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Archive for the ‘Cognition’ Category


Brain, learning and memory

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

March 23, 2016   Exploring long-range communications in the brain
http://www.kurzweilai.net/exploring-long-range-communications-in-the-brain

Red and green dots reveal a region in the brain that that is very dense with synapses. A optically activated fluorescent protein allows Ofer Yizhar, PhD, and his group to record the activity of the synapses. (credit: Weizmann Institute of Science)

Weizmann Institute of Science researchers have devised a new way to track long-distance communications between nerve cells in different areas of the brain. They used optogenetic techniques (using genetic engineering of neurons and laser light in thin optical fibers to temporarily silence long-range axons, effectively leading to a sustained “disconnect” between two distant brain nodes.

By observing what happens when crucial connections are disabled, the researchers could begin to determine the axons’ role in the brain. Mental and neurological diseases are often thought to result from changes in long-range brain connectivity, so these studies could contribute to a better understanding of the mechanisms behind health and disease in the brain.

The study, published in Nature Neuroscience, “led us to a deeper understanding of the unique properties of the axons and synapses that form the connections between neurons,” said Ofer Yizhar, PhD, in the Weizmann Institute of Science’s Neurobiology Department. “We were able to uncover the responses of axons to various optogenetic manipulations. Understanding these differences will be crucial to unraveling the mechanisms for long-distance communication in the brain.”


Abstract of Biophysical constraints of optogenetic inhibition at presynaptic terminals

We investigated the efficacy of optogenetic inhibition at presynaptic terminals using halorhodopsin, archaerhodopsin and chloride-conducting channelrhodopsins. Precisely timed activation of both archaerhodopsin and halorhodpsin at presynaptic terminals attenuated evoked release. However, sustained archaerhodopsin activation was paradoxically associated with increased spontaneous release. Activation of chloride-conducting channelrhodopsins triggered neurotransmitter release upon light onset. Thus, the biophysical properties of presynaptic terminals dictate unique boundary conditions for optogenetic manipulation.

 

DARPA’s ‘Targeted Neuroplasticity Training’ program aims to accelerate learning ‘beyond normal levels’

The transhumanism-inspired goal: train superspy agents to rapidly master foreign languages and cryptography
New DARPA “TNT” technology will be designed to safely and precisely modulate peripheral nerves to control synaptic plasticity during cognitive skill training. (No mention of NZT.) (credit: DARPA)

DARPA has announced a new program called Targeted Neuroplasticity Training (TNT) aimed at exploring how to use peripheral nerve stimulation and other methods to enhance learning.

DARPA already has research programs underway to use targeted stimulation of the peripheral nervous system as a substitute for drugs to treat diseases and accelerate healing*, to control advanced prosthetic limbs**, and to restore tactile sensation.

But now DARPA plans to to take an even more ambitious step: It aims to enlist the body’s peripheral nerves to achieve something that has long been considered the brain’s domain alone: facilitating learning — specifically, training in a wide range of cognitive skills.

The goal is to reduce the cost and duration of the Defense Department’s extensive training regimen, while improving outcomes. If successful, TNT could accelerate learning and reduce the time needed to train foreign language specialists, intelligence analysts, cryptographers, and others.

“Many of these skills, such as understanding and speaking a new foreign language, can be challenging to learn,” says the DARPA statement. “Current training programs are time consuming, require intensive study, and usually require evidence of a more-than-minimal aptitude for eligibility. Thus, improving cognitive skill learning in healthy adults is of great interest to our national security.”

Going beyond normal levels of learning

The program is also notable because it will not just train; it will advance capabilities beyond normal levels — a transhumanist approach.

“Recent research has shown that stimulation of certain peripheral nerves, easily and painlessly achieved through the skin, can activate regions of the brain involved with learning,” by releasing neurochemicals in the brain that reorganize neural connections in response to specific experiences, explained TNT Program Manager Doug Weber,

“This natural process of synaptic plasticity is pivotal for learning, but much is unknown about the physiological mechanisms that link peripheral nerve stimulation to improved plasticity and learning,” Weber said. “You can think of peripheral nerve stimulation as a way to reopen the so-called ‘Critical Period’ when the brain is more facile and adaptive. TNT technology will be designed to safely and precisely modulate peripheral nerves to control plasticity at optimal points in the learning process.”

The goal is to optimize training protocols that expedite the pace of learning and maximize long-term retention of even the most complicated cognitive skills. DARPA intends to take a layered approach to exploring this new terrain:

  • Fundamental research will focus on gaining a clearer and more complete understanding of how nerve stimulation influences synaptic plasticity, how cognitive skill learning processes are regulated in the brain, and how to boost these processes to safely accelerate skill acquisition while avoiding potential side effects.
  • The engineering side of the program will target development of a non-invasive device that delivers peripheral nerve stimulation to enhance plasticity in brain regions responsible for cognitive functions.

Proposers Day

TNT expects to attract multidisciplinary teams spanning backgrounds such as cognitive neuroscience, neural plasticity, electrophysiology, systems neurophysiology, biomedical engineering, human performance, and computational modeling.

To familiarize potential participants with the technical objectives of TNT, DARPA will host a Proposers Day on Friday, April 8, 2016, at the Westin Arlington Gateway in Arlington, Va. (registration closes on Thursday, March 31, 2016). ADARPA Special Notice announces the Proposers Day and describes the specific capabilities sought. A Broad Agency Announcement with full technical details on TNT will be forthcoming. For more information, please email DARPA-SN-16-20@darpa.mil.

* DARPA’s ElectRx program is looking for “demonstrations of feedback-controlled neuromodulation strategies to establish healthy physiological states,” along with “disruptive biological-interface technologies required to monitor biomarkers and peripheral nerve activity … [and] deliver therapeutic signals to peripheral nerve targets, using in vivo, real-time biosensors and novel neural interfaces using optical, acoustic, electromagnetic, or engineered biology strategies to achieve precise targeting with potentially single-axon resolution.”

** DARPA’s HAPTIX (Hand Proprioception and Touch Interfaces) program “seeks to create a prosthetic hand system that moves and provides sensation like a natural hand. … HAPTIX technologies aim to tap in to the motor and sensory signals of the arm, allowing users to control and sense the prosthesis via the same neural signaling pathways used for intact hands and arms. … The system will include electrodes for measuring prosthesis control signals from muscles and motor nerves, and sensory feedback will be delivered through electrodes placed in sensory nerves.”

 

Fading of Epigenetic Memories across Generations Is Regulated
Neurons involved in working memory fire in bursts, not continuously
http://www.genengnews.com/gen-news-highlights/fading-of-epigenetic-memories-across-generations-is-regulated/81252537

  • Epigenetic “remembering” is better understood than epigenetic “forgetting,” and so it is an open question whether epigenetic forgetting is, like epigenetic remembering, active—a distinct biomolecular process—or passive—a matter of dilution or decay. New research, however, suggests that epigenetic forgetting is an active process, one in which a feedback mechanism determines the duration of transgenerational epigenetic memories.

    The new research comes out of Tel Aviv University, where researchers have been working with the nematode worm Caenorhabditis elegans to elucidate epigenetic mechanisms. In particular, the researchers, led by Oded Rechavi, Ph.D., have been preoccupied with how the effects of stress, trauma, and other environmental exposures are passed from one generation to the next.

    In previous work, Dr. Rechavi’s team enhanced the state of knowledge of small RNA molecules, short sequences of RNA that regulate the expression of genes. The team identified a “small RNA inheritance” mechanism through which RNA molecules produced a response to the needs of specific cells and how they were regulated between generations.

    “We previously showed that worms inherited small RNAs following the starvation and viral infections of their parents. These small RNAs helped prepare their offspring for similar hardships,” Dr. Rechavi explained. “We also identified a mechanism that amplified heritable small RNAs across generations, so the response was not diluted. We found that enzymes called RdRPs [RNA-dependent RNA polymerases] are required for re-creating new small RNAs to keep the response going in subsequent generations.”

    Most inheritable epigenetic responses in C. elegans were found to persist for only a few generations. This created the assumption that epigenetic effects simply “petered out” over time, through a process of dilution or decay. “But this assumption,” said Dr. Rechavi, “ignored the possibility that this process doesn’t simply die out but is regulated instead.”

    This possibility was explored in the current study, in which C. elegans were treated with small RNAs that target the GFP (green fluorescent protein) gene, a reporter gene commonly used in experiments. “By following heritable small RNAs that regulated GFP—that ‘silenced’ its expression—we revealed an active, tunable inheritance mechanism that can be turned ‘on’ or ‘off,'” declared Dr. Rechavi.

    Details of the work appeared March 24 in the journal Cell, in an article entitled, “A Tunable Mechanism Determines the Duration of the Transgenerational Small RNA Inheritance in C. elegans.” The article shows that exposure to double-stranded RNA (dsRNA) activates a feedback loop whereby gene-specific RNA interference (RNAi) responses “dictate the transgenerational duration of RNAi responses mounted against unrelated genes, elicited separately in previous generations.”

    Essentially, amplification of heritable exo-siRNAs occurs at the expense of endo-siRNAs. Also, a feedback between siRNAs and RNAi genes determines heritable silencing duration.

    “RNA-sequencing analysis reveals that, aside from silencing of genes with complementary sequences, dsRNA-induced RNAi affects the production of heritable endogenous small RNAs, which regulate the expression of RNAi factors,” wrote the authors of the Cell paper. “Manipulating genes in this feedback pathway changes the duration of heritable silencing.”

    The scientists also indicated that specific genes, which they named MOTEK (Modified Transgenerational Epigenetic Kinetics), were involved in turning on and off epigenetic transmissions.

    “We discovered how to manipulate the transgenerational duration of epigenetic inheritance in worms by switching ‘on’ and ‘off’ the small RNAs that worms use to regulate genes,” said Dr. Rechavi. “These switches are controlled by a feedback interaction between gene-regulating small RNAs, which are inheritable, and the MOTEK genes that are required to produce and transmit these small RNAs across generations.

    “The feedback determines whether epigenetic memory will continue to the progeny or not, and how long each epigenetic response will last.”

