Developing Noninvasive Methods to Effectively Treat Complex Brain Disorders

Researchers at Massachusetts General Hospital are redefining our understanding of brain function and creating avenues for effective, noninvasive therapies targeting the most challenging neurological disorders. Their work is driving an unprecedented push toward the realization of precise, personalized approaches to treating intractable conditions ranging from brain cancer to Alzheimer's disease (AD).

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"Leveraging both neurophysiology and electrophysiology has opened doors allowing us to define not only brain architecture but also the network-level changes that occur with age or in the presence of neurological dysfunction," says Emiliano Santarnecchi, PhD, PsyD, associate professor of Radiology and Neurology at Harvard Medical School and director of the Precision Neuroscience & Neuromodulation Program at Mass General. "These methods offer an opportunity to effectively address conditions for which no effective treatments currently exist."

Learning the Brain's Language

How we process and interact with our environment results from electrochemical activity within and between neurons. Signals between neurons propagate via the flow of ions across a neuron's membrane. The resulting electrical impulses release neurotransmitters that further transmit neuron activity, communicating to connected neurons. The synchronous firing of neurons generates oscillating currents—brain waves—at different frequencies and coordinates the transmission of information between brain regions.

The interplay between neural networks gives coherence to sensory data, defines our perception, and determines how we act and react. To gain insight into these relationships, researchers employ neuroimaging approaches, such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). The result is a structural picture of the brain highlighting areas of neuron activity in response to a stimulus and a personalized map of structure-function relationships between brain regions.

To help read this map, research has revealed correlations between how specific brain wave frequencies dominate during specific activities. For example, delta waves (0.5–4 Hz) are observed during deep, dreamless sleep. In contrast, gamma waves (25–140 Hz) are generated during periods of concentration.

"Understanding the frequencies at which different brain regions communicate offers insight into how to speak the brain's language," says Dr. Santarnecchi. "This can also reveal how these oscillations align with symptoms and cognitive functions and how their disruption corresponds to certain disorders."

Shifting the Paradigm for Treating Neurological Disorders

Studies over the previous two decades have demonstrated the efficacy of noninvasive brain stimulation (NIBS) in modulating motor and visual activity, as well as higher functions, such as decision-making and working memory. Types of NIBS include:

• Transcranial magnetic stimulation (TMS): Uses a magnetic field to alter electrical oscillations in large regions of the brain; currently an FDA-approved therapy for treatment-resistant depression and obsessive-compulsive disorder
• Transcranial electrical stimulation (tES): Applies an electrical current via electrodes that can be oriented to target specific regions of interest in the brain; common methods include delivery of either a direct current (tDCS) or alternating current (tACS)

Although TMS can effectively alter wave activity across large brain regions, tES offers a more nuanced approach to neuromodulation. Specifically, while tDCS can alter the firing rate and pattern of individual neurons, tACS can deliver an electrical current that alters the frequencies elicited by neural networks. This allows tACS to amplify waves to enhance different types of brain function potentially. By contrast, in areas showing altered or dysregulated brain-wave activity, tACS can also resynchronize populations of neurons to recover function (neural entrainment).

In 2013, Dr. Santarnecchi and colleagues published in Current Biology that tACS using gamma-band oscillations could effectively increase fluid intelligence, such as memory and abstract reasoning, in healthy human subjects. In the subsequent decade, his focus shifted as evidence revealed a deficiency in gamma waves associated with with AD and neurodegeneration. He is currently a principal investigator on clinical trials assessing gamma wave induction via tACS as a treatment for AD and frontotemporal dementia.

Recent findings in patients with mild to moderate AD have been promising. In Alzheimer's Research & Therapy, Dr. Santarnechhi and colleagues showed that one-hour administration of 40-Hz tACS daily for two or four weeks increased blood flow and decreased tau protein in the targeted brain regions. The results also identified positive correlations between those changes and improved memory.

"Our ability to selectively increase gamma activity in a targeted region in these patients was a significant achievement," says Dr. Santarnecchi. "However, the resulting associated improvements in two major markers of dementia were very encouraging when considering the lack of effective treatments for many conditions in the Dementia spectrum."

Unmasking Aggressive Gliomas and Tailoring Precision Therapies

Among tumors of the brain and central nervous system, glioblastoma represents the most common and invasive, accounting for about 48% of all cases and a mean survival of 16 to 18 months from diagnosis. Studies showing that gliomas and glioblastoma demonstrate non-random electrical activity at specific frequencies represented a novel opportunity. Specifically, it suggested the possibility of creating patient- and glioma-specific maps of neural connections or 'glioma connectomes'. "Our experience in this area drove attempts to identify personalized electrical signatures for a patient's tumor that might allow us to predict its aggressiveness," explains Dr. Santarnecchi.

Discoveries included the extent to which tumor cells form interconnected networks with healthy neurons, which are recruited to aid tumor growth and invasion. Identifying tumor connectivity patterns revealed specific tumor characteristics correlated highly with post-surgery recurrence and patient survival rates. Not only could the investigators predict the number of days of survival for a patient based on tumor connectivity, but they could also accurately estimate recurrence likelihood.

"We are now creating these maps for hundreds of patients in a large-scale study as validation of the method and to leverage the data to increase predictive accuracy," explains Dr. Santarnecchi. "This could potentially allow preemptive stimulation of predicted areas of recurrence to prevent those outcomes."

Such high-resolution maps were also instrumental in a pilot study involving patients with either glioblastoma or metastatic lesions in their brains. The results showed that 20 minutes of transcranial electrical stimulation targeting the lesions decreased intratumoral blood flow by about 36% with no adverse effects on surrounding healthy tissue.

"This level of precision via non-invasive methods offers unprecedented opportunities for personalized approaches to address intractable brain tumors, especially in combination with other therapies including chemotherapy agents."

The Future of Precision Medicine

Dr. Santarnecchi acknowledges the immense benefits afforded by the ecosystem at Mass General and its atmosphere of innovation, collaboration and outside-the-box thinking. "I'm privileged to be in a position that allows constant interaction with motivated and talented people in multiple disciplines all doing exciting work. Mass General fosters a spirit of pushing boundaries in research that makes anything seem possible."

Some of his current work involves broadening the use of virtual representations of a patient's brain. This concept of creating a 'digital twin' would allow accurate simulation and pre-screening of nearly any type of clinical intervention in order to maximize its efficacy for a given patient.

"Unpacking the complexity behind something this ambitious requires collaborations between neuroscientists, radiologists, computational scientists, clinicians and so many other experts in their respective fields," he advises. "I'm fortunate to be surrounded by talented people willing and able to tackle the hardest problems."

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