Noninvasive Brain Stimulation for Disorders of Consciousness (DoC) After TBI: Is it really safe?

by David Ripley, MD, MS

Introduction

As emergency life-saving medical treatments have improved, there has been a steady increase in people surviving with several studies showing that many people remaining for years in states of DoC will evolve to higher states of functioning even 5 to 10 years after injury.  While there are few treatments available to enhance the recovery of consciousness, growing evidence shows that this population has the potential to benefit from noninvasive brain stimulation (NIBS).

NIBIS is Not a New Phenomenon: History of Electricity as a Medical Treatment

The potential for NIBS to facilitate recovery from states of DoC offers great promise, but many clinicians remain concerned about the potential for adverse effects using NIBS despite the historical use of electricity to treat medical conditions that actually dates to ancient times (Figure 1). In ancient Greece, torpedo fish were applied to patient’s heads to relieve headaches¹. This use predated the invention of the battery by several centuries, and it was not really understood that electricity was the underlying cause of the effect. In 1743, Kruger suggested that electricity might be helpful for people with movement problems^2,3. This led to a plethora of interventions with electricity, as well as numerous public demonstrations, which, while entertaining, probably had little to no therapeutic effect. The public’s perception of electricity as a “cure-all” for many conditions rode the wave of popular opinion for many years, and lack of regulatory mechanisms in medicine at the time allowed this to propagate. In the late 1700’s, Benjamin Franklin published a work that outlined that electricity was the cause of these effects⁴. His own research into the use of electricity in various conditions generally failed to demonstrate efficacy. In 1802 Dr. T Gale published a handbook intended for use by the general public to support the use of electricity to cure many conditions and gave instructions on how to build an electrotherapy device for use at home, arguably the first instance of a durable medical equipment electrical medical device for home use².  Early users of electricity in medicine demonstrated little concern for safety.

Dr. Gale was an exception to this, explaining regret that electricity had been used before its nature was truly understood. He felt that many of the earlier failures in the use of electricity as a cure were due to improper application of electricity, and that many of the earlier “treatments” were too strong. In reading his text, this is somewhat ironic, given his explanation of the force which we now know to be incorrect.

The use of electricity for treatment of medical conditions received a backlash in the late 1800’s with the public’s awareness of the use of electroconvulsive therapy without anesthesia for individuals with mental health disorders and epilepsy. Despite the efficacy of many of these treatments, much of the stigma of this period remains today, with the lay public maintaining a generally negative perception of electroconvulsive therapy despite safer, more modern approaches.

In the last several decades, the use of electricity in the treatment of medical conditions has seen an explosion with wide-ranging uses, from surgery for electrocautery to applications for wound care.  Many advances have also been seen in the field of neurological rehabilitation, where electrical impulses have been used to treat everything from mental health disorders, paralysis, pain, seizures, swallowing dysfunction, and movement disorders. In the 1960’s, Bindman et al5 demonstrated that application of direct current on the cortex could modify neuronal excitability, and that this effect could persist hours after completion of the stimulation. This was followed by the discovery that sufficient current to induce this effect could be delivered transcranially. Unfortunately, this finding lay dormant for many years.

History of the NIBS Development

The first device developed specifically to induce neuromodulation using electrical impulses was functional electric stimulation (FES).  Clinical studies suggested that FES could be utilized to improve neurological functioning following central nervous system injury⁶. Around the same time, similar devices were modified to induce an electrical impulse to provide pain relief, called transcutaneous electrical nerve stimulation (TENS) devices. These gained widespread support and continue to be used today.

Repetitive Transcranial Magnetic Stimulation (rTMS)

In 1985, the Sheffield Magnet was introduced by Anthony Barker, beginning the current era of noninvasive brain stimulation. Barker leveraged Faraday’s effect, by delivering a strong directional magnetic field to induce an electrical current on the surface of the brain. It was later determined that pulses or trains of magnetic stimuli delivered in precise amplitudes and frequencies could alter excitability of the targeted cortical tissue⁶. Numerous clinical applications have subsequently been created, from cortical functional mapping to treatment of neurological and psychological disorders. The physiological basis for rTMS-mediated neuromodulation is theorized to be long term potentiation resulting in neuroplasticity.

