Reacción a "Deep brain stimulation improves walking after spinal cord injury"

This work holds particular relevance because it innovatively proposes that the lateral hypothalamus is a therapeutic target for promoting gait recovery in individuals with incomplete spinal cord injuries. The research line of G. Courtine and J. Bloch focuses on strengthening brain-spinal cord connections in patients with incomplete spinal cord injuries to optimize the recovery of walking function. This requires identifying motor structures in the brain that send their axons to the spinal cord to participate in walking functions and enhancing their activity to aid in recovering damaged functions.  

The experimental approach started with a mouse model of incomplete spinal cord injury, in which brain structures' activation was studied during gait recovery. The results showed activation of well-known motor structures such as the motor cortex, the reticular formation in the brainstem, the pedunculopontine nuclei, and the cuneiform nucleus. Additionally, it was found that the lateral hypothalamus was activated during the gait recovery process in these animals.  

This result is entirely novel, as the main (known) functions of this brain nucleus do not include motor function or direct projections to the spinal cord. From this point, using optogenetics, they demonstrated that selective activation of excitatory neurons in the lateral hypothalamus enhances the gait recovery process in mice with incomplete spinal cord injury. Furthermore, they found a direct connection between the lateral hypothalamus and the reticular formation in the brainstem (vGi), which has abundant neuronal connections with the spinal cord and whose primary function is coordinating movements, particularly walking. 

The study demonstrates that the anatomical and functional connection of the lateral hypothalamus with the vGi is essential for the recovery of walking function in mice with incomplete spinal cord injuries.  

However, optogenetics is a technique that cannot (yet) be used in humans to activate nuclei or neuronal groups in the brain. Therefore, deep brain stimulation (DBS), a neuronal stimulation technique using electrodes implanted in the brain, was applied to the lateral hypothalamus to produce the same beneficial effect in mice. This technique is already used in humans for various conditions, such as Parkinson's disease and obsessive-compulsive disorder.  

The next step was using rats as an experimental model. In previous work, a robot-assisted rehabilitation program was developed, where rats are positioned upright and walk with their hind legs. The advantage of using the rat model with rehabilitation therapy is that DBS can also be applied to the lateral hypothalamus in animals with severe spinal contusions. The results confirm that rats treated with rehabilitation and DBS in the lateral hypothalamus had better functional recovery than those not treated with DBS and/or rehabilitation. Importantly, the effects of the combined treatment were effective even after DBS was discontinued and persisted over time.  

The data obtained in animal models allowed the researchers to advance to application in two individuals with chronic and incomplete spinal cord injuries who retained walking function with the help of a walker or support devices. The biggest challenge was correctly positioning the stimulation electrode in the lateral hypothalamus for DBS since the nucleus's anatomy does not easily allow access to the region of interest. Magnetic resonance imaging combined with diffusion tensor imaging was used to identify the precise location of the region of interest in the lateral hypothalamus. Moreover, during electrode placement surgery, the patients were awake, allowing stimulation upon reaching the brain coordinates and confirming that patients either moved their legs or felt the need to do so.  

Patients experienced improvements from the moment DBS was initiated following electrode implantation. Subsequently, they underwent a scheduled rehabilitation program incorporating lateral hypothalamus stimulation via DBS. In both cases, significant improvements were achieved compared to their previous condition, surpassing clinical evaluation test thresholds, even when the stimulator was turned off. This latter result suggests that combined DBS therapy may increase reticulospinal connections, thereby improving patients' functions.  

This study highlights two critical aspects: 

1. The gigantocellular reticular formation in the brainstem is a key structure for reactivating walking patterns and other movements after spinal cord injury, but it is a brain region of very difficult access with a high risk of causing further damage. Therefore, finding that the lateral hypothalamus can activate the gigantocellular reticular formation to promote gait recovery is a crucial step. Surgical and therapeutic access to the lateral hypothalamus for DBS is both easy and safe.  
2. Given that the lateral hypothalamus has diverse roles in regulating individual behaviors, it will be essential to define the next steps to rule out side effects on other functions of the nucleus and determine whether the DBS stimulation parameters that produce improvement should be generalized or individualized. 

This study underscores key points for understanding the advances:  

1. The use of animal models is essential for identifying new therapeutic targets through advanced experimental techniques. 
2. The development of new combined therapies in animal models optimizes the recovery of functions affected by spinal cord injury. 
3. Experimental protocols developed in animals can be translated to humans to test positive effects and rule out adverse or undesired effects.