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Current and Potential Therapeutic Options for ALS Individuals
By Anna Truong, Neurobiology, Physiology, and Behavior, ’22
Author’s Note: I wrote this piece of work for an assignment through my UWP 104F course, and felt very connected with it. I decided my topic to be about a disease known as ALS because my father was diagnosed when I was at a young age. At the age of nine, I did not understand the gravity of becoming sick, and how much the world can change when someone important in your life passes away. I did not understand how impactful a disease was until I had the experience as a family member. ALS became a topic of interest to me since then from class presentations about interesting scientific topics to college research papers and literature reviews. This literature review is something that I am proud of because it encompasses ALS as the disease that has involved me and my family. From this review, I hope readers learn more about ALS and how the current research can pave a way for future research in the treatment of ALS.
Introduction
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is characterized by progressive degeneration of motor neurons in the spinal cord and brain [1-5]. Motor neuron degeneration inhibits the ability of the brain to send signals to the muscles to control movement. There are two types of motor neurons responsible for this communication: the upper and lower motor neurons. Lesions in upper motor neurons prevent the signal cascade to the lower motor neurons that send another signal responsible for muscle movement. This can lead to muscular atrophy, paralysis, and eventually death [1-5]. Various injuries such as damage to the spinal cord or strokes, as well as other factors like oxidative stress induced by free radicals, contribute to the destruction of motor neurons [6]. Approximately 5 of every 100,000 individuals will be affected by ALS and the average life expectancy after diagnosis is between 2-5 years [2].
Many studies have focused on identifying the cause for motor neuron cell death and the genes involved in the development of the disease. Although bodily mechanisms by which motor neurons degenerate remain unclear, they are thought to encompass a non-cell autonomous process [3]. The purpose of this literature review is to analyze the current and potential treatments that can be effective toward individuals experiencing ALS. This article will focus on a current drug treatment called Edaravone, followed by potential treatments, astrocyte-based therapy and cell-based therapies.
Drug Treatments
Edaravone is a free radical-scavenging drug that functions to protect motor neurons from free radicals and oxidative stress damage in the central nervous system (CNS) [2,6]. Edaravone effectively acts on oxidative stress by reducing the number of free radicals to slow disease progression. With the absence of a cure, such treatment options have mainly contributed to prolonged survival [6].
ALS Functional Rating Scale
In this section, we will analyze the effect of Edaravone on disease progression through scoring of motor function by the revised ALS Functional Rating Scale (ALSFRS-R). The ALSFRS-R is an instrument designed for the clinical evaluation of functional status of ALS patients and efficacy of clinical trials [6]. It measures 12 aspects of physical function such as swallowing, breathing, and walking, scoring functioning ability from 4 (normal) to 0 (no ability) with a maximum total score of 48 and a minimum of 0.
Edaravone treatment on ALS patients
During normal disease progression, it is assumed that decline in functioning scores is almost linear [6]. When comparing ALSFRS-R scores between patients who received either placebo treatment or Edaravone treatment, there was a significantly faster decline in functional scores for those who received the placebo. This indicates a considerable loss in the ability to perform everyday tasks [2]. In conjunction with these results, a further study has shown greater improvements in ALSFRS-R scores for patients after beginning Edaravone treatment compared to the pre-treatment period [7]. The pre-treatment period lost an average of 4.7 points on the ALSFRS-R whereas the treatment period showed a smaller average loss of 2.3 points over the same time duration [7]. This indicates possible clinical efficacy for Edaravone due to its ability to effect a more gradual decline.
In addition, compared to placebo, Edaravone remains effective for up to a year, after which survival rates start to decline [2]. Edaravone’s effectiveness is also more prevalent in the early stages of ALS progression, but long-term effects of Edaravone are not yet fully evaluated so results past a year are unclear. Further limitations to these studies, including a nonlinear difference in decline between functional rates of early stages of ALS and end stages of ALS, require more research before affirming the long-term health benefits through Edaravone [2,6,7]. Therefore, as a marketed drug, it is difficult to be sure of its full effectiveness from the lack of positive results in life expectancy of the target population. On the other hand, no detrimental effects or worsening of symptoms due to Edaravone were analyzed during patient trials besides a few side effects including bruising, headaches, and hypoxia [6]. Due to these factors, Edaravone remains a partially beneficial drug.
Potential Therapeutic Options
Although Edaravone’s effectiveness is still actively being deciphered, there have been studies on whether other types of cellular targets within the brain and stem cells, such as astrocytes, could help slow down or halt disease progression and thus be effective treatments for ALS [1,3,4]. Astrocytes are a type of glial cell within the CNS that is inflamed under the diseased state [1]. Most of the following research involves the SOD1-G93A transgenic mice expressing the human SOD1 gene with G93A mutation. It is an important mouse model for studying ALS as it presents many of the pathological symptoms experienced by patients, including motor impairment and motor neuron death, allowing for an analogous simulation [1].
