User:Purple091/Temporal Interference Deep Brain Stimulation

Temporal Interference Deep Brain Stimulation (TI DBS), a type of non-invasive deep brain stimulation, is a novel neuromodulation technology to treat multiple neuropsychiatric disorders through electrical stimulation. It is widely considered to be a possible safer replacement for conventional invasive deep brain stimulation as it does not require surgical implantation of electrodes into the brain.

TI DBS was developed in 2017 as a potential treatment for patients with neurological disorders such as Parkinson's Disease, Treatment Resistant Depression, Alzheimer's Disease, Epilepsy etc. In this technique, electrical stimulation of deep brain regions is conducted via electrodes placed on the scalp. Its functioning is based on two principles, wave interference and intrinsic low-pass filtering property of neurons, which allows only low frequency electrical waves to stimulate neurons to produce activity. As high frequency waves having high penetrative capability is required to reach deep brain regions, this novel technique makes use of wave interference to produce a low frequency envelope, capable of stimulating neurons to excitation. Hence, a specific area in the deep brain region can be stimulated without exciting the peripheral overlying neurons. Choosing different parameters, like the frequency and current of the applied waves, affects the position and formation of the envelope and the efficiency of stimulation.

Experiments show that TI stimulation is largely successful in in-vivo studies conducted in mice. Based on these results, scientists extended their investigation to human models. TI stimulation was found to be more focal than conventional DBS. Subsequently, optimal current patterns were computed targeting specific regions in humans using simulation head models. Further studies revealed that currents much higher than the ones presently used for invasive stimulation in humans, are required for this technology. Although these higher currents may increase the risk of this treatment, research shows that TI stimulation is a safer alternative to invasive DBS. Animal-model studies have shown no evidence of pathophysiological effects or brain injuries linked to TI stimulation. Researchers believe that the ability of TI to selectively stimulate target deep brain regions without affecting overlying brain tissue, gives it an advantage over other non-invasive DBS techniques which use electromagnetism for stimulation.

However, TI faces several challenges as a potential clinical treatment for human patients. These challenges include possible off-targeting, adapting to functioning of the human brain and feasibility as a treatment. These arise due to the differences between a human and a mouse brain, such as size and conductivity of neurons. Complete understanding of the underlying mechanism, optimization of the technology and human clinical trials are required to overcome these challenges.

Medical Use
Although an array of non-invasive brain stimulation treatments have been developed, a limitation they share is the inability to stimulate deep brain regions exclusively. Hence, TI stimulation, a novel non-invasive technique, is seen as a possible replacement for current invasive deep brain stimulation (DBS). It eliminates the danger of high-risk brain surgery and associated adverse effects such as infections.

Current FDA- approved DBS treatments exist for:


 * Parkinson’s Disease
 * Essential Tremor
 * Obsessive-Compulsive Disorder
 * Epilepsy

Other neuropsychiatric disorders require further conclusive evidence proving efficacy of using DBS, invasive or non-invasive, as a treatment to cure these conditions.

For example:


 * Major Depressive Disorder
 * Alzheimer’s Disease

General Principles
TI deep brain stimulation, a non-invasive technology that uses electrical stimulation to achieve neuromodulation, was first developed in 2017. Two main principles are adopted in this technique - wave interference and intrinsic low-pass filtering. The human brain possesses the property of low-pass filtering, which allows stimulation of neurons to fire action potentials only on receiving low frequency waves (<100Hz). At very high frequencies(>1kHz), neurons are incapable of excitation. However, high frequencies, capable of high penetration, are necessary for the waves to reach the target deep brain regions. Hence, the phenomenon of wave interference is used to convert high-frequencies into a low frequency wave for neuronal activation. This enables stimulation of a targeted area without affecting overlying peripheral areas. The generation of a low frequency wave is achieved by the application of two high-frequency waves with a slight difference in frequencies (2 kHz and 2.01 kHz used in the original experiment), conveyed through two electrodes placed on the patients scalp. These waves meet at the target area, where they interact to form a wave interference pattern, an envelope. The frequency of this resultant wave, equal to the difference of the two applied waves, is called beat frequency. As the beat frequency is much lower than the applied frequencies, the resultant wave envelope is able to stimulate neuronal firing at the target area. During stimulation, the peripheral neurons remain unaffected as they only receive the applied high-frequency waves. This enables targeting of specific deep regions of the brain.

Selection of Parameters
The aforementioned envelope plays a crucial part in the mechanism. Therefore, the foremost step is to ascertain a well-defined envelope having the desired low frequency after interference. For selecting appropriate frequencies, the difference(Δf) of the two waves has to be within the range of neural firing frequency. Hence, the required difference should be less than 100Hz for neurostimulation, as the physiological frequency of neural firing is lower than 100 Hz. However, frequency of the applied waves should be very high, preventing activation of overlying neurons. Apart from the frequency, the location is also of paramount importance. The position of the electrodes and the applied current intensity affects the positioning of the envelope, thus enabling target stimulation in different brain regions (i.e. steerability).

The other aspect is to assess the efficiency of the envelope produced to stimulate neurons. Results from experiments revealed that efficiency does not solely depend on the resultant 'beat frequency' (i.e. the difference of frequencies between two applied waves). Two combinations ((1 kHz + 1.01 kHz) and (2 kHz + 2.01 kHz)), having the same resultant frequency, yielded different spike frequencies in neurons. This led to the conclusion that the magnitude of the frequencies used also affects the efficiency and degree of neuronal response. However, further studies are required to investigate how stronger magnitudes affect neuronal activity.

