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Emerging Technologies and Indications of Neuromodulation and Increasing Role of Non Invasive Neuromodulation
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.302453
Keywords: Neuromodulation, focused ultrasound, Transcranial magnetic stimulation, external neuromodulation
Neuromodulation is a rapidly developing field that uses targeted electrical, mechanical, magnetic or thermal stimulation of the nervous system in order to alter firing neuronal and interneuronal connectivity properties to address a diversity of neurological disorders. The alteration or modulation of function by inducing an anatomical or functional change will modulate the nervous system circuits. Circuits of the brain, spinal cord and peripheral nerves have been shown to be responsive to these intervention, with every part of the nervous system as an optional target. The different types of neuromodulation approaches are categorized into three groups: invasive (DBS, deep brain stimulation and SCS, spinal cord stimulation), minimally invasive (such as VNS, vagal nerve stimulation) and non-invasive (such as Trans magnetic stimulation). Noninvasive neuromodulatory devices include electroconvulsive therapy (ECT), transcranial electrical stimulation (TES), transcranial magnetic stimulation (TMS), static magnet stimulation, transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation, ultrasound and focused ultrasound (FUS), peripheral nerve stimulation, including stimulation of the cranial nerves. Noninvasive neuromodulation techniques are most well developed in the field of psychiatry. However, there is a wide range of applications for neurorehabilitation and the for the treatment of a diversity of neurologic disorders. While the precision and long-lasting effect of invasive neuromodulation are established, drawbacks related to intraoperative risk such as hemorrhage, hardware malfunction and infection cannot be ignored. The non-invasive techniques have surfaced as an alternative due to its high safety and feasibility profile. In this article, we will discuss the different emerging technologies in neuromodulation and the increasing role of non-invasive neuromodulation [Table 1].
Mechanism and advantages Sound wave frequencies above the range detected by the human ear, generally those exceeding of 20 kHz, are termed “ultrasound”. These sound waves, in addition to being used as a diagnostic tool, can be applied as a therapeutic tool in non-invasive neuromodulation, an idea that was initially introduced by William and Frank Fry in the 1950s.[1] Originally, the idea included making a cranial window in the skull (craniectomy), however it was later discovered that ultrasound can be delivered in lower intensities through the intact skull, transforming this intervention into a non-invasive technique. Focused Ultrasound (FUS), in high or low intensities (HIFUS/LIFUS), modifies the function of the nervous system by delivering a sufficient amount of acoustic energy trans-cranially into a precise brain region. FUS offers many advantages, including low cost, submillimeter resolution (while other non-invasive neuromodulation techniques such as TMS achieve 1-2 cm resolution),[2] rel time thermometry and inherent imaging and is therefore continuing to emerge as an important platform for neuromodulation. High intensity focused ultrasound (HIFU) and low intensity focused ultrasound (LIFU) HIFU describes an ultrasound intensity that is sufficient to damage tissue and produce permanent lesions in the brain through mechanical destruction, thermal heating or both,[2] and has applications for treating brain cancers. Low intensity focused ultrasound (LIFU) typically has an intensity lower than 100 W/cm2, is administered either continuously or intermittently and has a wide scope of effects based on suppression and excitation of neural activity. Other currently used methods of brain stimulation have barriers that LIFU enables us to overcome, like low spatial resolution (TMS and TCS), lack of ability to penetrate deep into the brain (TMS) or entail invasive processes (DBS).[3] Advantages of FUS include spatial specificity and depth penetration, combined with a lack of pathological changes on histology and reversible effects.[4] While the reigning explanation points at LIFU neuromodulation as having a nonthermal mechanical mechanism, this is still a subject of debate. It is theorized that mechanosensitive ion channels may cause changes in neuron firing,[2] along with other mechanisms that play varyingly large roles in the end result of this technique. There has been growing interest in applying LIFU neuromodulation for treatment of neurological or psychiatric disorders, stemming from its bi-modal neuronal activity. During the past decade, there have been both animal and human trials, showing the span of possibilities that can be achieved using LIFU. Studies in 2011-2015 showed Electro Encephalo Graphic (EEG) suppression in rabbits and rats. Min et al. exhibited, in a rat epilepsy model, partial inhibition of seizure activity.[5],[6] Human EEG studies conducted during the same period showed a similar phenomenon.[4] In 2014, Legon and colleagues showed that FUS could also be used to focally modulate human cortical function, demonstrating enhanced performance on sensory discrimination tasks.[7] The first time LIFU neuromodulation was used to exhibit an effect on neural network activity in humans was in 2017, by Sanguinetti and colleagues.[8] Their results showed enhancement of participants’ mood, suggesting that this method could be used to treat mood disorders. Another approach that has been the focus of recent studies utilizes magnetic resonance guided LIFU to temporarily open the Blood Brain Barrier (BBB) in order to enable local drug delivery within the brain or washout different toxic molecules into the Cerebro Spinal Fluid (CSF). The BBB serves as a barrier that restricts molecular passage only to specific molecules necessary for brain function. As a result, it blocks 98% of all small molecules, making the BBB one of the largest bottlenecks in the development of neuropsychiatric, neuro-degenerative and neuro-oncologic therapies.[9] BBB opening is achieved by intra venous injection of microbubbles and applying short, low frequency ultrasound pulses to the targeted site. This combination causes a mechanical formation of pores within the endothelium, which in turn open the tight junctions that form the BBB.[10] The majority of current studies on this topic, spotlight on the use of FUS BBB opening to deliver chemotherapeutic agents in the treatment of brain tumors. This approach is also being investigated in diseases such as Parkinson's disease,[11] Alzheimer's disease and amyotrophic lateral sclerosis.[12] Opening of the BBB with LIFIU has shown promising results in early stage human clinical trial.[6],[13] The main advantage of low-intensity focused ultrasound is that it can be delivered deep into the brain without causing permanent damage or effects, thus lowering the bar for testing and brain mapping [Figure 1].[14] Also being under investigating is the use of ultrasound's mechanical effects to activate or inhibit brain circuits.[13]