    Although its research was conducted on worms, the team believes that understanding the principles that control the inheritance of epigenetic information is crucial for constructing a comprehensive theory of heredity for all organisms, humans included.

    “We are now planning to study the MOTEK genes to know exactly how these genes affect the duration of epigenetic effects,” said Leah Houri-Ze’evi, a Ph.D. student in Dr. Rechavi’s lab and first author of the paper. “Moreover, we are planning to examine whether similar mechanisms exist in humans.”

    The current study notes that the active control of transgenerational effects could be adaptive, because ancestral responses would be detrimental if the environments of the progeny and the ancestors were different.

    A Tunable Mechanism Determines the Duration of the Transgenerational Small RNA Inheritance in C. elegans

    Leah Houri-Ze’ev, Yael Korem, Hila Sheftel,…, Luba Degani, Uri Alon, Oded Rechavi
    Cell 24 March 2016; Volume 165, Issue 1, p88–99.  http://dx.doi.org/10.1016/j.cell.2016.02.057
    Highlights
  • New RNAi episodes extend the duration of heritable epigenetic effects
  • Amplification of heritable exo-siRNAs occurs at the expense of endo-siRNAs
  • A feedback between siRNAs and RNAi genes determines heritable silencing duration
  • Modified transgenerational epigenetic kinetics (MOTEK) mutants are identified

Figure thumbnail fx1

In C. elegans, small RNAs enable transmission of epigenetic responses across multiple generations. While RNAi inheritance mechanisms that enable “memorization” of ancestral responses are being elucidated, the mechanisms that determine the duration of inherited silencing and the ability to forget the inherited epigenetic effects are not known. We now show that exposure to dsRNA activates a feedback loop whereby gene-specific RNAi responses dictate the transgenerational duration of RNAi responses mounted against unrelated genes, elicited separately in previous generations. RNA-sequencing analysis reveals that, aside from silencing of genes with complementary sequences, dsRNA-induced RNAi affects the production of heritable endogenous small RNAs, which regulate the expression of RNAi factors. Manipulating genes in this feedback pathway changes the duration of heritable silencing. Such active control of transgenerational effects could be adaptive, since ancestral responses would be detrimental if the environments of the progeny and the ancestors were different.

How we are able to keep several things simultaneously in working memory
Pictured is an artist’s interpretation of neurons firing in sporadic, coordinated bursts. “By having these different bursts coming at different moments in time, you can keep different items in memory separate from one another,” Earl Miller says. (credit: Jose-Luis Olivares/MIT)

Think of a sentence you just read. Like that one. You’re now using your working memory, a critical brain system that’s roughly analogous to RAM memory in a computer.

Neuroscientists have believed that as information is held in working memory, brain cells associated with that information must be firing continuously. Not so — they fire in sporadic, coordinated bursts, says Earl Miller, the Picower Professor in MIT’s Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences.

That makes sense. These different bursts could help the brain hold multiple items in working memory at the same time, according to the researchers. “By having these different bursts coming at different moments in time, you can keep different items in memory separate from one another,” says Miller, the senior author of a study that appears in the March 17 issue of Neuron.

Bursts of activity, not averaged activity

So why hasn’t anyone noticed this before? Because previous studies averaged the brain’s activity over seconds or even minutes of performing the task, Miller says. “We looked more closely at this activity, not by averaging across time, but from looking from moment to moment. That revealed that something way more complex is going on.”

To do that, Miller and his colleagues recorded neuron activity in animals as they were shown a sequence of three colored squares, each in a different location. Then, the squares were shown again, but one of them had changed color. The animals were trained to respond when they noticed the square that had changed color — a task requiring them to hold all three squares in working memory for about two seconds.

The researchers found that as items were held in working memory, ensembles of neurons in the prefrontal cortex were active in brief bursts, and these bursts only occurred in recording sites in which information about the squares was stored. The bursting was most frequent at the beginning of the task, when the information was encoded, and at the end, when the memories were read out.

The findings fit well with a model that Lundqvist had developed as an alternative to the model of sustained activity as the neural basis of working memory. According to the new model, information is stored in rapid changes in the synaptic strength of the neurons. The brief bursts serve to “imprint” information in the synapses of these neurons, and the bursts reoccur periodically to reinforce the information as long as it is needed.

The bursts create waves of coordinated activity at the gamma frequency (45 to 100 hertz), like the ones that were observed in the data. These waves occur sporadically, with gaps between them, and each ensemble of neurons, encoding a specific item, produces a different burst of gamma waves, like a fingerprint.

Implications for other cognitive functions

The findings suggest that it would be worthwhile to look for this kind of cyclical activity in other cognitive functions such as attention, the researchers say. Oscillations like those seen in this study may help the brain to package information and keep it separate so that different pieces of information don’t interfere with each other.

Robert Knight, a professor of psychology and neuroscience at the University of California at Berkeley, says the new study “provides compelling evidence that nonlinear oscillatory dynamics underlie prefrontal dependent working memory capacity.”

“The work calls for a new view of the computational processes supporting goal-directed behavior,” adds Knight, who was not involved in the research. “The control processes supporting nonlinear dynamics are not understood, but this work provides a critical guidepost for future work aimed at understanding how the brain enables fluid cognition.”


editor’s comments: I’m curious how this relates to forgetting things to make space to learn new things. (Turns out the hippocampus works closely with the prefrontal cortex in working memory, as this open-access Nature paper explains.) Also, what’s the latest on how many things we can keep in working memory (it used to be around five)? Is that number limited by forgetting or by the capacity to differentiate different spike trains? Any tricks for keeping more things in working memory?


Abstract of Gamma and Beta Bursts Underlie Working Memory

Working memory is thought to result from sustained neuron spiking. However, computational models suggest complex dynamics with discrete oscillatory bursts. We analyzed local field potential (LFP) and spiking from the prefrontal cortex (PFC) of monkeys performing a working memory task. There were brief bursts of narrow-band gamma oscillations (45–100 Hz), varied in time and frequency, accompanying encoding and re-activation of sensory information. They appeared at a minority of recording sites associated with spiking reflecting the to-be-remembered items. Beta oscillations (20–35 Hz) also occurred in brief, variable bursts but reflected a default state interrupted by encoding and decoding. Only activity of neurons reflecting encoding/decoding correlated with changes in gamma burst rate. Thus, gamma bursts could gate access to, and prevent sensory interference with, working memory. This supports the hypothesis that working memory is manifested by discrete oscillatory dynamics and spiking, not sustained activity.

Gamma and Beta Bursts Underlie Working Memory

Mikael Lundqvist5, Jonas Rose5, Pawel Herman, Scott L. Brincat, Timothy J. Buschman, Earl K. Miller

Highlights
  • Working memory information in neuronal spiking is linked to brief gamma bursts
  • The narrow-band gamma bursts increase during encoding, decoding, and with WM load
  • Beta bursting reflects a default network state interrupted by gamma
  • Support for a model of WM is based on discrete dynamics and not sustained activity

 

References  Authors  Title   Source

Amit, D.J. and Brunel, N.Model of global spontaneous activity and local structured activity during delay periods in the cerebral cortex.

Cereb. Cortex. 1997; 7: 237–252

Asaad, W.F. and Eskandar, E.N.A flexible software tool for temporally-precise behavioral control in Matlab.

J. Neurosci. Methods. 2008;174: 245–258

Axmacher, N., Henseler, M.M., Jensen, O., Weinreich, I., Elger, C.E., and Fell, J.Cross-frequency coupling supports multi-item working memory in the human hippocampus.

Proc. Natl. Acad. Sci. USA.2010; 107: 3228–3233

Brunel, N. and Wang, X.J.What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance.

J. Neurophysiol. 2003; 90:415–430

Buschman, T.J., Siegel, M., Roy, J.E., and Miller, E.K.Neural substrates of cognitive capacity limitations.

Proc. Natl. Acad. Sci. USA.2011; 108: 11252–11255

Johan Eriksson, Edward K. Vogel, Anders Lansner, Fredrik Bergström, Lars Nyberg
Neuron, Vol. 88, Issue 1, p33–46
Published in issue: October 07, 2015
Abstract Image
Alexander Bratch, Spencer Kann, Joshua A. Cain, Jie-En Wu, Nilda Rivera-Reyes, Stefan Dalecki, Diana Arman, Austin Dunn, Shiloh Cooper, Hannah E. Corbin, Amanda R. Doyle, Matthew J. Pizzo, Alexandra E. Smith, Jonathon D. Crystal
Current Biology, Vol. 26, Issue 3, p351–355
Published online: January 14, 2016
Abstract Image
Diego Lozano-Soldevilla, Niels ter Huurne, Roshan Cools, Ole Jensen
Current Biology, Vol. 24, Issue 24, p2878–2887
Published online: November 26, 2014

Open Archive

Abstract Image
Lily Kahsai, Troy Zars
Current Biology, Vol. 23, Issue 18, R843–R845
Published in issue: September 23, 2013

Open Archive

Abstract Image
Dimitry Fisher, Itsaso Olasagasti, David W. Tank, Emre R.F. Aksay, Mark S. Goldman
Neuron, Vol. 79, Issue 5, p987–1000
Published in issue: September 04, 2013

Open Archive

Synaptic Amplifier

Gene discovery reveals mechanism behind how we think

By ELIZABETH COONEY   March 16, 2016
http://hms.harvard.edu/news/synaptic-amplifier

Skyler Jackman and colleagues studied the phenomenon known as synaptic facilitation by using light to turn neuronal connections on and off. The optogenetic protein used in this technique appears yellow. Image: Regehr lab

Our brains are marvels of connectivity, packed with cells that continually communicate with one another. This communication occurs across synapses, the transit points where chemicals called neurotransmitters leap from one neuron to another, allowing us to think, to learn and to remember.
Now Harvard Medical School researchers have discovered a gene that provides that boost by increasing neurotransmitter release in a phenomenon known as synaptic facilitation. And they did so by turning on a light or two.
Image: Jasmine Vazquez
image: Jasmine Vazquez

The gene is synaptotagmin 7 (syt7 for short), a calcium sensor that dynamically increases neurotransmitter release; each release serves to strengthen communication between neurons for about a second. These swift releases are thought to be critical for the brain’s ability to perform computations involved in short-term memory, spatial navigation and sensory perception.