Studies on Animal Models
This technique holds potential to non-invasively stimulate deep brain regions in a spatially accurate manner, without affecting the overlying brain tissue. Therefore, research studies are underway to judge the efficacy of TI for deep brain stimulation. An in-vivo animal study conducted by MIT’s Picower Institute for Learning and Memory served as the pioneer study to investigate the effects of this technique on mouse brains

Using TI, they targeted stimulation of the hippocampus, located deep in the brain, without affecting the overlying cortex. Stimulated regions were identified through the detection of c-Fos marker, which is expressed in neurons after they undergo depolarization. Results revealed that cells of the hippocampus were strongly activated and expressed c-Fos marker at high concentrations. Whereas, no c-Fos marker was detected in cortical cells, located between the electrode and the interfering envelope produced. This indicated that the cortical cells were not stimulated.

Simulation Studies on Human Models
Although human subjects are yet to be tested, simulations using realistic human head models have been employed for experimentation. One such study used a two-electrode configuration and juxtaposed results of stimulation using TI with those obtained from conventional invasive therapy. Depending on the orientation of the brain, TI was found to be more focal in some areas. However, scientists were unable to identify the exact scenarios where TI outperformed conventional stimulation. Moreover, results showed that conventional stimulation, which simply depends on the additive effect of fields from multiple electrodes, achieved generally larger field magnitudes and modulation depth than TI. Thus, they noted that for TI, sophisticated optimization of electrode location was required to be able to obtain more accurate results.

Based on the above, a computational study was carried out to identify optimized current patterns and resulting fields for TI. Optimized currents were identified for specific regions of the brains most likely to benefit from this technique. The malfunctioning of these regions corresponds to different neurological disorders such as pallidum for Parkinson’s ; hippocampus for temporal-lobe epilepsy, Alzheimer’s and dementia ; and the motor cortex for neuropathic pain. The study showed that electric fields induced by TI stimulating currents were suitable to excite neurons in mouse models, but currents commonly used for cerebral stimulation in humans were not high enough to achieve this in human models. Nevertheless, the electric field achieved was similar in strength and more focal than conventional invasive electric stimulation, implying less risk of off-target stimulation. Optimal hypothetical current patterns were also computed to maximize effects of TI in regions of the pallidum (0.37 V/m), hippocampus (0.24 V/m) and motor cortex (0.57 V/m).

Advantages
Clinical trials show that patients with neurological disorders tend to achieve remission of symptoms with conventional invasive DBS. However, it being an invasive procedure, can lead to complications during surgery. Common adverse events associated with this neurosurgical procedure are infection (2.8–6.1% cases), brain haemorrhage (1.3–4% cases), seizures, perioperative headache  etc.To minimize these risks, a number of non-invasive DBS techniques have been developed, capable of replicating the therapeutic benefits credited to conventional DBS. Apart from TI, these include electromagnetic procedures such as transcranial direct current stimulation and transcranial magnetic stimulation. However, studies show that the electromagnetic approach for stimulation is limited by its inability to exclusively target deep brain regions. Therefore, a major advantage of TI is its capability to selectively stimulate target deep brain regions without affecting overlying brain tissue.

To justify the possible future use of TI stimulation to cure human neurological disorders, experiments were conducted in mice to evaluate basic safety. It was found that TI did not cause any aberrant cell injury or death, as no changes were observed in astrocytes and microglia, which mediate the immune response of the brain. Neither did it induce any adverse effects such as seizures, nor increase tissue temperature. Apart from those, histological results of the stimulated target region also showed preservation of neuronal density with no apparent DNA damage to individual neurons. Overall, no evidence for patho-physiological effects, markers of brain injury or temperature increase were found.

However, these results are based on short bouts of TI with histological studies carried out only 24-hours after stimulation. Thus, there is a need for further investigation requiring longer duration of safety testing in animal models, to judge the long-term effects of this technique.

Limitations
Preliminary experiments in mouse models indicate positive results for the potential use of TI to stimulate deep brain regions. However, the exact mechanism behind this form of stimulation works is yet to be understood by scientists. Researchers believe that mere intrinsic low pass filtering does not explain TI. Hence, other mechanisms involved need to be identified. Studies also reveal that some mammalian neurons are unresponsive to TI stimulation. Consequently, experiments on single neuron models are required to identify whether TI targets neural networks or individual neurons for excitation.

Another challenge for clinical use is the much larger size of the human brain compared to a mouse brain. Deep regions such as the hippocampus lie about 3 millimeters away from the cranial electrodes in mice, whereas for humans the depth can be ten times higher. Therefore, stronger electric fields are required to penetrate through the longer distance. This poses a major risk for patients and can cause adverse effects on brain tissue. Moreover, although an envelope is formed, it does not have a clear, defined boundary. This may cause undesirable stimulation of areas neighbouring the target brain region.

Apart from size, the geometry and conductivity of a human brain also differs from a mouse brain. Simulations on human models have shown that frequencies much higher than those used in mice will be required to excite human neurons. To achieve this, specialized electrodes capable of producing these frequencies will need to be developed.

Feasibility of TI as a treatment may further be affected by the need for weekly visits to the hospital for stimulation sessions. This is in contrast to invasive DBS, where patients can receive 24 hour stimulation with the implanted electrodes in the comfort of their homes.