Motor Neurophysiology Laboratory: Scott Cooper, PI

Overview

The motor neurophysiology lab studies the extrapyramidal motor system in human subjects with an emphasis on disease states and neurosurgical therapies. The lab's current focus is on the basal ganglia (BG) and on Parkinson's disease (PD) with most of the work centered on deep brain stimulation (DBS). DBS is used as a tool to understand BG physiology and, especially, PD pathophysiology; in addition, DBS therapeutic mechanisms are a major subject of investigation in their own right. The research has a strong translational slant aimed at developing improved approaches to DBS and neuromodulation. The motor neurophysiology lab is the newest addition to the U of M neuromodulation research group, a tightly-knit cluster of researchers including neurologists, neurosurgeons, neurophysiologists, neuroimaging specialists, and bioengineers.

Active Projects

Dynamic Neuromodulation and Response Inhibition

Response inhibition (RI) is a neuropsychological process at the intersection of two important areas of research directly relevant to neuromodulation. First it is an experimentally tractable, neurobiologically relatively well-understood component of a range of psychiatric disorders for which neuromodulation shows great therapeutic potential. Second, RI is a prominent part of the notoriously treatment-refractory neuropsychological component of Parkinson's disease. This project studies PD patients performing an RI task in the operating room, using externalized subthalamic DBS leads to deliver timed stimulation in relation to stimulus presentation, and assesses stimulation effect on task performance.

Dynamic Neuromodulation and Parkinsonian Gait

parkinsonian gait In late Parkinson's disease, gait impairment, including postural instability and freezing of gait (FOG) are refractory to treatment, including DBS. DBS in its present form is constant and unvarying, whereas these refractory symptoms are time-varying (cyclic, in the case of gait; episodic in the case of FOG or loss of balance). This project investigates therapeutic benefits of dynamically varying subthalamic and pallidal DBS modulated in relation to phase of gait, and timed in relation to FOG or loss-of-balance episodes.

Left: Virtual stepping stones projected onto treadmill; Right: Virtual obstacles appear suddenly.

New Projects

Quantitation of Parkinsonian Postural Instability

Loss of balance is one of the biggest problems in Parkinson's disease (PD). A bipedal creature is always unstable and stays upright by dint of constant postural adjustments. Sometimes this means shifting the feet to keep the center of support under the center of mass. That reflex is impaired in PD. Parkinson's medications, which improve many PD symptoms, do not improve this one. The effects of neuromodulation on this reflex are less studied, and, in particular, little is known about how different forms of deep brain stimulation affect it. To study this we are developing a system to study the stepping reflex in response to a standardized balance perturbation.

Projects on the Back Burner

Fitting Models of Parkinson's Rhythmical Movements Using a Particle Filter

Patients with Parkinson's disease exhibit characteristic abnormalities of rhythmical movements known as "hastening" or "festination" in which frequency is pathologically increased. Rhythmical finger-tapping (MDS-UPDRS item 3.4) is used clinically to quantify these abnormalities. A successful model of the dynamics of Parkinsonian rhythmical movements could serve as the basis for closed loop deep brain stimulation for treatment-refractory symptoms affecting rhythmical activities of daily living such as speech and gait.

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particle filter We constructed two models of Parkinson's finger-tapping dynamics, one with a single stable limit cycle attractor (single-basin model), and the other with two stable limit cycle attractors, representing normal and festinating movements (double-basin model). In 29 Parkinson's patients and 20 control patients performing finger-tapping we measured motion of the proximal thumb and index finger with angular velocity transducers. We fit the models to the data using a particle filter, assessing goodness of fit by cross-validation. We are now comparing goodness-of-fit between the single- and double-basin models in Parkinson's and control subjects, planning to assess the the filter for detecting transitions between normal and festinating regimes.

Double-basin model: Conditional probability distribution of model parameters as fit by particle filter to patient data. Multidimensional distribution projected onto one- and two-dimensional subspaces.

Cortical Desynchronization and Hasterning/Festination

Reduction (desynchronization) of “idling” EEG and LFP rhythms in the low-beta frequency range is associated with movement initiation; increase in low-beta activity is associated with motor impairment in Parkinson's Disease. Ongoing rhythmical movements in Parkinson's patients may be impaired episodically by “hastening” (“festination”) in which frequency markedy increases, usually in association with reduced amplitude. If incrased low-beta activity anticipated these episodes, it could be used as a biomarker for closed-loop deep brain stimulation aimed at aborting hastening/festination episodes in gait. This project is available to someone interested in analyzing an existing database of EEG data in Parkinson's patients and controls performing rhythical finger-tapping.

Quantitation of Parkinsonian Rigidity

Rigidity is one of the cardinal symptoms of Parkinson's Disease, and is more or less synonomous with "mechanical impedance." In a clinical setting, it is measured by passively moving a limb, and noting the amount of resisting force encountered. This is normally a subjective judgement by a physician or nurse. More precise quantitation is possible with a mechanical actuator and force transducer. This project designed and implemented such a device, and developed software for processing the force transducer output; it is available to someone interested in developing software for controlling the actuator, integrating that with the force transducer software, and testing the device in humans.

