In Context
DARPA goes in search of lost time The US Defense Advanced Research Projects Agency has set its sights on creating a cybernetic implant to restore the ability of injured brains to create and recall memories. David Holmes reports. increasing. Best estimates indicate that up to 2% of the global population live with a disability caused by TBI and, with an increase in its incidence fuelled partly by an increased number of road traffic accidents as cars become commonplace in developing economies, WHO predicts TBI will be the third leading cause of mortality and disability worldwide by 2020. It’s a problem that affects all ages and all populations, but there’s no doubt that one group has a disproportionately high incidence of TBIs: military personnel on active service. TBI has been diagnosed in more than 270 000 US military service members since 2000, according to DARPA, often resulting in an impaired ability to retrieve memories that were formed before the injury and a decreased capacity to form or retain new memories after the injury. The toll that TBI takes can be devastating, but decades of research have resulted in precious few improvements in clinical outcomes for patients, and there remains no effective therapy for TBI approved by any regulatory agency.
“...this project... should foster a greater understanding of the neurochemical substrates of memory deficits...” As part of its plan to put that right, DARPA will first support the development of advanced computational models to try to describe how neurons code declarative memories, along with new methods to analyse and decode neural signals to understand how targeted stimulation might be applied to help the brain re-establish its ability to encode new memories after TBI. This first phase is, “conceptually not entirely
www.thelancet.com/neurology Vol 13 November 2014
ground-breaking,” says David Menon, Head of the Division of Anaesthesia at the University of Cambridge in the UK, and an Honorary Consultant at the Neurosciences Critical Care Unit in Addenbrooke’s Hospital. One of three major themes of the human brain project, which is funded as part of the European Commission 7th Framework Programme (FP7) for cooperative health research, is focused on computational neuroscience with a similar strategic aim to DARPA’s project. However, says Menon, by focusing on one small bit of the puzzle DARPA may make more rapid progress, or at least carve out an area where they make the running. Menon is confident that the initial stages of the project will bear fruit in the next 5 years, and will, “undeniably lead to an improved understanding of the physiology of neural circuits involved in memory, and the pathophysiology of these circuits in disease—particularly in TBI and [post traumatic stress disorder] PTSD”. The results of this project, in combination with next generation brain imaging, should foster a greater understanding of the neurochemical
For more on TBI and incidence see Editorial Lancet Neurol 2012; 11: 651 For more on the DARPA project see http://www.darpa.mil/Our_ Work/BTO/Programs/Restoring_ Active_Memory_RAM.aspx For the human brain project see https://www.humanbrainproject. eu/en_GB/discover/the-project/
Thomas Deferinck, NCMIR/Science Photo Library
Jared Diamond, in his 1998 Pulitzer Prize winner Guns, Germs, and Steel wrote that war has been one of the greatest drivers of technological innovation in societies throughout our all-too-bloody history. From the concept of triage—first developed by a military surgeon in Napoleon’s army— to the advanced prosthetics available to casualties of more recent conflicts, war has been the unfortunate but important catalyst for numerous medical advances. Military forays into the neurosciences, however, have so far yielded little of therapeutic value, but that could be about to change. In July this year the US Defense Advanced Research Projects Agency (DARPA) launched the Restoring Active Memory (RAM) programme, with the ambitious aim to develop, “wireless, implantable ‘neuroprosthetics’ that can help service members, veterans, and others overcome memory deficits incurred as a result of traumatic brain injury (TBI) or disease”. And with just under US$40 million committed to the project for the next 4 years, DARPA are banking on success. The RAM programme is one of several within DARPA that have stemmed from US President Barak Obama’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative, which was announced in the spring of 2013 to much fanfare. After a call for proposals, DARPA selected The University of California, Los Angeles (UCLA), CA, USA, and the University of Pennsylvania, PA, USA, to each lead a multidisciplinary team tasked with developing an electronic interface able to sense and restore memory deficits caused by TBI. TBI is a growing problem, with an incidence from 150 to 300 per 100 000 people per year in the USA and Europe, and these figures are
