A neurosurgeon and an engineer walk into a lab ...

Steve Schiff has the soothing voice and gentle manner of someone who has spent a large part of his career dealing with children, and frequently, children in pain. As a pediatric neurosurgeon, he has lent his skills and bedside manner to treating diseases of the brain in children. As a researcher, he is joining forces with electrical engineer Srinivas Tadigadapa to develop technology to understand and treat diseases of the brain.

Schiff is director of the Penn State Center for Neural Engineering, a lab that takes up an entire floor of the Life Sciences wing of the Millennium Science Complex on Penn State’s University Park campus. A series of card-swipe controlled laboratories make up the 11,000-square-foot center, which includes facilities for the construction of custom electronics, live animal imaging and surgery, and advanced computerized microscopy.

In the Materials wing of the building, Tadigadapa’s group is developing microelectromechanical systems (MEMS) that allow miniaturization of devices that can sense and stimulate nerve cells, some of which the team hopes will one day be implanted into the human skull in order to explore the brain on a cell-by-cell basis.

The Millennium Science Complex was built with the concept of integrating the expertise of materials scientists, electrical and mechanical engineers, and nanotechnologists, who occupy the north wing of the building, with medical and biological researchers, who occupy the building’s west wing.

“This building reflects our interaction, because we are half materials science and half life sciences,” Schiff says. “We will literally build these technologies on one side and walk them up the stairs to our lab where we do experiments on neurons. We will use individual neurons that we will be recording from and stimulating to see how far we can push this technology. We are, to our knowledge, the only center at present that is in a position to manufacture these high-density arrays for sensing and stimulation in a nanofabrication facility and then literally transition them to an operating room.”

Stimulating the brain

The project is funded by the National Institutes of Health through the BRAIN Initiative, a program launched in 2013 by President Barack Obama to accelerate the development and application of new technologies to investigate how individual brain cells and complex neural circuits interact.

In addition to graduate students, research associates, and others at Penn State, the research team includes John Wikswo of Vanderbilt University, who is one of the world’s leading experts on magnetic fields in neurons. “John provides some of the key physics expertise that no one else in the world has,” Schiff says.

The group’s goal is to develop a MEMS device capable of measuring the activity of individual brain cells and stimulating those cells without physically penetrating the brain — a technology that could provide long-term benefit for individuals with any of several debilitating neurological disorders.  

For the past 70 to 80 years, scientists have been using electrodes on the surface of the brain to measure electrical currents, and, since the 1950s, to stimulate the brain. More recently, an approach called deep brain stimulation (DBS) was developed as a means to treat the tremors associated with Parkinson’s disease. In DBS, electrodes are implanted in the brain and a generator is implanted in the patient’s chest wall. A pattern of electrical pulses is used to stimulate portions of the brain. Now, DBS is being studied experimentally as a method to treat a variety of other ailments. It works for some patients with major depression, although the exact mechanism is still unknown. DBS has also been used to control robotics for patients with disabilities.

“Imagine you are trying to run an artificial hand,” says Schiff. “You want to pick up signals from the hand area of the cortex to give you the intention of the individual to move such a hand. We can only do that now by implanting arrays of electrodes into the hand area of the brain itself.”

A big drawback of the technique is that implanting electrodes deep inside or onto the surface of the brain has serious potential side-effects.

“There is a measurable risk of hemorrhage and damage, and there is always a few percent risk of infection,” says Schiff. “If I’m studying a child for epilepsy, I need to take those electrodes out by two weeks, definitely by three weeks, or I have to go in and free them from the scar tissue that’s already formed on the surface of the brain.”

A penetrating insight

Placing electrodes on the outside of the head is not a good option, either, because bone is a good insulator and electrical signals cannot easily pass through the skull. There is a better choice: using magnetic fields rather than electrodes. Bone is not a barrier to magnetic fields as it is to electrical signals. That’s where Tadigadapa’s expertise comes in. He and his lab team are developing tiny MEMS devices that can interact with brain cells via magnetism.

But magnetic fields come with a problem of their own: They decrease with distance — “Even a fraction of a millimeter makes a difference,” says Tadigadapa — so to get their device as close as possible to the cells it will interact with, the team is taking advantage of the layered structure of the bones that enclose the brain. These bones have a dense outer layer, a dense inner layer, and a spongy-looking layer in between. By removing a small piece from the outer and middle layers, researchers can place a device on the inner layer. This gets the device as close to the target cells as possible without penetrating the dura, the tough membrane that surrounds and protects the brain from infection. The device could be adjusted, repaired, or replaced without disturbing brain tissue.

Using magnetic fields to affect the brain is not new. What’s new and ambitious about the Penn State project is that the researchers will attempt to stimulate and record the activity of small groups of neurons — the smallest group that would be effective for producing a desired result — or even of single nerve cells.

“Usually what people do to magnetically stimulate neurons is to have very big coils that go outside the head,” says Eugene Freeman, a doctoral candidate in Tadigadapa’s lab. “They’re not implantable. They’re about the size of your fist, so you have to go in to a lab for the treatment, which is called transcranial magnetic stimulation. These large magnets activate a relatively large part of the brain. You can’t get fine specificity.”

Freeman is experimenting with magnetic field-inducing microcoils of different sizes and shapes, the smallest so far being about half a millimeter in diameter. Each coil creates a magnetic field that can create an electrical current in one or a small number of targeted brain cells.

The coils are made with copper patterned on microglass structures. The team is also taking advantage of recent advances in three-dimensional fabrication to look into whether a 3-D coil might be more effective than a flat coil.