Transcranial Electrical Stimulation (TES)

There are two types of transcranial electrical stimulation in use today, transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). tDCS was rediscovered as a tool to promote neuroplasticity just prior to the turn of the 21^st century. Priori et al⁷, and Nitsche and Paulus^8,9 revealed that anodal tDCS delivered to the cortex of healthy brain tissue results in a shift of the resting membrane potential towards depolarization, whereas cathodal tDCS shifts towards hyperpolarization. Short stimulation periods have not been found to meaningfully change the polarization potential for longer than the stimulation period, but longer duration of stimulation can induce excitability changes that last far beyond the stimulation period. This has been found to be true for stimulation of motor, visual and somatosensory cortices¹⁰.  Connectional effects of tDCS have also been demonstrated. This led to the development of multiple devices to provide direct current stimulation, many of which have been commercialized. More recently, transcranial alternating current stimulation (tACS) has received interest as an alternative clinical intervention¹¹. While some anecdotal evidence suggests that tACS may be better tolerated than tDCS, the current lack of literature in this area makes true comparisons difficult. The debate of which technique is more advantageous may become reminiscent of the war between Tesla and Edison for the type of current utilized in our power grids!¹².

TES and Home Use

TES has the benefits of low cost and portability. This has led to development of devices for home use.

For many, this has raised the issue of safety, ethical, and legal concerns with potential “misuse or overuse.” As would be expected with use of a home medical device, there is very little evidence of the safety of TES with home use. Jwa¹³ indicated that approximately one half of survey respondents reported mild transient symptoms, during the use of home tDCS. In an online forum of home users, no serious adverse events have been reported. However, the potential of these devices to be improperly used, especially in vulnerable populations, have led many clinicians and ethicists to express concern about unmonitored home use of TES, until efficacy and safety data is clearer¹⁴. However, if further supportand evidence for safety is provided, the convenience of providing in-home neuromodulation treatments could be extremely beneficial in a population where transport to and from a clinical setting iscomplicated by immobility. Current technology has the potential tomake this intervention even safer, by limiting current levels, program duration, and by including internal safety checks on impedance.

NIBS Guidelines

rTMS

The first guidelines for safe use of rTMS were published by Wasserman et al based on a conference held at the National Institutes of Health in 1996 and were published in 199815. Following the publication of these guidelines, reports of the use of rTMS dramatically increased, so in 2008 another consensus conference was held to update the safety guidelines.16, and a third update from a conference in 201817. Following this latest update, there were nosignificant changes to as the 2008 recommended guidelines have proven safe for the prevention of seizures.

Summaries of the safety and stimulation parameter recommendations are presented in Tables 1 and 2.  Conventional rTMS should be limited to the stimulation intensities of 90% to 130% of motor threshold for the standard figure 8 coil.

 

Other safety guidelines are as follows:

1. Physiological monitoring of every subject undergoing rTMS is desirable when stimulation parameters exceed the guidelines.
2. Visual monitoring of subjects is mandatory to observe for muscle twitching.
3. Neuropsychological monitoring is strongly recommended when cumulative daily sessions of rTMS are administered.
4. rTMS should be performed in an appropriate clinical setting.
5. rTMS should be done under the supervision of a responsible physician.
6. Special precautions must be taken for rTMS provided in neuroimaging centers with MRI.
7. rTMS should be performed by personnel who are adequately trained.
8. Currently the only absolute contraindication for TMS/rTMS is the presence of metallic hardware in close contact to the discharging coil (such as cochlear implants or an internal pulse generator or medication pumps).
9. Hearing protection should be provided.
10. Patients with the following situations should be avoided: persons with epilepsy; vascular, traumatic, tumoral infections, or metabolic lesions of the brain, and administration of medications that lower the seizure threshold, sleep deprivation, alcoholism.
11. Conditions of uncertain or increased risk include: implanted brain electrodes, pregnancy, severe or recent heart disease.

TES Guidelines

Indications for use of tDCS with empirical support were published by a European group18 followed by an international review with publication of an “updated” set of guidelines in 2017, including discussion of ethical and regulatory issues19. The initial guidelines were limited by the lack of available study evidence to support Level A (definite efficacy) for any indication.