Fluorescent microscopy image of hippocampus
1075
Roger Harris/Science Photo Library
In Context
For more on the ADvance study see http://www. advancestudy4ad.com/advance. php
1076
substrates of memory deficits, open the door to more rational approaches to the pharmacological enhancement of cognition, and help to better match patients with therapies says Menon. To reach the holy grail of an implantable neuroprosthetic is likely to take substantially more time than 5 years. Until now there have been two main surgical approaches to enhancing memory, explains Jeffrey Rosenfeld, the new Foundation Director of the Monash Institute of Medical Engineering (MIME) in Victoria, Australia, and one of the driving forces behind the development of a bionic vision device. The first, which is currently being evaluated in trials as a treatment in Alzheimer’s disease, non-specifically stimulates the memory circuits by placing deep brain stimulation (DBS) electrodes in the memory pathways. The second approach, says Rosenfeld, “would be to place an electronic device directly into the memory centre of the brain to stimulate the neurons involved directly in memory function”. The main target in this type of approach would be the hippocampus, the area of the brain most associated with short-term memory. “One of the problems of putting an electrode array into this part of the brain is that
it is highly epileptogenic, so placing repeated electrical currents into this part of the brain may induce seizures which would not be a good outcome. This will be a major technical challenge for these researchers”, Rosenfeld notes. The UCLA team’s approach will focus on stimulating the entorhinal area, which is considered to be the entrance to the hippocampus, and has a crucial role in transforming daily experience into lasting memories. The team will collect data in the first phase of the project from patients already implanted with brain electrodes to treat their epilepsy, then use these data to develop and refine a detailed computational model of the hippocampal–entorhinal system. “It will be possible to place electrode arrays in this part of the brain and stimulate small columns of neurons with micro-electrodes, although exactly, what this will do to memory function remains to be seen in humans,” says Rosenfeld. The UCLA team aim to ultimately develop a wireless neuromodulatory device— that is ten-times smaller in size, but has greater spatial resolution than existing devices—and can be implanted into the entorhinal area of patients with TBI.
“To reach the holy grail of an implantable neuroprosthetic is likely to take substantially more time than 5 years.” “The background technology of microelectrodes, wireless technology, computer programming and waveform analysis is at a stage now where I think it is reasonable to embark on this experimental development”, says Rosenfeld, though he cautions there are several major challenges. One of the most profound is the nature of the damage caused by TBI, explains Harvey Levin, a professor in the Department of Physical Medicine
& Rehabilitation, Baylor College of Medicine, TX, USA. Although at least 80% of TBIs in military personnel have been mild during the past decade, Levin explains, in many survivors of severe TBI, strategic memory is impaired. “Damage to prefrontal cortex and its connections is thought to contribute to poor strategic memory,” he says; “this is a complex deficit which may be difficult to ameliorate”. Similar problems are likely to be encountered in patients with severe TBI and advanced Alzheimer’s disease, says Rosenfeld. “Once Alzheimer’s Disease is advanced or severe cognitive impairment is present following a TBI, this means that the circuitry has been deranged so much by loss of the primary neurons and loss of the white fibre tracts that connect the neurons in the memory circuits, that no form of man-made electronic implant will be functional because there is just too much loss and destruction in the brain. Therefore, the stage of the illness that these devices are implanted or the severity of the TBI is going to be critical”. The question of just how long it will take to develop an implantable digital cognitive enhancement device is impossible to answer, but Menon rates the chances of seeing one in the next 10 years as slim, “both because it isn’t easy, and because hand-held digital enhancements to memory are likely to be lower-hanging fruit,” he says. Currently memory rehabilitation treatments already include compensatory techniques, such as providing training to use smart phone reminders and calendars, says Levin, and this type of technology is likely to become more sophisticated. “It’s a steep mountain to climb, and we are at the bottom of the mountain at present,” says Rosenfeld. “I believe that the mountain is worth climbing, but it will take some time”.
