Carpe Diem

Sleep is vital to associating emotion with memory

When you slip into sleep, it’s easy to imagine that your brain shuts down, but University of Michigan research suggests that groups of neurons activated during prior learning keep humming, tattooing memories into your brain.

U-M researchers have been studying how memories associated with a specific sensory event are formed and stored in mice. In a study conducted prior to the coronavirus pandemic and recently published in Nature Communications, the researchers examined how a fearful memory formed in relation to a specific visual stimulus.

They found that not only did the neurons activated by the visual stimulus keep more active during subsequent sleep, sleep is vital to their ability to connect the fear memory to the sensory event.

Previous research has shown that regions of the brain that are highly active during intensive learning tend to show more activity during subsequent sleep. But what was unclear was whether this “reactivation” of memories during sleep needs to occur in order to fully store the memory of newly learned material.

“Part of what we wanted to understand was whether there is communication between parts of the brain that are mediating the fear memory and the specific neurons mediating the sensory memory that the fear is being tied to. How do they talk together, and must they do so during sleep? We would really like to know what’s facilitating that process of making a new association, like a particular set of neurons, or a particular stage of sleep,” said Sara Aton, senior author of the study and a professor in the U-M Department of Molecular, Cellular and Developmental Biology. “But for the longest time, there was really no way to test this experimentally.”

Now, researchers have the tools to genetically tag cells that are activated by an experience during a specific window of time. Focusing on a specific set of neurons in the primary visual cortex, Aton and the study’s lead author, graduate student Brittany Clawson, created a visual memory test. They showed a group of mice a neutral image, and expressed genes in the visual cortex neurons activated by the image.

To verify that these neurons registered the neutral image, Aton and her team tested whether they could instigate the memory of the image stimulus by selectively activating the neurons without showing them the image. When they activated the neurons and paired that activation with a mild foot shock, they found that their subjects would subsequently be afraid of visual stimuli that looked similar to the image those cells encode. They found the reverse also to be true: after pairing the visual stimulus with a foot shock, their subjects would subsequently respond with fear to reactivating the neurons.

“Basically, the precept of the visual stimulus and the precept of this completely artificial activation of the neurons generated the same response,” Aton said.

The researchers found that when they disrupted sleep after they showed the subjects an image and had given them a mild foot shock, there was no fear associated with the visual stimulus. Those with unmanipulated sleep learned to fear the specific visual stimulus that had been paired with the foot shock.

“We found that these mice actually became afraid of every visual stimulus we showed them,” Aton said. “From the time they go to the chamber where the visual stimuli are presented, they seem to know there’s a reason to feel fear, but they don’t know what specifically they’re afraid of.”

This likely shows that, in order for them to make an accurate fear association with a visual stimulus, they have to have sleep-associated reactivation of the neurons encoding that stimulus in the sensory cortex, according to Aton. This allows a memory specific to that visual cue to be generated. The researchers think that at the same time, that sensory cortical area must communicate with other brain structures, to marry the sensory aspect of the memory to the emotional aspect.

Aton says their findings could have implications for how anxiety and post-traumatic stress disorder are understood.

Ask anyone from an NFL quarterback scanning the field for open receivers, to an air traffic controller monitoring the positions of planes, to a mom watching her kids run around at the park: We depend on our brain to hold what we see in mind, even as we shift our gaze around and even temporarily look away. This capability of “visual working memory” feels effortless, but a new MIT study shows that the brain works hard to keep up. Whenever a key object shifts across our field of view—either because it moved or our eyes did—the brain immediately transfers a memory of it by re-encoding it among neurons in the opposite brain hemisphere.

The finding, published in Neuron by neuroscientists at The Picower Institute for Learning and Memory, explains via experiments in animals how we can keep continuous track of what’s important to us, even though our visual system’s basic wiring requires mapping what we see on our left in the right side of our brain and what we see on our right in the left side of the brain.

“You need to know where things are in the real world, regardless of where you happen to be looking or how you are oriented at a given moment,” said study lead author Scott Brincat, a postdoctoral researcher in the lab of Picower Professor Earl Miller, the senior author. “But the representation that your brain gets from the outside world changes every time you move your eyes around.”

In their experiments, Brincat, Miller and co-authors found that when an object switches sides in the field of view, the brain rapidly employs a telltale change in the synchrony of brain wave frequencies to shepherd the memory information from one side of the brain to the other. The transfer, which occurs in mere milliseconds, recruits a new group of neurons in the prefrontal cortex of the opposite brain hemisphere to store the memory. This new ensemble of neurons encodes the object based on its new position, but the brain continues to recognize it as the object that used to be in the other hemisphere’s field of view.

