A technological system for mapping and testing brain function, a mobile device for predicting migraines and depression, and a wearable product for reading brain waves at home. Three breathtaking developments are doing things that, until recently, were considered science fiction, monitoring the brain, and forging the path to diagnosis and resolution of neurological and psychiatric problems

Sports physicians deliberate over when to allow an athlete to return to the court or back to the training field after incurring a blow to the head and sustaining a concussion. Is he fit to continue immediately following the injury? And if he returns to the court after only a few hours rest – does he risk irreversible brain damage? The ElMindA Corporation which is developing technologies for the mapping and examination of brain function, provides a solution for this dilemma and other similar issues also bothering physicians treating patients suffering from various neurological and psychiatric diseases such as Parkinson's, depression, Alzheimer's, epilepsy and other cognitive disorders.

"Head injuries are considered a national scourge in the United States, with more than five million cases of concussion each year, mainly in children. Therefore, when we started out, we focused on head injuries and concussion", explains Dr. Ziv Peremen, VP Research Programs at ElMindA. "In this context, we developed a tool for physicians that assist them in understanding the manner in which the brain recovers and, consequently, in decision-making. For example, in the case of injured athletes, the physicians need to decide if they can return to the training field or whether they are in need of continued rest to prevent ongoing damage. The Olympic Committee authorized the use of the BNA system (Brain Network Activation) that we developed for the last Olympic Games in Rio, Brazil, and the Olympic team also intends to consider widespread use of this system in the Games that will be held in Tokyo in 2020."

"Also, the technology we have developed can also be utilized in the fields of psychiatry.  For example, it can examine the effectiveness of a new treatment given to patients with depression, and brain activity can also be tracked after the treatment to identify a deterioration in time to provide advance treatment thereby preventing the patient's condition from progressing to more challenging and dangerous stages."

 

Objectification of Brain Processes

ElMindA was established eleven years ago and is considered one of the leading companies in Israel and the world in the field of brain monitoring. In 2014, the company received a regulatory authorization from the FDA (the Food and Drug Administration), and also possesses parallel authorization from Europe and other countries – Canada, Brazil and naturally Israel.

"The brain is a fascinating area, and our vision is to bring the digital world into the clinic, to make use of the tools that enable us to objectify brain processes and then create value for physicians from them," explains Dr. Peremen. "The unique BNA system that we have developed performs a multi channel and non-invasive electrophysiological test, with the objective of identifying patterns in the patient's neural networks' activity while he is performing different neurological processes. The identification of these patterns enables physicians to map this activity and compare them to that of healthy brains. In practice, the BNA system produces different objective, quantitative and qualitative insights for the physicians regarding the patient's brain activity to assist diagnosis and enable them to make better treatment decisions."

"Our development is based on the EEG technology – a device that was invented already a hundred years ago, that includes electrodes attached to the patient's skull with which the brain's electrical activity is recorded. We use the existing hardware from the world of epilepsy or sleep problems to gather the data on brain activity, but our results also include neuro-cognitive information, clinical data, and other imaging tools. Our most significant development is the EEG-based program that maps and analyzes the data thereby producing insights of life-saving importance", Dr. Peremen explains.

Four years ago, ElMindA joined as a partner in the BSMT (Brain Stimulation and Monitoring) Consortium, organized and supported by the MAGNET Incentive Program, one of the support programs of the Technological Infrastructure Division at the Israel Innovation Authority, led by Ilan Peled. Three other companies are also members in the BSMT (Alpha Omega, Insightec, and Brainsway) while other partners include academic centers from Israel active in neuro-research. The consortium creates collaborations that enable the combining of the brain monitoring device with technology for brain stimulation out of an objective to enhance and enable personal adaptation of the treatment for different neurological and neuro-psychiatric disorders. The consortium has created a robust and cooperative business environment that constitutes an advantage for the group from Israel versus parallel technologies from around the world.

