The striatum acts as hub for multisensory integration

A new study from Karolinska Institutet provides insight on how the brain processes external input such as touch, vision or sound from different sources and sides of the body, in order to select and generate adequate movements. The findings, which are presented in the journal Neuron, show that the striatum acts as a sensory ‘hub’ integrating various types of sensory information, with specialised functional roles for the different neuron types.

“The striatum is the main input structure in the basal ganglia, and is typically associated with motor function”, says Principal Investigator Gilad Silberberg at the Department of Neuroscience. “Our study focuses on its role in processing sensory input. This is important knowledge, since the striatum is implicated in numerous diseases and disorders, including Parkinson’s disease, Huntington’s disease, ADHD and Tourette syndrome.”

The striatum is the largest structure in a collection of brain nuclei called the basal ganglia, which are located at the base of the forebrain. It is involved in motor learning, planning and execution as well as selecting our actions out of all possible choices, based on the expected reward by the dopamine system. Most research performed in the striatum is focused on the motor aspects of its function, largely due to the devastating motor symptoms of the related diseases.

However, in order to select the correct actions, and generate proper motor activity it is essential to continuously process sensory information, often arriving from different sources, different sides of the body and from different sensory modalities, such as tactile (touch), visual, auditory, and olfactory. This integration of sensory information is in fact a fundamental function of our nervous system.

Patch-clamp recordings

In the current study, researchers Gilad Silberberg and Ramon Reig show that individual striatal neurons integrate sensory input from both sides of the body, and that a subpopulation of these neurons process sensory input from different modalities; touch, light and vision. The team used intracellular patch-clamp recordings from single neurons in the mouse striatum to show their responses to whisker stimulation from both sides as well as responses to visual stimulation. Neurons responding to both visual and tactile stimuli were located in a specific medial region of the striatum.

“We also showed that neurons of different types integrate sensory inputs in a different manner, suggesting that they have specific roles in the processing of such sensory information in the striatal network”, says Gilad Silberberg.

(Image: Shutterstock)

With the right rehabilitation, paralyzed rats learn to grip again

After a large stroke, motor skills barely improve, even with rehabilitation. An experiment conducted on rats demonstrates that a course of therapy combining the stimulation of nerve fiber growth with drugs and motor training can be successful. The key, however, is the correct sequence: Paralyzed animals only make an almost complete recovery if the training is delayed until after the growth promoting drugs have been administered, as researchers from the University of Zurich, ETH Zurich and the University of Heidelberg reveal.

Only if the timing, dosage and kind of rehabilitation are right can motor functions make an almost full recovery after a large stroke. Rats that were paralyzed down one side by a stroke almost managed to regain their motor functions fully if they were given the ideal combination of rehabilitative training and substances that boosted the growth of nerve fibers. Anatomical studies confirmed the importance of the right rehabilitation schedule: Depending on the therapeutic design, different patterns of new nerve fibers that sprouted into the cervical spinal cord from the healthy part of the brain and thus aid functional recovery to varying degrees were apparent. The study conducted by an interdisciplinary team headed by Professor Martin Schwab from the Brain Research Institute at the University of Zurich and ETH Zurich’s Neuroscience Center is another milestone in research on the repair of brain and spinal cord injuries.

“This new rehabilitative approach at least triggered an astonishing recovery of the motor skills in rats, which may become important for the treatment of stroke patients in the future,” says first author Anna-Sophia Wahl. At present, patients have to deal with often severe motor-function, language and vision problems, and their quality of life is often heavily affected.

Allow nerves to grow first, then train

On the one hand, the treatment of rats after a stroke involves specific immune therapy, where so-called Nogo proteins are blocked with antibodies. These proteins in the tissue around the nerve fibers inhibit nerve-fiber growth. If they are blocked, nerve fibers begin to sprout in the injured sections of the brain and spinal cord and relay nerve impulses again. On the other hand, the stroke animals, whose front legs were paralyzed, underwent physical training – namely, gripping food pellets. All the rats received antibody treatment first to boost nerve-fiber growth and – either at the same time or only afterwards – motor training. The results are surprising: The animals that began their training later regained a remarkable 85 percent of their original motor skills. For the rats that were trained straight after the stroke in parallel with the growth-enhancing antibodies, however, it was a different story: At 15 percent, their physical performance in the grip test remained very low.

On the one hand, the treatment of rats after a stroke involves specific immune therapy, where so-called Nogo proteins are blocked with antibodies. These proteins in the tissue around the nerve fibers inhibit nerve-fiber growth. If they are blocked, nerve fibers begin to sprout in the injured sections of the brain and spinal cord and relay nerve impulses again. On the other hand, the stroke animals, whose front legs were paralyzed, underwent physical training – namely, gripping food pellets. All the rats received antibody treatment first to boost nerve-fiber growth and – either at the same time or only afterwards – motor training. The results are surprising: The animals that began their training later regained a remarkable 85 percent of their original motor skills. For the rats that were trained straight after the stroke in parallel with the growth-enhancing antibodies, however, it was a different story: At 15 percent, their physical performance in the grip test remained very low.

