Brain Stimulation Turns Paralyzed Rats into Walkers, Swimmers

Researchers have tried, to little avail, to repair the spinal cord by growing nerve fibers across the site of injury. Now, they suggest that a few intact fibers may be enough to restore movement—if the fibers can be energized with an electrical jolt to the brainstem. According to a study in the October 23 Science Translational Medicine, paralyzed rats begin to scamper or swim almost normally after deep brain stimulation (DBS) of a key motion control center. The same kind of therapy might help people who have spinal injuries, suggest the study authors, based at the Swiss Federal Institute of Technology, Zürich. As long as the spinal cord was not completely severed, the treatment might even work for people who had suffered injury years before, they speculated.

While DBS for spinal reinvigoration would be new, this surgical treatment already helps people with Parkinson’s and is being tested for several other conditions (see Alzforum News series). DBS research got a boost on October 24, when the U.S. Defense Advanced Research Projects Agency announced that it will invest $70 million over the next five years to study DBS and other brain implants. DARPA’s new project, called Systems-Based Neurotechnology and Understanding for the Treatment of Neuropsychological Illnesses, is part of an Obama administration brain initiative announced earlier this year (see ARF news). The project aims to address challenges in monitoring the brain’s response to such stimulation (see The New York Times article).

Patients with spinal-cord injuries have few treatment options. For some with incomplete spinal injury, physical rehabilitation works well, noted Reggie Edgerton of the University of California in Los Angeles, who was not involved in the study. However, the authors, led by first author Lukas Bachmann and senior author Martin Schwab, noted many patients still leave rehab unable to walk on their own. DBS might be a second-line therapy for these people, Edgerton said. The brain stimulation could also complement attempts to stimulate the spinal cord directly, below the lesion, Bachmann noted in an email to Alzforum. Scientists have had success with that approach, using epidural and intraspinal electrodes in animals (Ichiyama et al., 2005, Guevremont et al., 2006, Barthélemy et al., 2007) and in people (Harkema et al., 2011). While DBS relies on a few fibers that cross the lesion site, epidural stimulation works even if the cord was fully severed.

How could stimulating the brain compensate for damage to the spinal cord? The scientists reasoned that targeting the mesencephalic locomotor region (MLR), the brainstem’s motion-command center, might boost the signals down the spinal cord and across any remaining fibers. They tested this idea in rats. It is unlikely that the short-term stimulation used in the study repairs the injury, Bachmann wrote; rather, it makes the most of remaining connections.

To model spinal-cord injuries commonly found in humans with paralyzed legs, the authors partly severed the spinal cord in rats. They cut through about 80 percent of the cord of 11 animals at the thoracic level. Right after surgery, the rats lost control of their hind limbs. After a month, they recovered some hind-limb function, but still got around mainly with their forelimbs, dragging their hind legs. Most of the injured rats moved their hind limbs in a water tank, where less effort is required to fight gravity, but they still compensated for the injury by paddling vigorously with their forelimbs. The range of motion resembled that seen in people with incomplete spinal injury, the authors noted.

The researchers had implanted electrodes in the MLR before the spinal-cord section. Four weeks after the injury, the authors switched on the current and let the rats walk—and walk they did. In particular, their stepping strength and speed was nearly back to pre-injury levels, Bachman wrote in an email to Alzforum. As the researchers turned up the amperage, the rats met and often even exceeded their pre-injury performance on a number of parameters, including range of motion, stepping frequency, and paw speed. In the water tank, the animals again matched or surpassed pre-injury measures of swim speed and stroke frequency.

The new motion was sometimes awkward—the rats often slipped, for example. Overall, during DBS rats could walk and swim “almost as normal,” Bachmann wrote. “The improvements are quite good,” agreed Edgerton. “You can get similar improvements … with epidural stimulation.”

The researchers are discussing next steps toward human testing with clinicians, but Bachmann cautioned that it is too early for people to get their hopes up. For a treatment, doctors would want to give patients the option of walking of their own free will, rather than being controlled by an electrical puppet master. At high current the rats had no choice but to step, but at intermediate currents they controlled their own movements. “The intermediate stimulation intensities are most promising for treatment as they facilitate the movement without forcing anything,” Bachmann wrote.