Also, ElMindA is a partner in IBT-Tech – the Union of Israel Brain Technologies – yet another program in the Israel Innovation Authority's Technological Infrastructure Division. IBT-Tech is the initiative of Dr. Peremen from ElMindA, Imad Younis from Alpha Omega, Dr. Dekel Teliaz from the Teliaz Corporation and Miri Polachek from IBT. The initiative's objective is to bring together the Israeli companies active in the field of brain research, to implement a program for distributing and assimilating advanced technologies and for the sharing of R&D-supporting resources.

Insights into the Human Black Box

The tools developed by ElMindA are entirely automatic: "The clinician activates the recording button, and all the mapping processes that previously required hundreds of hours, are performed automatically and are transferred for storage in the 'cloud,' says Dr. Peremen. "The BNA system creates charts of the brain activity from signals recorded during the EEG examination. When the process is complete, we compare the specific recording to the vast population database at our disposal.We compare an excess of 180 thousand data pieces from neurological recordings of both healthy people and sick patients – and identify patterns of normalcy and abnormality in brain activity. Our  objective is to  extract insights regarding the development of diseases and on the progress of healing processes. In this way, our system identifies signs (markers) and neuro-markers that will aid physicians, for example, to locate Parkinson's patients at a relatively early stage."

"In contrast to MRI, our system is much cheaper, simpler to use and can also be used with home means and at the cost of only several hundred dollars. The test is non-invasive. All that is required of the subjects is to put on a type of hat with electrodes for just a few minutes. It is painless and produces a vast number of insights about the happenings inside our black box", explains Dr. Peremen.

"Our objective is to operate the technology not just in time of injury, but also to conduct follow-up of the same patients over time to also identify other processes", Dr. Peremen elaborates. "For example, in the city of The Villages in Florida, there is a large elderly population aged at least 55, some of whom reach the age of 95. We track the deterioration in brain activity of some of the population suffering from Alzheimer's and MCI and conduct them periodic tests. The BNA system creates charts of cognitive functions, attention, memory, sensory activity and others, and these allow us to identify the patients' reactions to treatment and any deterioration in their condition."

"We intend in the future to continue enlarging our population database to enhance the system and so that our physicians can conduct comparisons and cross-checks with the brain activity of patients of a similar age, or from the same population sector, thereby facilitating more accurate insights. Although ElMindA is a commercial company, in order to succeed we require solid and accurate science, so the company relies on multi-disciplinary researchers, a significant portion of whom hold doctorates related to the science that lies at the foundation of the technology", Dr. Peremen explains.

 

An EEG Measurement for Predicting Migraine Attacks

The BrainMARC Corporation is another company developing an innovative EEG-based technology. BrainMARC's product is intended for the monitoring of mental activity, levels of attention and concentration, prediction of attacks of migraines, depression, and anxiety, and for the continuous monitoring of care and concentration during rehabilitative treatment. BrainMARC operates in the Alon Medtech Ventures incubator in Yokne'am in the Technological Incubators Program led by Itay Beck and under the Startup Division headed by Anya Eldan.

Dr. Yael Rozen, BrainMARC CEO, is an entrepreneur and director in the field of medical devices, and previously established and managed the unit of knowledge commercialization, clinical trials and research grants at Rambam Medical Center. Dr. Goded Shahaf, responsible for technological development, is a physician, brain researcher, entrepreneur, and co-heads the rehabilitative psychobiology lab at Reut rehabilitation hospital in Tel Aviv.

"The innovation of the technology we have developed is the ability to identify EEG signals from electric brain activity based on a single measuring channel and in short measuring time periods," explains Dr. Rozen. "We harness these biomarkers, especially the attention-related marker, for the early forecast of deterioration and the prediction of the reaction to treatment in a range of neurological and psychiatric diseases. This technological advancement enables us to make the EEG measuring accessible to home consumers via a mobile telephone and application that we have developed. In practice, a small daily measurement of the brain activity using EEG enables the patients to predict migraine attacks, states of depression, anxiety and attention and concentration disorders, and to prepare for them with preventative means."