That ability—to remember that something is the same thing no matter how it’s moving around relative to our eyes—is what gives us the freedom to control where we look, Miller said. Tampa Bay Buccaneers quarterback Tom Brady, for instance, can decide to shift his gaze from the left side of the field to the right side without having to fear that he’ll instantly forget that those left-side receivers are still there, even if changing the gaze position has substantially shifted them within, or even out of, his field of view.

“If you didn’t have that, we would just be simple creatures who could only react to whatever is coming right at us in the environment, that’s all,” Miller said. “But because we can hold things in mind, we can have volitional control over what we do.  We don’t have to react to something now, we can save it for later.”

Shifting sides

In the lab, the researchers measured the activity of hundreds of neurons in the prefrontal cortex of both brain hemispheres as animals played a game. They had to fix their gaze on one side of a screen as an image of an object (e.g. a banana) appeared briefly in the middle of the screen. The object thus appeared on one or the other side of their field of view, and due to the brain’s crossed wiring, it was processed in the opposite cortical hemisphere. The animal had to hold the image in mind, then indicate if a subsequently presented image was of a different object (e.g. an apple). On some trials, though, while the original object was held in working memory the animals were cued to switch their gaze from one side to the other, effectively changing which side of their field of view the remembered image was on.

Animals were accurate in remembering whether the images they were presented matched, but their performance suffered just a little bit in cases where they had to shift their gaze. Brincat said the error suggests that having to keep up with the shift is not as easy for the brain as it seems.

“It feels trivial to us, but it apparently isn’t,” he said.

To analyze their measurements in the brain, the team trained a computer program called a decoder to identify patterns in the raw data of neural activity that indicated the memory of the object image. As expected, that analysis showed that the brain encoded information about each image in the hemisphere opposite of where it was in the field of view. But more remarkably, it also showed that in cases where the animals shifted their gaze across the screen, neural activity encoding the memory information shifted from one brain hemisphere to the other.

The team also measured the overall rhythms of the neurons’ collective activity, or brain waves. They found that the transfer of a memory from one hemisphere to the other consistently occurred with a signature change in those rhythms. As the transfer occurred, the synchrony across hemispheres of very low frequency “theta” waves (~4-10 Hz) and high frequency “beta” waves (~17-40 Hz) rose and the synchrony of “alpha/beta” waves (~11-17 Hz) declined.

This push-and-pull pattern of rhythms closely resembles one that Miller’s lab has found in many studies of how the cortex employs rhythms to transmit information. Increases in the combination of very low and higher frequency rhythms allows sensory information (i.e. representations of what the animal just saw) to be encoded or recalled. A power increase in the alpha/beta frequency range inhibits that encoding, acting as a sort of gate on sensory information processing.

“This is another form of gating,” Miller said. “This time alpha/beta is gating the memory transfer between hemispheres.”

Spotting a surprise

While the rhythm patterns seemed consistent with prior studies, the researchers were surprised by another finding of the study: Given the same object image in the same spot in the field of view, the prefrontal cortex employed different neurons if it was initially seen at that location vs. transferred from the other hemisphere. In other words, animals seeing a banana in the left side of their vision recruited a different neural ensemble to represent that memory than they did if the banana was previously seen on the right and then transferred to that spot.

To Miller, the finding has an intriguing implication. Neuroscientists once thought that individual neurons were the basic unit of function in the brain and more recently have begun to think that instead ensembles of neurons are. The new findings, however, suggest that even the same information could still be encoded by different, arbitrarily assembled ensembles.

Synchronization of Brain Hemispheres Changes What We Hear

Most of the time, our brain receives different input from each of our ears, but we nevertheless perceive speech as unified sounds. This process takes place through synchronization of the areas of the brain involved with the help of gamma waves, neurolinguists at the University of Zurich have now discovered. Their findings may lead to new treatment approaches for tinnitus.

How come we don’t hear everything twice: After all, our ears sit on opposite sides of our head and most sounds do not reach both our ears at exactly the same time. “While this helps us determine which direction sounds are coming from, it also means that our brain has to combine the information from both ears. Otherwise, we would hear an echo,” explains Basil Preisig of the Department of Psychology at the University of Zurich.

In addition, input from the right ear reaches the left brain hemisphere first, while input from the left ear reaches the right brain hemisphere first. The two hemispheres perform different tasks during speech processing: The left side is responsible for distinguishing phonemes and syllables, whereas the right side recognizes the speech prosody and rhythm. Although each hemisphere receives the information at a different time and processes different features of speech, the brain integrates what it hears into a unified speech sound.

Brain waves establish connection

The exact mechanism behind this integration process was not known until now. In earlier studies, however, Preisig had found indications that measurable oscillations elicited by the brain – known as gamma waves – played a role. Now he has managed to demonstrate that the process of integrating what we hear is directly linked to synchronization by gamma waves. Neurolinguists from UZH worked on the project alongside researchers from the Netherlands and France.