David Holmes
www.thelancet.com/neurology Vol 13 November 2014
DARPA goes in search of lost time The US Defense Advanced Research Projects Agency has set its sights on creating a cybernetic implant to restore the ability of injured brains to create and recall memories. David Holmes reports. increasing. Best estimates indicate that up to 2% of the global population live with a disability caused by TBI and, with an increase in its incidence fuelled partly by an increased number of road traffic accidents as cars become commonplace in developing economies, WHO predicts TBI will be the third leading cause of mortality and disability worldwide by 2020. It’s a problem that affects all ages and all populations, but there’s no doubt that one group has a disproportionately high incidence of TBIs: military personnel on active service. TBI has been diagnosed in more than 270 000 US military service members since 2000, according to DARPA, often resulting in an impaired ability to retrieve memories that were formed before the injury and a decreased capacity to form or retain new memories after the injury. The toll that TBI takes can be devastating, but decades of research have resulted in precious few improvements in clinical outcomes for patients, and there remains no effective therapy for TBI approved by any regulatory agency.
“...this project... should foster a greater understanding of the neurochemical substrates of memory deficits...” As part of its plan to put that right, DARPA will first support the development of advanced computational models to try to describe how neurons code declarative memories, along with new methods to analyse and decode neural signals to understand how targeted stimulation might be applied to help the brain re-establish its ability to encode new memories after TBI. This first phase is, “conceptually not entirely
www.thelancet.com/neurology Vol 13 November 2014
ground-breaking,” says David Menon, Head of the Division of Anaesthesia at the University of Cambridge in the UK, and an Honorary Consultant at the Neurosciences Critical Care Unit in Addenbrooke’s Hospital. One of three major themes of the human brain project, which is funded as part of the European Commission 7th Framework Programme (FP7) for cooperative health research, is focused on computational neuroscience with a similar strategic aim to DARPA’s project. However, says Menon, by focusing on one small bit of the puzzle DARPA may make more rapid progress, or at least carve out an area where they make the running. Menon is confident that the initial stages of the project will bear fruit in the next 5 years, and will, “undeniably lead to an improved understanding of the physiology of neural circuits involved in memory, and the pathophysiology of these circuits in disease—particularly in TBI and [post traumatic stress disorder] PTSD”. The results of this project, in combination with next generation brain imaging, should foster a greater understanding of the neurochemical
For more on TBI and incidence see Editorial Lancet Neurol 2012; 11: 651 For more on the DARPA project see http://www.darpa.mil/Our_ Work/BTO/Programs/Restoring_ Active_Memory_RAM.aspx For the human brain project see https://www.humanbrainproject. eu/en_GB/discover/the-project/
Thomas Deferinck, NCMIR/Science Photo Library
Jared Diamond, in his 1998 Pulitzer Prize winner Guns, Germs, and Steel wrote that war has been one of the greatest drivers of technological innovation in societies throughout our all-too-bloody history. From the concept of triage—first developed by a military surgeon in Napoleon’s army— to the advanced prosthetics available to casualties of more recent conflicts, war has been the unfortunate but important catalyst for numerous medical advances. Military forays into the neurosciences, however, have so far yielded little of therapeutic value, but that could be about to change. In July this year the US Defense Advanced Research Projects Agency (DARPA) launched the Restoring Active Memory (RAM) programme, with the ambitious aim to develop, “wireless, implantable ‘neuroprosthetics’ that can help service members, veterans, and others overcome memory deficits incurred as a result of traumatic brain injury (TBI) or disease”. And with just under US$40 million committed to the project for the next 4 years, DARPA are banking on success. The RAM programme is one of several within DARPA that have stemmed from US President Barak Obama’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative, which was announced in the spring of 2013 to much fanfare. After a call for proposals, DARPA selected The University of California, Los Angeles (UCLA), CA, USA, and the University of Pennsylvania, PA, USA, to each lead a multidisciplinary team tasked with developing an electronic interface able to sense and restore memory deficits caused by TBI. TBI is a growing problem, with an incidence from 150 to 300 per 100 000 people per year in the USA and Europe, and these figures are
