Researchers screening more than 1000 potential drugs for spinal cord injury treatment identified an existing one – cimetidine – that improved spinal repair in zebrafish. The results, published in the journal Theranostics, showed that the drug also helped improve recovery of movement and reduce the extent of spinal cord damage when tested in spinal-injured mice.
Healing of spinal cord injuries can be inefficient due to inflammation caused by an overreaction of the immune system. Anti-inflammatories that suppress the whole immune response also inhibit the immune cells which promote repair.
The University of Edinburgh-led study tested multiple drugs in zebrafish larvae for their ability to prevent excessive inflammation during an immune response. Scientists discovered that cimetidine acts by helping to regulate histamine levels.
The findings have enabled the team to pinpoint a specific signalling pathway that moderates the immune response after spinal injury to support repair.
The investigators say that other drugs that work in a similar way could also be tested for their ability to support recovery from spinal injury. They caution that further studies are needed to investigate their impact in human clinical trials. The researchers add that the study highlights the usefulness of zebrafish in the drug discovery process.
The research team included scientists from the University of Edinburgh, the Research Institute of the McGill University Health Centre and Technische Universität Dresden.
Study participant Gert-Jan Oskam walking with the brain-spine interface. Credit: Swiss Federal Institute of Technology in Lausanne
A 40 year-old man, Gert-Jan Oskam, has regained the ability to walk independently after being paralysed from a spinal cord injury with the use of a new brain-spine interface. The ‘digital bridging’ technology, developed at the Swiss Federal Institute of Technology in Lausanne and described in Nature, consists of implants and a computer to translate brain signals of the intention to move into stimulations that move the legs accordingly..
This BSI system could be calibrated in minutes, and remained stable for one year, including use at home. The BSI enabled the participant to exert natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains.
In addition to the digital bridging, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.
The system consists of a pair cortical of sensors, each an array with 64 electrodes housed in 5cm-diameter titanium discs. These discs are implanted snugly in the skull to pick up brain activity. They transmit the data wirelessly to a personalised headset, which also provides power for the sensors. The headset then sends the data to a portable processing unit (which may be carried in a backpack). Using specialised software, it uses this brain signal data to generates real-time predictions of motor intentions. These decoded intentions are translated into stimulation commands and sent on to another implant, a paddle array of 16 electrodes implanted next to the spinal cord, delivering current to the targeted dorsal root entry zones.
Neurosurgical implantation procedure
Oskam had sustained an incomplete cervical (C5/C6) spinal cord injury during a biking accident 10 years previously. He had already participated in a neurological recovery programme, the STIMO trial, which had used neurostimulation to get him to the stage where he could walk with the aid of a front-wheel walker. The neurorehabilitation from the trial also enabled him to use his hip flexors and lift his legs against gravity, but recovery had plateaued for the three years prior to his participation in the present study.
For the BSI to function, the researchers needed to locate neural features related to the intention to move the legs. To pinpoint the cortical regions associated with the intention to move, they used CT scans and magnetoencephalography. Taking into account anatomical restraints, they then decided on the positions of the implants.
Under general anaesthesia, surgeons performed a bicoronal incision of the scalp to allow two circular-shaped craniotomies over the planned locations of the left and right hemispheres. They then replaced the bone flaps with the two implantable recording devices, before closing the scalp.
The paddle lead had already been emplaced over the dorsal root entry zones of the lumbar spinal cord during the STIMO clinical trial. Its optimal positioning was identified using high-resolution structural imaging of the spine, and its final position was decided during the surgery based on electrophysiological recordings. The implantable pulse generator was inserted subcutaneously in the abdomen. Oskam was able to return home 24 hours after each procedure.
For people with paralysis caused by neurologic injury or disease, brain-computer interfaces (BCIs) can potentially restore mobility and function by transmitting neural data to external devices such as mobility aids, which have already shown promise in trials.
Although implanted brain sensors, the core component of many brain-computer interfaces, have been used in neuroscientific studies with animals for decades and have been approved for short term use (< 30 days) in humans, the long-term safety of this technology in humans is unknown.
New results published in Neurology from the BrainGate feasibility study, the largest and longest-running clinical trial of an implanted BCI, suggest that these sensors’ safety is similar to other chronically implanted neurologic devices, with skin irritation around the implant interface.