A team of researchers who made this discovery was led by Skyler Jackman, a postdoctoral researcher in the lab of Wade Regehr, professor of neurobiology at HMS. They recently reported their findings in Nature.

 The calcium sensor synaptotagmin 7 is required for synaptic facilitationSkyler L. JackmanJosef TurecekJustine E. Belinsky & Wade G. Regehr
Nature 529, 88–91 (07 January 2016)
        doi:10.1038/nature16507
It has been known for more than 70 years that synaptic strength is dynamically regulated in a use-dependent manner1. At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release2. Facilitation can enhance neurotransmitter release considerably and can profoundly influence information transfer across synapses3, but the underlying mechanism remains a mystery. One proposed mechanism is that a specialized calcium sensor for facilitation transiently increases the probability of release24, and this sensor is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed56. Here we show that synaptotagmin 7 (Syt7) is a calcium sensor that is required for facilitation at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wild-type Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of Syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation.

“We really think one of the most important things the brain can do is change the strength of connections between neurons,” Jackman said. “Now that we have a tool to selectively turn off facilitation, we can test some long-held beliefs about its importance for thinking and working memory.”

Although synaptic facilitation was first described 70 years ago by Te-Pei Feng, known as the father of Chinese physiology, Jackman and colleagues were able to identify the mechanism behind synaptic strengthening by taking advantage of advanced laboratory techniques unavailable to previous generations of scientists.

A dozen years ago, Regehr suspected that syt7 might drive this synaptic strengthening process: The gene turns on slowly and then ramps up in speed, which would fit gradual release of neurotransmitters.

About eight years ago scientists in another lab engineered “knockout” mice that lack the syt7 gene, setting the stage for experiments to test Regehr’s speculations. But when grown in a lab dish, neurons from these knockout mice behaved no differently than other neurons; results that, at the time, dashed hopes that syt7 could explain the synaptic boost.

A year ago Jackman took another tack. He tested synaptic connections in brain tissue taken from the knockout mice but still having intact brain circuits, an experiment more reflective of how neurons and synapses might work in a living animal.

“It was striking. It was amazing,” Jackman said. “As soon as we probed these connections we saw there was a huge deficit, a complete lack of synaptic facilitation in the knockout mice, completely different from their wild-type brothers and sisters.”

To be certain that knocking out syt7 was responsible for this change, Jackman had to find a way to reinsert syt 7 and restore its function. He did that by using optogenetics, a genetic manipulation tool that allows neuronal connections to be turned on and off with light. He augmented this technique with bicistronic expression, a method that packages one optogenetic protein and one syt7protein into a single virus that infects all neurons equally. Using these two techniques, Jackman could selectively study what happened when syt7 was reinserted into a neuron and measure its effects reliably.

 

We need to forget things to make space to learn new things, scientists discover

Mice study, if confirmed in people, might help forget traumatic experiences
http://www.kurzweilai.net/we-need-to-forget-things-to-make-space-to-learn-new-things-scientists-discover

The three routes into the hippocampus seem to be linked to different aspects of learning: forming memories (green), recalling them (yellow) and forgetting them (red) (credit: John Wood)

While you’re reading this (and learning about this new study), your brain is actively trying to forget something.

We apologize, but that’s what scientists at the European Molecular Biology Laboratory (EMBL) and the University Pablo Olavide in Sevilla, Spain, found in a new study published Friday (March 18) in an open-access paper in Nature Communications.

“This is the first time that a pathway in the brain has been linked to forgetting — to actively erasing memories,” says Cornelius Gross, who led the work at EMBL.

Working with mice, Gross and colleagues studied the hippocampus, a region of the brain known to help form memories. Information enters this part of the brain through three different routes. As memories are formed, connections between neurons along the “main” route become stronger.

When they blocked this main route (dentate gyrus granule cells), the scientists found that the mice were no longer capable of learning (in this case, a specific Pavlovian response).* But surprisingly, blocking that main route  also resulted in its connections weakening, meaning the memory was actually being erased.

Limited space in the brain

Gross proposes that one explanation: “There is limited space in the brain, so when you’re learning, you have to weaken some connections to make room for others,” says Gross.

Interestingly, this active push for forgetting only happens in learning situations. When the scientists blocked the main route into the hippocampus under other circumstances, the strength of its connections remained unaltered.

The findings were made using genetically engineered mice, but the scientists demonstrated that it is possible to produce a drug that activates this “forgetting” route in the brain without the need for genetic engineering. This approach, they say, might help people forget traumatic experiences.

* But if the mice had learned that association before the scientists stopped information flow in that main route, they could still retrieve that memory. This confirmed that this route is involved in forming memories, but isn’t essential for recalling those memories. The latter probably involves the second route into the hippocampus, the scientists surmise.


Abstract of Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells

The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories.

 

Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells

Noelia MadroñalJosé M. Delgado-GarcíaAzahara Fernández-GuizánJayanta ChatterjeeMaja KöhnCamilla Mattucci, et al.

Nature Communications7,Article number:10923    http://www.nature.com/ncomms/2016/160318/ncomms10923/full/ncomms10923.html

The hippocampus is an evolutionarily ancient part of the cortex that makes reciprocal excitatory connections with neocortical association areas and is critical for the acquisition and retrieval of episodic and contextual memories. The hippocampus has been the subject of extensive investigation over the last 50 years as the site of plasticity thought to be critical for memory encoding. Models of hippocampal function propose that sensory information reaching the hippocampus from the entorhinal cortex via dentate gyrus (DG) granule cells is encoded in CA3 auto-association circuits and can in turn be retrieved via Schaffer collateral (SC) projections linking CA3 and CA1 (refs 1, 2, 3, 4; Fig. 1a). Learning-associated plasticity in CA3–CA3 auto-associative networks encodes the memory trace, and plasticity in SC connections is necessary for the efficient retrieval of this trace2, 5, 6, 7, 8, 9, 10. In addition, both CA3 and CA1 regions receive direct, monosynaptic inputs from entorhinal cortex that are thought to convey information about ongoing sensory inputs that could modulate CA3 memory trace acquisition and/or retrieval via SC (refs 11,12, 13; Fig. 1a). In DG granule cells, sensory information is thought to undergo pattern separation into orthogonal cell ensembles before encoding (or reactivating, in the case of retrieval) memories in CA3 (ref. 14). However, how the hippocampus executes both the acquisition and recall of memories stored in CA3 remains a question of debate with some models attributing a role for DG inputs in memory acquisition, but not retrieval2, 15, 16, 17.

Rapid and selective inhibition of DG neurotransmission in vivo.

(a) The hippocampal tri-synaptic circuit receives PP inputs from entorhinal cortex to DG, CA3 and CA1. (b) A stimulating electrode was implanted in the PP and a recording electrode in CA3 pyramidal layer. (c) Strength of CA3 pyramidal layer fEPSPs evoked in anaesthetized mice by electrical stimulation of PP inputs showed fast and slow latency population spike components corresponding to direct PP-CA3 and indirect PP–DG-CA3 inputs, respectively. Systemic administration of the selective Htr1a agonist, 8-OH-DPAT (0.3mgkg−1, subcutaneous), to Htr1aDG (Tg) mice caused a rapid and selective decrease in the long-latency component that persisted for several hours. Quantification indicated a significant decrease in DG neurotransmission following agonist treatment of Htr1aDG, but not Htr1aKO (KO) littermates or vehicle treated wild-type mice that reached 80% suppression and persisted for >2h (mean±s.e.m.; n=10;*P<0.05; two-way analysis of variance followed by Holm–Sidak post hoc test). (d) Representative fEPSPs evoked at CA3 pyramidal layer after stimulation of PP inputs before and after agonist treatment. The fast and the slow latency population spike components are indicated (black arrow, short; grey arrow, long).

 

Figure 2

Inhibition of DG induces rapid and persistent loss of hippocampal memory and plasticity.

Figure 4

Loss of plasticity depends on entorhinal cortex inputs and local adenosine signalling.

In the present study we examined the contribution of DG granule cells to learning and recall and its associated synaptic plasticity in animals that had previously acquired a hippocampal memory. We found that transient pharmacogenetic inhibition of DG granule cells did not impair conditioned responding to CS presentation nor alter SC synaptic plasticity demonstrating that DG is not required for memory recall (Fig. 3c,d). However, when DG inhibition occurred during paired presentation of CS and US, we observed a rapid loss of SC synaptic plasticity and conditioned responding to CS (Fig. 2d,e and Supplementary Fig. 3). Strikingly, the synaptic plasticity and behavioural impairment persisted in the absence of further stimulus presentation and later relearning occurred at a rate indistinguishable from initial learning, suggesting a loss of the memory trace (Fig. 2f,g).

One possible explanation for the memory loss seen on DG inhibition is that presentation of paired CS–US has a dual effect on CA1 plasticity, on the one hand strengthening SC synapses via a DG-dependent mechanism (indirect inputs to CA1 via the tri-synaptic circuit) and on the other hand weakening SC synapses in a non-DG-dependent manner (direct PP-CA1 inputs). This explanation is consistent with several studies in the literature reporting mechanistic and functional differences between the direct and the indirect inputs to CA1 (refs 12, 13, 30, 31, 32). Furthermore, earlier in vitro12, 23 and in vivo33 electrophysiology studies found that stimulation of PP-CA1 inputs to the hippocampus could depotentiate synaptic plasticity that had been previously acquired at SC synapses suggesting that the direct PP pathway might promote depotentiation during hippocampal learning. To test this possibility, we used dual, orthogonal pharmacogenetic inhibition of DG and entorhinal cortex to show that the memory loss phenomenon we observed depended on PP inputs (Fig. 4e). Furthermore, one of the earlier studies23 had shown that PP stimulation-induced SC depotentiation could be inhibited by blockade of adenosine A1 receptors, but not several other receptors, and we found that bilateral administration of DPCPX to the CA1 region of the hippocampus blocked synaptic depotentiation in our model (Fig. 4g).

