Neuroscience

Reducing fear and stress following a traumatic event could be as simple as providing a protein synthesis blocker to the brain, report a team of researchers from McLean Hospital, Harvard Medical School, McGill University, and Massachusetts General Hospital in a paper published in the March 4 issue of Proceedings of the National Academy of Sciences.

“This is an important basic neuroscience finding that has the potential to have clinical implications for the way individuals with posttraumatic stress disorder are treated,” said Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean Hospital. “We used a well-known behavioral paradigm that we think models PTSD, fear conditioning, to explore how fearful memories are formed. In our study, the level of fear exhibited by experimental subjects was significantly reduced as a result of decreased signal transfer between cells in the amygdala, a key brain region in fear-related behaviors.”

Influenced by the original findings of Karim Nader, PhD, professor of Psychology at McGill University, whose pioneering work showed that old memories should be un-stored in their brain after their recollection in order to last, Bolshakov’s team exposed rats to auditory stimulus that the animals learned to associate with a mildly traumatic event. After a single exposure to the training procedures, the rats exhibited fear during subsequent exposures to auditory stimuli. The researchers then provided the animals with rapamycin, a protein synthesis blocker, immediately after memory was retrieved in order to control bonding between the cells in the brain. The animals exhibited significantly less fear in response to the fear-invoking stimulus when retested the next day.

“The animals showed stereotypical signs of fear after the initial exposure to the auditory stimulus,” explained Nader, a co-author on the paper. “Following the administration of rapamycin, we show a significant decrease in fear, but not a complete elimination. We were surprised to note that activity between cells was significantly affected by postsynaptic mechanisms.”

The findings of this study, which was funded by a grant from the United States Department of Defense spearheaded by Roger Pitman, suggest that different plasticity rules within cells in the brain are recruited during the formation of the original fear memory and after  fear memory was reactivated.

“Although further work at the molecular level needs to be completed, we are hopeful that this unexpected discovery is the foundation needed to identify ways in which we can better treat anxiety disorders in which fear condition plays a role, such as post-traumatic stress disorder,” said Bolshakov.

A shortage of a protein called TDP-43 caused muscle wasting and stunted nerve cells. This finding supports the idea that malfunction of this protein plays a decisive role in ALS and FTD. The study is published in the “Proceedings of the National Academy of Sciences of the USA" (PNAS).

ALS is an incurable neurological disease which manifests as rapidly progressing muscle wasting. Both limbs and respiratory muscles are affected. This leads to impaired mobility and breathing problems. Patients commonly die within a few years after the symptoms emerged. In rare cases, of which the British physicist Stephen Hawking is the most notable, patients can live with the disease for a long time. In Germany estimates show over 150,000 patients suffering from ALS – an average of 1 in 500 people.

Proteins gone astray

Over the last few years, there has been increasing evidence that ALS and FTD – a form of dementia associated with changes in personality and social behaviour – may have similar or even the same origins. The symptoms overlap and common factors have also been found at the microscopic level. In many cases, particles accumulate and form clumps in the patient’s nerve cells: this applies particularly to the TDP-43 protein.

"Normally, this protein is located in the cell nucleus and is involved in processing genetic information," explains molecular biologist Dr. Bettina Schmid, who works at the DZNE Munich site and at LMU. "However, in cases of disease, TDP-43 accumulates outside the nucleus forming aggregates." Schmid explains that it is not yet clear whether these clumps are harmful. "However, the protein’s normal function is clearly disrupted. It no longer reaches the nucleus to perform its actual task. There seems to be a relationship between this malfunction and the disease."

Studies on zebrafish

However, until now little was known about the function of TDP-43. What are the consequences when this protein becomes non-functional? In order to answer this question, the team led by Bettina Schmid cooperated with the research group of Prof. Christian Haass to investigate the larvae of specially bred zebrafish. Their genetic code had been modified in such a way that no TDP-43 was produced in the organism of the fish. The result: the young fish showed massive muscle wasting and died a few days after hatching. Moreover, the extensions of the nerve cells which control the muscles were abnormal.

"To some extent, these are symptoms typical of ALS and FTD. Therefore, a loss of function of TDP-43 does seem to play a critical role in the disease," says Haass, Site Speaker of the DZNE Munich Site and chair of Metabolic Biochemistry at LMU.

The study revealed one more finding which surprised the researchers: the blood flow of the fish was massively disturbed. “It is well known that circulatory disorders play a part in other forms of dementia, notably in the case of Alzheimer’s,” says Haass. “We now want to investigate whether such problems with blood flow may be a general problem of neurodegenerative diseases and whether such problems occur particularly in patients with ALS and FTD.”

A team of neuroengineers based at Brown University has developed a fully implantable and rechargeable wireless brain sensor capable of relaying real-time broadband signals from up to 100 neurons in freely moving subjects. Several copies of the novel low-power device, described in the Journal of Neural Engineering, have been performing well in animal models for more than year, a first in the brain-computer interface field. Brain-computer interfaces could help people with severe paralysis control devices with their thoughts.

