[test] Future treatment of Neurological disorders: Neuromodulation through Deep Brain Stimulation by Alexandra-Maria Tautan

In recent years, neuromodulation has proved to be a feasible alternative in the treatment of the increasingly common neurological conditions. This essay describes deep brain stimulation as a treatment option for neurological disorders. First, a brief history of brain stimulation is presented followed by a description of the mechanisms of action and the surgical procedure. The current technology is not perfect and many of the complications which arise from deep brain stimulation are hardware related. These complications can be addressed by the further development of intelligent leads, new power generation methods and a less invasive technique.

Although neurological disorders have been studied for a long time, the number of patients suffering from these conditions continues to increase. It is estimated that around 27% of the adult population from Europe, aged between 18-65, currently suffers from a mental disorder [1]. During the next 40 years the population aged over 60 will nearly double and the number of patients suffering from neurological disorders will thus increase [2]. Most neurological disorders are chronic conditions which might cause severe physical and emotional disability. They affect not only the patients but also their families and caregivers, as they require constant attention and treatment, having a huge impact on the proper functioning of an individual in society. As millions of people around the world are affected by neurological disorders, the burden they bring on the health care system is also enormous. Chronic neurological conditions account for over one third of the global chronic disease health burden [3]. The majority of costs however come from outside the formal health care sector due to reduced productivity during work years and to early retirement [4]. Thus, neurological disorders directly affect the patients, the people surrounding them and have a huge economic impact. In order to reduce their effects, viable treatment options need to be provided.

Neurological disorders represent disorders of the central or peripheral nervous system. Basically, they can be considered damage to the whole or part of the nervous system, due to structural, biochemical or electrical abnormalities. The disorders might imply a change in the circuitry of the neural pathways, which makes the treatment of these conditions much more difficult as the physical connections between neurons are no longer present or they are entirely changed. Although there has been extensive research carried out in the field of neurology, many aspects of the inner working of the central nervous system still remain unknown. Thus, scientists are encountering difficulties in providing efficient solutions in the treatment of neurological conditions.

So far, medication is one of the most commonly used methods in the treatment of neurological disorders. Due to the advancements in neuropharmacology, numerous treatment options are given to patients to improve their overall lifestyle. However the adverse effects of drugs are not to be neglected. As most medicine is systemically administrated, it affects the health of the entire body and most of them require the ill to drastically limit their lifestyle choices. Furthermore, about 20% of patients are not responsive to medication or become resistant to treatment over time, along with the progression of the disease [3]. In these cases, neuromodulation might be a viable solution.

Neuromodulation is considered a new method of treatment for neurological disorders which involves the direct application of electrical, chemical or biological stimuli to the affected region of the nervous system. These stimuli are more often applied through a surgically implantable device. Sakas, Panouris and Simpson define neuromodulation as the procedure of “altering electrically or chemically the signal transmission in the nervous system by implanted devices in order to excite, inhibit or tune the activities of neurons or neural networks and produce therapeutic effects” [5]. The diseases treated through this method range from chronic pain to movement disorders and even psychiatric disorders like the obsessive-compulsive disorder or depression. One type of neuromodulation is deep brain stimulation (DBS). This method delivers targeted, adjustable electrical impulses to the brain through surgically implanted electrodes in order to gain therapeutic benefits.

This essay aims to describe neuromodulation performed through deep brain stimulation. The existing DBS techniques have been successfully employed in the treatment of several neurological disorders like advanced Parkinson’s disease, dystonia or epilepsy. Due to the fact that this type of neuromodulation has a number of drawbacks, the patients selected for this kind of treatment are generally those for whom all other treatment methods have failed or their impaired physical or emotional functions do not allow them to live a normal life. The reasons for this will be explained later when the advantages and disadvantages of deep brain stimulation will be presented. Some improvements which might make DBS feasible for large scale usage in the treatment of moderate to advanced neurological disorders will also be discussed.

