By Jeffrey Nishida
Bio: Jeffrey Nishida is a senior in USC's biomedical engineering program, originally from Honolulu, Hawaii. Over the past year he has worked in Dr. Sanger's lab, which specializes in pediatric movement disorders. Jeffrey has been working on analyzing EEG readings of evoked potentials created by low frequency DBS in pediatric patients with dystonia.
Keywords: Deep Brain Stimulation, stimulators, neurology, brain, Parkinson's Disease, dystonia, epilepsy, depression, electrical stimulation, high frequency stimulation, neuron, basal ganglia, biomedical engineering
Suggested Multimedia: An animation of pulses moving from an IPG, up the extension, down into the leads, and stimulating a cluster of neurons between two of the four electrodes at the end of the lead resulting in high frequency neuron stimulation
Deep Brain Stimulators (DBS) are a relatively new medical device where implantable electrodes are placed deep into the brain to provide high frequency electrical stimulation to a target cluster of neurons. This stimulation is effective in treating a surprisingly wide variety of neurological disorders including epilepsy, depression, memory-loss, and most prominently, movement disorders. The mechanism of DBS action is poorly understood and continues to confound researchers even to this day and continues to reveal new insights into neurological pathways and disorders.
Introduction
When most people hear about electrical stimulation for neurological disorders, they often picture scenes from
One Flew Over the Cuckoo’s Nest
or “American Horror
Story: Asylum” where the shock "therapy" is a thinly veiled torture device ran by depraved psychiatrics. In reality, electrical stimulation has proven to be a safe, effective treatment for several neurological illnesses including Parkinson’s, depression, and epilepsies. Prominently, Deep Brain Stimulation (DBS) has shown remarkable efficacy and is now used in over 40,000 people worldwide [1]. DBS involves implantable medical devices that stimulate specific areas of the brain with high frequency impulses. Research

in DBS has not only improved patient livelihood, but has also led to better understanding of neurological pathways. While highly effective in many disorders, the exact mechanism for how Deep Brain Stimulation works is still unknown and shows just how little we actually understand the human brain.
A Brief History:
Electrical stimulation of the brain has been a growing therapeutic method since the early 20th century. In 1948 J. Lawrence Pool implanted a stimulator electrode into an elderly woman diagnosed with depression and anorexia, marking the first recorded use of an implanted system to be used on a human brain. The stimulator was used daily for 8 weeks and was found to have positive therapeutic effects [1].
In the late 1960's Rolf Hassler found that electrical stimulation of the pallidus, a neurological structure in the motor pathway, during routine ablation surgery caused tremors that sometimes overpowered anesthesia. Surprisingly, it was found that low stimulation (<30Hz) caused tremors, while high frequency stimulation (>100Hz) reduced tremors [1]. This discovery led to the realization that electrical stimulation could be used to combat movement disorders.
Based on these findings, in 1973 Irving Cooper implanted the first generation of
Deep Brain Stimulation (DBS) devices in several epileptic patients. The devices were made to stimulate the cerebellum with high frequency impulses generated from an exterior battery pack. Emboldened by the positive results of his experiment, Cooper expanded DBS to include patients with chronic pain, spasms, and dystonia [1].

However, it was not until 1987, when Alim Benabid demonstrated stimulation of the ventral intermediate nucleus (VIM) for successfully treating Parkinson’s Disease that
DBS exploded into popularity. Parkinson’s disease is a disorder characterized by excessive movement, tremors, and muscular contortions often to the point where selfsufficiency is impossible. Prior to DBS, Parkinson’s was treated by surgical ablation, which were permanent lesions that were not always effective and had multiple sideeffects. With DBS, patients showed dramatic improvement [1]. Many regained control of their movement and experienced immediate cessation of tremors. DBS was also target flexible and program flexible, which meant that the stimulation could be surgically moved to another area and the therapeutic stimulation frequency could be altered to suit patient need. Importantly, if the patient showed poor prognosis, simply turning off the stimulation could reverse the effects. To this day, DBS is mainly used for the treatment of
Parkinson’s and other movement disorders, but has also been found effective in treating a wide range of psychiatric disorders such as depression and epilepsy.
What do DBS devices look like now?
Components and Structure:
There are many competing DBS devices, but almost every DBS has three main parts: The implantable pulse generator (IPG), the leads, and the extension. All three are shown below in figure 1. The IPG is a battery-powered device encased in titanium and

