Single dose of antidepressant changes the brain

A single dose of antidepressant is enough to produce dramatic changes in the functional architecture of the human brain. Brain scans taken of people before and after an acute dose of a commonly prescribed SSRI (serotonin reuptake inhibitor) reveal changes in connectivity within three hours, say researchers who report their observations in the Cell Press journal Current Biology on September 18.

"We were not expecting the SSRI to have such a prominent effect on such a short timescale or for the resulting signal to encompass the entire brain," says Julia Sacher of the Max Planck Institute for Human Cognitive and Brain Sciences.

While SSRIs are among the most widely studied and prescribed form of antidepressants worldwide, it’s still not entirely clear how they work. The drugs are believed to change brain connectivity in important ways, but those effects had generally been thought to take place over a period of weeks, not hours.

The new findings show that changes begin to take place right away. Sacher says what they are seeing in medication-free individuals who had never taken antidepressants before may be an early marker of brain reorganization.

Study participants let their minds wander for about 15 minutes in a brain scanner that measures the oxygenation of blood flow in the brain. The researchers characterized three-dimensional images of each individual’s brain by measuring the number of connections between small blocks known as voxels (comparable to the pixels in an image) and the change in those connections with a single dose of escitalopram (trade name Lexapro).

Their whole-brain network analysis shows that one dose of the SSRI reduces the level of intrinsic connectivity in most parts of the brain. However, Sacher and her colleagues observed an increase in connectivity within two brain regions, specifically the cerebellum and thalamus.

The researchers say the new findings represent an essential first step toward clinical studies in patients suffering from depression. They also plan to compare the functional connectivity signature of brains in recovery and those of patients who fail to respond after weeks of SSRI treatment.

Understanding the differences between the brains of individuals who respond to SSRIs and those who don’t “could help to better predict who will benefit from this kind of antidepressant versus some other form of therapy,” Sacher says. “The hope that we have is that ultimately our work will help to guide better treatment decisions and tailor individualized therapy for patients suffering from depression.”

Scientists use lasers to control mouse brain switchboard

Ever wonder why it’s hard to focus after a bad night’s sleep? Using mice and flashes of light, scientists show that just a few nerve cells in the brain may control the switch between internal thoughts and external distractions. The study, partly funded by the National Institutes of Health, may be a breakthrough in understanding how a critical part of the brain, called the thalamic reticular nucleus (TRN), influences consciousness.

“Now we may have a handle on how this tiny part of the brain exerts tremendous control over our thoughts and perceptions,” said Michael Halassa, M.D., Ph.D., assistant professor at New York University’s Langone Medical Center and a lead investigator of the study. “These results may be a gateway into understanding the circuitry that underlies neuropsychiatric disorders.”

The TRN is a thin layer of nerve cells on the surface of the thalamus, a center located deep inside the brain that relays information from the body to the cerebral cortex. The cortex is the outer, multi-folded layer of the brain that controls numerous functions, including one’s thoughts, movements, language, emotions, memories, and visual perceptions. TRN cells are thought to act as switchboard operators that control the flow of information relayed from the thalamus to the cortex.

“The future of brain research is in studying circuits that are critical for brain health and these results may take us a step further,” said James Gnadt, Ph.D., program director at NIH’s National Institute Neurological Disorders and Stroke (NINDS), which helped fund the study. “Understanding brain circuits at the level of detail attained in this study is a goal of the President’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative.”

To study the circuits, the researchers identified TRN cells that send inhibitory signals to parts of the thalamus known to relay visual information to the cortex. Using a technique known as multi-electrode recordings, they showed that sleep and concentration affected these cells in opposite ways.

They fired often when the mice were asleep, especially during short bursts of simultaneous brain cell activity called sleep spindles. These activity bursts briefly widen electrical brain wave traces making them look like spindles, the straight spikes with rounded bottoms used to make yarn. In contrast, the cells fired infrequently when the mice were tasked with using visual cues to find food. The results suggested that these cells blocked visual information from reaching the cortex during sleep and allowed its transmission when the mice were awake and attentive.