Although there have been many theories throughout history regarding the driving force of neural activity, bioelectricity was first observed in the 18th century by L. Galvani. While conducting experiments with static electricity, one of Galvani’s assistants touched an exposed sciatic nerve trunk of a frog with a charged scalpel and thus made the animal’s leg muscles twitch. This experiment led A. Volta to establish a connection between animation and electricity and thus define bioelectricity in his treaty published in 1791 [6]. Along with the desire to learn more about the neural electrical activity, the interest of modifying normal activity through applying an electrical stimulus also developed. The first experiments were conducted on animals as early as 1870 by Fritsch and Hitzig who reported successful results in the stimulation of the cerebral cortex of a dog.

The first stimulation of a human brain occurred in 1874, when Bartholow applied an electric stimulus to the exposed brain of a patient [3]. More developments where noted along with the better understanding of the neural system’s organization. Once certain functions where mapped to certain regions of the brain, it became obvious that applying the right stimulation could lead to the desired manifestation. The first case of chronic deep brain stimulation was documented in 1969 in the treatment of movement disorders [3].

Although the connection between electricity and the neural tissue has been known for some time, the development of an accurate chronic brain stimulator occurred only in the 1980s [7]. This was partly due to the absence of stereotactic surgeries but also to the fact that the functioning of the brain, of the neural pathways was not understood. Even today the full working principle of deep brain stimulation (DBS) still remains uncertain.

The brain is formed of complex neural connections and so, it can easily be compared to a complex electrical system. Figuring out the characteristics of neurocircuitry provides the key to understanding the underlying principles of deep brain stimulation, as neurological disorders can be described through various modifications in the circuitry of the brain [5]. When a neurological disorder can be pinned to a certain region of the brain, applying an electric stimulus proves to offer therapeutic effects. Performing DBS proved to have similar effects as the ablation of neural tissue, only in this case the procedure does not cause lesions to the brain but provides a means of performing reversible therapy with adjustable characteristics [8]. The mechanism of action probably involves several submechanisms which combined give the beneficial result [9]. The electric impulse may cause the abnormal oscillations of the neurons to cancel while modifying their firing rate [10] and/or jam the neuronal message [11]. Also, by applying high or low frequency excitation, neurotransmitors and hormones can be inhibited or produced [12].

Each neurological disorder affects the functioning of the brain differently and so, the location of the anomaly it causes is different. DBS is applied in several regions in accordance to the symptoms it has to treat. For instance, in the case of Parkinson’s disease, the most commonly used sites for stimulation are the subthalamic nucleus (STN) and the globus pallidus interna (GPi). The STN plays an important role in the control of movement as it receives input from the motor and premotor areas of the cerebral cortex and provides output to the GPi [13]. An over-activity of the STN neurons causes the life-altering symptoms associated to Parkinson’s disease. By applying a high frequency stimulus to the STN, the abnormal activity of the GPi responsible for motor impairments is reduced by silencing the subthalamic neurons [13],[14]. In the treatment of dystonia, the most often targeted region is the GPi, although sometimes the thalamic stimulation is also used [15]. By stimulating regions like the anterior nucleus (AN) of the thalamus, centromedian (CM) thalamus, STN and hippocampus, epilepsy can successfully find a treatment [3].

Besides the treatment of Parkinson’s disease and dystonia, DBS has found many other clinical applications including the treatment of major depression, Tourette’s syndrome, obsessive compulsive disorder, chronic pain and even improvements in the treatment of Alzeihmer’s disease [3], [16], [17]. Due to the advantages it brings, this technique has been tried on many different disorders of the nervous system despite the lack of understanding of its working principle. Many of the patients suffering from neurological disorders are dependent on medication. However, in the case of Parkinson’s disease and other diseases the symptoms cannot always be controlled through medication or the drugs have severe side effects. It is estimated that about 30% of the patients suffering from epilepsy are unresponsive to medication or experience adverse effects [18]. Moreover, in some cases, the epileptic focus is very widespread or it superimposes on important parts of the brain making ablation of the tissue impossible. An implantable neurostimulator can help in this case to ameliorate the symptoms. As the causes of dystonia are not yet known, an effective treatment has not yet been developed. DBS has been used effectively to alleviate the symptoms of this disease.