Our data lead us to propose a novel function for PP-CA1 inputs to the hippocampus. During CS–US presentation, but not during presentation of unpaired CS–US or CS alone, information arriving via this pathway actively promotes depotentiation of SC synapses, while information arriving via the DG pathway opposes this depotentiation. Thus, in an animal that has successfully acquired a hippocampal-dependent memory, and in which the direct and indirect pathways are intact, SC synaptic strength is stable and memories can be retrieved. However, when the DG pathway is blocked, as we have done artificially in our study, depotentiation is favoured and memory is lost (see scheme, Fig. 6). The precise function of PP-dependent SC depotentiation remains unclear at this point, but we speculate that it may play a role in weakening previously acquired associations to facilitate the encoding of new memories. Existing data show that selective blockade of synaptic activity in entorhinal cortex neurons projecting to CA1 impairs the acquisition of trace fear conditioning34 and support our hypothesis of a positive role for this pathway in learning13, 30, 32, 33. Moreover, our DPCPX experiments suggest that blockade of the depotentiation mechanism promotes SC synaptic plasticity during CS–US presentation in otherwise intact animals (Fig. 4g). However, further loss and gain-of-function manipulations of this pathway coupled with in vivoelectrophysiology and learning behaviour are needed to directly test a role of PP-CA1 inputs in memory clearing.

Figure 6: Model for function of PP-CA1 inputs to the hippocampus.

Figure 6

Model for function of PP-CA1 inputs to the hippocampus.

Model for function of PP-CA1 inputs to the hippocampus.

Area CA1 of the hippocampus receives information directly from the entorhinal cortex (direct PP-CA1 pathway) and also indirectly via the tri-synaptic circuit. (a) Presentation of paired CS–US promotes potentiation of SC synapses (+) via the indirect pathway depotentiation of SC synapses (–) via the PP-CA1 pathway. In an animal having successfully undergone learning, potentiation and depotentiation are balanced, SC synaptic strength is stable and memories can be retrieved. (b) Inhibition of DG during CS–US presentation suppresses potentiation via the indirect pathway, unmasking depotentiation of SC synapses and promoting memory loss.

Our finding that DG granule cells are not required for retrieval of hippocampal memory is consistent with previous data arguing that retrieval of associative information encoded in CA3–CA3 and SC plasticity is achieved via direct PP projections to CA3 (refs 1, 2, 3, 4, 35, 36, 37, 38). However, our data appear to contradict at least one recent study demonstrating a role for DG granule cells in retrieval during contextual fear conditioning39. We believe this discrepancy is due to a requirement for DG granule cells in the processing of the contextual CS (ref. 40). However, to rule out the possibility that other methodological differences between the studies underlie the discrepancy, it would be important to determine whether the cell-type specific optogenetic inhibition method used in their study left intact the recall of hippocampal-dependent memories for discrete cues.

Our study raises several questions. First, while we show SC depotentiation is adenosine receptor dependent, the location of adenosine signalling is not clear. Adenosine A1 receptors are expressed highly in CA3 pyramidal cells as well as more modestly in CA1 (ref. 28), and a study in which this receptor was selectively knocked out in one or the other of these structures demonstrated a role for presynaptic CA3, but not postsynaptic CA1 receptors in dampening SC neurotransmission41suggesting a presynaptic mechanism for our effect. The source of adenosine, on the other hand, could involve pre- and/or postsynaptic release as well as release from non-neuronal cells such as astrocytes27, 42. Second, although our DPCPX experiment pointed to a role for PP-CA1 projections in SC depotentiation, our entorhinal cortex pharmacogenetic inhibition experiment did not allow us to distinguish between contributions of PP-CA1 and PP-CA3 inputs. Although we cannot rule out a contribution of PP-CA3 projections to SC depotentiation, earlier in vitro and in vivo electrophysiology studies clearly demonstrate a role for PP-CA1 in SC depotentiation12, 22, 33. Third, the method we used to assess SC postsynaptic strength, namely electrical stimulation evoked field potentials does not allow us to rule out that changes in synaptic plasticity at non-SC inputs underlie our plasticity effects. Experiments using targeted optogenetic stimulation of CA3 efferents could be used to more selectively measure SC synaptic strength. Fourth, our observation that SC depotentiation and memory loss occurred only during paired, but not unpaired CS–US presentation (Fig. 2d,e) suggests that the memory loss phenomenon we describe is distinct from other well-described avenues for memory degradation, including enhancement of extinction43 and blockade of reconsolidation44. Finally, our findings demonstrating generalization of DG inhibition-induced memory loss across tasks coupled with our identification of an endogenous pharmacological target that can induce similar memory loss raise the possibility that the novel memory mechanism we have uncovered may be useful for erasing unwanted memories in a clinical setting.

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Sleep and memory

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Learning with the Lights Out

Researchers are uncovering the link between sleep and learning and how it changes throughout our lives.

By Jenny Rood | March 1, 2016    http://www.the-scientist.com/?articles.view/articleNo/45335/title/Learning-with-the-Lights-Out

NIGHTY NIGHT: Goffredina Spanò from Jamie Edgin’s University of Arizona lab uses polysomnography to measure sleep in a toddler with Down syndrome.PAMELA SPEDER

By the early 2000s, scientists had found that sleep helps young adults consolidate memory by reinforcing and filing away daytime experiences. But the older adults that Rebecca Spencer was studying at the University of Massachusetts Amherst didn’t seem to experience the same benefit. Spencer wondered if developmental stage altered the relationship between sleep and memory, and chose nearby preschool children as subjects. She found that habitual nappers benefitted the most from daytime rest, largely because their memories decayed the most without a nap. “By staying awake, they have more interference from daytime experiences,” Spencer explains.

Until recently, most of the research into the relationship between memory and sleep has been conducted using young adults or animal models. These studies have suggested that dampened sensory inputs during sleep allow the brain to replay the day’s events during a period relatively free of distracting information, helping to solidify connections and transfer daytime hippocampal memories into long-term storage in the cortex. But how sleep and memory interact at different ages has been an open question.

In children younger than 18 months, learning is thought to occur in the cortex because the hippocampus isn’t yet fully developed. As a result, researchers hypothesize that infants don’t replay memories during sleep, the way adults do. Instead, sleep merely seems to prevent infants from forgetting as much as they would if they were awake. “The net effect is that sleep permits infants to retain more of the redundant details of a learning experience,” says experimental psychologist Rebecca Gómez of the University of Arizona. By the time they are two years old, “we think that children have the brain development that supports an active process of consolidation,” she adds.

At that age, adequate nighttime sleep becomes critical for learning. Toddlers who sleep less than 10 hours display lasting cognitive deficits, even if they catch up on sleep later in their development (Sleep, 30:1213-19, 2007). The effects are particularly strong in children with developmental disorders, who often suffer from sleep disruptions. “Kids with Down syndrome that are sleep-impaired look like they have very large differences in language,” says Jamie Edgin of the University of Arizona who studies sleep and cognition in such children. When comparing Down syndrome children who are sleep deprived with those who sleep normally, she has observed a vocabulary difference of more than 190 words on language tests, even after controlling for behavioral differences.

Understanding the impact of sleep on memory could also help another at-risk group of learners at the other end of the age spectrum. Previous research has suggested that older adults don’t remember newly acquired motor skills as well as young adults do, perhaps because the posttraining stages of the learning process appear diminished. But neuroscientist Maria Korman and her colleagues at the University of Haifa in Israel recently demonstrated that a nap soon after learning can allow the elderly to retain procedural memories just as well as younger people (Neurosci Lett, 606:173-76, 2015). Korman hypothesizes that by shortening the interval between learning and consolidation, the nap prevents intervening experiences from weakening the memory before it solidifies. Overnight sleep might be even better, if the motor skills—in this case a complex sequence of finger and thumb movements on the nondominant hand—are taught late enough in the day, something she is testing now.

Optimizing the timing of sleep and training in the elderly takes advantage of something Korman sees as a positive side of growing old. “As we age, our neural system becomes more aware of the relevance of the task,” Korman says. Unlike young adults who solidify all the information they acquire throughout the day, older people consolidate “those experiences that were tagged by the brain as very important.”

Tests for older adults’ memory acuity are generating new findings about the relationship between sleep and memory at other ages as well. After learning at a conference about a memory test for cognitive impairment and dementia in older adults, neuroscientist Jeanne Duffy of Brigham and Women’s Hospital in Boston wondered if sleep could help strengthen the connection between names and faces. She and her colleagues found that young adults who slept overnight after learning a list of 20 names and faces showed a 12 percent increase in retention when tested 12 hours later compared with subjects who didn’t sleep between training and testing (Neurobiol Learn Mem, 126:31-38, 2015). The findings have “an immediate real-world application,” Duffy says, as they address a common memory concern among people of all ages.

A poll by the National Sleep Foundation found that adolescents have a deficit of nearly two hours of sleep per night during the school week compared with the weekend, suggesting the potential for serious learning impairments, according to Jared Saletin, a postdoctoral sleep researcher at Brown University. In fact, one study found that restricting 13- to 17-year-olds to six and a half hours of sleep a night for five nights reduced the information they absorbed in a school-like setting (J Adolesc Health, 47:523-25, 2010). However, other studies have suggested that four nights of just five hours of sleep didn’t impair 14- to 16-year-olds’ performance on tests of skills and vocabulary (Sleep Med, 12:170-78, 2011). A lack of consistency in study design and the ages of the subjects makes these conflicting results difficult to interpret, Gómez writes in a review, and much remains to be discovered about the true impact of sleep deficits on teenagers’ learning (Trans Issues in Psych Sci, 1:116-25, 2015).

Developing a fuller picture of what happens to memories during sleep—and how best to tweak sleep habits to aid the recall process—could benefit some of society’s most sleep-deprived members of every age. “We need to understand this role of sleep in memory because there is such potential for intervention,” Spencer says. “Now that we have a well-founded concept of what sleep can do for memory, it’s time to put it to the test.”