This new report from a Massachusetts General Hospital (MGH)-led team, examined data from 14 adults with quadriparesis from spinal cord injury, brainstem stroke, or ALS who were enrolled in the BrainGate trial from 2004 to 2021 through seven clinical sites in the United States.
Participants underwent surgical implantation of one or two microelectrode arrays in a part of the brain responsible for generating the electrical signals that control limb movement. With these “Utah” microelectrode arrays, the brain signals associated with the intent to move a limb can then be sent to a nearby computer that decodes the signal in real-time and allows the user to control an external device simply by thinking about moving a part of their body.
The authors of the study report that across the 14 enrolled research participants, the average duration of device implantation was 872 days, yielding a total of 12 203 days for safety analyses. There were 68 device-related adverse events, including 6 device-related serious adverse events.
The most common device-related adverse event was skin irritation around the portion of the device that connects the implanted sensor to the external computer system. Importantly, they report that there were no safety events that required removal of the device, no infections of the brain or nervous system, and no adverse events resulting in permanently increased disability related to the investigational device.
“This interim report demonstrates that the investigational BrainGate Neural Interface system, which is still in ongoing clinical trials, thus far has a safety profile comparable to that of many approved implanted neurologic devices, such as deep brain stimulators and responsive neurostimulators,” says lead author Daniel Rubin, MD, PhD.
“Given the rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development,.” said Rubin.
Leigh Hochberg, MD, PhD, director of the BrainGate consortium and clinical trials and the article’s senior author emphasised the importance of ongoing safety analyses as surgically placed brain-computer interfaces advance through clinical studies.
“While our consortium has published more than 60 articles detailing the ever-advancing ability to harness neural signals for the intuitive control of devices for communication and mobility, safety is the sine qua non of any potentially useful medical technology,” says Hochberg.
“The extraordinary people who enroll in our ongoing BrainGate clinical trials, and in early trials of any neurotechnology, deserve tremendous credit. They are enrolling not to gain personal benefit, but because they want to help,” said Hochberg.
Severed axons are unable to regenerate, which means that central nervous system (CNS) injuries such as to the spinal cord, can result in permanent loss of sensory and motor function. Presently, there are very limited options to help these patients regain their motor abilities. In mice, researchers have found that deleting a certain gene can cause axons to regrow. The results have recently been published in the scientific journal Neuron.
In a study using mice, a research team led by Associate Professor Kai Liu found that the deletion of PTPN2, a phosphatase-coding gene, in neurons can prompt axons to regrow. Combination with the type II interferon IFNγ, can accelerate the process and increase the number of axons regenerated.
Unlike the CNS, peripheral nerves have a greater ability to regrow and repair by themselves after injury. Scientists have yet to fully understand the relationship between this self-repair and the intrinsic immune mechanism of the nervous system. Thus, the team aimed to resolve how immune-related signalling pathways affected neurons after injury, and whether they could enhance axonal regeneration directly.
This study investigated whether the signalling pathway IFNγ-cGAS-STING had any role in the regeneration process of peripheral nerves. Researchers found that peripheral axons could directly modulate the immune response in their injured environment to promote self-repair after injury.
In previous research, Prof Liu’s team had already demonstrated that elevating the neuronal activity and regulating the neuronal glycerolipid metabolism pathway could boost axon regenerative capacity. The current study is providing further insights into the search of treatment solutions for challenging conditions such as spinal cord injuries, with one possible option being the joining of several types of different signalling pathways.
In recent years, researchers have made strides in promoting tissue regeneration in spinal cord injuries (SCI) through implanted neural stem cells or grafts in animal models. Separate efforts have shown that intensive physical rehabilitation can improve function after SCI by promoting greater or new roles for undamaged cells and neural circuits.
University of California San Diego researchers tested whether rehabilitation can pair with pro-regenerative therapies, such as stem cell grafting. They published their findings in in JCI Insight,
The researchers induced a cervical lesion in rats that impaired the animals’ ability to grasp with its forelimbs. The animals were divided into four groups: animals who underwent the lesion alone; animals who received a subsequent grafting of neural stem cells designed to grow and connect with existing nerves; animals who received rehabilitation only; and animals who received both stem cell therapy and rehabilitation.
Rehabilitation therapy for some animals began one month after initial injury, a time point that approximates when most human patients are admitted to SCI rehabilitation centers. Rehabilitation consisted of daily activities that rewarded them with food pellets if they performed grasping skills.