A typical DBS system is formed of three main components: the stimulator lead, the implantable pulse generator and an extension which connects these two components (see Fig.1). The lead is made up of thin coiled insulated wires with a number of electrodes at the tip made up of platinum-iridium, which are placed on the targeted areas of the brain. The extension is connected to the lead and is run subcutaneously from the head, through the neck and into the chest. The conductor wire can be made up of a silver core which has no connection to the human tissue, and insulated in a layer of silicon rubber. The implantable pulse generator is a battery charged, programmable device that provides the electric impulse pattern necessary for stimulation. It is encased in titanium and is placed in the chest, under the collar bone [19].

The surgery required for the implantation of a deep brain stimulator should be as minimally invasive as possible. The approach depends on the surgical team, but the main steps are common to all. In the first stage, the patient is awake. After placing the stereotactic frame, standard imaging techniques are used to determine the exact coordinates of the target. These imaging techniques include CT scans, MRI or ventriculographies and they determine the site for the skin incision and burr hole placement in order to target the right area of the brain. The trajectory is chosen in such a way as to avoid important blood vessels which might cause severe hemorrhages if hit [3]. The exact target location is identified with the help of a test electrode which is inserted through the burr hole. Tests are carried out to observe where the most pronounced effect is obtained at the lowest stimulation intensity [20]. During these tests the physician also observes if any other side effects appear due to the stimulation, like additional uncontrolled movements or any other speech or cognitive impairments. After the location is identified, the coordinates are recorded and the permanent electrode is inserted.

In the second stage, the patient is placed under general anesthesia. The extension is connected to the lead and is tunneled subcutaneously to the neurostimulator. The neurostimulator must be placed under the collar bone at a certain depth.Generally, this depth deends on the specifications of the device (due to telemetry or a rechargeable battery) [19].

Although there are important benefits to DBS, there are also associated complications which must be taken into account. These might be immediate side-effects due to the placement of the device (like bleeding or strokes) or to a wound infection caused by the exposure of the brain or other tissue. The latter is prevented by the use of antibiotics. Long-term complications due to hardware malfunctions can also appear. The wire or cable of the DBS system can break or can migrate, situations which require an additional surgery for replacement or anchoring. Erosion of the cable through the skin can also appear at patients which do not have an adequate amount of soft tissue under the skin. This problem leads to the removal of the stimulation system [21]. A deep brain stimulation follow-up study lasting over a period of 33 months showed that 25% of the patients encountered hardware-related complications due to the electrodes and cables [22]. Another possible long-term effect of DBS is the increase in the “likelihood of functional disruption or habituation due to continuous stimulation” [18].

One of the biggest discomforts of patients using DBS therapy is the battery life. On average, the batteries are depleted after three to five years of usage, depending on the condition it is treating. For instance, the treatment of dystonia requires more energy for stimulation [15], thus the battery must be replaced more frequently making the patients subject to yet another surgery. Recurrent surgeries might prove to be a problem due to the side-effects of anesthesia and to the fact that a great majority of patients are over the age of 60.

In order to make the treatment of neurological conditions through DBS more reliable, the technology used to apply the electric stimulus must be improved. With the use of nanotechnology in the development of the pulse generator and the battery, all cables could be removed, eliminating the need of a distant neurostimulator. More efficient ways of battery recharging can also be investigated. The next section presents three options to improve the deep brain stimulation system

At the moment, most chronic deep brain stimulation is open loop which means that the electrical stimulus is programmed either by the physician based on prior observations or is controlled and activated by the patient when required. The development of a closed-loop system allows the neurostimulator to receive feedback in order to properly adjust the stimulation parameters. This kind of responsive stimulation reduces the risk of habituation or functional disruption [18] caused by continuous stimulation and reduces the consumption of energy, increasing the battery life. Also, it increases the autonomy in the daily life of the patients, as less interference is required.