For Dr. Halassa, a practicing psychiatrist who treats schizophrenia, these surprising results may provide fundamental insights into how the brain controls information transmission, a process that is disrupted in patients with neuropsychiatric disorders. Previous studies suggested that people who experienced more spindles while sleeping were less susceptible to being disturbed by outside noises. Moreover, people with schizophrenia and autism spectrum disorder may experience fewer spindles.

“Spindles may be peepholes into the mysteries of these disorders,” said Dr. Halassa.

To test this idea, the researchers used optogenetics, a technique that introduces light-sensitive molecules into nerve cells. This allowed them to precisely control the firing patterns of visual TRN cells with flashes of laser light. The experiments were performed in well-rested as well as sleep-deprived mice. Similar to what is seen in humans, sleep deprivation can disrupt the ability of mice to focus and block out external distractions.

Well-rested mice needed just a second or two to find the food whereas sleep-deprived mice took longer, suggesting that lack of sleep had detrimental effects on their ability to focus. When the researchers used flashes of laser light to inhibit the firing of optogenetically engineered visual TRN cells in sleep-deprived mice, the mice found the food faster. In contrast, if they used optogenetics to induce sleep-like firing patterns in well-rested mice, then the mice took longer to find food.

“It’s as if with a flick of a switch we could alter the mental states of the mice and either mimic or cure their drowsiness,” said Dr. Halassa.

In a parallel set of experiments the researchers found neighbors of the visual TRN cells had very different characteristics. These neighboring cells control the flow of information to the cortex from limbic brain regions, which are involved with memory formation, emotions and arousal. The cells fired very little during sleep and instead were active when the mice were awake. Dr. Halassa thinks that their firing pattern may be important for the strengthening of new memories that often occurs during sleep. Combined, the results suggest that the TRN is divided into sub-networks that oversee discrete mental states. The researchers think understanding the sub-networks is an initial step in thoroughly exploring the role of the TRN in brain disorders.

Staying focused: Cortico-thalamic pathway filters relevant sensory cues from perceptual input

On the one hand, the nervous has limited computational capability – but at the same time, the sensory environment contains an immense amount of information. In this demanding situation, the brain somehow manages to selectively focus attention on relevant stimuli. Recently, scientists at Technische Universität München, Munich and Ruhr University Bochum, Bochum investigated thalamic tactile sensory relay by employing optogenetics (the use of light to control neurons which have been genetically sensitized to light) to control specific cortical input to the thalamus. They show that the deepest cortical layer (known as layer six, or simply L6) plays a key role in controlling thalamic signal transformation (specifically, by controlling adaptive responses of thalamic neurons) and thalamic gating of dynamic sensory input patterns by changing the firing mode.

Dr. Rebecca A. Mease and Dr. Alexander Groh discussed the paper they and Prof. Patrik Krieger published in Proceedings of the National Academy of Sciences. In this study they investigated how the brain actively controls and gates information reaching higher stages of cortical processing by using optogenetics to turn on specific cortical input to the thalamus and measure how this impacts the processing of sensory signals in the thalamus.

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Image caption: When adult mice were kept in the dark for about a week, neural networks in the auditory cortex, where sound is processed, strengthened their connections from the thalamus, the midbrain’s switchboard for sensory information. As a result, the mice developed sharper hearing. This enhanced image shows fibers (green) that link the thalamus to neurons (red) in the auditory cortex. Cell nuclei are blue. Image by Emily Petrus and Amal Isaiah

A Short Stay in Darkness May Heal Hearing Woes

Call it the Ray Charles Effect: a young child who is blind develops a keen ability to hear things others cannot. Researchers have known this can happen in the brains of the very young, which are malleable enough to re-wire some circuits that process sensory information. Now researchers at the University of Maryland and Johns Hopkins University have overturned conventional wisdom, showing the brains of adult mice can also be re-wired, compensating for a temporary vision loss by improving their hearing.

The findings, published Feb. 5 in the peer-reviewed journal Neuron, may lead to treatments for people with hearing loss or tinnitus, said Patrick Kanold, an associate professor of biology at UMD who partnered with Hey-Kyoung Lee, an associate professor of neuroscience at JHU, to lead the study.

"There is some level of interconnectedness of the senses in the brain that we are revealing here," Kanold said.