biocompatible plastic that generates the electrical pulses at programmable frequencies, essentially working as a pacemaker for the brain [2].
Figure 1: The DBS consists of an IPG, the leads, and the extension. All three are surgically implanted [3].
The extension is an insulated wire that connects the IPG to the leads and allows signals from the IPG to feed into the leads. The leads are coiled wires insulated by polyurethane and connected to four exposed platinum electrodes. The electrical pulses generated from the IPG create voltage pulses between any two of the four electrodes, forcing a potential difference across neurons in the surrounding area [1].
Surgery and Placement:
All three components of the DBS are implanted in the patient. The IPG is usually implanted under general anesthesia in the chest, but can also be implanted in the abdomen. The extension runs from the IPG, up the neck, behind the ear and into the skull

where a hole about 1.5 cm in diameter is drilled to allow lead placement [3]. The leads are typically placed in one of three places for motor disorders: the VIM for non-
Parkinson related tremors, or either the globus pallidus internus (GPi) or the subthalamic nucleus (STN) for dystonia and Parkinson's related symptoms [2]. For other disorders such as chronic pain, epilepsy, or depression, the leads can be implanted in other structures relevant to their individual pathways. The extension and leads can either be implanted under general or local anesthesia [3].
Mechanism of Action
While clinical studies have found DBS to be an effective method of treatment, the exact cause of DBS therapeutic effects is still unclear and research is ongoing to determine the mechanism of action [4]. As stated earlier, it has been shown that the effects of DBS are reversible if the stimulation is removed and that the therapeutic effects are site dependent. It has also been shown that some symptoms such as tremors disappear instantly when the DBS is activated, but other symptoms such as gait irregularities can take anywhere from hours to weeks to see effects [2]. Conversely, when DBS is deactivated, the symptoms that disappeared immediately reappear immediately while symptoms that disappeared over time reappear over time.
DBS in treating Parkinson’s:

The bulk of DBS research is still in Parkinson’s disease. Parkinson's is the result of degeneration of the substantia nigra, which releases dopamine to regulate the activity of the STN. Low regulation causes hyperactivity in the STN, which causes the GPi to produce synchronized excessive activity. The excessive STN-GPi activity results in stimulation spikes which disrupt the function of the basal ganglia, which normally regulates the motor cortex and prevents excessive motion [5]. This pathway is shown in figure 2.
Figure 2: The Corto-Basal Ganglia Loop, the pathway that manages motor function. The structures in the grey/yellow box to the right are the structures located in the basal ganglia [6].

It was first thought that DBS functioned like its predecessor treatment, ablation, by inhibited neural activity of the surrounding area, effectively causing a reversible lesion at the targeted site.
However, research has shown that DBS actually works in a more nuanced manner. The fact that DBS is therapeutic at high frequency and detrimental at low frequency does not fit with the lesion hypothesis. Rather than DBS shutting off neuron activity, researchers now believe that DBS instead promotes neuron activity. The hyperactivity of the STN-GPi is characterized by both sporadic 20 Hz signals and regular
10-30Hz signals called beta rhythm. When DBS stimulates at frequencies around or lower than 20 Hz, the DBS only adds more signals in the beta rhythm band causing more tremors and movement irregularities. When DBS stimulates at frequencies much higher than 20 Hz, the regular high frequency signal drowns out the sporadic STN-GPi signal.
The high frequency signal is essentially information-less and cannot be read by the neural pathways, preventing STN-GPi misfires from disrupting the basal ganglia [2]. Exactly how the high frequency signal drowns out the STN-GPi signal is still under research. One hypothesis is that the antidromal high frequency stimulation could be colliding with the
STN-GPi spikes preventing stimulus down the axon of neurons connecting the STN and
GPi as shown in figure 3 [1].