Fluorescent microscopy image of hippocampus
1075
Roger Harris/Science Photo Library
In Context
For more on the ADvance study see http://www. advancestudy4ad.com/advance. php
1076
substrates of memory deficits, open the door to more rational approaches to the pharmacological enhancement of cognition, and help to better match patients with therapies says Menon. To reach the holy grail of an implantable neuroprosthetic is likely to take substantially more time than 5 years. Until now there have been two main surgical approaches to enhancing memory, explains Jeffrey Rosenfeld, the new Foundation Director of the Monash Institute of Medical Engineering (MIME) in Victoria, Australia, and one of the driving forces behind the development of a bionic vision device. The first, which is currently being evaluated in trials as a treatment in Alzheimer’s disease, non-specifically stimulates the memory circuits by placing deep brain stimulation (DBS) electrodes in the memory pathways. The second approach, says Rosenfeld, “would be to place an electronic device directly into the memory centre of the brain to stimulate the neurons involved directly in memory function”. The main target in this type of approach would be the hippocampus, the area of the brain most associated with short-term memory. “One of the problems of putting an electrode array into this part of the brain is that
it is highly epileptogenic, so placing repeated electrical currents into this part of the brain may induce seizures which would not be a good outcome. This will be a major technical challenge for these researchers”, Rosenfeld notes. The UCLA team’s approach will focus on stimulating the entorhinal area, which is considered to be the entrance to the hippocampus, and has a crucial role in transforming daily experience into lasting memories. The team will collect data in the first phase of the project from patients already implanted with brain electrodes to treat their epilepsy, then use these data to develop and refine a detailed computational model of the hippocampal–entorhinal system. “It will be possible to place electrode arrays in this part of the brain and stimulate small columns of neurons with micro-electrodes, although exactly, what this will do to memory function remains to be seen in humans,” says Rosenfeld. The UCLA team aim to ultimately develop a wireless neuromodulatory device— that is ten-times smaller in size, but has greater spatial resolution than existing devices—and can be implanted into the entorhinal area of patients with TBI.
“To reach the holy grail of an implantable neuroprosthetic is likely to take substantially more time than 5 years.” “The background technology of microelectrodes, wireless technology, computer programming and waveform analysis is at a stage now where I think it is reasonable to embark on this experimental development”, says Rosenfeld, though he cautions there are several major challenges. One of the most profound is the nature of the damage caused by TBI, explains Harvey Levin, a professor in the Department of Physical Medicine
& Rehabilitation, Baylor College of Medicine, TX, USA. Although at least 80% of TBIs in military personnel have been mild during the past decade, Levin explains, in many survivors of severe TBI, strategic memory is impaired. “Damage to prefrontal cortex and its connections is thought to contribute to poor strategic memory,” he says; “this is a complex deficit which may be difficult to ameliorate”. Similar problems are likely to be encountered in patients with severe TBI and advanced Alzheimer’s disease, says Rosenfeld. “Once Alzheimer’s Disease is advanced or severe cognitive impairment is present following a TBI, this means that the circuitry has been deranged so much by loss of the primary neurons and loss of the white fibre tracts that connect the neurons in the memory circuits, that no form of man-made electronic implant will be functional because there is just too much loss and destruction in the brain. Therefore, the stage of the illness that these devices are implanted or the severity of the TBI is going to be critical”. The question of just how long it will take to develop an implantable digital cognitive enhancement device is impossible to answer, but Menon rates the chances of seeing one in the next 10 years as slim, “both because it isn’t easy, and because hand-held digital enhancements to memory are likely to be lower-hanging fruit,” he says. Currently memory rehabilitation treatments already include compensatory techniques, such as providing training to use smart phone reminders and calendars, says Levin, and this type of technology is likely to become more sophisticated. “It’s a steep mountain to climb, and we are at the bottom of the mountain at present,” says Rosenfeld. “I believe that the mountain is worth climbing, but it will take some time”.
David Holmes
www.thelancet.com/neurology Vol 13 November 2014