In the current state of medication development, the SOD1-G93A transgenic mice are utilized for their relation to astrocytes, a promising target for effective treatments. The increasing number of studies performed on astrocytes show them to be crucially involved in ALS through their influence on motor neuron fate and disease progression. The studies discussed will present multiple experiments on the SOD1-G93A transgene, and explain how elimination and/or alteration of this gene can help slow prominent signs of disease and extend lifespan [1,5].
Role of Astrocytes in ALS
Upon a specific signal within the CNS, astrocytes can transform into either their reactive A1 state characterized by promotion of neurodegeneration and toxicity or their neuroprotective A2 state which promotes healing and repair of injury [3,9]. Among ALS patients, the reactive A1 astrocytes are dominant along with the mutant transgenic SOD1-G93A, contributing toxic components that participate in ALS pathology [1].
Amongst these pathologies, researchers investigate neuroinflammation, characterized by inflammation of the nervous tissue, to prove its benefits for minimizing reactive astrocytes [1]. Neuroinflammatory stimuli like lipopolysaccharide (LPS) lead to a signal transduction cascade that can secrete immunologically active molecules like IL-1α, TNFα, and C1q that transform resting astrocytes to their neurotoxic A1 state [1]. These reactive astrocytes will lose regular functions and secrete factors toxic to neurons [1,3]. Moreover, isolated astrocytes from ALS patients were found to be toxic to healthy, cultured motor neurons [3]. This indicates the involvement of astrocytes in motor neuron death that can lead to a progressive decline of motor function [3]. Lowering the prevalence of neuroinflammation may contribute to a decrease in motor neuron death, and therefore delayed progression of ALS.
Healthy individual’s communication between the motor neuron, astrocytes, and immune cells compared to those of an ALS individual
Astrocyte-Based Therapy
To minimize neuroinflammatory effects of ALS, Guttenplan et al. determined that knockout, or the genetically modified absence of IL-1α, TNFα, and C1q in SOD1-G93A mice did not produce any reactive astrocytes [1]. This triple knockout was also linked to the possibility of neuroinflammatory reactive astrocytes becoming a therapeutic target for ALS. The triple knockout mice presented with lower levels of reactive astrocyte marker C3 and had a significantly extended lifespan of over 50% compared to regular SOD1-G93A mice [1]. Treatments that implement this mechanism of lowering neuroinflammation can contribute to a turning point in increasing efficacy rates of therapies involved in ALS.
In addition, diagnosis is primarily followed after the presence of symptoms [1]. An approach to treatment included restoring normal functionality of endogenous astrocytes through the transplantation of healthy astrocytes in patients [3]. These transplanted healthy astrocytes can provide neuroprotection through reduction of misfolded proteins in motor neurons. However, they can also transform into neurotoxic A1 astrocytes when in the diseased environment of the CNS [3]. The mechanisms through which transplanted astrocytes act continue to be thoroughly understood, yet provide a promising target for an ALS targeted therapy [1,3]. Delay in disease progression may be more effective with a combination of therapies attacking both reactive astrocytes and motor neurons compared to individual therapies [1].
Cell-Based Therapy
Another approach that has been studied as a potential therapeutic target for ALS is through stem cells. Mesenchymal stem cells (MSCs) are adult multipotent precursors that can be prompted to release neurotrophic factors released by A2 astrocytes and have shown to be beneficial in the regeneration of healthy cells [3]. Transplantation of the same individual’s MSCs induced to secrete neurotrophic factors showed early signs of safety and treatment effectiveness [3].
Furthermore, a specific stem cell therapy “Neuro-Cells”, a combination of MSCs and hematopoietic stem cells (HSCs), along with anti-inflammatory measures was administered to both SOD1-G93A mice and FUS-tg mice, a variant of the standard SOD1-G93A strain [4]. In SOD-1 and FUS-tg, inflammation contributes to disease progression, allowing for comparison investigation in these two mutations [4]. When tested on rats subjected to spinal cord injury, this mixture had an anti-inflammatory effect, thus improving motor function and decreasing concentrations of proinflammatory cytokines in the cerebrospinal fluid [4]. Muscle degeneration among FUS-tg mice was also compared during Neuro-Cell injections. Muscular atrophy was noticed to be partly rescued by the mixed stem cell therapy. To verify these results, Neuro-Cells were administered to SOD1-G93A mice. Results showed an indication of improved motor function similar to that of the FUS-tg mice, thus providing further evidence of disease counteraction [4]. These signs of efficacy and preclinical studies of transplantation of MSCs and HSCs are indicators of beneficial treatments from the usage of stem cells through reduction of motor neuron death, prolonged survival and improved motor performances [3]. Coincidingly, according to de Munter et al., stem cell therapy should be utilized as a part of the cell-based treatment of ALS due to the knowledge present already in this field [4]. Even so, more research is needed to define the anti-inflammatory mechanisms in ALS pathology and other effects that “Neuro-Cells” have on ALS.