The researchers found that rehabilitation enhanced regeneration of injured corticospinal axons at the lesion site in rats, and that a combination of rehabilitation and grafting produced significant recovery in forelimb grasping when both treatments occurred one month after injury.
“These new findings indicate that rehabilitation plays a critically important role in amplifying functional recovery when combined with a pro-regenerative therapy, such as a neural stem cell transplant,” said first author Paul Lu, PhD, associate adjunct professor of neuroscience at UC San Diego School of Medicine and research health science specialist at the Veterans Administration San Diego Healthcare System.
“Indeed, we found a surprisingly potent benefit of intensive physical rehabilitation when administered as a daily regimen that substantially exceeds what humans are now provided after SCI.”
Senior author Mark H. Tuszynski, MD, PhD, professor of neurosciences and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, and colleagues have long worked to address the complex challenges of repairing SCIs and restoring function.
In 2020, for example, they reported on the observed benefits of neural stem cell grafts in mice and in 2019, described 3D-printed implantable scaffolding that would promote nerve cell growth.
“There is a great unmet need to improve regenerative therapies after SCI,” said Tuszynski. “We hope that our findings point the way to a new potential combination treatment consisting of neural stem cell grafts plus rehabilitation, a strategy that we hope to move to human clinical trials over the next two years.”
By studying damage involving the connection between the brain’s hemispheres, researchers are finding new ways to leverage neural plasticity to promote functional recovery after a spinal cord injury.
In a study published in JCI Insight, the team of researchers used models in the lab to investigate a unilateral spinal cord injury similar to Brown-Sequard Syndrome, a rare neurological condition where damage to the spinal cord in a person results in weakness or paralysis on one side of the body and a loss of sensation on the opposite side.
Assistant Professor Wei Wu at Indiana University School of Medicine, said that the spinal cord injury model damaged the connection between the left hemisphere of the brain and the right side of the body, leading to significant loss of function in the right forelimb.
“The skilled function of upper limbs is very important for the quality of life in the patients with cervical spinal cord injury, but such functional recovery is very difficult to achieve in the severe injury,” said Asst Prof Wu, first author of the paper. “We found that the intact corticospinal system in the opposite side of the brain and spinal cord can be modulated to at least partially take over the control of the forelimb that is damaged by the spinal cord injury, resulting in a forelimb functional improvement.”
Since each hemisphere controls the opposite side of the body, researchers discovered a spontaneous shift of the neural circuits after injury from the left hemisphere to the right. Although there are connections between the right hemisphere of the brain and the right side of the body through some relayed pathways after injury, Asst Prof Wu said that’s not sufficient to support the motor recovery.
Using optogenetics to stimulate the right hemisphere of the brain, the researchers modulated the motor cortex. Additional neural circuits were shifted from the left side to the right side of the brain to dramatically increase and improve forelimb function.
“New circuits in the whisker, jaw forelimb and neck areas in the right hemisphere of the brain are recruited to control the right forelimb,” Asst Prof Wu said. “Interestingly, the beneficial neural plastic changes emerge both in the brain and the distal spinal cord after the optogenetic neuromodulation was applied on the motor cortex.”
Asst Prof Wu said results of the study showed significant improvement to the forelimb; however, there are still many challenges ahead, since complete digital recovery was not achieved.
The research team will continue explore this transhemispheric neural reorganisation to further improve the functional recovery after the spinal cord injury, Asst Prof Wu said. He hopes that these findings will be applied to treatments for spinal cord injuries.
A candidate cancer drug currently in development has been also shown to stimulate regeneration of damaged nerves after spinal trauma. Four weeks after spinal cord injury, animals treated with the candidate drug, AZD1390, were “indistinguishable” from uninjured animals, according to the researchers.
The study, published in Clinical and Translational Medicine, demonstrated in cell and animal models that the candidate drug, AZD1390, can block the response to DNA damage in nerve cells and promote regeneration of damaged nerves. This restored sensory and motor function after spinal injury.
The announcement comes weeks after the same research team showed a different investigational drug, AZD1236, can reduce damage after spinal cord injury, by blocking the inflammatory response.
AZD1390 is also under investigation by AstraZeneca to block ATM-dependent signalling and repair of DNA double strand breaks (DSBs), an action which sensitises cancer cells to radiation treatment. The ATM protein kinase pathway – a critical biochemical pathway regulating the response to DNA damage. The DNA Damage Response system (DDR) is activated by DNA damage, including DSBs in the genome, which also happen in several common cancers and also after spinal cord injury.
