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Neuroscientists Unearth a New Pathway in the Human Brain

A University of Iowa study reveals novel human prefrontal-subthalamic circuitry.

Courtesy of Narayanan Lab, University of Iowa
This image illustrates changes in prefrontal brain activity when the subthalamic nucleus (STN) is stimulated at: high frequencies (right head), not stimulated at all (left head), or stimulated at 4 Hz (middle head). Stimulating the STN at 4 Hz produces a significant increase in frontal activity (also at 4 Hz), which correlates with improved patient performance on a simple cognitive task that is usually disrupted by Parkinson's disease (PD). The findings by neuroscientists at the University of Iowa and published Nov. 28 in the journal Brain, suggest that low-frequency stimulation of the STN may provide an approach for treating cognitive symptoms of PD, and possibly other cognitive diseases.
Source: Courtesy of Narayanan Lab, University of Iowa

Researchers at the Iowa Neuroscience Institute of the University of Iowa have identified direct evidence of a connection in the human brain between thinking regions of the prefrontal cortex (PFC) and a deeper brain structure called the “subthalamic nucleus” (STN), which is involved in controlling movements. Their potentially game-changing study, “A Human Prefrontal-Subthalamic Circuit for Cognitive Control,” published November 28, 2017, in the journal Brain, paves the way for entirely new approaches to improving human cognition.

For this study, Iowa neuroscientists used low-frequency deep brain stimulation (DBS) along with rare intraoperative brain recordings to monitor PFC-STN connections in patients with Parkinson’s disease (PD). To their surprise, the researchers found that deep brain stimulation of “non-thinking” STN regions at a low frequency actually improved cognitive functions in patients with PD. These findings offer fresh clues to a broader and previously unrecognized potential use of DBS for treating other cognitive diseases.

Parkinson's is a progressive neurodegenerative disease that affects approximately one million people in the United States. Deep brain stimulation of the STN at high frequencies is already approved to treat movement problems in some patients with PD. In February 2016, the FDA approved deep brain stimulation for use in PD patients who had the disease for at least four years and were experiencing a recent onset of motor complications that were not being adequately controlled by medication.

In addition to Parkinson's causing movement problems, Parkinson’s also affects patients' thinking. Therefore, these new findings on the cognitive benefits of low-frequency DBS could offer a fresh way to improve cognitive dysfunction in patients with PD. There is one caveat: In their paper, the authors write: "Notably, STN-DBS at low frequencies does not improve and may worsen motor symptoms of PD (Barnikol et al., 2008); thus, alternative DBS strategies are likely needed to clinically target both motor and cognitive function."

That being said, the UI neuroscientists speculate that low-frequency deep brain stimulation of the STN could someday be used to treat other neurologic and psychiatric diseases. Of course, more research is needed.

One thing that makes the research unique is that the neurologists teamed up with neurosurgeons and were able to test various hypotheses about DBS via a novel combination of human neuroscience methods that directly measure PFC-STN connectivity in human patients undergoing neurosurgical procedures. In this cohort of patients, the multidisciplinary team was able to demonstrate that lateral and medial areas of the PFC are functionally connected with the STN.

"It's not very often that you identify a new connection in the human brain," Nandakumar Narayanan, UI assistant professor of neurology and senior study author said in a statement. "The existence of this hyperdirect pathway from the prefrontal cortex to the STN has been bandied about for around a decade, but this is the first time we've experimentally shown that it exists and functions in people.”

"We were also able to show that if we stimulate the STN, we change the frontal cortical activity, and we think it's by this pathway," Narayanan noted. "And if we stimulate the STN and change cortical activity, we can actually change behavior in a beneficial way, improving the patients' cognitive performance."

The Universtiy of Iowa team was able to map the STN-cortex connections by "listening in" on brain activity during neurosurgery operations in real time, as deep brain stimulation electrodes were implanted in patients with PD. Jeremy Greenlee is a UI neurosurgeon who performs more than 30 of these surgeries every year.

In a statement, Greenlee explained, "We were able to evoke a response to show the [PFC-STN] functional connection. The very fast response suggests a single, direct synaptic connection — that is what hyperdirect means. It is exciting to potentially have a way to improve cognition that could be life-changing for patients."

In addition to Narayanan and Greenlee, the UI study team included Ryan Kelley, Oliver Flouty, Eric Emmons, Youngcho Kim, Johnathan Kingyon, Jan Wessel, and Hiroyuki Oya.

Lastly, huge thanks to senior writer/editor Jennifer Brown at University of Iowa Health Care for bringing this fascinating research to my attention prior to publication.


Kelley, Ryan, Oliver Flouty, Eric B. Emmons, Youngcho Kim, Johnathan Kingyon, Jan R. Wessel, Hiroyuki Oya, Jeremy D. Greenlee, Nandakumar S. Narayanan. "A Human Prefrontal-Subthalamic Circuit for Cognitive Control." Brain (Published: November 28, 2017) DOI: 10.1093/brain/awx300