 

Associations Between Sleep Duration Patterns and Behavioral/Cognitive Functioning at School Entry

Évelyne Touchette, MPs,1,2 Dominique Petit, PhD,1 Jean R. Séguin, PhD,3,4,5 Michel Boivin, PhD,6,7 Richard E. Tremblay, PhD,2,3,4,5,8 and Jacques Y. Montplaisir, MD, CRCP(c), PhD1,5
Sleep. 2007 Sep 1; 30(9): 1213–1219.     http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978413/
See commentary “Sleep and the Developing Brain

The aim of the study was to investigate the associations between longitudinal sleep duration patterns and behavioral/cognitive functioning at school entry.
Design, Setting, and Participants:   Hyperactivity-impulsivity (HI), inattention, and daytime sleepiness scores were measured by questionnaire at 6 years of age in a sample of births from 1997 to 1998 in a Canadian province (N=1492). The Peabody Picture Vocabulary Test – Revised (PPVT-R) was administered at 5 years of age and the Block Design subtest (WISC-III) was administered at 6 years of age. Sleep duration was reported yearly by the children’s mothers from age 2.5 to 6 years. A group-based semiparametric mixture model was used to estimate developmental patterns of sleep duration. The relationships between sleep duration patterns and both behavioral items and neurodevelopmental tasks were tested using weighted multivariate logistic regression models to control for potentially confounding psychosocial factors.  Results:   Four sleep duration patterns were identified: short persistent (6.0%), short increasing (4.8%),10-hour persistent (50.3%), and 11-hour persistent (38.9%). The association of short sleep duration patterns with high HI scores (P=0.001), low PPVT-R performance (P=0.002), and low Block Design subtest performance (P=0.004) remained significant after adjusting for potentially confounding variables.   Conclusions:   Shortened sleep duration, especially before the age of 41 months, is associated with externalizing problems such as HI and lower cognitive performance on neurodevelopmental tests. Results highlight the importance of giving a child the opportunity to sleep at least 10 hours per night throughout early childhood.

Citation: Touchette E; Petit D; Séguin JR; Boivin M; Tremblay RE; Montplaisir JY. Associations between sleep duration patterns and behavioral/cognitive functioning at school entry. SLEEP 2007;30(9):1213-1219.

Nap it or leave it in the elderly: A nap after practice relaxes age-related limitations in procedural memory consolidation

M. Kormana, , Y. DaganbA. Karnib   

 Highlights

•   Elderly individuals gain in practicing a new motor task as do young adults.
•   But elderly individuals fail to show delayed (offline) memory related gains.
•   A post-training nap uncovered robust offline skill consolidation in the elderly.
•   Consolidation processes are preserved in aging but are more stringently controlled.
•   Sleep scheduling can relax age related constraints on mnemonic processes.       
Using a training protocol that effectively induces procedural memory consolidation (PMC) in young adults, we show that older adults are good learners, robustly improving their motor performance during training. However, performance declined over the day, and overnight ‘offline’ consolidation phase performance gains were under-expressed. A post-training nap countered these deficits. PMC processes are preserved but under-engaged in the elderly; sleep can relax some of the age-related constraints on long-term plasticity.

 

A new face of sleep: The impact of post-learning sleep on recognition memory for face-name associations

Leonie Maurera, c, Kirsi-Marja Zittinga, b, Kieran Elliotta, Charles A. Czeislera, b, Joseph M. Rondaa, b, Jeanne F. Duffya, b, ,

Highlights

•   We tested whether sleep influences the accuracy of remembering face-name associations.
•   Presentation and recall were 12 h apart, one time with 8 h sleep and once without.
•   More correct face-name pairs were recalled when there was a sleep opportunity.
•   Sleep duration or sleep stage was not associated with improvement between conditions.     

Sleep has been demonstrated to improve consolidation of many types of new memories. However, few prior studies have examined how sleep impacts learning of face-name associations. The recognition of a new face along with the associated name is an important human cognitive skill. Here we investigated whether post-presentation sleep impacts recognition memory of new face-name associations in healthy adults.

Fourteen participants were tested twice. Each time, they were presented 20 photos of faces with a corresponding name. Twelve hours later, they were shown each face twice, once with the correct and once with an incorrect name, and asked if each face-name combination was correct and to rate their confidence. In one condition the 12-h interval between presentation and recall included an 8-h nighttime sleep opportunity (“Sleep”), while in the other condition they remained awake (“Wake”).

There were more correct and highly confident correct responses when the interval between presentation and recall included a sleep opportunity, although improvement between the “Wake” and “Sleep” conditions was not related to duration of sleep or any sleep stage.

These data suggest that a nighttime sleep opportunity improves the ability to correctly recognize face-name associations. Further studies investigating the mechanism of this improvement are important, as this finding has implications for individuals with sleep disturbances and/or memory impairments.

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Art Therapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

University Of Houston Brain Study Explores Intersection Of Art And Science

The theory that the brain has a positive response to art is not new to science. But a researcher at the University of Houston is using a different approach to test that belief.

This is your brain. This is your brain on art. Any questions? 🍳🤗🎨🗝 yes in fact this raises a TON of questions!

Jennifer Schwartz

 

When I’m at an art museum, I never know what piece will catch my eye.

On this particular visit to the University of Houston’s Blaffer Art Museum, it’s an art installation by Matthew Buckingham. It consists of is a 16-millimeter film projector on a pedestal, projecting a flickering black and white image of the numbers “1720” on a small screen suspended in mid-air. The music coming from the projector is a baroque flute sonata by Bach.

Picture of Matthew Buckingham's "1720"

Matthew Buckingham’s exhibit, “1720” (2009) is a continuous 16 mm film projection of the date on a suspended screen. A movement from Bach’s Sonata in G for Flute and Continuo plays as the soundtrack accompanied by the flickering sound of the film reel.

http://www.houstonpublicmedia.org/wp-content/uploads/2016/01/15141909/BRAIN-ON-ART-FEATURE-MP3.mp3

http://www.houstonpublicmedia.org/articles/news/2016/01/20/134348/university-of-houston-brain-study-explores-intersection-of-art-and-science/

 

So, if someone could look into my head at this moment and see what’s going on in my brain, would they be able to see that I like what I’m looking at?

Dr. Jose Luis Contreras-Vidal, (better known as “Pepe”) is in the process of finding out. The University of Houston College of Engineering professor is collecting neural data from thousands of people while they engage in creative activities, whether it’s dancing, playing music, making art, or, in my case, viewing it.

“(The hypothesis is) that there will be brain patterns associated with aesthetic preference that are recruited when you perceive art and make a judgement about art,” Contreras-Vidal says.

Last October, three local artists – Dario Robleto, JoAnn Fleischhauer, and Lily Cox-Richard – took part in an event that allowed people to watch what was going on in their brains as they created art. The process involved fitting each artist with EEG caps, which look like swim caps with 64 electrodes attached. As they worked on their pieces, a screen on the wall showed their brain activity in blots of blue and yellow.

Picture of Contreras-Vidal

Contreras-Vidal at the Blaffer’s “Your Brain on Art” event in October.     Amy Bishop | Houston Public Media

To Cox-Richard, it’s a unique chance to help bridge the worlds of art and science.

“Being able to contribute and have it be a two-way street is part of what seemed like a really excellent opportunity for all of us to push this conversation forward,” she says.

It was just one of a series of similar experiments Contreras-Vidal has launched. The project is being made possible by funding from the National Science Foundation to advance science and health by studying the brain in action. Contreras-Vidal explains that, even though art is used as a form of therapy, there’s still a mystery surrounding what’s taking place up there to make it therapeutic.

While there have already been studies showing how creativity influences the brain, this one is different. What separates it from others is the fact that the brain is being monitored outside of the lab, such as while walking through a museum, creating art in a studio, or even dancing onstage.

“It’s as real as it gets,” Contreras-Vidal says. “We are not showing you pictures inside a scanner, which is a very different environment.”

Which brings me back to that art installation of the film projector at the Blaffer. While staring at it, I wonder, “What does my brain activity look like right now?”

I decided to find out. In the second part of this story, we’ll pick up with my EEG gallery stroll, followed by a visit to Contreras-Vidal’s laboratory to get the results.

http://www.houstonpublicmedia.org/wp-content/uploads/2016/01/15173424/IMG_1276.jpg

As Houston Public Media Arts and Culture reporter, Amy Bishop spotlights Houston’s dynamic creative community. Her stories have brought national exposure to the local arts scene through NPR programs such as Here and Now.

 

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An inconvenient truth about dreams

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

It is natural to dream. Dreaming is a flashback recording of recent occurrences associated with cleaning out the memory of daily events.  There is much written in both literature and in neuroscience as I write this.  Dreaming is both natural and perhaps also adaptive, and dreams may be distressing or unintelligible in circumstances that we view as pathological.  This is thought to be related to a loss of plasticity of the memory circuits. This occurs with mood disorders, sleep disorders with and without leg movement disorder, and with schizophrenia.

The term given by Martin Luther King, “I had a dream” is out of place under the cirumstances I describe. I am identical twin with a nonidentical triplet sister.  Our brother died more than a decade ago, prematurely aged from living with schizophrenia.  I and my sister could talk to him and understand what he said, even though it meant nothing to others. What I did not share was the total fragmentation of mental thoughts at an early age.  Both I and my sister had guilt over the situation for years. I sought psychiatric assistance that went on for years.  But I was not schizophrenic and I had a successful career by any standard, but was burdened trying to make up in achievement what was denied to my immigrant father and to my identical twin brother. It was by no means easy in the 1960s for my parents to deal with the situation, with a societal lack of understanding, a feeling of what have I done wrong, and a serious cost burden.

I went to medical school, which I had decided as a child, when I read Paul de Kruif’s Microbe Hunters.
I had a sister two years older who was a “wunder” kind, who I tried to follow.  She had a GM scholarship and set the class curve as an undergraduate in a graduate course in numbers theory.  Fortunately, my best friend, who was as brilliant as they come and a Merit Scholar college entry, cautioned not to overburden myself with the chemistry/math major that I never declared. My brother entered the hospital as I entered medical school, and the first year that would be expected to be difficult, certainly was for me.

Only in the last 5 years did I learn from extensive testing that I had a very high intelligence to match my achievement , but that I had Asperger’s.  I also learned that I had an uncommon double mutation of the hydroxymethyl-folate reductase gene that is associated nonspecifically with neurological disorders. I take methyl folate for the genetic disorder to give access of folic acid to cross the blood brain barrier.
I’m retired for several years and had enormous difficulty in retiring, and was a workaholic.  Work had great meaning and rewards for me.

