‘Chance Finding’ a True Breakthrough for Spinal Cord Injury?

Deep brain stimulation (DBS) of the lateral hypothalamus (LH) improves walking and promotes recovery in patients with spinal cord injury (SCI), new research showed.

This intervention excites glutamatergic neurons in the LH, which appear to be key to restoring movement. The results represent a shift in the approach to treating SCIs, which in the recent past has focused on spinal, rather than brain, stimulation.

“This study highlights the idea that spinal cord injury is as much a disease of the brain as it is of the spine, so we need to look at both the brain and the spine to really optimize function,” study investigator Newton Cho, MD, PhD, a clinical fellow in spine surgery, University of Calgary, Alberta, Canada, told Medscape Medical News.

The findings were published online on December 2 in Nature Medicine.

A True Breakthrough?

SCIs disrupt neuronal projections from the brain to the region of the spinal cord that facilitates walking, leading to varying degrees of paralysis. Because an incomplete SCI only partially severs the spinal cord, patients with such an injury may retain a degree of function and feeling below the site of injury.

Researchers first studied rodents with an incomplete SCI — an injury that damages 83.2% of the spinal cord leading to paralysis of the lower limbs. They used “very powerful” anatomical and functional mapping “to interrogate the whole mouse brain to see which areas are changing both in terms of activity and in terms of connections to the spinal cord,” said Cho.

By chance, he and his colleagues discovered that glutamatergic neurons in the LH are critical for improved walking. Cho said that when he embarked on this project as part of his graduate work, he happened upon this area while investigating the whole mouse brain to determine which areas of the brain might optimize the remaining circuits after SCI.

The LH is a highly specialized region of the brain primarily known to regulate arousal, feeding, and motivated behavior.

Although he admits he’s biased, Cho believes this discovery represents a true breakthrough in the field. Until now, he noted, the LH was not known to be associated with leg movement control.

The researchers’ previous animal research revealed that DBS of the LH immediately augmented walking in mice and rats with SCI.

“We think the electricity is stimulating those glutamatergic neurons, and in doing so, is increasing the motivation to walk, increasing the overall, let’s say, engine, to kind of move forward and bypass some of the injury in the spinal cord,” said Cho.

He explained that while circuits are interrupted to some degree in an incomplete SCI, they’re not wholly severed, so some circuits remain. Stimulating the LH “boosts those remaining circuits to optimize their function and allow walking,” he said.

To evaluate the intervention in humans, researchers enrolled patients with incomplete SCI in a pilot study. The first two participants could walk to some degree with assistive devices but had persistent gait deficits despite having completed standard rehabilitation programs.

The first participant, a young adult woman, had a motor and sensory incomplete American Spinal Injury Association Impairment Scale (AIS) C T1 lesion that occurred 5 years earlier. The second participant, a man,suffered a motor and sensory incomplete (AIS D) C5 lesion due to a skiing accident. He underwent the intervention about 15 years after his injury.

Both participants had goals they hoped to achieve during the study. The first patient wanted to walk without body weight support or extensive orthoses, while the second patient wanted to walk longer distances and climb and descend stairs independently at home.

Researchers used anatomical data from MRI and diffusion tensor imaging to determine optimal placement of electrodes in the LH. Surgeons connected the leads to an implanted pulse generator.

Delivery of DBS of the LH elicited immediate sensations in the paralyzed lower limbs, with the first participant reporting she felt the urge to move her legs.

This real-time feedback confirmed the correct region was targeted, said another investigator Jocelyne Bloch, MD, a neurosurgeon and associate professor, University of Lausanne, and Lausanne University Hospital in Lausanne, Switzerland, said in a press release. “At this moment, I knew that we were witnessing an important discovery for the anatomical organization of brain functions,” she noted.

In addition to increased activation of lower limb muscles, which led to improved kinematics and endurance, both participants reported that walking required less effort.

“Even in the absence of any significant training, these individuals were able to demonstrate some immediate effects from the stimulation,” said Cho.

The study included a 3-month structured rehabilitation program that involved 3 days of gait training per week. The program was personalized based on individual improvements.

The training led to pronounced improvement in walking, captured by superior performance during the 10-meter and 6-minute walking tests, which were evaluated in both the DBS on and off conditions, and increased lower-extremity motor scores.

“After about 6 months, even when the stimulation was off, they were able to have noticeable improvements in their walking,” said Cho. These “robust” results could serve as a basis for “changing the paradigm of how we approach patients with spinal cord injury,” he added.