More challenges

Recording the magnetic fields generated by neurons is a tougher challenge than stimulating the cells, says Tadigadapa. Conventional methods of doing this without potentially damaging the brain either don’t have cellular resolution, require shielded rooms, or cannot be performed at safe temperatures — one technique requires cooling to liquid helium temperatures (-269 degrees C) and another requires heating to 180 degrees C. A recently developed method uses a synthetic diamond material to pick up very small magnetic fields, but it requires using microwaves, like the ones in a kitchen microwave oven, which have a tendency to cook things in the vicinity. Not an optimal solution. 

Then there’s the seemingly inescapable problem of living on a planet that is itself a huge magnet.

“The Earth’s magnetic field is around 60 microTesla,” says Tadigadapa, referring to the standard unit of measurement, “and the magnetic field of human brain activity is around a picoTesla, around 60 million times weaker. So there is need to block Earth’s huge magnetic field. Currently that is done within an isolated room that costs several millions of dollars to build. We hope to be able to do it with an on-chip circuit.”

He proposes to build active and passive circuits on a microchip that will cancel out magnetic noise using a simple feedback loop, the same technique used in noise-cancelling headphones. The microdevice will generate an on-board magnetic field within the MEMS chip that will compensate for the Earth’s magnetic field and other interfering magnetic fields in the nearby environment. Other circuits in the implantable chip will amplify the magnetic signal from the cells.

“We have a number of designs that Srinivas is going to be placing on these chips,” says Schiff. “They operate at ambient temperature, which means they assume the temperature of their surroundings, rather than freezing them by being dropped into liquid helium. And when implanted, they will allow us to take this technology out of the laboratory for the use of people in an ambulatory setting.”

“It’s a good technical challenge,” says Tadigadapa with a smile.

Putting it into practice

Schiff, who is also professor of neurosurgery, says he and many of his colleagues at Penn State Milton S. Hershey Medical Center are excited about the potential of this new technology to help patients with a range of neurological problems, including spinal cord injuries, ALS, stroke, and cognitive disorders such as depression and obsessive-compulsive disorder.

“I’ve worked in epilepsy for most of my career,” Schiff continues. “This is a way to potentially not only sense from a part of the brain that makes seizures, but to modulate the activity to prevent seizures.”

Being able to stimulate and sense neuron activity without penetrating the brain will be especially valuable to individuals with long-term needs, he adds.

“If I have someone like one of our young veterans who has lost an arm, you want him or her to be able to run a prosthetic device for 50 years. You need to be able to maintain the device, not damage the patient any further, through repeated brain surgeries, and importantly, you need a way to give sensory feedback to the brain. This is a way to interact with the brain and to give it signals reflective of what a prosthetic is sensing as it touches something.”

Schiff and Tadigadapa are making rapid progress toward that goal. A great deal of the physics of identifying magnetic signatures in the brain has been worked out by John Wikswo, and the resources of the Penn State Nanofabrication Laboratory will enable them to make very small, high-density arrays of sensors and stimulators. Their experimental devices have already achieved sensitivity in the range of 300 picoTesla at room temperature.

“The first chips will probably be on the scale of a centimeter for the part of the chip that just does sensing,” says Schiff. “For implantation, the scale we are targeting is 100 micrometers. We won’t be submillimeter for the array the first two years.” With the progress they’ve made so far, he and Tadigadapa can make a strong case for funding for the next stage of the work, further miniaturizing and refining the devices through multiple rounds of experiment and nanofabrication.

Initial testing with living tissue is being conducted on slices of rat brain, to understand the strength of signals coming from neurons and the magnetic field strength required to stimulate nerve cells, and whether it is necessary to use single cells or whether they can produce the results they want with a small number of cells. Andrew Whalen, a doctoral candidate in mechanical engineering, and postdoc Herve Kadji are working with Schiff to prepare these experiments using the micro-magnetic coils that Eugene Freeman has designed. Because there are billions of neurons and other types of cells in the brain, the team will need to develop mathematical “filters” that can help them distinguish one type of cell from another.

The first devices they test with human subjects will be too large to implant due to the amount of electronics and chip packaging necessary, so they’ll be placed on the outside of the skull. That will allow the team to measure the person’s magnetoencephalogram, a map of brain activity based on the magnetic fields produced by brain cells. Even at that size, the device can be very helpful in evaluating epilepsy patients, says Schiff.

“We also can perfect our adaptive noise cancellation, which is key to enabling us to operate without expensive shielded environments,” he says. “So we can test and get the bugs out of this technology before we go to implanted devices.”

When the electronics packaging issue is solved, Schiff expects to have a biocompatible array that has the desired sensitivity and strength and is small enough to be placed in a shallow trough in the skull, where it is as close to the target cells as it can be without penetrating the brain.

It’s an ambitious project, but their progress so far makes Schiff optimistic that they will have a working device in the near future — and that it will offer patients, and their doctors, something that has not been available to them before.

“There is no other technology that can be implanted and work directly with the motor and sensory regions of the brain, yet last a lifetime.” 

Steven Schiff is Brush Chair Professor of Engineering, professor of neurosurgery, professor of engineering science and mechanics, professor of physics, and director of the Penn State Center for Neural Engineering. Srinivas Tadigadapa is professor of electrical engineering and biomedical engineering.

This story first appeared in the Spring 2017 issue of Research/Penn State magazine. An earlier version of this story appeared in Focus on Materials, a magazine published by Penn State's Materials Research Institute.