I am now 74 and had a difficult 3 years with illness and hospitalization for me and my spouse of 45 years.  We moved to be near my younger daughter, son-in-law, and grandson.  This has brought great satisfaction. All the same, my asthma, sleep apnea, and general condition declined, and the move was more difficult than any I previously experienced.  I have vivid dreams that requires clonipin for relief initially.

I have had increased frequency of dreams that can be resolved.  However, with my awareness of the suicide of Robin Williams, I was given an awareness of his situation beyond what one would expect who has not seen such patients or has not experienced this.  In my situation it was worsened by added depression.  In the recent events I thought for the first time how incredible it was for my brother to have experienced this much of his schizophrenic life, even though I am not schizophrenic by any measure.

What’s in a dream?

I have had dreams before that I thought were interesting because of the people who I knew and the situations, that might have been unusual and gave me an inclination to write down.  If I collected these, it could perhaps warrant a collection of stories.  Those that are very recent have suggested that the one when I entertained my grandson is worthwhile. It was not so noxious, but it does fit the pieces together.
I watched some of the reporting of election returns of republican and democratic candidates.  I sort of tossed around and played with the exceptional 6 year old who need not be exposed to such nonsence as we are seeing.  It was early evening and to finish his limited allowable screentime, Nanny and Grandpa, and grandchild watched a children,s movie before bedtime. It was … … a takeoff on Red Ridinghood, with good cartoon figures, some recognizable voices, and an interesting storyline.  Yes, LRRH does go through the woods to see her grandma, and she meets the wolf, who goes to her grandma’s house.  Her grandma is tied up in the closet, and the woodsman, in the role of Paul Bunyan, gives a visit at the time of rescue.  The storyline becomes a detective story to cull out the events leading up to a criminal event – who stole grandma’s recipe book, with a long family line of cooking.   The grandma was an Olympic skiing champ who beets out the characters who stole her cookbooks.  I’ll say no more than that the search comes upon grandma and LRRH escape with a parachute finish and the bad guys, led by a crafty rabbit, slide down on a ski-tram into a waiting police car.  So that evening I have a dream that is a cockamaimie replay in which I am driving on the highway and enter a tunnel (like the rail in the movie), and the lane is cluttered with a wolf, and other creatures, making passage quite impossible.

 

I talked to my sister who called the next day. It was terrific when she said that if I had a pad and wrote them down immediately, they would form a pattern. Again, I have a dream, and I recall there was a pattern of feeling of failure. I am on Gabapentin for the restless leg. This time I have my brother (impossible) in it, I left my coat in a conference room and can’t get it immediately, and I have to return home with an exam the next day.  In a recurring pattern, my brother is to drive.  I can’t drive because of now having a diplopia from thyroid eye disease related to Grave’s disease.  The exam has two questions about plasma from unclotted blood that is spun down and serum from clotted blood. This is very basic. The pattern is related to systemic notions of failure.  My sister had a repeated pattern of rushing to get to the classes she teaches and not getting there on time (consistent with her rush rush).

I go back to bed and get another few hours of sleep. We had watched a number of Miss Marple movies recently.  In the move I had the stressful experience of going through 40 years of save photographic equipment and photography, research literature, computer stuff, ya da, ya da, ya da.   Very thorough, and tiring.  The old lady in RRH and Miss Marple were merged into a character in a story related to the corroded pipes in Flint, and a criminal search for the cause of this problem (having watched the debate). Incredibly, this character was going through the material so rapidly, uncovering clues, and I was amazed.
I was struggling to keep up.  Then I woke up. So my spouses assurances were correct.  This is actually normal dreaming.

It is disturbing, consistent with a recent New York Times article on how the brain cleans out the garbage.  I have too much garbage.  My medication does have to be adjusted.  It is perhaps not the same as my late brother’s experience. My sister’s observations have been helpful.  My brother’s dreams were recognizable to me, but not to others, but they also had patterns, but patterns that were more distorted.  If mine have been “normal”, but more frequent, this suggests a failure in the brain’s plasticity as I am aging, perhaps from from the stress in a major move.  It is perhaps to be viewed as distressing at best compared with the worst case (my brother, or Robin Williams).

This is substantiated by my remembrance of driving on Woodward avenue or the expressway in Detroit, Michigan. I grew up on 2967 Sturtevant off of Dexter Ave. My elementary school no longer exists. We moved to the Northwest section and I graduated from Mumford High School in 1961.  I lived in Trumbull, adjacent to Bridgeport, CT for 33 years, where my children grew up.  The bizarreness of my recurring dream pattern has to do with a repeated driving and confusion between Detroit and Connecticut.  I drove from Connecticut to New York for the last five years before retirement, but I failed to record these experiences.  I had two car accidents related to narcolepsy in asbout 7 years related to my sleep apnea prior to getting it treated. In the last, I went to New Jersey to see an associate and driving back to Trumbull I veered off the highway and managed to veer into a tree in the snow. Fortunately I was able to control the car at the last minute.  Fortunately, this could be much worse.

 

 

 

 

 

 

 

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Alzheimer’s Disease – tau art thou, or amyloid

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Alzheimer’s Disease and Tau  

http://www.nyas.org/Publications/Ebriefings/Detail.aspx

Pathogenic Mechanisms and Therapeutic Approaches

Organizers: Robert Martone (St. Jude Children’s Research Hospital) and Sonya Dougal (The New York Academy of Sciences)Presented by the Brain Dysfunction Discussion Group

Reported by Caitlin McOmish | Posted February 2, 2016

 

http://www.nyas.org/image.axd?id=7391dacc-ddda-4b9a-ad45-06a05953b756&t=635690168670270000

 

Microtubule-associated protein tau helps maintain the stability and flexibility of microtubules in neuronal axons. Alternative splicing of the tau gene, MAPT, produces 6 isoforms of tau in the brain and many more in the peripheral nervous system. Tau can be phosphorylated at over 30 sites, and it undergoes many posttranslational modifications to operate as a substrate for multiple enzymes. However, tau also mediates pathological functions including neuroinflammatory response, seizure, and amyloid-β (Aβ) toxicity, and tau pathology is a hallmark of conditions including frontotemporal dementia, traumatic brain injury (TBI), Down syndrome, focal cortical dysplasia, and Alzheimer’s disease (AD), as well as some tumors and infections. On September 18, 2015, speakers at the Brain Dysfunction Discussion Group’s Alzheimer’s Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches symposium discussed the mechanisms by which tau becomes pathological and how the pathology spreads. They also described emerging therapeutic strategies for AD focused on tau.

 

http://www.nyas.org/image.axd?id=4a8bd710-d75a-4655-8bee-ef48fac6a783&t=635888888349400000

Microtubule-associated protein tau has a complex biology, including multiple splice variants and phosphorylation sites. Tau is a key component of microtubules, which contribute to neuronal stability. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles. (Image presented by Robert Martone courtesy of the National Institute on Aging)

 

Tau is ubiquitous in the brain, with widespread effects, but has historically been overlooked as a driving force in AD. In his introduction to the symposium, Robert Martone from St. Jude Children’s Research Hospital highlighted tau’s activity and emergence as a treatment target for this devastating disorder. Hyperphosphorylated tau (p-tau) has long been recognized as a principle component of neurofibrillary tangles in AD; tau monomers are misfolded into oligomers that form tau filaments. As Hartmuth Kolb from Johnson & Johnson explained, the development in 2012 of a tau-specific positron emission tomography (PET) tracer led to important insights into the presence and spread of tau pathology over the course of tauopathies, including AD, in humans. Notably, researchers demonstrated that tau pathology propagates through the brain in a predictable pattern, corresponding to the Braak stages of AD.

http://www.nyas.org/image.axd?id=16b77dfd-391b-4495-913f-95a2fba38458&t=635888888240470000

Tau pathology spreads through the brain in a predictable pattern. Abnormal tau protein is first observed in the transentorhinal region (stages I and II) and spreads to the limbic regions in stages III and IV, when early signs of AD begin to be observed. Pathology subsequently extends throughout the neocortex, driving fully developed AD. This staging was first described by Braak and Braak in 1991. (Image courtesy of Hartmuth Kolb)

 

It is likely that the symptoms of AD are produced by the combined effects of tau and Aβ pathologies. George Bloom from the University of Virginia described how Aβ and tau interact to cause mature neurons to reenter the cell cycle, leading to cell death. In a healthy brain, insulin acts as a gatekeeper that maintains adult neurons in the G0 phase after the cells permanently exit the cell cycle. In AD, amyloid oligomers sequester neuronal insulin receptors, causing insulin resistance. In parallel, tau phosphorylation at key sites—pY18 (fyn site), pS409 (PKA site), pS416 (CAM Kinase site), and pS262—drives mTOR signaling at the plasma membrane but not at the lysosome, resulting in cell cycle reentry. In a normal cell, activation of mTOR at the lysosome overrides the cell cycle reentry signal—creating an important regulatory mechanism for maintaining healthy neurons. However, lysosomal activation of mTOR is insulin dependent and thus affected by Aβ-induced insulin insensitivity. Amyloid oligomers, via insulin regulation, release the brakes on a cascade of events driven by p-tau that leads to cell cycle reentry and cell death.

http://www.nyas.org/image.axd?id=35ed7190-cb27-4bed-bc0d-1fa27091e733&t=635888888067800000

Hallmark dysfunction produced by Aβ is dependent on tau. Pathological Aβ drives the formation of p-tau in the brain, resulting in synaptic dysfunction, cell death, and broad neurocognitive symptoms. This process can be influenced by a range of factors including genetic predisposition, environmental risk factors, and biochemical signaling pathways. (Image courtesy of George Bloom)

 

Khalid Iqbal from the New York State Institute for Basic Research in Developmental Disabilities described research showing that p-tau spreads through the brain in a rodent model, well beyond the injection site, in a prion-like manner, and that the spread of pathology can be mitigated by the addition of PP2A—a phosphatase known to be decreased in gray and white matter in AD. PP2A regulation is affected in AD, stroke, and brain acidosis, providing a link between these disorders and tau pathology.