Processing ambiguous information

The study, which took place at the Donders Center for Cognitive Neuroimaging in Nijmegen, the Netherlands, involved 28 healthy subjects who had to repeatedly solve a listening task: An ambiguous syllable (a speech sound between ga and da) was played in their right ear while a click containing a fragment of the syllables da or ga was played unnoticed in the left ear. Depending on what was played in their left ear, the participants heard either ga or da and then had to report what sound they had heard. During the process, the researchers were tracking activity in both hemispheres of the brain using functional magnetic resonance imaging (fMRI).

Electric stimulation impairs synchronization

During the experiments, the researchers disrupted the natural activity pattern of gamma waves by stimulating both hemispheres of the brain with electrodes attached to the head. This manipulation affected participants’ ability to correctly identify the syllable they heard. The fMRI analysis showed that there were also changes in the activity of the neural connections between the right and the left brain hemispheres: The strength of the connection changed depending on whether the rhythm of the gamma waves was influenced by electric stimulation in the two brain hemispheres synchronously or asynchronously. This disruption also impaired the integration process. Thus, synchronization of the gamma waves seems to serve to balance the different inputs from the two hemispheres of the brain, providing a unified auditory impression.

Possible therapy for tinnitus

“Our results suggest that gamma wave-mediated synchronization between different brain areas is a fundamental mechanism for neural integration,” says Preisig. “Moreover, this research shows for the first time, using human hearing as an example, that the connection between the two hemispheres of the brain can be successfully modulated by electric stimulation,” adds Alexis Hervais-Adelman, head of neurolinguistics at the UZH Department of Psychology, who was also involved in the study.

:/ A fear submitted by Gladia to Deep Dark Fears - thanks!

Nasal spray delivers antipsychotic drugs straight to the brain, cutting required dose by up to 75 per cent and reducing adverse side effects

A team of neuroscientists and engineers at McMaster University has created a nasal spray to deliver antipsychotic medication directly to the brain instead of having it pass through the body.

The leap in efficiency means patients with schizophrenia, bipolar disorder and other conditions could see their doses of powerful antipsychotic medications cut by as much as three quarters, which is expected to spare them from sometimes-debilitating side effects while also significantly reducing the frequency of required treatment.

The new method delivers medication in a spray that reaches the brain directly through the nose, offering patients greater ease of use and the promise of improved quality of life, including more reliable, effective treatment.

Ram Mishra, a professor in the Department of Psychiatry and Behavioural Neurosciences and co-director of McMaster’s School of Biomedical Engineering, and Todd Hoare, a Canada Research Chair and professor of chemical engineering, describe their research in a newly published article in the Journal of Controlled Release.

They and their co-authors Michael Majcher, Ali Babar, Andrew Lofts, and Fahed Abuhijleh have proven the concept of their new delivery mechanism in rats with PAOPA, an experimental drug used to treat schizophrenia. In related work, the researchers have also produced similar results with other, commonly prescribed antipsychotic drugs.

A problem for patients using antipsychotic medications, Mishra explains, is that taking them orally or by injection means the drugs must pass through the body before they reach the brain through the blood. To be sure enough oral or injected medication reaches the brain, a patient must take much more than the brain will ultimately receive, leading to sometimes serious adverse side effects, including weight gain, diabetes, drug-induced movement disorders and organ damage over the long term.

When delivered through the nose, the spray medication can enter the brain directly via the olfactory nerve.

“The trick here is to administer the drug through the back door to the brain, since the front door is sealed so tightly,” Mishra says. “This way we can bypass the blood-brain barrier. By delivering the drug directly to the target, we can avoid side effects below the brain.”

Mishra and collaborator Rodney Johnson of the University of Minnesota had previously created a water-soluble form of the medication, which was used in the current research. The new form they created was easier to manipulate, but they still lacked an effective vehicle for getting it to the brain. A particular issue was that drugs delivered via the nose are typically cleared from the body quickly, requiring frequent re-administration.

Hoare, in the meantime, had been working with an industrial partner to develop the use microscopic nanoparticles of corn starch for agricultural applications.

The two scientists, who work across campus from one another, came together after researchers in their labs met at an internal McMaster conference. Two of the researchers, Babar and Lofts, worked on the project in both labs.

The engineering team was able to bind the drug to the corn starch nanoparticles that, when sprayed together with a natural polymer derived from crabs, could penetrate deep into the nasal cavity and form a thin gel in the mucus lining, slowly releasing a controlled dose of the drug, which remains effective for treating schizophrenia symptoms over three days.

“The cornstarch nanoparticles we were using for an industrial application were the perfect vehicle,” Hoare says. “They are naturally derived, they break down over time into simple sugars, and we need to do very little chemistry on them to make this technology work, so they are great candidates for biological uses like this.”