Possible stem cell therapies that could be used to treat ALS
Discussion/Conclusion
While there are currently effective drug treatments available for ALS, there is still research being conducted on these drugs to better ensure quality and effectiveness. Edaravone’s ability to slow disease progression remains minimal or ineffective to patients who are past the beginning stages of ALS progression, and toward end-stage ALS, respectively. Decline in patients experiencing ALS occurs non-linearly with a rapid decline toward the end-stage, and so clinical effects of Edaravone may not be beneficial. Its therapeutic effects are yet to be better understood and whether or not their effectiveness is due in part to the drug. Although it is currently being used as a treatment option, Edaravone could be further improved for efficacy.
In association, potential treatment options of astrocyte-based therapies and cell-based therapies play an important role in the future of ALS. Targeting astrocytes and neuroinflammation, and utilizing stem cell therapy can provide benefits to slowing disease progression. However, much like the current drugs, there is still much to understand about other subpopulations of astrocytes and stem cells that could contribute to ALS pathology. The intertwined participation of therapies is important to note as it could provide greater benefits to patients seeking out future treatments. Although options of treatment are currently limited, these studies suggest potential therapeutic approaches that can be optimized to halt or slow disease progression. Currently, stem cells are encouraged to be part of treatment in ALS patients, suggesting its potential in reducing inflammation and therefore can be highly effective in minimizing motor neuron death. Additionally, astrocytes are becoming a major direction in the studies of ALS, due to its direct involvement in motor neuron death associated with the disease. Astrocytes may become the center of research in the near future and lead to a more efficient slowing of disease progression compared to the currently approved drugs. With more studies, the cellular mechanisms contributing to the deterioration of motor neurons involved in ALS can lead to promising treatments with greater efficacy against the disease. In due time, we can hope to see an increase in the average life expectancy of 2-5 years to much longer.
References:
- Guttenplan, K. A., Weigel, M. K., Adler, D. I., et al. (2020). Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nature communications, 11(1), 3753. https://doi.org/10.1038/s41467-020-17514-9
- Shefner, J., Heiman-Patterson, T., Pioro, E. P., Wiedau-Pazos, M., Liu, S., Zhang, J., Agnese, W., & Apple, S. (2020). Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19). Muscle & nerve, 61(2), 218–221. https://doi.org/10.1002/mus.26740
- Izrael, M., Slutsky, S. G., & Revel, M. (2020). Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease. Frontiers in neuroscience, 14, 824. https://doi.org/10.3389/fnins.2020.00824
- de Munter, J., Shafarevich, I., Liundup, A., et al. (2020). Neuro-Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice. CNS neuroscience & therapeutics, 26(5), 504–517. https://doi.org/10.1111/cns.13280
- Apolloni, S., Amadio, S., Fabbrizio, P., Morello, G., Spampinato, A. G., Latagliata, E. C., Salvatori, I., Proietti, D., Ferri, A., Madaro, L., Puglisi-Allegra, S., Cavallaro, S., & Volonté, C. (2019). Histaminergic transmission slows progression of amyotrophic lateral sclerosis. Journal of cachexia, sarcopenia and muscle, 10(4), 872–893. https://doi.org/10.1002/jcsm.12422
- Luo, L., Song, Z., Li, X., Huiwang, Zeng, Y., Qinwang, Meiqi, & He, J. (2019). Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis-a systematic review and meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 40(2), 235–241. https://doi.org/10.1007/s10072-018-3653-2
- Sawada H. (2017). Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert opinion on pharmacotherapy, 18(7), 735–738. https://doi.org/10.1080/14656566.2017.1319937
- Liu, J., & Wang, F. (2017). Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications. Frontiers in immunology, 8, 1005. https://doi.org/10.3389/fimmu.2017.01005
- Liddelow, S., & Barres, B. (2015). SnapShot: Astrocytes in Health and Disease. Cell, 162(5), 1170–1170.e1. https://doi.org/10.1016/j.cell.2015.08.029
Non-Invasive Brain Stimulation Therapies as Therapeutics for Post-Stroke Patients
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:
- 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.
- Kubis N. Non-Invasive Brain Stimulation to Enhance Post-Stroke Recovery. 2016. Front Neural Circuits. 10:56.
- Chen R., Cohen L. G., Hallett M. 2002. Nervous system reorganization following injury. Neuroscience 111, 761–773.
- Takeuchi N, Izumi S. 2012. Noninvasive brain stimulation for motor recovery after stroke: mechanisms and future views. Stroke Res Treat. 584727.
- 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.
- 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.
- 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.
- Bucur M, Papagno C. 2018. A systematic review of noninvasive brain stimulation for post-stroke depression. Journal of affective disorders. 238: 69–78.
- 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.
- Vines BW, Norton AC, Schlaug G. 2011. Non-invasive brain stimulation enhances the effects of melodic intonation therapy. Frontiers in psychology. 2:230.