For level B (probable efficacy), guidelines were proposed as follows:

1. Anodal tDCS of the left primary motor cortex in fibromyalgia
2. Anodal tDCS of the left dorsolateral prefrontal cortex in major depression.
3. Anodal tDCSof the right DLPFC in addiction/craving.

Level C recommendations (possible efficacy) was proposed for

1. Anodal tDCS of left M1 in chronic lower limb neuropathic pain secondary to spinal cord lesion.

Conversely, level B evidence for absence of clinical effects for

1. Anodal tDCS of the left temporal cortex in tinnitus.
2. Anodal tDCS of the left DLPFC in drug resistant major depression.

The published guidelines from Antal et al (2017) suggested that safety considerations for tDCS must include parameters of the application, including the intensity, repetition timing, and duration of stimulation. tDCS effects depend on complex interactions between the targeted tissue area and its surroundings, pathology of the tissue, genetic factors, and even medication effects. While changing intensity of stimulation may change the efficacy of treatment, it may also change the direction of excitability of the nerve tissue targeted, potentially leading to the opposite of the intended effect.

In addition, as intensity increases, the induced electrical effect spreads to deeper areas of the brain and can affect neural networks other than the intended targets. By maintaining treatment within set parameters, unintentional consequences can be avoided.

Generally, by using low intensity stimulation combined with approved indications and standard montage applications, tDCS is felt to be extremely safe. Low intensity TES is defined as intensities <4 mA, a total stimulation duration of up to 60 min per day and using electrode sizes between 1 cm2 and 100 cm2, delivering 7.2 coulombs of charge to apply frequencies between 0 and 10,000 Hz²⁰.

Adverse Events for NIBS

rTMS

The main reported risks of rTMS are heating of tissue, magnetic energy affecting implanted ferromagnetic material, induced voltages in implanted wires causing tissue injury or device malfunction or damage, or various side effects including seizures, transient hypomania, headaches, transient hearing changes, transient cognitive/neurocognitive changes, burns from scalp electrodes.

Although rare, seizures are reported to occur in healthy subjects during and after rTMS sessions. Prior publications suggest that TMS delivered within recommended guidelines to low-risk individuals caused fewer than 1 seizure per 60,000 sessions²¹. rTMS-related seizures in general populations typically occur during or within a few minutes of stopping rTMS, and within the first few sessions of rTMS.

Given that seizures have been reported to occur in healthy subjects makes this risk more of a concern when applying these interventions to individuals with Traumatic Brain Injury (TBI), as these individuals are already at increased risk for seizures compared to the healthy population.

The risk of seizures is as high as 20% following TBI^{22,23, 24}, and seizure risk progressively increases with severity of injury. Because of the increased clinical likelihood of seizures in persons incurring severe TBI, many clinicians would be concerned about an intervention that may further increase seizure risk.

TES

The reported risks tDCS or tACS include tingling, itching, burning, transient skin redness, fatigue, headache, nausea, insomnia, pain at electrode site, skin burns, mood changes, irritability. More serious adverse events included mania/hypomania. There has been one report of a seizure in a 4-year-old boy with history of seizures controlled with antiepileptic medications who had a seizure 4 hours after a tDCS session²⁵. It is unclear whether the tDCS contributed to the seizure or not. Antal et al¹⁹ found that no serious adverse events, as reported in the literature, occurred in over 18,000 tDCS sessions. When reviewing conventional bipolar tDCS in human clinical trials, no reports of serious adverse events were reported in over 33,200 sessions. Therefore, Antal suggested “there is no solid evidence to suggest that the AE’s in patients or in vulnerable populations are significantly higher and different in magnitude in comparison to healthy subjects” although it was noted that in some studies in specific populations, the reported adverse events (AE) were higher. Concerns have been expressed however regarding the quality of AE reporting in clinical trials of TES.

Studies evaluating the use of tDCS in subjects with implanted intracranial devices have also been shown to be safe. Implanted devices in these subjects include various intracranial EEG electrodes and grids.