"We can perhaps use this to benefit our efforts to recover a lost sense," said Lee. "By temporarily preventing vision, we may be able to engage the adult brain to change the circuit to better process sound."

Kanold explained that there is an early “critical period” for hearing, similar to the better-known critical period for vision. The auditory system in the brain of a very young child quickly learns its way around its sound environment, becoming most sensitive to the sounds it encounters most often. But once that critical period is past, the auditory system doesn’t respond to changes in the individual’s soundscape.

"This is why we can’t hear certain tones in Chinese if we didn’t learn Chinese as children," Kanold said. "This is also why children get screened for hearing deficits and visual deficits early. You cannot fix it after the critical period."

Kanold, an expert on how the brain processes sound, and Lee, an expert on the same processes in vision, thought the adult brain might be flexible if it were forced to work across the senses rather than within one sense. They used a simple, reversible technique to simulate blindness: they placed adult mice with normal vision and hearing in complete darkness for six to eight days.

After the adult mice were returned to a normal light-dark cycle, their vision was unchanged. But they heard much better than before.

The researchers played a series of one-note tones and tested the responses of individual neurons in the auditory cortex, a part of the brain devoted exclusively to hearing. Specifically, they tested neurons in a middle layer of the auditory cortex that receives signals from the thalamus, a part of the midbrain that acts as a switchboard for sensory information. The neurons in this layer of the auditory cortex, called the thalamocortical recipient layer, were generally not thought to be malleable in adults.

But the team found that for the mice that experienced simulated blindness these neurons did, in fact, change. In the mice placed in darkness, the tested neurons fired faster and more powerfully when the tones were played, were more sensitive to quiet sounds, and could discriminate sounds better. These mice also developed more synapses, or neural connections, between the thalamus and the auditory cortex.

The fact that the changes occurred in the cortex, an advanced sensory processing center structured about the same way in most mammals, suggests that flexibility across the senses is a fundamental trait of mammals’ brains, Kanold said.

"This makes me hopeful that we would see it in higher animals too," including humans, he said. "We don’t know how many days a human would have to be in the dark to get this effect, and whether they would be willing to do that. But there might be a way to use multi-sensory training to correct some sensory processing problems in humans."

The mice that experienced simulated blindness eventually reverted to normal hearing after a few weeks in a normal light-dark cycle. In the next phase of their five-year study, Kanold and Lee plan to look for ways to make the sensory improvements permanent, and to look beyond individual neurons to study broader changes in the way the brain processes sounds.

Study Appears to Overturn Prevailing View of How the Brain is Wired

A series of studies conducted by Randy Bruno, PhD, and Christine Constantinople, PhD, of Columbia University’s Department of Neuroscience, topples convention by showing that sensory information travels to two places at once: not only to the brain’s mid-layer (where most axons lead), but also directly to its deeper layers. The study appears in the June 28, 2013, edition of the journal Science.

For decades, scientists have thought that sensory information is relayed from the skin, eyes, and ears to the thalamus and then processed in the six-layered cerebral cortex in serial fashion: first in the middle layer (layer 4), then in the upper layers (2 and 3), and finally in the deeper layers (5 and 6.) This model of signals moving through a layered “column” was largely based on anatomy, following the direction of axons—the wires of the nervous system.

“Our findings challenge dogma,” said Dr. Bruno, assistant professor of neuroscience and a faculty member at Columbia’s new Mortimer B. Zuckerman Mind Brain Behavior Institute and the Kavli Institute for Brain Science. “They open up a different way of thinking about how the cerebral cortex does what it does, which includes not only processing sight, sound, and touch but higher functions such as speech, decision-making, and abstract thought.”

The researchers used the well-understood sensory system of rat whiskers, which operate much like human fingers, providing tactile information about shape and texture. The system is ideal for studying the flow of sensory signals, said Dr. Bruno, because past research has mapped each whisker to a specific barrel-shaped cluster of neurons in the brain. “The wiring of these circuits is similar to those that process senses in other mammals, including humans,” said Dr. Bruno.

