New study links brain waves directly to memory

Neurons produce rhythmic patterns of electrical activity in the brain. One of the unsettled questions in the field of neuroscience is what primarily drives these rhythmic signals, called oscillations. University of Arizona researchers have found that simply remembering events can trigger them, even more so than when people are experiencing the actual event.

The researchers, whose findings are published in the journal Neuron, specifically focused on what are known as theta oscillations, which emerge in the brain's hippocampus region during activities like exploration, navigation and sleep. The hippocampus plays a crucial role in the brain's ability to remember the past.

Prior to this study, it was believed that the external environment played a more important role in driving theta oscillations, said Arne Ekstrom, professor of cognition and neural systems in the UArizona Department of Psychology and senior author of the study. But Ekstrom and his collaborators found that memory generated in the brain is the main driver of theta activity.

"Surprisingly, we found that theta oscillations in humans are more prevalent when someone is just remembering things, compared to experiencing events directly," said lead study author Sarah Seger, a graduate student in the Department of Neuroscience.

The results of the study could have implications for treating patients with brain damage and cognitive impairments, including patients who have experienced seizures, stroke and Parkinson's disease, Ekstrom said. Memory could be used to create stimulations from within the brain and drive theta oscillations, which could potentially lead to improvements in memory over time, he said.

UArizona researchers collaborated on the study with researchers from the University of Texas Southwestern Medical Center in Dallas, including neurosurgeon Dr. Brad Lega and research technician Jennifer Kriegel. The researchers recruited 13 patients who were being monitored at the center in preparation for epilepsy surgery. As part of the monitoring, electrodes were implanted in the patients' brains for detecting occasional seizures. The researchers recorded the theta oscillations in the hippocampus of the brain.

The patients participated in a virtual reality experiment, in which they were given a joystick to navigate to shops in a virtual city on a computer. When they arrived at the correct destination, the virtual reality experiment was paused. The researchers asked the participants to imagine the location at which they started their navigation and instructed them to mentally navigate the route they just passed through. The researchers then compared theta oscillations during initial navigation to participants' subsequent recollection of the route.

During the actual navigation process using the joystick, the oscillations were less frequent and shorter in duration compared to oscillations that occurred when participants were just imagining the route. So, the researchers conclude that memory is a strong driver of theta oscillations in humans.

One way to compensate for impaired cognitive function is by using cognitive training and rehabilitation, Ekstrom said.

"Basically, you take a patient who has memory impairments, and you try to teach them to be better at memory," he said.

In the future, Ekstrom is planning to conduct this research in freely walking patients as opposed to patients in beds and find how freely navigating compares to memory with regard to brain oscillations.

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Human brain cells in a dish learn to play Pong in real time

Human and mouse neurons in a dish learned to play the video game Pong, researchers report October 12 in the journal Neuron. The experiments are evidence that even brain cells in a dish can exhibit inherent intelligence, modifying their behavior over time.

"From worms to flies to humans, neurons are the starting block for generalized intelligence," says first author Brett Kagan (@ANeuroExplorer), chief scientific officer at Cortical Labs in Melbourne, Australia. "So, the question was, can we interact with neurons in a way to harness that inherent intelligence?"

To start, the researchers connected the neurons to a computer in such a way where the neurons received feedback on whether their in-game paddle was hitting the ball. They monitored the neuron's activity and responses to this feedback using electric probes that recorded "spikes" on a grid.

The spikes got stronger the more a neuron moved its paddle and hit the ball. When neurons missed, their playstyle was critiqued by a software program created by Cortical Labs. This demonstrated that the neurons could adapt activity to a changing environment, in a goal-oriented way, in real time.

"We chose Pong due to its simplicity and familiarity, but, also, it was one of the first games used in machine learning, so we wanted to recognize that," says Kagan, who worked with collaborators from 10 other institutions on the project.

"An unpredictable stimulus was applied to the cells, and the system as a whole would reorganize its activity to better play the game and to minimize having a random response," he says. "You can also think that just playing the game, hitting the ball and getting predictable stimulation, is inherently creating more predictable environments."

The theory behind this learning is rooted in the free-energy principle. Simply put, the brain adapts to its environment by changing either its world view or its actions to better fit the world around it.