Selected Publications

Matias CM, Silva D, Machado AG, and Cooper SE 2015. “Rescue” of bilateral subthalamic stimulation by bilateral pallidal stimulation: a case report. J Neurosurg in press

Mehanna R, Machado AG, Oravivattanakul S, Genc G, and Cooper SE 2014. Comparing two deep brain stimulation leads to one in refractory tremor. The Cerebellum 13:425-432fast-vs-slow

Floden D, Cooper SE, Griffith SD, and Machado AM 2014. Predicting quality of life outcomes after subthalamic nucleus deep brain stimulation. Neurology 83:1627-1633

Cooper SE, Driesslein KG, Noecker AM, McIntyre CC, Machado AM, and Butson CR 2014. Anatomical targets associated with abrupt versus gradual washout of sub thalamic deep brain stimulation effects on bradykinesia. Plos One 9:e99663

Left. Percent of fast-vs.-slow-washout DBS effect according to location of stimulation.

Cooper SE, McIntyre CC, Fernandez HH, and Vitek JL 2013. Association of deep brain stimulation washout effects with parkinson disease duration. JAMA Neurol (formerly Arch Neurol) 70:95-99 DBS waqshout

Cooper SE, Noecker AM, Abboud H, Vitek JL, and McIntyre CC 2011. Return of bradykinesia after subthalamic stimulation ceases: Relationship to electrode location. Exper Neurol 231:207-213

Butson CR, Cooper SE Henderson JM, Wolgamuth B, and McIntyre, CC. 2011. Probabilistic analysis of activation volumes generated during deep brain stimulation. Neuroimage 54:2096-2104

Right. Subthalamic nucleus DBS washout rate constant (1/half-life) vs. disease duration in 19 Parkinson's patients.

Full publication list:Publications

Collaborators, Positions Available, and Contact Information

COLLABORATORS

At the University of Minnesota

Matthew Johnson, PhD (Bioengineering)
Michael Park MD, PhD (Neurosurgery)
Jerrold Vitek MD, PhD (Neurology)
Colum MacKinnon, PhD (Neurology)

At Other Institutions

Christopher Butson, PhD (Bioengineering, University of Utah)
Darlene Floden, PhD (Neuropsychology, Cleveland Clinic)
Andre Machado MD, PhD (Neurosurgery, Cleveland Clinic)
Cameron McIntyre, PhD (Bioengineering, Case Western Reserve University)

POSITIONS AVAILABLE

Postdoctoral positions are currently filled. Inquiries from potential graduate students, undergraduates, and residents interested in working in the lab are welcome.

CONTACT INFORMATION

Patients seeking diagnosis or treatment
Neurology Clinic
M Health Clinics and Surgery Center
909 Fulton St SE
Minneapolis, MN 55455
612-676-4300

Patients and others interested in participating in research

Kelly Ryberg
Research Coordinator
University of Minnesota
Department of Neurology
MMC 295, 420 Delaware Street SE
Minneapolis, MN 55455
612.626.3439
rybe0010@umn.edu

Students, colleagues, job applicants

Scott Cooper MD, PhD
Assistant Professor
University of Minnesota
Department of Neurology
MMC 295, 420 Delaware Street SE
Minneapolis, MN 55455
secooper@umn.edu

Just for Fun

Match the quotation with the person who said it.
If you think you've got them all, email me.

“I just got the answer by staring at the data for a long time.”

“One doesn't change that much, really.”

“There is no Book whatsoever, be it never so bad or decried,
but may in time be sought for by some person or other.”

“It is difficult to see why a soul should come to rest in a human body, when from both
intellectual and moral viewpoints a computer would be preferable.”

“Some problems are hard because they're just terribly complicated, and some problems
are hard just because it's not in the nature of the thing that it can be done at all.”

“Have you ever heard a blindfolded octopus unwrap a cellophane-covered bathtub?”

“... and are no longer illuminated.”

“A collector of forged McCoys”

“When somebody rings your bell at 6 A.M. and it is the milkman, you are in a democracy.”

“Things are about average. Not as good as yesterday, better than tomorrow.”

“He phoned me to complain bitterly that Fahrenheit 451 was not the temperature
at which book paper burned.”

“All models are wrong, but some are useful.”

“However beautiful the strategy, you should occasionally look at the results.”

“That truss: I wouldn't stand on it...Purely for linear algebra reasons, of course.”

“C'est le provisoire qui dure.”

“This sometimes happens in math. Make a mistake? Slightly change the problem.”

“I myself prefer to live amongst abstractions that have nothing to do with reality.”

“Sometimes I don't think of aardvarks.”

“It is very difficult to make good mistakes.”

“People reach the top of the ladder because they have none of the talents
that might have detained them on the rungs.”

Gilbert Strang

Chris Tisdell

Marvin Minsky

Harry Secombe

Douglas Adams

Gerald Allen Cohen

Gabriel Naude

Norman Juster

Ben Moore

Gustave Oudet

Maurits Cornelis Escher

Yoshisuke Ueda

Winston Churchill

Peter Ustinov

Paula Rego

Hannes Alfven as Olaf Johanesson

Goro Shimura

Michael Moorcock of JG Ballard

George Box and Norman Draper

Claude Bourdet