Bad Tidings For Darpa's Ram Program: Electrical Stimulation Of Entorhinal Share Impairs Memory

The neural mechanism that forms novel memories is delicate as well as vulnerable to insults arising from encephalon injuries, cerebral anoxia, as well as neurodegenerative diseases such every bit Alzheimer's. Unlike language, which shows a corking bargain of plasticity after strokes as well as other injuries, episodic memory retentiveness for autobiographical events as well as contextual details of yesteryear experiences doesn't recover after permanent harm to the hippocampus as well as surrounding structures.1 Is it possible to improve retentiveness yesteryear conduct stimulating specific regions inward the medial temporal lobes (MTL), fifty-fifty inward damaged or diseased brains?

Restoring Active Memory (RAM) is a DARPA enquiry programme that aims to heighten retentiveness encoding as well as retrieval inward armed services service members who convey suffered traumatic encephalon injuries. The approach is to blueprint an implant, or “memory prosthesis,” that volition care for retentiveness loss via electrical stimulation.
The halt goal of RAM is to prepare as well as evidence a wireless, fully implantable neural-interface medical device for human clinical utilization ... DARPA volition back upward the evolution of multi-scale computational models amongst high spatial as well as temporal resolution that force how neurons code declarative memories—those well-defined parcels of noesis that tin live consciously recalled as well as described inward words, such every bit events, times, as well as places. Researchers volition also explore novel methods for analysis as well as decoding of neural signals to empathise how targeted stimulation mightiness live applied to assist the encephalon reestablish an powerfulness to encode novel memories next encephalon injury.

Initial Funding

The origin RAM awards went to teams led yesteryear investigators at spatial map. The EC as well as its neighbors inward the parahippocampal part also have projections from neocortical association areas, thence serving every bit a convergence site for cortical input as well as a distribution view for cortical afferents to the hippocampus.4

from Fig. 1 (Eichenbaum, 2000). The anatomy of the hippocampal retentiveness system.

Suthana et al. (2012) began yesteryear reviewing all the potential benefits of entorhinal stimulation:
In rodents, electrical stimulation of the perforant pathway, which originates inward the entorhinal cortex as well as projects into the hippocampus, results inward long-term potentiation, release of acetylcholine, as well as resetting of the theta phase, all of which are associated amongst improved memory. It has also been shown that electrical stimulation tin heighten neurogenesis inward the hippocampus. Whether conduct stimulation of this entorhinal output to the hippocampus enhances learning is non known.

In the study, 7 individuals amongst epilepsy performed a spatial chore where they learned destinations inside virtual environments. There were iv blocks, each containing 6 unlike destinations (that repeated across blocks). In one-half the trials of blocks 1-3, electrical stimulation (at 50 Hz) was delivered to the EC or hippocampus. No stimulation was given inward block 4.

Spatial learning was quantified yesteryear determining the actual path traveled yesteryear the participant, relative to the shortest possible path. This variable was called excess path length, amongst shorter “excess” path length indicating improve performance. Latency to hand a finish was measured every bit well.

The graph below shows the results averaged across 6 patients amongst entorhinal stimulation. During the 3 “learning” blocks, stimulation made no departure for (A) latency or (C) excess path length. During the identically structured “retention” block (when no stimulation was genuinely given), in that location seemed to live a little difference, amongst shorter latency as well as smaller excess path length for the destinations that had been learned with stimulation. No differences inward functioning were found when the hippocampus was stimulated, which is a piffling odd. Previous studies convey shown that conduct stimulation of the hippocampus impairs memory.

Basically, it looks every bit if the participants were non learning at all without EC stimulation. But the benefits of stimulation were quite little (p=.03 for both measures), as well as the fault bars were large for non-stimulation trials. Will these findings replicate inward a larger sample of patients?

New Findings

Jacobs et al. (2016) tested 49 patients across 7 unlike hospitals as well as found that 50 Hz electrical stimulation of the entorhinal part during encoding impaired retentiveness inward both spatial as well as verbal tasks. The effects were little (and non e'er significant), yet surprising inward lite of the results from Suthana et al. (2012):
Across all patients as well as both tasks, entorhinal stimulation impaired retentiveness accuracy (as measured yesteryear MS) yesteryear an average of 9% (permutation p < 0.02; t[15] = 2.3, p < 0.02). Entorhinal stimulation impaired retentiveness inward both the spatial chore (permutation p = 0.03; t[5] = 1.7, p = 0.08) as well as the verbal chore (permutation p = 0.09; t[9] = 1.49, p < 0.09).