Closed loop systems for adaptive stimulation could prove to be extremely useful in the treatment of epilepsy. Several studies have shown that applying the electric stimulus at a specific time can be more efficient than providing continuous, scheduled or randomized stimulation [18]. In 2008, a clinical trial tested a deep brain stimulation system, the NeuroPace RNS system, which provided real-time feedback by detecting seizures from electrographic input. The neurostimulator was a battery powered, microcontroller device which continuously monitored electrographic activity. When the number of detected waves which exceeded a certain amplitude or duration was larger than the number preprogrammed by the physician, an electric stimulus was provided. The study showed “preliminary evidence of efficiency” [18], as there were no unexpected side effects due to the device. Another way to automatically control the treatment of epileptic seizures is by monitoring cardiac activity. By determining if the cardiac output has a magnitude or a shape inconsistent with day-to-day physical activity, the neurostimulator can provide the required electric stimulus, as abnormal cardiac activity is an indication of an imminent seizure [23].

Other diseases could also be treated with the development of a feedback controlled stimulation system. A self-adaptive system for the automatic detection of discomfort and automatic generation of chronic pain control has been described in a U.S. patent [24]. Although the invention was initially designed for pain management through spinal cord stimulation, the principal can also be applied to DBS for the control of essential tremor or Parkinson’s disease. Pain is a subjective feeling and furthermore it can modify in time, making it hard to quantify. However, pain causes physiological reactions which can be measured. The device provides feedback through several sensors some of which measure parameters like: temperature, blood pressure, heart beat, skin conductance, EEG etc. .These inputs are analyzed and proper feedback is provided to the system to accurately deliver the stimulation. The same principle might be used when treating movement disorders or psychiatric disorders like depression, schizophrenia or anxiety disorders [25]. The state of a patient is monitored, and when drastic changes occur in comparison to a reference state, the stimulation is applied.

Movement disorders can be treated adequately using tremor detection based on accelerometer signals. The sensors that provide feedback are accelerometers integrated in small devices or even into the clothes of the patient. They could be worn as bracelets for wrists or ankles or they can be implanted subcutaneously [26]. A number of these types of sensors (nodes) can form a Body area sensor network (BASN) which can provide information from within or in proximity to the human body. BASNs provide great opportunities for the development of closed-loop systems for deep brain stimulation, as they are currently studied for a number of healthcare related applications [27].

Sensors incorporated into the lead system can also provide advantages. By detecting changes in the impedance of the electrode-tissue interface, the magnitude of the electric stimulus can be adjusted to provide proper treatment. A change in the impedance can show an obstruction of the current flow and thus the quantity of electric stimulation needed changes [28]. By adaptively applying the stimulus, the treatment is more efficient and the battery life is increased.

As stated before, one of the greatest drawbacks of the current deep brain stimulation technology are the recurrent surgeries needed for battery replacement. The lifetime of the battery is strongly dependent on the type of condition that is being treated (on the impulse required and the duration of the stimulation). A good solution to the power related problems could be the use of energy harvesters. These devices exploit natural or artificial power sources around the individual to recharge or even replace the batteries. Several energy harvesting technologies offer promising perspectives.

Naturally occurring temperature differences inside the human body can prove to be a good alternative to conventional batteries, as they can be exploited through devices based on the Seebeck effect. When two different metals or semiconductors experience a temperature difference, a voltage drop appears across them [29]. When two of these types of materials are put together, they form a thermocouple. An energy harvester based on the thermoelectric effect is made up of many thermocouples placed electrically in series and thermally in parallel, forming a thermopile. When implemented as power sources for implantable stimulators, these thermopiles could exploit the temperature difference between the core of the body and the temperature of the skin. Even though the temperature difference is only of 1˚C, the power generated can be around 70-100μW [30]. However, the power range that can be obtained using the temperature differences from the human body is quite limited and generally does not exceed the microwatt range [29].

