Brain mapping technique reveals circuitry of Parkinson’s disease tremors

The new Stanford technique probes the neural pathways that cause these tremors, and also provides a way to map and troubleshoot other circuits in the brain.

A new circuit-mapping approach to probe the brain should help improve treatments for Parkinson’s disease. It also provides a methodology to identify, map and ultimately repair neural circuits associated with other brain diseases. 
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If a piece of electronics isn’t working, troubleshooting the problem often involves probing the flow of electricity through the various components of the circuit to locate any faulty parts.

Now, Stanford researchers have adapted that idea to studying diseases of the brain by turning on specific types of neurons and observing how the entire brain responds to their activation.

The goal is to give neuroscientists a way to probe brain ailments similar to how engineers troubleshoot faulty electronics. “Electrical engineers try to figure out how individual components affect the overall circuit to guide repairs,” said Jin Hyung Lee, PhD, a professor of neurology and neurological sciences, of bioengineering and of neurosurgery.

In the short term, the technique could help improve treatments for Parkinson’s disease, which Lee studies. In the long run, it could help identify, map and guide the repair of neural circuits associated with other brain diseases.

The work is described in a paper published online Jan. 26 in Neuron. Lee is the senior author. The lead author is postdoctoral scholar David Bernal-Casas.

The circuit-mapping approach combines two experimental tools with a computational method. The first tool is optogenetics, which modifies specific types of neurons in the brain so they can be turned on in response to light. The second tool is called functional MRI, which detects areas of activity in the brain based on blood flow. The researchers used optogenetics to turn on a specific type of neuron and fMRI to observe how areas of the brain responded. Then, they used computational analysis to diagram the brain network that was activated, which allowed them to determine the function of the circuit specific to each neuronal type.

Controlling Parkinson’s tremors

One hallmark of Parkinson’s disease is uncontrollable tremors. Neuroscientists believe these tremors are caused by malfunctions in the neural pathways that control motion. They know that different regions of the brain are constantly forming circuits to carry out tasks, whether motion or speech. However, prior to Lee’s technique, researchers had no way to show how activating a specific type of neuron might cause a specific circuit to form in the whole brain.

Jin Hyung Lee

Testing her approach on rats, Lee probed two different types of neurons known to be involved in Parkinson’s disease. Her team found that one type of neuron activated a pathway signaling for greater motion, while the other activated a signal for less motion. Lee’s team then designed a computational approach to draw circuit diagrams that underlie these neuron-specific brain-circuit functions.

“This is the first time anyone has shown how different neuron types form distinct, whole brain circuits with opposite outcomes,” Lee said.

Lee said the findings in this paper should help to improve treatments for Parkinson’s disease. Neurosurgeons are already using a technique called deep brain stimulation to calm Parkinson’s tremors in their patients. DBS delivers tiny electric jolts to neurons thought to be responsible for the tremors. A more precise understanding of the how those neurons work to control motion could help guide more effective stimulation.

More broadly speaking, Lee thinks that her technique — optogenetic fMRI combined with computational modeling — gives researchers a new way to reverse-engineer the functions of the many different types of neurons in the brain and the bafflingly diverse array of neural circuits formed to carry out different commands.

Other co-authors are research scientist Hyun Joo Lee and graduate student Andrew Weitz.

Lee is a member of Stanford Bio-X and the Stanford Neurosciences Institute, and a faculty fellow at Stanford ChEM-H.

This work was supported by the National Institutes of Health, the National Science Foundation, an Alfred P. Sloan Research Fellowship and an Okawa Foundation Research Grant Award.

Stanford’s departments of Neurology and Neurological Sciences, Bioengineering and Neurosurgery also supported the work. The Department of Bioengineering is jointly operated by the School of Medicine and the School of Engineering.    



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