"Clinical studies that we conducted revealed a difference in the electric brain activity measured in reaction to sound stimulus between healthy people and those suffering from neurological related problems and a change in the clinical dynamic of the latter group. With those suffering from migraines, for example, there was an increase in activity approximately 1-2 days before an attack, while with those suffering from depression, a low-level of activity was usually observed. A patient who doesn't respond to medicinal treatment will show a dynamic of decline in electrical activity, which precedes the accepted clinical evaluation by weeks", explains Dr. Rozen.

"The technology's simple implementation allows us to create a product that is appropriate for both clinical and home use, and that provides recommendations for treatment after only a short period of measurement," she emphasizes. "The significance is that the patients can, using the mobile application, perform a small daily one-minute measurement of brain activity, and to receive an evaluation of the risk of a migraine attack in the next 1-2 days. As yet, the technology does not presume to be therapeutic, although the company is also currently developing a personalized recommendations system for daily behavioral activities, the aim of which is to prevent or reduce the occurrence of migraines, including recommendations regarding nutrition and relaxation activities – meditation, sleep, physical activity, etc."

"Another option being considered by the company is the integration of a biofeedback component in the product (based on the monitoring of brain activity) that will provide an immediate response for reducing stress (and risk of a migraine if a high-risk situation is identified). The company will soon begin a follow up-trial to develop and implement the recommendations component in preventing migraines, which will be based on a system that learns the user and measures the home users", Dr. Rozen elaborates.

 

Program for Continuous Monitoring of Attention and Emotion

"By the same technology, we have also developed a program that enables the continuous monitoring of attention and emotion from electric brain activity via a single measuring channel," continues Dr. Rozen. "This program was modeled mainly during rehabilitative treatment following a stroke. In a trial conducted at the Reut Medical Center, it was found that use of brain measurements in the guidance of rehabilitative treatment improved the patients' clinical condition significantly more than regular treatment without the brain measurements."

"The efficiency of the rehabilitative treatment, especially following a stroke, correlated directly with the patient's attention recruitment. The damage from a stroke is brain damage that then leads to motor impairment. To recover from the motor impairment, the patient needs to create new 'routes of operation' for the damaged movement. The patients  must  recruit all of their attention to perform an action that prior to the brain damage, was performed automatically with no specific attention", explains Dr. Rozen.

BrainMARC's program provides the physician with a glimpse into the patient's brain and enables him to identify the times during which the patient is attention recruited, and the exercise therefore effective, as well as the times during which the task is too easy or difficult for the patient. In such situations, the physician will attempt to recruit the patient to revert  to effective treatment and, should he fail to do so, he will then attempt to alter the exercise level, type of exercise, or even to grant the patient rest. In order to use the tool, the patient wears the EEG device during the treatment. The electric signals are recorded by the computer and processed to the markers relevant to the rehabilitative treatment process. The program guides the physician, via a three- color system, regarding the quality of the exercise with the objective of maximizing the duration of efficient treatment. In the clinical trial that tested whether use of the program indeed improved the clinical result of the treatment session, it was found that in those sessions that made use of the program for guiding the treatment, the patients achieved a significant clinical improvement. The clinical improvement was five times greater than in sessions in which no use was made of the program.

Dr. Rozen mentions that "the Israel Innovation Authority is operating to significantly advance new technologies in innovative fields, that without this support, would not mature, reach the market and achieve significant sales. The innovation authority support is without doubt even more significant for products in the medical field that require expensive animal and human trials beyond the self-financing ability of most entrepreneurs."

The products developed by BrainMARC are part of the cellular-based area of health  (mHealth) that constitutes one of the most significant trends in the digital medicine market. "The estimation is that there is today approximately 165 thousand cellular application programs in the area of health , roughly 20 percent of which are related to monitoring and treatment of diseases", says Dr. Rozen. "The existing monitoring tools in the world of neuro-psychiatry are of high quality in nature (questionnaires, interviews), but there are nearly no scientific measuring instruments. From this perspective, the development of digital medicine tools for quantitative and objective monitoring constitutes a real revolution."

"Technologies in the field of digital medicine are contributing to the enhancement of efficiency of the health system, increased accessibility, reduced costs, improved quality and the advancement of personalized healthcare", emphasizes Dr. Chana Rothmann Scherz, Digital Health Senior Expert at the Israel Innovation Authority. "Patients and consumers can use digital medicine to manage their health better and to track their condition and the actions they are implementing to improve it."

