory therapies, including rTMS, tDCS, and others, helping to physiologically understand the impacts of neurological damage in the brain. Although the study hosted a relatively small sample size of twenty participants, it  can be considered sufficient as per the extremity of the experimental design and scarcity of possible participants. The study participants, ranging between 45 and 80 years old, were tested for any underlying neurological disorders to reduce confounding factors. By testing these participants using a standardized scaling method and MEP potentials, the study qualified as a well-regulated results-directive for a conclusive study despite a relatively small sample size.

A similar study conducted by Boggio et al. further investigated the effects of NIBS on motor and behavioral neural networks by using variant-charged (anodal (+) and cathodal (-)) current stimulations on stroke patients and then identifying enhanced results. The investigation studied a specific brain stimulatory therapeutic (tDCS) on its excitability and potential benefits on post-stroke patients [7]. Investigators were able to test the motor performance and improvements in stroke patients using two experiments [7]. Experiment 1 was conducted during four weekly sessions using sham (controlled magnetic stimulation), anodal (increased magnetic stimulation), and cathodal (decreased magnetic stimulation) transcranial direct current stimulation (tDCS) therapies [7]. In Experiment 2, five daily sessions of only cathodal tDCS treatments were investigated on affected brain regions [7]. The effects were reported following the procedure and blindly evaluated using the Jebson-Taylor Hand Function Test, a standardized test to measure gross motor hand function [7]. Between the two experiments, the most significant motor and behavioral improvements were found using the three stimulations in Experiment 1 [7]. However, when stimulations were compared individually, viable motor functional improvement was still evident with either cathodal or anodal tDCS on unaffected and affected hemispheres respectively when compared to the sham tDCS therapy [7]. Using daily sessions instead of weekly was found to be more beneficial in terms of lasting treatment results [7]. Investigators were able to conclude that their findings show strong support in relation to other tDCS research on motor function improvement in stroke patients [7]. tDCS is considered safe, representative, and inexpensive allowing for the possibility of further research on the technique with a wider range of patients. The study could have included additional evaluations of the different motor capabilities rather than just focusing on the hand itself to allow for variation, additional variables, and details that could supply the research rather than simply validating the technique. Both experiments analyzed above resulted in statistically significant results and represented the excitable capabilities of stimulatory therapies currently used for post-stroke patients. 

Effectivity of Alternative Neural Therapeutics in Conjunction with NIBS Therapies 

Although standard NIBS therapies have been shown to provide impressive solutions for post-stroke patients, there have been few studies understanding the prospects of using NIBS in conjunction with other therapies for these patients. Aphasia, a rapid decline of the ability to acknowledge or express speech, is a common neurological disorder often seen in post-stroke patients as a result of damage to speech and language control centers of the brain [10]. A number of therapeutics not only search for solutions to certain post-stroke motor dysfunctionalities, but also the behavioral dysfunctions of stroke including aphasias. For several years, previous studies have investigated the use of intonation-based intervention (melodic intonation therapy (MIT)), on severe non-fluent aphasia patients showing immense benefits [10]. A study conducted by Vines et al. (2011) expanded on these findings and implemented this therapy of MIT alongside an additional brain stimulatory therapy of transcranial direct current stimulation (tDCS) to understand if there are augmented benefits of MIT in patients with non-fluent aphasia [10]. Six patients with moderate to severe non-fluent aphasia underwent three days of anodal-tDCS therapy with MIT and another three days with sham-tDCS therapy with MIT [10]. The two types of treatments were separated by one week and assigned randomly [10]. The study showed that compared to the effects of the sham-tDCS with MIT therapies, the anodal-tDCS with MIT led to statistically significant improvements in the patients’ fluency of speech [10]. The study was able to solidify that the brain can properly reorganize and heal damage to its language centers through combined therapies of anodal-tDCS and MIT thus revamping the neurological activity of non-fluent aphasia patients [10]. However, one important component that was lacking in this experiment was a large number of subjects for reliable results. With six patients in the study, scientists could have increased the number tested to allow for greater sufficiency and valid results. Although this study lacked in size, it did include a range of participant ages relieving confounding effects of age-related neurological differences. 