Professor Zubair Ahmed, from the University’s Institute of Inflammation and Ageing and Dr Richard Tuxworth from the Institute of Cancer and Genomic Sciences hypothesised the persistent activation of this system may prevent recovery from spinal cord injury, and that blocking it would promote nerve repair and restore function after injury.
Their initial studies found that AZD1390 stimulated nerve cell growth in culture, and inhibited the ATM protein kinase pathway – a critical biochemical pathway regulating the response to DNA damage.
AZD1390 was tested in animal models following spinal cord injury. Oral treatment with AZD1390 significantly suppressed the ATM protein kinase pathway, stimulated nerve regeneration beyond the site of injury, and improved the ability of these nerves to carry electrical signals across the injury site.
Professor Ahmed commented: “This is an exciting time in spinal cord injury research with several different investigational drugs being identified as potential therapies for spinal cord injury. We are particularly excited about AZD1390 which can be taken orally and reaches the site of injury in sufficient quantities to promote nerve regeneration and restore lost function.
“Our findings show a remarkable recovery of sensory and motor functions, and AZD1390-treated animals being indistinguishable from uninjured animals within 4 weeks of injury.”
Dr Tuxworth added: “This early study shows that AZD1390 could be used as a therapy in life-changing conditions. In addition, repurposing this existing investigational drug potentially means we can reach the clinic significantly faster than developing a new drug from scratch.”
Having a spinal cord injury increases risk of developing mental health conditions such as depression and anxiety by nearly 80% compared to those without the traumatic injury, a new study shows. However, chronic pain may have an equally large, negative effect on mental health.
The study, published in Spinal Cord, compared private insurance claims from more than 9000 adults with a traumatic spinal cord injury with those of more than 1 million without. Researchers accounted for a range of psychological conditions, from anxiety and mood disorders to insomnia and dementia.
People living with a spinal cord injury had a diagnosis of a mental health condition more often than those without – 59.1% versus 30.9%. While depression and adverse mental health effects are not inevitable consequences of every traumatic spinal injury, previous studies have consistently echoed higher levels of psychological morbidity among this group than the general population without spinal cord injuries.
However, this study found that chronic centralised and neuropathic pain among adults living with a spinal cord injury were robustly associated with post-traumatic stress disorder, substance use disorders and other mental health conditions. In most cases, chronic pain was an even greater influence on these conditions than exposure to living with the injury itself.
The study authors said the findings should prompt physicians to identify mental health conditions when seeing patients with spinal cord injuries and refer them for treatment.
“Improved clinical efforts are needed to facilitate screening of, and early treatment for, both chronic pain and psychological health in this higher-risk population,” said lead author Dr Mark Peterson, associate professor of physical medicine and rehabilitation at Michigan Medicine.
However, researchers note a lack of insurance coverage and limited available services will likely cause the issue to remain largely unaddressed.
“Stakeholders need to work together to lobby for more federal research funding and special policy amendments to ensure adequate and long-term insurance coverage for both physical and mental health to meet the needs of folks living with spinal cord injuries,” Dr Peterson said.
In a world first, Michel Roccati, a man with a completely severed spinal cord was able to walk again outside the lab with the help of a portable electrical stimulation system that causes his legs to take a step in conjunction with his intention to move and a walker to steady him.
This was a further development of a technology that in 2018 helped David M’zee, who had been left paralysed by a partial spinal cord injury suffered in a sports accident, to walk again. A research team led by Professors Grégoire Courtine, at École Polytechnique Fédérale de Lausanne (EPFL) and Jocelyne Bloch, at Lausanne University Hospital (CHUV) had developed an electrical stimulation system to help people with spinal cord injuries walk again.
They had wanted to see if electrodes could stimulate movement in the parts of the spine damaged so badly that signals no longer reach the nervous system from the brain. That pioneering study was detailed in Nature and Nature Neuroscience. Thanks to the electrodes making up for the weakness of the signals in his damaged spinal cord, M’zee was able to voluntarily move his legs and could walk several hundred metres at a time, sometimes without the aid of the rails on the treadmill.