This review went on to state that implanted stimulators of the central and peripheral nervous system were deemed to be safe with TMS and as such tDCS with its lower intensities is unlikely to be associated with complications associated with implanted devices.

AE’s for NIBS after DOC

Despite an increase in the use of NIBS in individuals with DOC after TBI, there remains very little data published with respect to the safety of these interventions. Many of the published reports contain little data regarding safety monitoring and adverse events, leaving limited data with which to advance our understanding of the safety of these techniques.

As noted previously, the risk of seizures is as high as 20% following TBI. This risk increases with the severity of injury and associated factors. Given that individuals with DOC following TBI generally represent the most severely injured, it logically stands to reason that these are also the ones at highest risk of having seizures. DOC is often associated with a higher risk of other complications that may further increase this risk.

Additionally, due to the severity of injury, the DOC population often has more altered neuroanatomy even than other individuals with TBI. Widespread areas of cortical injury make occurrence of seizures more likely, as well as targeting areas for application of stimulation more difficult. Skull damage and surgical sequelae may also affect the pathways of electrical currents, making proper application and understanding of electrical stimuli both less accurate and ultimately alter the physiological effects of the treatment.

One other factor that limits our understanding of the risk of the interventions is the lack of placebo-controlled studies in this population. A recent study regarding the relationship between seizures and rTMS delivered to patients in a state of DoC after TBI is the only published study to date reporting a study of rTMS induced seizure risk, and is limited, like many studies in this area, by small sample size26. This study found a low-likelihood that a specific rTMS protocol exacerbates baseline seizure rates but also a strong correlation between occurrence of seizure and the presence of a ventricular shunt. It was noted that hydrocephalus is itself a risk factor for seizures, and placement of a ventricular shunt does not necessarily mitigate this risk²⁷. Although presence of shunts had previously been listed as a potential contraindication for rTMS, this was largely a theoretical risk, as no studies had previously been done.

 

Summary

Although NIBS interventions do not yet have FDA approval for clinical use in the treatment of DoC after TBI, there is little evidence to suggest that these interventions are unsafe to use in this population, particularly when given within the recommended clinical guidelines. Given the poor prognosis for recovery for individuals with DoC, if efficacy can be clearly demonstrated, it would justify the small risk reported. As tDCS has not been shown to be associated with serious AE’s, the primary concern remains the possibility of inducing a seizure with rTMS. The finding of low likelihood of rTMS exacerbating baseline seizure risk was based on a specific rTMS protocol and the finding of association between seizures and the presence of ventricular shunts suggests that use of rTMS in patients with shunts should be approached with extreme caution.

Limited sample size also limits our knowledge of safety of rTMS interventions, and it is hoped that further research will include more robust safety data to better inform our understanding of the risks. Ultimately, the decision to administer rTMS is left to the individual researcher or clinician. Also, almost all tDCS and rTMS studies are focused on short term outcomes, there needs to be further research on long term outcomes and possible consequences.

It is possible, for example, that seizure threshold is altered for a sustained duration following the rTMS treatments during which time some patients may require aggressive seizure hygiene (e.g., maintaining optimal sleep patterns, minimizing infections) and/or conservative pharmacological management where anti-epileptics are provided with pharmacological neurostimulants²⁸. The potential downside to this, however, is that these medications may also limit the efficacy of the treatment. Clearly, this is an area where more study is needed. Ultimately, we may find in the end that Dr. Galen was correct; electricity applied in the proper controlled protocols may prove safe and efficacious, and use of home electrical stimulation devices may help this unfortunate population on the road to enhanced, meaningful functional outcomes.

References

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Author Bio

David Ripley, MD, MS is the Chief Medical Officer of New Summit Rehabilitation and Healthcare. He brings extensive expertise in physical medicine and rehabilitation, with a focus on innovative therapies for brain injury recovery.  Throughout his career, Dr. Ripley has been dedicated to advancing the field of neurorehabilitation, integrating evidence-based practices and cutting-edge treatments to improve patient outcomes. At New Summit, he oversees the development and implementation of comprehensive care plans that address the complex needs of individuals with traumatic brain injuries and other neurological conditions. Dr. Ripley is recognized for his commitment to patient centered care and his leadership in driving excellence in rehabilitation services.