Arto Nurmikko, professor of engineering at Brown University who oversaw the device’s invention, is presenting it this week at the 2013 International Workshop on Clinical Brain-Machine Interface Systems in Houston.

“This has features that are somewhat akin to a cell phone, except the conversation that is being sent out is the brain talking wirelessly,” Nurmikko said.

Neuroscientists can use such a device to observe, record, and analyze the signals emitted by scores of neurons in particular parts of the animal model’s brain.

Meanwhile, wired systems using similar implantable sensing electrodes are being investigated in brain-computer interface research to assess the feasibility of people with severe paralysis moving assistive devices like robotic arms or computer cursors by thinking about moving their arms and hands.

This wireless system addresses a major need for the next step in providing a practical brain-computer interface,” said neuroscientist John Donoghue, the Wriston Professor of Neuroscience at Brown University and director of the Brown Institute for Brain Science.

Tightly packed technology

In the device, a pill-sized chip of electrodes implanted on the cortex sends signals through uniquely designed electrical connections into the device’s laser-welded, hermetically sealed titanium “can.” The can measures 2.2 inches (56 mm) long, 1.65 inches (42 mm) wide, and 0.35 inches (9 mm) thick. That small volume houses an entire signal processing system: a lithium ion battery, ultralow-power integrated circuits designed at Brown for signal processing and conversion, wireless radio and infrared transmitters, and a copper coil for recharging — a “brain radio.” All the wireless and charging signals pass through an electromagnetically transparent sapphire window.

In all, the device looks like a miniature sardine can with a porthole.

But what the team has packed inside makes it a major advance among brain-machine interfaces, said lead author David Borton, a former Brown graduate student and postdoctoral research associate who is now at Ecole Polytechnique Federale Lausanne in Switzerland.

“What makes the achievement discussed in this paper unique is how it integrated many individual innovations into a complete system with potential for neuroscientific gain greater than the sum of its parts,” Borton said. “Most importantly, we show the first fully implanted microsystem operated wirelessly for more than 12 months in large animal models — a milestone for potential [human] clinical translation.”

The device transmits data at 24 Mbps via 3.2 and 3.8 Ghz microwave frequencies to an external receiver. After a two-hour charge, delivered wirelessly through the scalp via induction, it can operate for more than six hours.

“The device uses less than 100 milliwatts of power, a key figure of merit,” Nurmikko said.

Co-author Ming Yin, a Brown postdoctoral scholar and electrical engineer, said one of the major challenges that the team overcame in building the device was optimizing its performance given the requirements that the implant device be small, low-power and leak-proof, potentially for decades.

“We tried to make the best tradeoff between the critical specifications of the device, such as power consumption, noise performance, wireless bandwidth and operational range,” Yin said. “Another major challenge we encountered was to integrate and assemble all the electronics of the device into a miniaturized package that provides long-term hermeticity (water-proofing) and biocompatibility as well as transparency to the wireless data, power, and on-off switch signals.”

With early contributions by electrical engineer William Patterson at Brown, Yin helped to design the custom chips for converting neural signals into digital data. The conversion has to be done within the device, because brain signals are not produced in the ones and zeros of computer data.

Ample applications

The team worked closely with neurosurgeons to implant the device in three pigs and three rhesus macaque monkeys. The research in these six animals has been helping scientists better observe complex neural signals for as long as 16 months so far. In the new paper, the team shows some of the rich neural signals they have been able to record in the lab. Ultimately this could translate to significant advances that can also inform human neuroscience.

Current wired systems constrain the actions of research subjects, Nurmikko said. The value of wireless transmission is that it frees subjects to move however they intend, allowing them to produce a wider variety of more realistic behaviors. If neuroscientists want to observe the brain signals produced during some running or foraging behaviors, for instance, they can’t use a cabled sensor to study how neural circuits would form those plans for action and execution or strategize in decision making.

In the experiments in the new paper, the device is connected to one array of 100 cortical electrodes, the microscale individual neural listening posts, but the new device design allows for multiple arrays to be connected, Nurmikko said. That would allow scientists to observe ensembles of neurons in multiple related areas of a brain network.

The new wireless device is not approved for use in humans and is not used in clinical trials of brain-computer interfaces. It was designed, however, with that translational motivation.

“This was conceived very much in concert with the larger BrainGate* team, including neurosurgeons and neurologists giving us advice as to what were appropriate strategies for eventual clinical applications,” said Nurmikko, who is also affiliated with the Brown Institute for Brain Science.

Borton is now spearheading the development of a collaboration between EPFL and Brown to use a version of the device to study the role of the motor cortex in an animal model of Parkinson’s disease.

Meanwhile the Brown team is continuing work on advancing the device for even larger amounts of neural data transmission, reducing its size even further, and improving other aspects of the device’s safety and reliability so that it can someday be considered for clinical application in people with movement disabilities.