Might DBS of the MLR also help neurodegenerative conditions that weaken motor function, such as Parkinson's and amyotrophic lateral sclerosis? Bachmann speculated that in both PD and spinal-cord injury too few of the brainstem’s motor commands reach the spinal cord. Researchers have tried to stimulate part of the MLR in a handful of PD patients and the recipients walked better after treatment (Stefani et al., 2007, Plaha and Gill, 2005). Others have attempted cortical stimulation in a few ALS cases, but not enough to make a firm conclusion about efficacy (Sidoti and Agrillo, 2006). Theoretically, it seems possible that MLR stimulation might benefit ALS patients, Edgerton said, but he that it would depend on how many motor neurons remain viable. He speculated that if effective, the stimulation might slow symptom progression.—Amber Dance

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References

Paper Citations

  1. Ichiyama RM, Gerasimenko YP, Zhong H, Roy RR, Edgerton VR. Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation. Neurosci Lett. 2005 Aug 5;383(3):339-44. PubMed.
  2. Guevremont L, Renzi CG, Norton JA, Kowalczewski J, Saigal R, Mushahwar VK. Locomotor-related networks in the lumbosacral enlargement of the adult spinal cat: activation through intraspinal microstimulation. IEEE Trans Neural Syst Rehabil Eng. 2006 Sep;14(3):266-72. PubMed.
  3. Barthélemy D, Leblond H, Rossignol S. Characteristics and mechanisms of locomotion induced by intraspinal microstimulation and dorsal root stimulation in spinal cats. J Neurophysiol. 2007 Mar;97(3):1986-2000. PubMed.
  4. Harkema S, Gerasimenko Y, Hodes J, Burdick J, Angeli C, Chen Y, Ferreira C, Willhite A, Rejc E, Grossman RG, Edgerton VR. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011 Jun 4;377(9781):1938-47. PubMed.
  5. Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, Mazzone P. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain. 2007 Jun;130(Pt 6):1596-607. PubMed.
  6. Plaha P, Gill SS. Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson's disease. Neuroreport. 2005 Nov 28;16(17):1883-7. PubMed.
  7. Sidoti C, Agrillo U. Chronic cortical stimulation for amyotropic lateral sclerosis: a report of four consecutive operated cases after a 2-year follow-up: technical case report. Neurosurgery. 2006 Feb;58(2):E384; discussion E384. PubMed.

Other Citations

  1. Alzforum News series

External Citations

  1. The New York Times article

Further Reading

Papers

  1. Hescham S, Lim LW, Jahanshahi A, Blokland A, Temel Y. Deep brain stimulation in dementia-related disorders. Neurosci Biobehav Rev. 2013 Sep 20; PubMed.
  2. Suthana N, Fried I. Deep brain stimulation for enhancement of learning and memory. Neuroimage. 2013 Aug 3; PubMed.
  3. Laxton AW, Lipsman N, Lozano AM. Deep brain stimulation for cognitive disorders. Handb Clin Neurol. 2013;116:307-11. PubMed.
  4. Okun MS. Deep-brain stimulation for Parkinson's disease. N Engl J Med. 2012 Oct 18;367(16):1529-38. PubMed.
  5. Laxton AW, Sankar T, Lozano AM, Hamani C. Deep brain stimulation effects on memory. J Neurosurg Sci. 2012 Dec;56(4):341-4. PubMed.
  6. van den Brand R, Heutschi J, Barraud Q, DiGiovanna J, Bartholdi K, Huerlimann M, Friedli L, Vollenweider I, Moraud EM, Duis S, Dominici N, Micera S, Musienko P, Courtine G. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012 Jun 1;336(6085):1182-5. PubMed.

Primary Papers

  1. Bachmann LC, Matis A, Lindau NT, Felder P, Gullo M, Schwab ME. Deep brain stimulation of the midbrain locomotor region improves paretic hindlimb function after spinal cord injury in rats. Sci Transl Med. 2013 Oct 23;5(208):208ra146. PubMed.

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