We hear what we expect to hear

Humans depend on their senses to perceive the world, themselves and each other. Despite senses being the only window to the outside world, people do rarely question how faithfully they represent the external physical reality. During the last 20 years, neuroscience research has revealed that the cerebral cortex constantly generates predictions on what will happen next, and that neurons in charge of sensory processing only encode the difference between our predictions and the actual reality.

A team of neuroscientists of TU Dresden headed by Prof Katharina von Kriegstein presents new findings that show that not only the cerebral cortex, but the entire auditory pathway, represents sounds according to prior expectations.

For their study, the team used functional magnetic resonance imaging (fMRI) to measure brain responses of 19 participants while they were listening to sequences of sounds. The participants were instructed to find which of the sounds in the sequence deviated from the others. Then, the participants’ expectations were manipulated so that they would expect the deviant sound in certain positions of the sequences. The neuroscientists examined the responses elicited by the deviant sounds in the two principal nuclei of the subcortical pathway responsible for auditory processing: the inferior colliculus and the medial geniculate body. Although participants recognised the deviant faster when it was placed on positions where they expected it, the subcortical nuclei encoded the sounds only when they were placed in unexpected positions.

These results can be best interpreted in the context of predictive coding, a general theory of sensory processing that describes perception as a process of hypothesis testing. Predictive coding assumes that the brain is constantly generating predictions about how the physical world will look, sound, feel, and smell like in the next instant, and that neurons in charge of processing our senses save resources by representing only the differences between these predictions and the actual physical world.

Dr Alejandro Tabas, first author of the publication, states on the findings: "Our subjective beliefs on the physical world have a decisive role on how we perceive reality. Decades of research in neuroscience had already shown that the cerebral cortex, the part of the brain that is most developed in humans and apes, scans the sensory world by testing these beliefs against the actual sensory information. We have now shown that this process also dominates the most primitive and evolutionary conserved parts of the brain. All that we perceive might be deeply contaminated by our subjective beliefs on the physical world."

These new results open up new ways for neuroscientists studying sensory processing in humans towards the subcortical pathways. Perhaps due to the axiomatic belief that subjectivity is inherently human, and the fact that the cerebral cortex is the major point of divergence between the human and other mammal's brains, little attention has been paid before to the role that subjective beliefs could have on subcortical sensory representations.

How Do We Separate the Factual from the Possible? New Research Shows How Our Brain Responds to Both

Our brains respond to language expressing facts differently than they do to words conveying possibility, a team of neuroscientists has found. Its work offers new insights into the impact word choice has on how we make distinctions between what’s real vs. what’s merely possible.

“At a time of voluminous fake news and disinformation, it is more important than ever to separate the factual from the possible or merely speculative in how we communicate,” explains Liina Pylkkanen, a professor in NYU’s Department of Linguistics and Department of Psychology and the senior author of the paper, which appears in the journal eNeuro.

“Our study makes clear that information presented as fact evokes special responses in our brains, distinct from when we process the same content with clear markers of uncertainty, like ‘may’ or ‘might’,” adds Pylkkanen, also part of the NYU Abu Dhabi Institute.

“Language is a powerful device to effectively transmit information, and the way in which information is presented has direct consequences for how our brains process it,” adds Maxime Tulling, a doctoral candidate in NYU’s Department of Linguistics and the paper’s lead author. “Our brains seem to be particularly sensitive to information that is presented as fact, underlining the power of factual language.”

Researchers have long understood that the brain responds in a variety of ways to word choice. Less clear, however, are the distinctions it makes in processing language expressing fact compared to that expressing possibility. In the eNeuro study, the scientists’ primary goal was to uncover how the brain computes possibilities as conveyed by so-called “modal” words such as “may” or “might”—as in, “There is a monster under my bed” as opposed to, “There might be a monster under my bed.”

To explore this, the researchers used formal semantic theories in linguistics to design multiple experiments in which subjects heard a series of sentences and scenarios expressed as both fact and possibility—for example, “Knights carry large swords, so the squires do too” (factual) and “If knights carry large swords, the squires do too” (possible).

In order to measure the study subjects’ brain activity during these experiments, the researchers deployed magnetoencephalography (MEG), a technique that maps neural activity by recording magnetic fields generated by the electrical currents produced by our brain.

The results showed that factual language led to a rapid increase in neural activity, with the brain responding more powerfully and showing more engagement with fact-based phrases and scenarios compared to those communicating possibility.

“Facts rule when it comes to the brain,” observes Pylkkanen. “Brain regions involved in processing discourse rapidly differentiated facts from possibilities, responding much more robustly to factual statements than to non-factual ones. These findings suggest that the human brain has a powerful, perspective-adjusted neural representation of factual information and, interestingly, much weaker, more elusive cortical signals reflecting the computation of mere possibilities.”