Meticulous design very promising

The researchers consider timing a crucial factor for the success of the rehabilitation: An early application of growth stimulators – such as antibodies against the protein Nogo-A – triggers an increased sprouting and growth of nerve fibers. The subsequent training is essential to sift out and stabilize the key neural circuits for the recovery of the motor functions. For instance, an automatic, computer-based analysis of the anatomical data from the imaging revealed that new fibers in the spinal cord sprouted in another pattern depending on the course of treatment. By reversibly deactivating the new nerve fibers that grow, the neurobiologists were ultimately able to demonstrate for the first time that a group of these fibers is essential for the recovery of the motor function observed: Nerve fibers that grew into the spinal cord from the intact front half of the brain – changing sides – can reconnect the spinal cord circuits of the rats’ paralyzed limbs to the brain, enabling the animals to grip again.    

“Our study reveals how important a meticulous therapeutic design is for the most successful rehabilitation possible,” sums up study head Martin Schwab. “The brain has enormous potential for the reorganization and reestablishment of its functions. With the right therapies at the right time, this can be increased in a targeted fashion.

Literature:

Wahl, A.S., Omlor, W., Rubio, J.C., Chen, J.L., Zheng, H., Schröter, A., Gullo, M., Weinmann, O., Kobayashi, K., Helmchen, F., Ommer, B., Schwab, M.E. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science, June 13, 2014.

Hope for paraplegic patients

People with severe injuries to their spinal cord currently have no prospect of recovery and remain confined to their wheelchairs. Now, all that could change with a new treatment that stimulates the spinal cord using electric impulses. The hope is that the technique will help paraplegic patients learn to walk again. From June 3 – 5, Fraunhofer researchers will be at the Sensor + Test measurement fair in Nürnberg to showcase the implantable microelectrode sensors they have developed in the course of pre-clinical development work (Hall 12, Booth 12-537).

Thomas T. was just 25 years old when a severe motorcycle accident changed his life in an instant. Doctors diagnosed him with paraplegia following an injury to his spinal cord in the lumbar region. The young man has been confined to a wheelchair ever since. The diagnosis of paraplegia came as a shock, and it was only in the course of a month-long period of rehabilitation that Thomas T. was able to come to terms with his condition. Patients like him currently have no prospect of recovery, as there is still no effective course of treatment available for improving motor function among the severely disabled.

Now a consortium of European research institutions and companies want to get affected patients quite literally back on their feet. In the EU’s NEUWalk project, which has been awarded funding of some nine million euros, researchers are working on a new method of treatment designed to restore motor function in patients who have suffered severe injuries to their spinal cord. The technique relies on electrically stimulating the nerve pathways in the spinal cord. “In the injured area, the nerve cells have been damaged to such an extent that they no longer receive usable information from the brain, so the stimulation needs to be delivered beneath that,” explains Dr. Peter Detemple, head of department at the Fraunhofer Institute for Chemical Technology’s Mainz branch (IMM) and NEUWalk project coordinator. To do this, Detemple and his team are developing flexible, wafer-thin microelectrodes that are implanted within the spinal canal on the spinal cord. These multichannel electrode arrays stimulate the nerve pathways with electric impulses that are generated by the accompanying by microprocessor-controlled neurostimulator. “The various electrodes of the array are located around the nerve roots responsible for locomotion. By delivering a series of pulses, we can trigger those nerve roots in the correct order to provoke motion sequences of movements and support the motor function,” says Detemple.

Researchers from the consortium have already successfully conducted tests on rats in which the spinal cord had not been completely severed. As well as stimulating the spinal cord, the rats were given a combination of medicine and rehabilitation training. Afterwards the animals were able not only to walk but also to run, climb stairs and surmount obstacles. “We were able to trigger specific movements by delivering certain sequences of pulses to the various electrodes implanted on the spinal cord,” says Detemple. The research scientist and his team believe that the same approach could help people to walk again, too. “We hope that we will be able to transfer the results of our animal testing to people. Of course, people who have suffered injuries to their spinal cord will still be limited when it comes to sport or walking long distances. The first priority is to give them a certain level of independence so that they can move around their apartment and look after themselves, for instance, or walk for short distances without requiring assistance,” says Detemple.

Researchers from the NEUWalk project intend to try out their system on two patients this summer. In this case, the patients are not completely paraplegic, which means there is still some limited communication between the brain and the legs. The scientists are currently working on tailored implants for the intervention. “However, even if both trials are a success, it will still be a few years before the system is ready for the general market. First, the method has to undergo clinical studies and demonstrate its effectiveness among a wider group of patients,” says Detemple.

Electric spinal cord stimulation to offer relief for Parkinson’s disease

Patients with Parkinson’s disease could also benefit from the neural prostheses. The most well-known symptoms of the disease are trembling, extreme muscle tremors and a short, stooped gait that has a profound effect on patients’ mobility. Until now this neurodegenerative disorder has mostly been treated with dopamine agonists – drugs that chemically imitate the effects of dopamine but that often lead to severe side effects when taken over a longer period of time. Once the disease has reached an advanced stage, doctors often turn to deep brain stimulation. This involves a complex operation to implant electrodes in specific parts of the brain so that the nerve cells in the region can be stimulated or suppressed as required. In the NEUWalk project, researchers are working on electric spinal cord simulation – an altogether less dangerous intervention that should however ease the symptoms of Parkinson’s disease just as effectively. “Initial animal testing has yielded some very promising results,” says Detemple.

The researchers from Mainz will be at the Sensor + Test 2014 measurement fair in Nürnberg to showcase their neural prostheses. These include implantable microelectrode sensors controlled by microprocessors as well as rigid multi-channel sensors that can be used to record electrophysiological signals and to stimulate neural structures.