Safety concerns surrounding LIFU originate from the fact that acoustic energy of FUS can transform into thermal energy, mechanical force or even cause tissue cavitations.[4] As opposed to HIFU which uses these energy transformations (typically the thermal effects) in order to cause ablation, LIFU uses much lower levels of energy and therefore the possibility of tissue damage is substantially reduced. Multiple studies that examined tissue targeted with LIFU at the histological level showed no damage.[15] While the FDA has published regulations for maximum allowed parameters of sonication, no long-term safety studies have been performed, as can be expected with an emerging technology. HIFU uses high frequency delivery of ultrasound waves into deep structures in the brain. During the last decade several animal models have been developed to demonstrate the possibility of treating intracerebral hemorrhage and different neurological disorders with this modality.[16],[17] These models were later used as the core for treating movement and oncological disorders with HIFU. MRgHIFU has thermal ablation applications for treating brain cancers.[18] Other applications include treating neurologic disorders, such as Essential Tremors, Parkinson's disease and Dystonia where by ablation of a specific brain area can lead to significant symptom improvements.[11],[19] It can also be utilized for delivering drugs with shorter FUS pulses by opening the blood brain barrier (BBB) via mechanical mechanisms.[6] Future applications of FUS include the potential to be a novel approach in manipulating CNS networks involved in treatment of chronic pain[20] and the possibility of using subthreshold sonications to interrogate parts of the brain not previously accessible for electric stimulation,[21] among others.
TMS is also known as repetitive transcranial magnetic stimulation (rTMS). TMS was introduced in 1985 by Barker and colleagues as a non-invasive and painless method of electrically stimulating the human motor cortex.[22] It's neuromodulatory effect results from multiple high-intensity magnetic pulses delivered to the brain, causing an electric current at a specific area of the brain through electromagnetic induction. An electric pulse generator (stimulator) is connected to a magnetic coil that is attached to the scalp. The stimulator generates a changing electric current within the coil which induces a magnetic field. This field then causes a second inductance of inverted electric charge within the brain itself. The physiologic effects of brain stimulation extend far beyond the site where stimulation is administered. Later, it was discovered that changing the frequency alters the effect on the brain, which results in different therapeutic approaches for a variety of conditions.[23] Mechanism of Action The exact mechanism of action is still not clear. current evidence points toward its role in causing long-term inhibition and excitation of neurons in certain brain areas.[24] TMS uses an extracorporeal magnetic coil to produce electric currents inside the brain via electromagnetic induction. Traditional ring and figure-8 coil designs suffer from diffuse fields that decay exponentially in amplitude as they continue deep to the surface of the brain, limiting their scope to the cortical surface. More recent coil configurations, for example the H-coil, provide potential for stimulating deeper brain targets.[25],[26] Applications The application of TMS can be utilized for diagnostic proposes or therapeutic uses. AS a diagnostic tool, TMS can be used to localize motor and sensory areas in the brain. It can also help in localizing lesion level within the nervous system in conditions such as stroke, injury, or demyelination/sclerosis.[27] As for the therapeutic applications of TMS, it is useful in the treatment of chronic psychiatric and neurological conditions, such as major unipolar depression and obsessive-compulsive disorder (OCD). There have been reports of the role of TMS in chronic schizophrenia in controlling intractable hallucinations and negative symptoms, as well as a therapy for treating migraine. The FDA has approved the use of a portable hand-held TMS device for the acute and preventive treatment of migraine. A randomized, double-blind, parallel group, sham-controlled trial showed TMS to be effective in treating migraine with aura patients, attaining sustained pain-free response rates at 24 h and 48 h post-treatment. Its efficacy was also shown by an open-labelled study as an acute treatment with non-aura migraine patients. Recent post-market studies also pointed to the fact that TMS may be an effective option for migraine prevention.[28] Other therapeutic uses include treatment of anxiety disorders like post traumatic stress disorder (PTSD) and substance use disorders.[29],[30] There are also studies investigating the therapeutic application of TMS in children, including epilepsy, Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, schizophrenia, and Tourette syndrome.[31] Safety and efficacy Overall, TMS is a safe procedure. Some TMS stimulation protocols have been associated with discomfort in patients.[32] The most commonly reported side effect of rTMS is mild headache with no harmful cognitive side effects.[33] Advantages In addition to the safety benefits of all non-invasive technique, TMS is also a flexible tool. Depending on the specific target and stimulation parameters, TMS has the ability to induce short and long term, facilitative or suppressive, neuronal and behavioral effects.[34] It is also cost-effective.