Discussion of the pathophysiology of AD commonly focuses on Aβ plaques and neurofibrillary tangles (NFTs) composed of misassembled hyperphosphorylated tau; it has generally been thought that these plaques and tangles are the primary causes of symptoms. However, recent evidence indicates that oligomeric variants of tau are actually far more toxic than the form of tau present in NFTs. Michael Hutton from Eli Lilly and Company studies the properties needed for tau to become pathological. He used animal models to show that the abnormal p-tau “seed,” from which a prion-like spread develops, must be of a high molecular weight (with at minimum three tau units) and highly phosphorylated to induce healthy tau to become pathological. These characteristics are necessary but not sufficient for effective seeding. There is also evidence that tau pathology propagates via an autocatalytic cycle of seeded aggregation and fragmentation.

Propagation, in addition to requiring a large number of p-tau units in aggregates, may be affected by the isomerization of those monomers. Kun Ping Lu from Harvard Medical School provided data suggesting that cis but not trans pT231-tau is a precursor of tauopathy, linking TBI to the later development of neurodegenerative diseases such as chronic traumatic encephalopathy and AD. He demonstrated a role for Pin1, a phosphorylation-specific prolyl isomerase, in this process using animal models of TBI and AD. Pin1, which is regulated in response to stress, prevents the accumulation of toxic cis p-tau by converting it to the trans isoform, but this process is inhibited in AD and TBI. Lu showed that cis p-tau’s ability to cause and spread neurodegeneration can be blocked by a cis p-tau monoclonal antibody in vitro and in animal models, pointing to the therapeutic potential of targetingcis p-tau for treatment of TBI and AD.

Culturing p-tau seeds in vitro produces a broad array of tau aggregate structures. Marc Diamond from the University of Texas Southwestern Medical Center discussed the diverse structures produced by different tau seeds, which his team has studied in a series of experiments using in vitro models, animal models, and human postmortem analyses. His lab showed that distinct conformations of aggregate seeds propagate stably, infecting normal cells and leading them to acquire abnormal tau aggregates with distinct, reproducible structures and different biochemical properties. In another study, the team showed that the morphology of the p-tau aggregates was related to diagnosis. Seeds sourced from postmortem human tissue produced reliable phenotypes in culture, which tracked with different diagnoses, retroactively predicting biological outcome. Thus, the characteristics of the p-tau seed have a large influence on the biological outcome, providing a new prospect for presymptomatic diagnosis.

 

 

http://www.nyas.org/image.axd?id=53f0c661-b6ca-4366-b289-a610fa12572f&t=635888888166270000

Tau seeds obtained from postmortem brain tissue from AD, argyrophilic grain disease (AGD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP) produce unique aggregate pathologies in cell culture, including toxic, mosaic, ordered, disordered, and speckled. AD-derived seeds largely produce the speckled phenotype. (Images courtesy of Marc Diamond)

 

With the mechanisms by which p-tau forms, converts healthy tau, and seeds dysfunction established, the question of how p-tau exits the cell and moves through the brain arises. The pattern of spread and the speed with which the pathology progresses suggests that p-tau propagates trans-synaptically. Nicole Leclerc from the University of Montreal provided evidence to support this view. It is likely, her lab has shown, that tau is secreted and taken up by neurons in an active process, in response to neuronal activity. Tau secretion in vitro increases under conditions such as starvation and lysosomal dysfunction, phenomena found in the early stages of AD. Moreover, hyperphosphorylation appears to increase the targeting of tau to the secretory pathway, potentially accelerating the spread of p-tau. Intriguingly, however, the extracellular tau is hypophosphorylated, suggesting large-scale dephosphorylation during the secretory process. This hypo-tau may activate muscarinic acetylcholine receptors, increasing intracellular Ca2+ and promoting cell death.

These findings suggest that the synapse plays a critical role in the development of AD; the extrasynaptic environment is known to be exquisitely regulated by microglia. The focus of studies into neurodegenerative disorders is often neurons, but genetic studies have repeatedly identified changes in expression of microglial genes in AD, including in one of the leading AD candidate genes, TREM2, demonstrating a fundamental contribution of these cells to AD. Richard Ransohoff of Biogen discussed the importance of this cell type. Microglia enter the brain at around embryonic day (E) 9.5 in rodents and are crucially involved in maintaining brain health. During development the cells play a major role in large-scale synaptic pruning required for effective neural maturation. They are also highly responsive to the environment, and stress in adulthood can reengage microglial synaptic pruning—a process that is adaptive during development but maladaptive in adulthood. The process is regulated by complement system cascades. TGF-β expressed by astrocytes drives neurons to express C1q presynaptically, initiating complement elements to accumulate at the site, ultimately activating microglia to prune the synaptic connection. In AD, inappropriate activation of this cascade may lead to the removal of otherwise healthy connections. Ransohoff described a role for CXCR3, the fractalkine receptor, in regulating reactivity of microglia, and thus mitigating pruning of adult synapses. Regulation of microglia reactivity is driven by epigenetically induced changes in inflammatory response genes. Correspondingly, in the absence of CXCR3, tau pathology is aggravated in htau mice (which express human tau isoforms), suggesting a protective effect of the CXCR3 pathway. Ransohoff closed with the caveat that microglia are not intrinsically helpful or harmful; their properties are context dependent and must be unraveled by empirical observations in appropriate models.

Peter Davies from the Feinstein Institute for Medical Research discussed the need to better incorporate current knowledge into research model design, particularly to develop monoclonal antibodies for the treatment of AD. Monoclonal antibodies are a promising strategy, but translating preclinical findings into successful clinical outcomes will require careful consideration of the context of the early research. Most transgenic animal models for AD express p-tau in all neurons, but such extensive p-tau spread is not found in human AD brains. There are several hurdles to determine the drugs’ efficacy and safety in humans; it is difficult to assess specificity and find appropriate dosages. In a series of studies with a focus on external reproducibility, Davies presented evidence from animal models showing that immunotherapy can block the spread of p-tau but cannot undo pathology already present in the brain. In the htau mouse model several putative antibodies lacked efficacy and in some cases appeared to worsen pathology. These findings underscore the need for both better models and improved understanding of mechanisms of action before moving drugs to the clinic.

 

The New York Academy of Sciences. Alzheimer’s Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches. Academy eBriefings. 2015. Available at: www.nyas.org/Tau2015-eB

 

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brain implants without wires

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Powering brain implants without wires with thin-film wireless power transmission system

Avoids risk of infections through skull opening and leakage of cerebrospinal fluid, and allows for free-moving subjects and more flexible uses of brain-computer interfaces
February 8, 2016

http://www.kurzweilai.net/powering-brain-implants-without-wires-with-thin-film-wireless-power-transmission-system

 

Schematic of proposed architecture of an implantable wireless-powered neural interface system that can provide power to implanted devices. Adding a transmitter chip could allow for neural signals to be transmitted via the antenna for external processing. (credit: Toyohashi University Of Technology)

 

A research team at Toyohashi University of Technology in Japan has fabricated an implanted wireless power transmission (WPT) device to deliver power to an implanted neural interface system, such as a brain-computer interface (BCI) device.

Described in an open-access paper in Sensors journal, the system avoids having to connect an implanted device to an external power source via wires through a hole in the skull, which can cause infections through the opening and risk of infection and leakage of the cerebrospinal fluid during long-term measurement. The system also allows for free-moving subjects, allowing for more natural behavior in experiments.

 

Photographs of fabricated flexible antenna and bonded CMOS rectifier chip with RF transformer (credit: Kenji Okabe et al./Sensors)

 

The researchers used a wafer-level packaging technique to integrate a silicon large-scale integration (LSI) chip in a thin (5 micrometers), flexible parylene film, using flip-chip (face-down) bonding to the film. The system includes a thin-film antenna and a rectifier to convert a radio-frequency signal to DC voltage (similar to how an RFID chip works). The entire system measures 27 mm × 5 mm, and the flexible film can conform to the surface of the brain.

 

http://www.kurzweilai.net/images/Warwick-turns-on-light.jpg

Coventry University prof. Kevin Warwick turns on a light with a double-click of his finger, which triggers an implant in his arm (wired to a computer connected to the light). Adding an RF transmitter chip (and associated processing) to the Toyohashi system could similarly allow for controlling devices, but without wires. (credit: Kevin Warwick/element14)

 

The researchers plan to integrate additional functions, including amplifiers, analog-to-digital converters, signal processors, and  a radio frequency circuit for transmitting (and receiving) data.

Tethered Braingate brain-computer interface for paralyzed patients (credit: Brown University)

 

Such a system could perform some of the functions of the Braingate system, which allows paralyzed patients to communicate (see “People with paralysis control robotic arms using brain-computer interface“).

This work is partially supported by Grants-in-Aid for Scientific Research, Young Scientists, and the Japan Society for the Promotion of Science.

https://youtu.be/LW6tcuBJ6-w

element14 | Kevin Warwick’s BrainGate Implant

 

Abstract of Co-Design Method and Wafer-Level Packaging Technique of Thin-Film Flexible Antenna and Silicon CMOS Rectifier Chips for Wireless-Powered Neural Interface Systems

In this paper, a co-design method and a wafer-level packaging technique of a flexible antenna and a CMOS rectifier chip for use in a small-sized implantable system on the brain surface are proposed. The proposed co-design method optimizes the system architecture, and can help avoid the use of external matching components, resulting in the realization of a small-size system. In addition, the technique employed to assemble a silicon large-scale integration (LSI) chip on the very thin parylene film (5 μm) enables the integration of the rectifier circuits and the flexible antenna (rectenna). In the demonstration of wireless power transmission (WPT), the fabricated flexible rectenna achieved a maximum efficiency of 0.497% with a distance of 3 cm between antennas. In addition, WPT with radio waves allows a misalignment of 185% against antenna size, implying that the misalignment has a less effect on the WPT characteristics compared with electromagnetic induction.