 

Three Electrodes on the Forehead

Another company active in the field of continuous brain monitoring using EEG electrodes is the Neurosteer Corporation. Professor Nathan Intrator, the Neurosteer CEO is a brain researcher from Tel Aviv University who deals with mathematical models of advanced signal processing for reading brain activity. "I understood that using mathematics it is possible to extract much more information from an EEG, and I began reading the brain with electrodes placed on the forehead," he describes. "I also realized that in the medical field as well as in those areas related to wellness, it is possible to produce a vast amount of data with a small strip on the forehead that contains three only electrodes. And if I can do that, I will receive a small, mobile, continuous and inexpensive brain reader that can become significantly more available and usable."

Last year,  Prof. Intrator spent on sabbatical from the university  so he can cultivate the idea he established together with his partner Lenny Ridel, an expert in the field of 'big-data'. Their objective was to  transform the mobile brain reader to a real product capable of solving a variety of problems. Currently, in the phase of feasibility testing, the Israel Innovation Authority has lent its support to Neurosteer.

"The product monitors cognitive load and emotional response but also activity connected to stress and executive functions, as well as level of consciousness," Professor Intrator explains. "It is our intention to develop a monitor for clinical and home use (similar to the device that monitors diabetes, heart activity, and other phenomena), to assist patient rehabilitation. The monitor that is attached to the patient's forehead,  gathers the data and transfers it for storage in the 'cloud' where it is processed. By using methods of machine learning and artificial intelligence, responses are received that enable comparison to the same person's previous condition or conditions of other people in a similar situation. The insights are transferred to the patient himself, to his  physician  using neurofeedback or as various warnings that provide indications about the reaction to medication or the patient's current condition."

Neurosteer is currently at the clinical trials stage to assess the clinical usability. However the options are manifold: the monitor can be attached to the foreheads of patients who are in a low state of consciousness or with whom it is impossible to communicate, thereby ascertaining the state of their brain activity. Following the brain monitoring procedure, we will be able to provide them with the correct treatment and even help them regain consciousness. Another clinical possibility is to make use of the monitor to enable these patients to communicate with the surroundings despite the fact that they are unable to move a single organ of their body."

 

Much More than a Medical Product

The usages of Neurosteer's "brain reader" exceed beyond the boundaries of medicine, and trials are already being conducted in other fields such as testing the level of a pupil's concentration while solving mathematical exercises or other academic tasks. In this case, the data received will aid teachers in understanding what causes each pupil to be focused. This understanding will enable teachers to  provide access to study materials in a manner that  facilitates the maximum attention and concentration of each individual pupil. Some pupils found that  animation will be the best way to understand the subject taught while others preferred  written text. The device also offers reverse possibilities: if we want the pupil to train specific areas of the brain, such as short-term memory, rather than speed reading, the monitor processes the cognitive process, learns the  location of the difficulty and offers ways to improve study and training.

The product, which is mobile, small and wearable, will enable patients to manage certain illnesses such as epilepsy, clinical anxieties, depression and others while sleeping or performing afternoon meditation. "Once we know how to monitor and analyze the brain, it will be possible to adopt lifestyle habits that help in preventing different attacks," Dr. Intrator explains.

Following the stage of clinical trials, the company intends to develop a medical product and apply for FDA approval. In the subsequent stage, the objective is to increase the product's availability and harness it to areas related to lifestyle aspects.

Neurosteer, just as Teliaz and other companies mentioned in this magazine, is participating in the Israeli pavilion of the Israel Innovation Authority at the world's largest Life Sciences Convention held this year in San Diego. Jonathan Cohen, the representative of the Authority's US-Israel Industrial R&D Cooperation Department, coordinating the delegation to the convention, points out that the Israeli pavilion is attracting high interest and attention and that he expects that the companies will conduct hundreds of meetings during the convention. "Eexperience proves that participation in the convention is highly productive in the recruitment of investment and for advancing commercial and technological cooperation with American and other partners attending the convention," he says.