An additional study important to the investigation of understanding the prospects of conjunctive stimulatory therapy was conducted in 2012 by Avenanti et al. The study sought to understand the possible benefits of combining non-invasive brain stimulation therapies (rTMS) with physical therapy. Many studies have investigated the effects of TMS alone on chronic stroke patients but few have investigated the combination of TMS with physical therapy.  In a double-blind, randomized, experiment, Avenanti et al. (2012) investigated a group of 30 patients who were given either real or sham transcranial magnetic stimulations (rTMS) either before or after physical therapy (PT) [5]. The outcomes of this experiment were evaluated based on dexterity and force manipulations of motor control [5]. The results of the study found that overall, patients that were given real rTMS treatments developed statistically better behavioral and neurophysiological outcomes when used in conjunction with PT but were more greatly enhanced when stimulated before physical therapy in a sequential manner [5]. Improvements were detected in all conjunctive groups (real or sham/before or after PT), and even with PT alone in certain experimental groups [5]. Researchers were able to conclude that treating chronic stroke patients with motor disabilities with rTMS before PT provided optimal results of motor excitability, though its conjunctive outcome was effective as well [5]. With statistically significant results, the study indicates valid conjunctive benefits of both PT and rTMS therapy for the patients evaluated [5]. Regarding the reliability of this study, each method was properly implemented for results to be sustained allowing for proper controls in sham trials [5].  

Conjunctive therapies offer new insight into possible avenues for advantageous treatments for post-stroke patients rather than when used alone. With new investigations in this field of study, unknown outlets are slowly being uncovered, allowing for better solutions to cerebral and ischemic damage. 

Conclusion:

Non-invasive brain stimulation (NIBS) therapies are a well-refined and successful therapeutic for post-stroke patients. Although much of the mainstream solutions to damaged cerebral regions are NIBS therapies, current research is still searching to identify qualifying conjunctive therapies with NIBS to ameliorate treatments. Standard stimulatory procedures use measurable magnetic or electric currents to depolarize or excite regions of the brain to stimulate neurons for proper activity. By doing so, our innate system of neural plasticity works with this stimulation to enhance the recovery of damaged cerebral regions. In recent years, scientists have taken a step further and combined stimulatory therapies with additional stroke therapy to further enhance results. Although early research processes have begun, more studies and trials are necessary to provide for sufficient data to strongly confirm their efficacies, even when promising results have already been found. Several studies lack the number of participating patients, data, and resources needed to successfully prove these conjunctive therapies. Further understanding of these treatments through repeated trials, larger sample sizes, and statistically significant results may lead to a better understanding in the future of possible effective conjunctive treatments for post-stroke patients. 

References:

1. Santos MD dos, Cavenaghi VB, Mac-Kay APMG, Serafim V, Venturi A, Truong DQ, Huang Y, Boggio PS, Fregni F, Simis M. 2017. Non-invasive brain stimulation and computational models in post-stroke aphasic patients: single session of transcranial magnetic stimulation and transcranial direct current stimulation. A randomized clinical trial. Sao Paulo Medical Journal. 135(5): 475–480.
2. Kubis N. Non-Invasive Brain Stimulation to Enhance Post-Stroke Recovery. 2016. Front Neural Circuits. 10:56.
3. Chen R., Cohen L. G., Hallett M. 2002. Nervous system reorganization following injury. Neuroscience 111, 761–773.
4. Takeuchi N, Izumi S. 2012. Noninvasive brain stimulation for motor recovery after stroke: mechanisms and future views. Stroke Res Treat. 584727. 
5. Avenanti A., Coccia M., Ladavas E., Provinciali L., Ceravolo M. G. 2012. Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke: a randomized trial. Neurology 78, 256–264.
6. van Lieshout ECC, Visser-Meily JMA, Neggers SFW, van der Worp HB, Dijkhuizen RM. 2017. Brain stimulation for arm recovery after stroke (B-STARS): protocol for a randomised controlled trial in subacute stroke patients. BMJ open. 7(8): e016566.
7. Boggio P. S., Nunes A., Rigonatti S. P., Nitsche M. A., Pascual-Leone A., Fregni F. 2007. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci. 25, 123–129.
8. Bucur M, Papagno C. 2018. A systematic review of noninvasive brain stimulation for post-stroke depression. Journal of affective disorders. 238: 69–78.
9. Delvaux V., Alagona G., Gérard P., De Pasqua V., Pennisi G., Maertens de Noordhout A. 2003. Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clin. Neurophysiol. 114, 1217–1225.
10. Vines BW, Norton AC, Schlaug G. 2011.  Non-invasive brain stimulation enhances the effects of melodic intonation therapy. Frontiers in psychology. 2:230.