Figure 3: Stimulation of the axon of a STN neuron connected to the GPi. DBS interrupts the STN-GPi beta rhythm signals. Also shown are the four electrodes on the lead [1].
Another hypothesis is that the high frequency stimulation prevents spontaneous spikes by constantly depleting the action potentials of the neurons and limiting signals by their refractory period [1]. Other studies suggest that the regularity of DBS is more important than the high frequency stimulation, arguing that the role of DBS is to regulate the GPi firing rather than prevent it from signaling [4].
Regardless of the cause, this mechanism of action does not explain the late-onset therapeutic effects of DBS or the retention of therapeutic effects when after DBS has turned off. It is suspected that DBS alters the physiology of the basal ganglia-thalamiccircuit, which is supported by studies showing that the lasting effects of DBS are more prominent in patients with high plasticity, such as children [2][7].
DBS in treating other disorders:
It is suspected that DBS uses similar mechanisms for other neurological disorders.
However because DBS requires surgery, clinical trials are difficult to conduct with

significant sample sizes, which has prevented DBS from gaining FDA approval for nonmovement disorder diseases.
For example, DBS has been effective in treating otherwise treatment-resistant depression, but only in clinical trials of 5-6 persons [8]. People with depression typically have over activity in the subgenual cingulate (Cg25), which is a structure located behind the frontal lobe and involved with depressive mood. Like movement disorders, DBS for depression retains its therapeutic effects for some time after the DBS has ceased. This is likely attributed to physical changes in the neural network caused by prolonged stimulation though the exact changes are still unknown [8].
Refractory (treatment-resistant) epilepsy has also been a major target of DBS.
Typical epilepsy DBS stimulates the anterior nucleus of the thalamus (ANT), which in epileptics causes seizures via over-excitement of the hippocampus. Like in Parkinson’s the effect of DBS on the ANT is frequency dependent, with 100 Hz signals reducing seizures, and 8 Hz signals causing seizures. DBS in epileptics has been found to be 50-
70% effective, but only in small sample sizes [9].
For dystonia and other motor-related diseases, the mechanism of action is suspected to the same as with Parkinson's. However, the therapeutic frequency in dystonia is generally lower and the therapeutic effects occur much slower over days or weeks. The exact reason remains unclear [10].
There have also been many cases of DBS treating various disorders through unknown mechanisms, such as Tourette’s syndrome, OCD, cluster headaches, and phantom limbs. In one bizarre, isolated incident in 2008, DBS was implanted next to the hypothalamus of an obese man to curb his appetite. Instead, the DBS inadvertently

improved his memory, allowing him to remember previously lost memories and recall
70% of words read to him in a test. When DBS was turned off, the man could only recall
43% of words read to him, which was similar to his pre-DBS scores. Presumably this was caused by accidental stimulation of the hippocampus, but exactly how this occurred and how it improved memory function is unknown. The incident recently sparked research into DBS for Alzheimer patients which may show promise [3].
How has DBS research changed the way we look at the brain?
Research is still ongoing as to why DBS has been found effective even when pharmacological or fetal cell transplant therapies have failed [4]. Other strategies for combating Parkinson’s or treatment-resistant disorders must not be addressing a key component or are blocked by a physiological process that DBS can somehow circumvent.
Further research could be applied to make other therapies both more effective and more generalized for patients who are inoperable or incompatible with DBS [4].
DBS has also caused many to reconsider the inhibition/excitation nature of neuronal pathways. DBS research has shown the limitations of macro-neuron approaches, which is where single neurons model multi-neuron connections between neurological pathways. DBS of the GPi causes reduction of the ventrolateral thalamus (VL) neural activity, which is consistent with current theoretical pathways. However this is only true for the majority of neurons. Roughly 25% of VL neurons instead have increased activity during DBS, which is incompatible with several suspected pathways [11]. However, the