Some of the most studied methods for power generation in implantable devices are those making use of inductive links. This type of technology makes use of two coils: one inside the body and another one on the outside. The external coil generates a magnetic field due to an alternating current flowing through it inducing an electromagnetic force in the implanted coil [29]. Additionally, a two way data transmission link is formed, for download and upload of information from inside to outside the body without the need of supplementary equipment. The only requirement is that the frequencies used should be in the order of a few megahertz, to avoid the absorption of the signal by the tissue [31]. Medtronic has already developed a spinal cord stimulator, Restore Ultra, powered by a rechargeable battery functioning on the principle of inductive links. The life of the neurostimulator was increased to nine years and the recharging is performed by the patient using a recharger every two weeks [32]. This improvement increases the comfort of patients wearing implantable stimulators and reduces the costs which otherwise would be required for additional surgeries. Future developments might employ the same principles in the case of deep brain stimulation systems.

Other power harvesting techniques are also intensively investigated, techniques including fuel cells, batteries powered by infrared radiation [29] or body motion [33]. The ideal case will be when power harvesting techniques can solely provide the entire power required to drive the deep brain stimulation system. Although at the moment none of the power harvesting methods provides sufficient energy to power neurostimulators on their own, combined with conventional batteries they can prolong the battery life.

A large number of patients using DBS systems encounters complications due to the cables connecting the leads to the distant pulse generator. If the leads and the pulse generator could be incorporated into a single component, the complications due to hardware related malfunctions could be significantly reduced. Recent advances in nanotechnology opened new possibilities for the development of microstimulators.

Advanced Bionics manufactured a new type of stimulator, the Bion microstimulator. Having the mass of only 1 gram, the Bion is much smaller than traditional stimulator devices. It incorporates a rechargeable battery, a radio and antenna for data transmission, a programmable microchip and stimulating electrodes [34]. The invasiveness of the procedure is reduced as it can be directly positioned at the site of the stimulation. The size of the microstimulator allows it to be implanted through a small incision or through injection [35]. The complications associated with traditional neurostimulator systems, like lead misplacement or erosion, are thus avoided. The Bion has been investigated for clinical applications in urinary urge incontinence, chronic headache and peripheral pain [34]. Future developments might find uses for the Bion in the treatment of other neurological conditions which are now addressed with a traditional deep brain stimulation lead system, conditions like epilepsy, Parkinson’s disease or dystonia.

As the number of people suffering from neurological disorders will increase in the near future, neuromodulation seems to provide a viable alternative to traditional pharmacological cures. Deep brain stimulation, neuromodulation through electrical stimulation of the brain, is currently employed in the treatment of several neurological disorders. The essay looked into the possibilities offered by deep brain stimulation by describing the implantable system and some possible mechanisms of action. Even though it’s working principle is not fully understood, positive results were obtained in the treatment of several neurological diseases. The current technology indicates that many improvements can be made, as a lot of the complications caused by DBS arise from hardware problems. Future developments should focus on the refinement of the lead system, the discovery of self-rechargeable power sources and the development of a less invasive technique.

Present state of the art technology can already give a glimpse of what the future may look like. By combining the already available Bion technology with the latest developments in the design of closed loop systems and power generation methods, deep brain stimulation can be made available to a much larger range of medical applications. The second stage of the DBS surgery can be eliminated as the battery and neurostimulator would no longer have to be implanted under the collar bone. General anesthesia would no longer be required, making the surgery available to more people, regardless of age. The job of the surgeon will be made much easier and patient recovery time will be shortened. Finally, the patient could be less dependent on medical treatments, allowing more freedom in lifestyle choices. Gaining a better understanding of the functioning of the brain and combining it with new and innovative technologies could make diseases like Parkinson or Alzheimer curable, allowing patients to live unaffected by symptoms.

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Alexandra-Maria Tautan