Promising, but Not a Cure

Both participants have achieved their goals. In the press release, the second study participant, Wolfgang Jäger, from Kappel, Austria, now 54, shared how DBS restored his mobility and independence. “Last year on vacation, it was no problem to walk a couple of steps down and back to the sea using the stimulation,” he said.

Beyond walking, the therapy has improved everyday tasks, he added. “I can also reach things in my cupboards in the kitchen.”

Although the study highlights a promising new target for DBS in people with SCIs, Cho was quick to point out this intervention is not a cure. “It’s not like these subjects went from being unable to walk to being completely normal.”

It’s also not clear if, or to what extent, this intervention would help patients with a complete SCI. If the spinal cord isn’t totally severed, some circuitry between the brain and spinal cord may remain.

However, said Cho, “we can imagine that the effects of brain stimulation in complete injuries would be less effective than in incomplete injuries, but that remains to be tested.”

Different research teams are investigating stimulation of other brain regions to treat SCIs, including the mesencephalic locomotor region, and the motor cortex, but so far, results have been “mixed,” said Cho.

Although the motor cortex seems like a logical stimulation target to regain walking ability, the science is not that simple. “Here you have an injured spinal cord, but you also have an injured brain, and so maybe the motor cortex itself is not really the main target,” said Cho, adding evidence now suggests the LH and possibly other circuits “play a compensatory role.”

Researchers assessed the safety of DBS of the LH in the two patients through reported adverse events as well as vital signs, weight, and hormonal monitoring and found there were no related serious adverse events.

However, Cho added that additional trials with more participants are needed to establish its safety and efficacy profile, said Cho. This would include such things as evaluating potential changes in body weight, psychological status, hormonal profiles, and autonomic functions.

It’s unlikely that all individuals with SCI will respond to rehabilitation augmented by DBS of the LH. Pivotal trials must establish which patients may benefit from this therapy, the investigators noted.

Future research will also explore combining DBS with other technologies, such as spinal stimulation that has shown potential to restore movement after SCI, a third study author Grégoire Courtine, PhD, professor of neuroscience and neurotechnology, Lausanne University Hospital, and University of Lausanne, said in a release.

“Integrating our two approaches — brain and spinal stimulation — will offer a more comprehensive recovery strategy for patients with spinal cord injuries.”

‘Remarkable Translational Efforts’

Commenting on the research for Medscape Medical News, Peter J. Grahn, PhD, assistant professor of physical medicine and rehabilitation, Mayo Clinic, in Rochester, Minnesota, who has studied spinal stimulation and lives with quadriplegia following an SCI, praised the researchers’ “remarkable translational efforts.”

“They identified this brain region in animals that was previously not associated with trying to recover function, then they translated that to humans,” he said.

Not only did he find the proof of principle study in humans exciting but also said the possibility of combining brain and spinal stimulation is promising. “This group is obviously very motivated and has the expertise to jump over the hurdles that would be necessary to use two different investigational devices.”

But while he sees promise for those with incomplete SCIs who can still walk, albeit with an impaired gait, he is more skeptical about patients like himself who have a more severe injury.

“From what these data show, I would expect there to be limited recovery. The cost-benefit analysis would be that I shouldn’t get it because in my scenario, I have a neck injury, so my hands and my legs are impaired, and I can’t partially walk, so improving nothing would be nothing.”

Also commenting on the research, James David Guest, MD, PhD, who is also investigating DBS in SCI, noted that his team’s research, which targets the mesencephalic reticular formation, also shows that glutamatergic neurons activate brainstem reticular neurons.

“This indicates these brainstem neurons are an important convergent target for recovery enhancement after spinal cord injury,” said Guest, professor of neurological surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, in Miami. Together, the research “indicates that deep brain stimulation is a promising and new path forward for recovery from paralysis.”

Interestingly, the idea that stimulating glutamatergic neurons in the LH can improve walking after a SCI actually originated back in 1945, said Guest. At that time, researchers observed that emotional states could enhance locomotion in a polio-affected animal.

The study was supported in part by ONWARD Medical, the Swiss National Science Foundation, Canadian Institutes of Health Research, and the European Research Council.

Cho, Bloch, and Courtine reported they hold various patents in relation to the present work. Courtine is a consultant of ONWARD Medical, a company with partial relationships with the presented work. Courtine and Bloch are minority shareholders of ONWARD Medical. Grahn reports no relevant conflicts of interest.