The Vagus Nerve (VN) travels from the medulla to the colon and serves as a major parasympathetic branch of the autonomic nervous system. It plays a key role in maintaining the psychophysiological balance by regulating breathing, heart rate and digestion, among other functions. VN stimulation (VNS) has been used to present the role of the VN in pain, memory and mood and is therefore applicable in a wide range of disorders. The potential of VNS has been exhibited in refractory epilepsy and depression, and is being investigated in headache, arthritis, asthma, bipolar disorder and dementia.[35] Both invasive and, more recently, non-invasive VNS devices have been developed as a way to avoid surgical implant related complications (bradycardia, asystole, lead migrations and infection) that can occur during surgery and impedance testing.[36] These complications, although rare, highlight the importance of non-invasive approaches to VNS. Non-invasive VNS (nVNS) is suggested to be an alternative and can potentially pull VNS forward as a first-line treatment. Mechanism New nVNS devices target one of the two branches of the VN: the cervical branch at the neck or the auricular branch at the concha of the outer ear, the latter being more recently studied.[37],[38] These devices rely on the cutaneous distribution of vagal fibres at their location (cervical or auricular). The treatment entails the use of a portable neuromodulation device that emits a transcutaneous pulsating low-voltage electric signal.[38] Cervical VNS most likely stimulates both efferent and afferent vagal fibers in the carotid sheath, while auricular VNS stimulated the auricular branch of the vagus nerve (ABVN), also termed “Arnolds nerve”.[36] The mechanism of auricular nVNS is thought to have its therapeutic effects as a result of concentration shifts of the neurotransmitters noradrenaline, g-aminobutyric acid (GABA) and acetylcholine (ACh) in the CNS, which induce neuroplastic changes in the cerebral cortex.[38],[39] Techniques of nVNS differ in their parameters and protocols, leading to many unanswered questions regarding this approach. The underlying neurophysiological mechanisms are still poorly understood and there is no solid evidence regarding the optimal position of stimulation for best clinical results.[40] Therefore, further large studies are imperative in order to continue the development and widen the clinical use of this technique. Applications Prevention and treatment of stress-related psychiatric disorders is a promising indication for nVNS. While efficacy of invasive VNS for treatment of these disorders has been shown in treating depression and epilepsy and has been approved by the FDA, disadvantages such as cost and the invasive nature of the procedure have limited its implementation.[34],[41] The value of both cervical VNS and auricular VNS is being studied for treatment of schizophrenia, obsessive-compulsive disorder and depression and human studies also imply improvement of hyperarousal in PTSD patients with mild traumatic brain injury.[42] Non-invasive VNS holds promise as an emerging, widely applicable treatment in psychiatry.
Obstructive Sleep Apnea (OSA) is a medical condition with serious health ramifications, including an increase in mortality, and is characterized by repeated partial or complete collapse of the upper airway during sleep.[43],[44] Upper airway stimulation (UAS) targets the Hypoglossal nerve, which causes the contraction of the genioglossus muscle, resulting in protrusion of the tongue base and opening of the airway in the retroglossal region.[43] However, the exact mechanism, including the effects on retropalatal areas, is not known. This intervention has emerged as an alternative for conventional therapies like CPAP (continuous positive airway pressure), preventing obstruction and improving airflow and quality of life. There are both invasive and non-invasive methods of UAS. Invasive stimulators typically include a circumferential nerve cuff electrode, a stimulation lead and an implantable pulse generator. The non-invasive technique uses unipolar or bipolar electrodes on the skin of the submental region to directly stimulate the genioglossus muscle. The first study on non-invasive UAS was conducted by Miki H et al. and had promising results stating a significant reduction of the apnea index and apnea time per total sleep time.[45] Other studies also published optimistic outcomes.[46],[47] However, other groups have published contradicting results to these improvements in symptoms.[48],[49],[50] The first randomized sham-controlled trial that proved the efficacy and tolerability of this treatment was published in 2016 by Pengo et al., making this an approach that can potentially serve as a viable, low morbidity alternative for patients with moderate to severe OSA who have low tolerance for CPAP or cannot undergo surgical procedures.[51]
As the population gradually ages, interventions like neuromodulation that improve quality of life with comparatively small risks, make increasingly more sense clinically.[52] The constant development of new, non-invasive approaches, such as those detailed in this paper, gives rise to substantially safer and more cost-effective alternatives to standard treatments. Even though some of these new approaches, such as non-invasive upper airway stimulation, still have a substantial way to go before they will be widely available clinically, they demonstrate promising findings and proof the growing role of non-invasive neuromodulation. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1]
[Table 1]
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