Pong wasn't the only game the research team tested. "You know when the Google Chrome browser crashes and you get that dinosaur that you can make jump over obstacles (Project Bolan). We've done that and we've seen some nice preliminary results, but we still have more work to do building new environments for custom purposes," says Kagan.

Future directions of this work have potential in disease modeling, drug discoveries, and expanding the current understanding of how the brain works and how intelligence arises.

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Modern humans generate more brain neurons than Neanderthals

The question of what makes modern humans unique has long been a driving force for researchers. Comparisons with our closest relatives, the Neanderthals, therefore provide fascinating insights. The increase in brain size, and in neuron production during brain development, are considered to be major factors for the increased cognitive abilities that occurred during human evolution. However, while both Neanderthals and modern humans develop brains of similar size, very little is known about whether modern human and Neanderthal brains may have differed in terms of their neuron production during development.

Researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden now show that the modern human variant of the protein TKTL1, which differs by only a single amino acid from the Neanderthal variant, increases one type of brain progenitor cells, called basal radial glia, in the modern human brain. Basal radial glial cells generate the majority of the neurons in the developing neocortex, a part of the brain that is crucial for many cognitive abilities. As TKTL1 activity is particularly high in the frontal lobe of the fetal human brain, the researchers conclude that this single human-specific amino acid substitution in TKTL1 underlies a greater neuron production in the developing frontal lobe of the neocortex in modern humans than Neanderthals.

Only a small number of proteins have differences in the sequence of their amino acids -- the building blocks of proteins -- between modern humans and our extinct relatives, the Neanderthals and Denisovans. The biological significance of these differences for the development of the modern human brain is largely unknown. In fact, both, modern humans and Neanderthals, feature a brain, and notably a neocortex, of similar size, but whether this similar neocortex size implies a similar number of neurons remains unclear. The latest study of the research group of Wieland Huttner, one of the founding directors of the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, carried out in collaboration with Svante Pääbo, director at the Max Planck Institute for Evolutionary Anthropology in Leipzig, and Pauline Wimberger of the University Hospital Dresden and their colleagues, addresses just this question. The researchers focus on one of these proteins that presents a single amino acid change in essentially all modern humans compared to Neanderthals, the protein transketolase-like 1 (TKTL1). Specifically, in modern humans TKTL1 contains an arginine at the sequence position in question, whereas in Neanderthal TKTL1 it is the related amino acid lysine. In the fetal human neocortex, TKTL1 is found in neocortical progenitor cells, the cells from which all cortical neurons derive. Notably, the level of TKTL1 is highest in the progenitor cells of the frontal lobe.

Modern human TKTL1, but not Neanderthal TKTL1, leads to more neurons in embryonic mouse neocortex

Anneline Pinson, the lead author of the study and researcher in the group of Wieland Huttner, set out to investigate the significance of this one amino acid change for neocortex development. Anneline and her colleagues introduced either the modern human or the Neanderthal variant of TKTL1 into the neocortex of mouse embryos. They observed that basal radial glial cells, the type of neocortical progenitors thought to be the driving force for a bigger brain, increased with the modern human variant of TKTL1 but not with the Neanderthal variant. As a consequence, the brains of mouse embryos with the modern human TKTL1 contained more neurons.

More neurons in the frontal lobe of modern humans

After this, the researchers explored the relevance of these effects for human brain development. To this end, they replaced the arginine in modern human TKTL1 with the lysine characteristic of Neanderthal TKTL1, using human brain organoids -- miniature organ-like structures that can be grown from human stem cells in cell culture dishes in the lab and that mimic aspects of early human brain development. "We found that with the Neanderthal-type of amino acid in TKTL1, fewer basal radial glial cells were produced than with the modern human-type and, as a consequence, also fewer neurons," says Anneline Pinson. "This shows us that even though we do not know how many neurons the Neanderthal brain had, we can assume that modern humans have more neurons in the frontal lobe of the brain, where TKTL1 activity is highest, than Neanderthals." The researchers also found that modern human TKTL1 acts through changes in metabolism, specifically a stimulation of the pentose phosphate pathway followed by increased fatty acid synthesis. In this way, modern human TKTL1 is thought to increase the synthesis of certain membrane lipids needed to generate the long process of basal radial glial cells that stimulates their proliferation and, therefore, to increase neuron production.

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