 

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What a brain is this?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

New cryopreservation procedure wins Brain Preservation Prize

First preservation of the connectome demonstrated in a whole brain
February 9, 2016

http://www.kurzweilai.net/new-cryopreservation-procedure-wins-brain-preservation-prize

 

(Left): Control rabbit brain, showing neuropil near the CA1 band in the hippocampus. (Right): Vitrified rabbit brain, same location. Synapses, vesicles, and microfilaments are clear. The myelinated axon shows excellent preservation. (credit: Robert L. McIntyre and Gregory M. Fahy/Cryobiology)

 

The Brain Preservation Foundation (BPF) has announced that a team at 21st Century Medicine led by Robert McIntyre, PhD., has won the Small Mammal Brain Preservation Prize, which carries an award of $26,735.

The Small Mammalian Brain Preservation Prize was awarded after the determination that the protocol developed by McIntyre, termed Aldehyde-Stabilized Cryopreservation, was able to preserve an entire rabbit brain with well-preserved ultrastructure, including cell membranes, synapses, and intracellular structures such as synaptic vesicles (full protocol here).

The judges for the prize were Kenneth Hayworth, PhD., Brain Preservation Foundation President and neuroscientist at the Howard Hughes Medical Institute; and Prof. Sebastian Seung, PhD., Princeton Neuroscience Institute and Computer Science Department.

First preservation of the connectome

“This is a milestone in the development of brain preservation techniques: it is the first time that the preservation of the connectome has been demonstrated in a whole brain (prior to this only small parts of brains have been preserved to this level of detail),” said the BPF announcement.

“Current models of the brain suggest that the connectome contains all the information necessary for personal identity (i.e., memory and personality). This technique is not the same as conventional cryonics (rapidly freezing the brain), which has never demonstrated preservation of the ultrastructure of the brain. Thus the winning of this prize represents a significant advance in the methods available for large scale studies of the connectome and could lead to procedures that preserve a complete human brain.

Kenneth Hayworth (KH) (President of the Brain Preservation Foundation (BPF)) and Michael Shermer (member of BPF advisory board) witnessed (on Sept. 25, 2015) the full Aldehyde Stabilized Cryopreservation surgical procedure performed on this rabbit at the laboratories of 21 Century Medicine under the direction of 21CM lead researcher Robert McIntyre. This included the live rabbit’s carotid arteries being perfused with glutaraldehyde and subsequent perfusion with cryoprotectant agent (CPA). KH witnessed this rabbit brain being put in -135 degrees C storage, removal from storage the following day (verifying that it had vitrified solid), and KH witnessed all subsequent tissue processing steps involved in the evaluation process. (credit: The Brain Preservation Foundation)

“The key breakthrough was the rapid perfusion of a deadly chemical fixative (glutaraldehyde) through the brain’s vascular system, instantly stopping metabolic decay and fixing all proteins in place by covalent crosslinks. This stabilized the tissue and vasculature so that cryoprotectant could be perfused at an optimal temperature and rate. The result was an intact rabbit brain filled with such a high concentration of cryoprotectants that it could be stored as a solid ‘vitrified’ block at a temperature of ­-135 degrees Celsius.”

Winning the award also required that the procedure be published in a peer reviewed scientific publication. McIntyre satisfied this requirement and published the protocol in an open-access paper in the Journal of Cryobiology.

 

3D microscope evaluation of the rabbit brain tissue preservation (credit: Brain Preservation Foundation)

 

The Brain Preservation Foundation plans to continue to promote the idea that brain preservation following legal death, by using scientifically validated techniques, is a reasonable choice for consenting individuals to make. Focus now shifts to the final Large Mammal phase of the contest, which requires an intact pig brain to be preserved with similar fidelity in a manner that could be directly adapted to terminal patients in a hospital setting.

The 21st Century Medicine team has recently submitted to the BPF such a preserved pig brain for official evaluation. Lead researcher Robert McIntyre has started Nectome to further develop this method.

“Of course, [the demonstrated brain preservation procedure] is only useful if you think all the relevant information is preserved in the fixation,” said Anders Sandberg, PhD., of the Future of Humanity Institute/Oxford Martin School. “Protein states and small molecule chemical information may be messed up.”

https://youtu.be/l-VpUOQ3Ihg

GPA | Will You Preserve Your Brain?

 

Background and significance (statement by BPF)

Proponents of cryonics have long sought a technique that could put terminal patients into long­term stasis, the goal being a form of medical time travel in which patients are stabilized against decay with the hope of being biologically revived and cured by future technologies. Despite decades of research, this goal of reversible cryopreservation remains far out of reach — too much damage occurs during the cryopreservation itself.

This has led a new generation of researchers to focus on a more achievable and demonstrable goal–preservation of brain structure only. Specifically preservation of the delicate pattern of synaptic connections (the “connectome”) which neuroscience contends encodes a person’s memory and identity. Instead of biological revival, these new researchers often envision a future “synthetic revival” comprising nanometer-­scale scanning of the preserved brain to serve as the basis for mind uploading.

This shift in focus toward “synthetic” revival has completely transformed the cryonics debate, opening up new avenues of research and bringing it squarely within the purview of today’s scientific investigation. Hundreds of neuroscience papers have detailed how memory and personality are encoded structurally in synaptic connections, and recent advances in connectome imaging and brain simulation can be seen as a preview of the synthetic revival technologies to come.

Until now, the crucial unanswered questions were “How well does cryonics preserve the brain’s connectome?” and “Are there alternatives/modifications to cryonics that might preserve the connectome better and in a manner that could be demonstrated today?” The Brain Preservation Prize was put forward in 2010 to spur research that could definitively answer these questions. Now, five years later, these questions have been answered: Traditional cryonics procedures were not able to demonstrate (to the BPF’s satisfaction) preservation of the connectome, but the newly invented “Aldehyde­-Stabilized Cryopreservation” technique was.

This result directly answers what has for decades been the main skeptical and scientific criticism against cryonics –that it does not provably preserve the delicate synaptic circuitry of the brain. As such, this research sets the stage for renewed interest within the scientific community, and offers a potential challenge to medical researchers to develop a human surgical procedure based on these successful animal experiments.

 

Abstract of Aldehyde-stabilized cryopreservation

We describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. ASC is a new brain-banking technique designed to facilitate neuroanatomic research such as connectomics research, and has the unique ability to combine stable long term ice-free sample storage with excellent anatomical resolution. To demonstrate the feasibility of ASC, we perfuse-fixed rabbit and pig brains with a glutaraldehyde-based fixative, then slowly perfused increasing concentrations of ethylene glycol over several hours in a manner similar to techniques used for whole organ cryopreservation. Once 65% w/v ethylene glycol was reached, we vitrified brains at −135 °C for indefinite long-term storage. Vitrified brains were rewarmed and the cryoprotectant removed either by perfusion or gradual diffusion from brain slices. We evaluated ASC-processed brains by electron microscopy of multiple regions across the whole brain and by Focused Ion Beam Milling and Scanning Electron Microscopy (FIB-SEM) imaging of selected brain volumes. Preservation was uniformly excellent: processes were easily traceable and synapses were crisp in both species. Aldehyde-stabilized cryopreservation has many advantages over other brain-banking techniques: chemicals are delivered via perfusion, which enables easy scaling to brains of any size; vitrification ensures that the ultrastructure of the brain will not degrade even over very long storage times; and the cryoprotectant can be removed, yielding a perfusable aldehyde-preserved brain which is suitable for a wide variety of brain assays.

Comments

Ion Christopher –

Totally weird – IOW those “covalent bonds” act like a preservation matrix. So this brain indeed has been “fixed” – just at a smaller scale and level.

A couple of other factors:

* Quite a lot of the brain that counts (memory) may be on a larger scale than this – and may be preserved. While it is not, per the Connetome idea, at the macro axon scale – it is a general idea that at the molecular scale, something “plays” through the consciousness mechanism (Search = Hameroff Memory.)
I personally suspect a DNA like encoding in an as yet unproven language software. Perhaps even multiple “scale” functionality that would be a combination of organelle specialization (perhaps time perception) and THEN the inter-connectedness.

* As for personality, I know that that is entirely reproducible – in spite of such extreme complexity – but that is a proof for another day.

Just for kicks, note how the “search” code above results in prefabricated libraries being sent to your mind.

 

Gorden Russell –

You had me until I got to this part: “…a deadly chemical fixative (glutaraldehyde) through the brain’s vascular system…”

So this process perfectly preserves your brain after killer it dead.

So in the future it can be scanned and printed out into a perfect copy — but the copy won’t be you, it’ll be somebody else who is just like you. You will still be dead.

I’d rather be a live brain in a jar atop a robot wired into the spinal column so that I could still have all of my senses while awaiting the time a human body can be regrown.

 

CT

We have to differentiate on how we define “me” or “you”. Do we mean our memories (data) or consciousness (process). Our memories, personality, knowledge… alone (e.g. while we sleep and are unconscious)… are like fixed data until the brain (or a computer) begins to run and consciousness comes into existence .
We could copy the data to a computer (through scanning), which in the next step (after the simulation is beginning to operate) would create consciousness as well (defining itself as “me” or “you”). It wouldn’t be the same consciousness (process) due to other environmental inputs (and over time other memory/data- background). But the same is true for a biological based consciousness. My consciousness right now is not the consciousness anymore I had last year. It’s always a unique set-up.
From my point of view, the sentiment that there is some kind of metaphysical soul over an entire lifetime is an illusion based on the fact that we have memories, knowledge and personality (which we would have after the scanning process of our brain as well), that were formed in the past, and we are able to (subjectively altered) recreate it (and remember it) in our current state of consciousness. As a result we conclude, that we are/ have the same state of consciousness as the past me, which is (as I see it) an illusion.
So if we would be able to make a perfect copy of our brain that is able to create consciousness (in any kind of computer substrate, digital, analog or quantum) it wouldn’t be more or less the me (the consciousness) at the present than my future me in 5 minutes or years would be (in its biological form). From my point of view, the status quo wouldn’t change.

 

It is a copy because maybe one day they can do it without killing the original. The only way out of this conundrum was explained to me on this web site a while back in comments: if they substituted every neuron in my brain one at a time over a certain timescale so that eventually my brain would be synthetic, ‘”I” probably wouldn’t even notice.

 

But you are dreaming during your sleep.

Glutaraldehyde will put an end to all of your dreams.

A printed copy of you may have similar dreams, but not your dreams.

 

 

 

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