Inside Neuroscience: Improved Methods to Stimulate the Brain

Advanced techniques in brain stimulation are helping scientists to target and correct brain dysfunction in more exact and personalized ways, with broader applications. At a press conference at Neuroscience 2017, “Brain Stimulation: Improved Methods and Promising Results,” scientists explained how they are developing treatments ranging from the noninvasive to the highly invasive and are still learning how to study precise brain regions more safely and effectively.

According to Helen Mayberg, founding director of the Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai and moderator of the press conference, brain stimulation is undergoing a renaissance. “We’re going to watch a real explosion in how to leverage these emerging new technologies,” she said. “We’re already seeing advances that are possible by the development of new tools.”

Research presented during the press conference shows that scientists can now activate specific regions of the brain from both outside the head and deep within the brain. With additional time and research, these technological advances could potentially help to improve memory, treat neurological disorders, manage Parkinson’s symptoms, and more.

As people age, most experience a decline in long-term memory. Researchers know the hippocampus is critical for the creation of memories, but the hippocampus is a deep brain structure and can’t be stimulated directly. With this in mind, researchers at Northwestern University used repetitive transcranial magnetic stimulation (TMS), short bursts of electromagnetic energy, during a 20-minute period every day for five days to target the hippocampal network, which connects the hippocampus and the cortex. Scientists believe this network plays a key role in the process of memory formation and storage.

A small group of adults over the age of 64 were tested before and after treatment with TMS. Associative memory in the subjects improved, and the improvements lasted for one week. “The prior stimulation changed activity in the hippocampal network while the participants were studying the items,” said lead author John A. Walker. “This demonstrates that we can actually interact with and change activity in the hippocampal network.”

TMS isn’t painful or invasive, and similar work on young children has also found a correlation between TMS and stimulated brain activity coupled with increased memory function. The next step will be testing TMS for clinical utility to help to slow memory decline in older adults.

Ultrasound is well-known for its imaging power, and new research is assessing its efficacy at stimulating neurons. Research has already shown that transcranial focused ultrasound can effectively and safely stimulate neurons in rats — and now, scientists at the Stanford University School of Medicine, in California, are applying the procedure in primates.

The researchers focused ultrasound on a visual area on the left or right side of two macaque monkeys while the animal decided whether to look at a left or a right target. Ultrasound stimulating either the left or right eye field corresponded with more visible eye movements to the right or left, showing that the technique was effective in influencing the animals’ decisions.

Lead author Jan Kubanek said, “These findings suggest that transcranial ultrasound can indeed be used in primates in a noninvasive way through the intact skull and skin to influence behavior.” This work helps researchers to move closer to clinical applications in humans for treatment of neurological and psychiatric disorders.

Aiming to provide a way to deliver transcranial focused ultrasound in awake and moving subjects, scientists at Harvard Medical School created a wearable ultrasound device to stimulate a highly localized focus (as small as a grain of rice) in deep brain regions in sheep.

When applied continuously, focused ultrasound (FUS) heats the brain. In order to avoid applying the stimulation continuously, researchers divided it into pulses, adjusting power, timing, and duration to excite or suppress brain activity without heating brain tissue.

“For translation to humans and large animals, we need a FUS platform that is wearable and equipped with imaging guidance to visualize acoustic focus,” said lead author Seung-Schik Yoo.

The researchers used a sheep model because of the similar cranial structure of sheep and humans. A lightweight FUS system was used in conjunction with image guidance and software to focus the stimulation on a targeted region, enable neuromodulation, and track the focus and intensity for feedback in semi-real time. Following optimization of the parameters and process for safety, devices such as this one could potentially make intervention possible without the need for surgery or medication.

Unlike in experiments unable to accommodate fluctuation in brain activity resulting from applied stimulation, researchers at Stanford University have identified a way to deliver variable stimulation based on real-time variation in mouse brain activity using optogenetics.

The researchers worked with mice that possessed one gene that caused neurons to fluoresce when activated and another gene that allowed the neurons to be controlled by light. This allowed the scientists to record neural activity and modify stimuli accordingly, in real time, to achieve a constant level of activity.

Lead author Noah Young explained the process: “This works like cruise control in your car, or a thermostat in your house. You set some desired speed or desired temperature, and a control system determines whether more gas needs to be added to the engine or more heat added to the room to reach that desired setting. We’re applying that closed-loop control method in the brain.”

Closed-loop systems allow researchers to modify the timing and amplitude of neural activity, generating insight with potential relevance to brain stimulation for treatment of disorders involving dysregulation of brain activity.

Scientists at the University of California, San Francisco implemented fully embedded closed-loop systems in freely moving patients. Deep brain stimulation (DBS) is one treatment for patients with Parkinson’s disease. Currently the stimulation is delivered continuously and at a constant level irrespective of changes in symptoms. To help to control the involuntary movements called dyskinesia that may result from stimulation or medications, the researchers developed a device that records activity from the surface of the brain and uses these signals to adjust the level of brain stimulation.

This adaptive device simultaneously monitors changes in neural activity related to symptoms or side effects and delivers high-frequency pulses to the brain. By incorporating these feedback signals from the patient’s own brain, the device attempts to minimize dyskinesia by administering more or less DBS, depending on the patient’s individual need at a given moment.

“We also found that we saved quite a bit of energy — up to 45 percent in one case — and importantly this is without decreasing how well symptoms were controlled,” said lead author Nicole C. Swann. This initial study was small, so the researchers are now testing more patients for a longer time and using more complex algorithms to deliver better and more customized stimulation.

Together, these studies aim to refine existing tools, to show how different techniques may be used in conjunction with one other, and to minimize invasiveness while maximizing clinical application in humans. “I think we’ve seen the future of what’s possible with these exquisite tools and mechanistic and engineered techniques,” Mayberg said.

As methods in brain stimulation continue to be developed, these tools and techniques will offer safer and more effective ways to study the brain, improve memory, and help people with neurological disorders. Read about other research presented at Neuroscience 2017 related to advances in understanding the effects of opioid abuse and how the brain reacts to stress.