combined over and under activity of VL neurons is compatible with the fact that DBS has been found to be effective in treating both hyperkinetic and hypokinetic diseases such as dystonia and Parkinson’s respectively [5]. This seemingly contradicts previous theories that hyper- and hypo-kinesia have a reciprocal relationship, demonstrating that neurological pathways cannot be boiled down to simple excitation and inhibition as shown in figure 2.
Other studies have found that stimulation of all structures in the motor pathway provide some therapeutic effects despite the fact that activating certain structures should inhibit other structures and vice versa. Stimulation has been found effective to varying degrees in the GPi, STN, globus pallidus external segment (Gpe), VL, pedunculopontine nucleus (PPN) and motor cortex [4]. Either there are multiple mechanisms in which DBS functions or there is a common mechanism between the entirety of the motor pathway. In either case, DBS effectiveness calls for a more systemic look at malfunctions in the motor pathway.
Conclusion
Like many great inventions, DBS was brought into the world not with “That’s it!”, but with “Oh that’s weird”. Electrical stimulation has grown into a surprisingly versatile treatment for psychiatric disorders, many of which were thought to be incurable or contained sub-populations that were thought to be incurable. The surprising effectiveness of DBS has led to medical insights on how both individual neurons work

and how the brain as a whole mediates various pathways. Ongoing research on DBS continues to provide more effective electrical stimulation treatment as well as provide insight into the arcane workings of the human brain.
References
[1] M. A. Butler, J. M. Rosenow, M. S. Okun, “History of the Therapeutic Use of Electricity on the Brain and the Development of Deep Brain Stimulation” Current Clinical Neurology:
Deep Brain Stimulation in Neurological and Psychiatric Disorders. Totowa, NJ: Humana
Press, pp. 63-74.
[2] S. Miocinovic, et al, “Mechanisms of Deep Brain Stimulation” Current Clinical Neurology:
Deep Brain Stimulation in Neurological and Psychiatric Disorders. Totowa, NJ: Humana
Press, pp. 63-74.
[3] T. Valeo, (2008, May 01), Use of Deep Brain Stimulation Widens [Online]. Available: http://www.dana.org/news/brainwork/detail.aspx?id=12136
[4] E. Montgomery and J. Gale. “Mechanisms of action of deep brain stimulation” Neuroscience
& biobehavioral Reviews, vol. 32, pp. 388-407, 2008
[5] M. R. DeLong, T. Wichmann. “Circuits and Circuit Disorders of the Basal Ganglia”. Arch
Neurol.
vol 64, pp. 20-24, 2007
[6] Corto-Basal Ganglia Motor Loop. [Online] Available: http://biomed.brown.edu/Courses/BI108/BI108_2003_Groups/Deep_Brain_Stimulation/moto rloop.html
[7] H. J. Kim, et al. “Bilateral subthalamic deep brain stimulation in Parkinson disease patients with severe tremor,” Neurosurgery , vol. 67, pp. 626-632, 2010.
[8] H. S. Mayberg et al. “Deep Brain Stimulation for Treatment-Resistant Depression”.
Neuron, vol. 45, pp. 651-660, 2005.
[9] C. H. Halpern, “Deep Brain Stimulation for Epilepsy”,
The Journal of the American Society for Experimental NeuroTherapeutics, vol. 5, pp. 59-67, 2008
[10]
What is the Difference Between DBS for Dystonia and DBS For Parkinson’s Disease and
Essential Tremor?
[Online] Available: http://www.dystonia-foundation.org/pages/dbs_for_dystonia_7/321.php
[11] E. B. Montgomery, “Effects of GPi Stimulation on human thalamic neural activity”
Clinical
Neurophysiology, vol. 117, pp. 2691-2702, 2006.