You tin acquire an thought of the private variability inward the spatial chore below, where p < 0.1 as well as p < 0.05 (one-sided rank-sum test).

The impairments appeared to live to a greater extent than robust amongst hippocampal stimulation, inward contrast to the lack of lawsuit inward Suthana et al.:
Stimulation inward the hippocampus significantly impaired functioning yesteryear 8% overall across both tasks (permutation p = 0.002; t[42] = 2.97, p < 0.003). This impairment was acquaint separately inward both the spatial chore (permutation p < 0.05; t[22] = 1.94, p < 0.05) as well as the verbal chore (permutation p < 0.001; t[19] = 2.3, p < 0.02).

You mightiness notice from the df to a higher house that non all patients had electrodes located inward the regions of interest: 28 subjects for hippocampus (43 sites) as well as exclusively 12 subjects for entorhinal (16 sites).

Nothing is Ever Simple

Why the discrepancy betwixt studies?? Jacobs et al. (2016) discussed only about potential differences: issue of participants, issue of independent observations (i.e., greater statistical powerfulness inward their study), a improve evidence of MTL-based spatial memory, as well as duration of stimulation (fixed at 10 seconds per trial vs. longer as well as variable). They also ran a simulation of Suthana et al.'s statistical methods using similar information as well as reported that “an lawsuit at to the lowest degree every bit large every bit the 64% EPL reduction they observed is found inward 19% of randomly shuffled data” (meaning that the final result is non statistically significant).

What does this hateful for the RAM of the future? In an extensive review of the encephalon stimulation literature, Kim et al. (2016)...
...tentatively advise that stimulating multiple retentiveness nodes inward concert could heighten cognitive processes supporting memory.

Thus, the stimulation studies published so far brand the dot that for effective modulation of retentiveness functioning to live achieved, a network perspective rather than a purely focal stimulation approach should live considered. Declarative retentiveness relies on a distributed network of multiple neocortical as well as medial temporal regions that serve cohesive roles inward retentiveness processes...

ADDENDUM (Dec 24 2016): DARPA has responded, as well as they're all the same bullish on closed-loop stimulation for retentiveness restoration. 

One hope of this applied scientific discipline is that when you lot forget where you lot went for luncheon on Thursday, as well as what you lot ate, as well as where you lot sat, as well as what you lot wore, your implant volition kicking inward as well as cry back the memories for you. 

And inward reply to a reader question, an extended quote from the comments below.


1 For an extreme example, run into Patient H.M.

2 run into these posts yesteryear : A Tale of Two BRAINS: #BRAINI as well as DARPA's SUBNETS as well as DARPA allocates $70 1000000 for improving deep encephalon stimulation technology.

3 Synaptic connections inward the hippocampus as well as entorhinal cortex.

from Fig. 1 of Dobrunz (1998). Lateral perforant path (dotted green) as well as medial perforant path (solid green) supply inputs from the entorhinal cortex to the dentate gyrus of the hippocampus. Perforant path axons shape synapses onto dentate granule cells (lateral inward yellow, medial inward red). Axons from the CA3 part of hippocampus shape synapses onto cells inward CA1 (purple).

4 Functional overview of the extended hippocampal-diencephalic retentiveness system.


Jacobs, J., Miller, J., Lee, S., Coffey, T., Watrous, A., Sperling, M., Sharan, A., Worrell, G., Berry, B., Lega, B., Jobst, B., Davis, K., Gross, R., Sheth, S., Ezzyat, Y., Das, S., Stein, J., Gorniak, R., Kahana, M., & Rizzuto, D. (2016). Direct Electrical Stimulation of the Human Entorhinal Region as well as Hippocampus Impairs Memory. Neuron, 92 (5), 983-990. DOI: 10.1016/j.neuron.2016.10.062

Kim, K., Ekstrom, A., & Tandon, N. (2016). H5N1 network approach for modulating retentiveness processes via conduct as well as indirect encephalon stimulation: Toward a causal approach for the neural footing of memory. Neurobiology of Learning as well as Memory, 134, 162-177. DOI: 10.1016/j.nlm.2016.04.001

Suthana, N., Haneef, Z., Stern, J., Mukamel, R., Behnke, E., Knowlton, B., & Fried, I. (2012). Memory Enhancement as well as Deep-Brain Stimulation of the Entorhinal Area. New England Journal of Medicine, 366 (6), 502-510. DOI: 10.1056/NEJMoa1107212

Further Reading

Restoring Active Memory Program Poised to Launch (July 9, 2014)
DARPA has selected ii universities to initially Pb the agency’s Restoring Active Memory (RAM) program, which aims to prepare as well as evidence wireless, implantable “neuroprosthetics” that tin assist servicemembers, veterans, as well as others overcome retentiveness deficits incurred every bit a final result of traumatic encephalon injury (TBI) or disease.