Now a new milestone has just been reached with the technology, and the research team enhanced their system with more sophisticated implants controlled by advanced software. These implants can stimulate the region of the spinal cord that activates the trunk and leg muscles. Thanks to this new technology, three patients with complete spinal cord injury were able to walk again outside the lab. “Our stimulation algorithms are still based on imitating nature,” said Prof Courtine. “And our new, soft implanted leads are designed to be placed underneath the vertebrae, directly on the spinal cord. They can modulate the neurons regulating specific muscle groups. By controlling these implants, we can activate the spinal cord like the brain would do naturally to have the patient stand, walk, swim or ride a bike, for example.”
On a cold, snowy day last December, Michel Roccati – an Italian man who became paralysed after a motorcycle accident four years earlier – braved the icy wind to try out the system outdoors, in central Lausanne. He had recently undergone the surgical procedure in which Prof Bloch placed the new, implanted lead on his spinal cord.
Scientists attached two small remote controls to Michel’s walker and connected them wirelessly to a tablet that forwards the signals to a pacemaker in Michel’s abdomen. The pacemaker in turn relays the signals to the implanted spinal lead that stimulates specific neurons, causing Michel to move. Grasping the walker, Michel pressed a button corresponding to either the left or right leg with the firm intention of taking a step forward, and his feet rose and fell in short steps.
“The first few steps were incredible – a dream come true!” he says. “I’ve been through some pretty intense training in the past few months, and I’ve set myself a series of goals. For instance, I can now go up and down stairs, and I hope to be able to walk one kilometre by this spring.”
Two other patients have also successfully tested the new system, which is described in Nature Medicine. “Our breakthrough here is the longer, wider implanted leads with electrodes arranged in a way that corresponds exactly to the spinal nerve roots,” said Bloch. “That gives us precise control over the neurons regulating specific muscles.” Ultimately, it allows for greater selectivity and accuracy in controlling the motor sequences for a given activity.
While extensive training is necessary for patients to get comfortable using the device, the speed and scope of rehabilitation is amazing. “All three patients were able to stand, walk, pedal, swim and control their torso movements in just one day, after their implants were activated!” said Prof Courtine. “That’s thanks to the specific stimulation programs we wrote for each type of activity. Patients can select the desired activity on the tablet, and the corresponding protocols are relayed to the pacemaker in the abdomen.”
While the progress achievable in a single day is astonishing, the gains after several months are even more impressive. The three patients followed a training regimen based on the stimulation programs and were able to regain muscle mass, move around more independently, and take part in social activities like having a drink standing at a bar. What’s more, because the technology is miniaturized, the patients can perform their training exercises outdoors and not only inside a lab.
Presently there is one key limitation, Prof Bloch said: “We need at least six centimetres of healthy spinal cord under the lesion. That’s where we implant our electrodes.”
As for Roccati, after nine months of Lausanne-based rehab, he now lives independently in Italy. “I continued rehab at home, working alone, with all the devices,” he said. “And I see improvements every day.”
Researchers at the Chinese Academy of Sciences have developed an innovative scaffold that regulates the immune microenvironment following a spinal cord injury, thereby reduces secondary injury effects. Their work is reported in Biomaterials.
By modifying a hydrogel with a cationic polymer, polyamidoamine, and interleukin-10 (IL-10; an anti-inflammatory cytokine), the scaffold could enhance tissue remodelling and promote axonal regeneration.
Spinal cord injuries cause axon damage and neural cell death, leading to dysfunction. A secondary stage of injury follows the primary stage and lasts for several weeks. Infiltration and activation of immune cells triggered by a spinal cord injury creates an inflammatory microenvironment characterised with damage-associated molecular patterns (DAMPs) that exacerbates secondary damage and impairs neurological functional recovery.
With the capabilities of effective scavenging of DAMPs and sustained release of IL-10, such a dual-functional immunoregulatory hydrogel not only reduced pro-inflammatory responses of macrophages and microglia, but also enhanced neurogenic differentiation of neural stem cells.
In a mouse model of spinal cord injury, the scaffold suppressed cytokine production, counteracting the inflammatory microenvironment and regulating immune cell activation, resulting in neural regeneration and axon growth without scar formation.
The dual-functional immunoregulatory scaffold with neuroprotection and neural regeneration effects significantly promoted electrophysiological enhancement and motor function recovery after spinal cord injury.
This study suggests that functional scaffold reconstruction of the immune microenvironment is a promising and effective method for treating severe spinal cord injury.