UCLA as well as Penn volition each caput a multidisciplinary squad to prepare as well as evidence electronic interfaces that tin sense retentiveness deficits caused yesteryear injury as well as travail to restore normal function. Under the price of split cooperative agreements amongst DARPA, UCLA volition have upward to $15 1000000 as well as Penn volition have upward to $22.5 1000000 over iv years...
. . .

Unique to the UCLA team’s approach is a focus on the share of the encephalon known every bit the entorhinal area. UCLA researchers previously demonstrated that human retentiveness could live facilitated yesteryear stimulating that region, which is known to live involved inward learning as well as memory. Considered the entrance to the hippocampus—which helps shape as well as shop memories—the entorhinal surface area plays a crucial role inward transforming daily sense into lasting memories. Data collected during the origin twelvemonth of the projection from patients already implanted amongst encephalon electrodes every bit component of their handling for epilepsy volition live used to prepare a computational model of the hippocampal-entorhinal organisation that tin as well as then live used to evidence retentiveness restoration inward patients.
. . .

The Penn team’s approach is based on an understanding that retentiveness is the final result of complex interactions amidst widespread encephalon regions. Researchers volition study neurosurgical patients who convey electrodes implanted inward multiple areas of their brains for the handling of diverse neurological conditions. By recording neural activity from these electrodes every bit patients play computer-based retentiveness games, the researchers volition mensurate “biomarkers” of successful retentiveness function—patterns of activity that accompany the successful formation of novel memories as well as the successful retrieval of erstwhile ones. Researchers could as well as then utilization those models as well as a novel neural stimulation as well as monitoring organisation ... to restore encephalon retentiveness function.

DARPA Project Starts Building Human Memory Prosthetics (August 27, 2014)
“They’re trying to produce xx years of enquiry inward 4 years,” says Michael Kahana inward a tone that’s a mixture of excitement as well as disbelief. Kahana, managing director of the Computational Memory Lab at the University of Pennsylvania, is mulling over the tall social club from the U.S.A. Defense Advanced Research Projects Agency (DARPA). In the adjacent iv years, he as well as other researchers are charged amongst understanding the neuroscience of retentiveness as well as and then edifice a prosthetic retentiveness device that’s ready for implantation inward a human brain.

Work Begins on Brain Stimulator to Correct Memory (April 3, 2015)
If the Penn squad is able to position markers of retentiveness formation, it volition seek to influence them yesteryear stimulating the encephalon amongst depression doses of electricity. The goal is to evidence whether it’s possible to coax the brain’s circuitry into whatever nation represents a specific patient’s best possible retentiveness function.

Kahana, who is managing director of the university’s Computational Memory Lab, says it’s likewise shortly to state whether the thought volition work. “We desire the encephalon to exhibit a certainly pattern of electrical activity,” he says. “It’s a large saltation [to say] nosotros tin somehow nudge it into that nation yesteryear giving it a piffling push.”

Targeted Electrical Stimulation of the Brain Shows Promise every bit a Memory Aid (September 11, 2015)
. . .

Just over ane twelvemonth into the effort, the novel approach to facilitating retentiveness formation as well as recall has already been tested inward a few dozen human volunteers, said programme manager Justin Sanchez. ...

The study aims to give researchers the powerfulness to “read” the neural processes involved inward retentiveness formation as well as retrieval, as well as fifty-fifty predict when a volunteer is nigh to brand an fault inward recall. The implanted electrodes also supply a agency of sending signals to specific groups of neurons, amongst the goal of influencing the accuracy of recall.

Initial results signal that it is indeed possible to capture as well as translate fundamental signals or “neural codes” coming from the human encephalon during retentiveness encoding as well as retrieval, as well as improve recall yesteryear providing targeted electrical stimulation of the brain.

Top image (from Penn): Illustration showing placement of deep encephalon electrodes inward an epilepsy patient.


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