The study relied on a sensitive technique that allows researchers to monitor how signals move across synapses from one neuron to the next in a live animal. Using a glass micropipette with a tip only 1 micron wide (one-thousandth of a millimeter) filled with fluid that conducts nerve signals, the researchers recorded nerve impulses resulting from whisker stimulation in 176 neurons in the cortex and 76 neurons in the thalamus. The recordings showed that signals are relayed from the thalamus to layers 4 and 5 at the same time.  Although 80 percent of the thalamic axons went to layer 4, there was surprisingly robust signaling to the deeper layer.

To confirm that the deeper layer receives sensory information directly, the researchers used the local anesthetic lidocaine to block all signals from layer 4. Activity in the deeper layer remained unchanged.

“This was very surprising,” said Dr. Constantinople, currently a postdoctoral researcher at Princeton University’s Neuroscience Institute. “We expected activity in the lower layers to be turned off or very much diminished when we blocked layer 4. This raises a whole new set of questions about what the layers actually do.”

The study suggests that upper and lower layers of the cerebral cortex form separate circuits and play separate roles in processing sensory information. Researchers think that the deeper layers are evolutionarily older—they are found in reptiles, for example, while the upper and middle layers, appear in more evolved species and are thickest in humans.

One possibility, suggests Dr. Bruno, is that basic sensory processing is done in the lower layers: for example, visually tracking a tennis ball to coordinate the movement needed to make contact. Processing that involves integrating context or experience or that involves learning might be done in the upper layers. For example, watching where an opponent is hitting the ball and planning where to place the return shot.

“At this point, we still don’t know what, behaviorally, the different layers do,” said Dr. Bruno, whose lab is now focused on finding those answers.

Nobel-prize-winning neurobiologist Bert Sakmann, MD, PhD, of the Max Planck Institute in Germany, describes the study as “very convincing” and a game-changer. “For decades, the field has assumed, based largely on anatomy, that the work of the cortex begins in layer 4. Dr. Bruno has produced a technical masterpiece that firmly establishes two separate input streams to the cortex,” said Dr. Sakmann. “The prevailing view that the cortex is a collection of monolithic columns, handing off information to progressively higher modules, is an idea that will have to go.”2006-06-16 TC axon – high contrast MS1 repeat3-1

“Bruno’s work goes a long way toward overturning the conventional wisdom and provides new insight into the functional segregation of sensory input to the mammalian cerebral cortex, the region of the brain that processes our thoughts, decisions, and actions,” said Thomas Jessell, PhD, Claire Tow Professor of Motor Neuron Disorders in Neuroscience and a co-director of the Mortimer B. Zuckerman Mind Brain Behavior Institute and the Kavli Institute for Brain Science. “Developing a more refined understanding of cortical processing will take the combined efforts of anatomists, cell and molecular biologists, and animal behaviorists. The Zuckerman Institute, with its multidisciplinary faculty and broad mission, is ideally suited to building on Bruno’s fascinating work.”

A Deep Brain Disorder

An SDSU research team has discovered that autism in children affects not only social abilities, but also a broad range of sensory and motor skills.

Multiple Sclerosis research: the thalamus moves into the spotlight

A growing body of research by multiple sclerosis (MS) investigators at the University at Buffalo and international partners is providing powerful new evidence that the brain’s gray matter reflects important changes in the disease that could allow clinicians to diagnose earlier and to better monitor and predict how the disease will progress.

Over the past three years, the UB researchers and their partners around the world, supported by an active fellowship program at UB’s Buffalo Neuroimaging Analysis Center (BNAC), have published journal papers and given presentations demonstrating that the thalamus region, in particular, is key to a host of issues involving MS.

“The thalamus is providing us with a new window on MS,” says Robert Zivadinov, MD, PhD, UB professor of neurology, BNAC director and leader of the research team. “In our recent studies, we have used large datasets to investigate the evolution of atrophy of the thalamus and its association with clinical impairment in MS, starting with the earliest stages of the disease. The location of the thalamus in the brain, its unique function and its vulnerability to changes wrought by the disease make the thalamus a critical barometer of the damage that MS causes to the brain.”

Zivadinov and UB professor of neurology Ralph Benedict discuss the new research in a video.

At the annual meeting of the American Academy of Neurology today, Zivadinov will discuss a study he performed in collaboration with colleagues from Charles University in Prague. The study found that atrophy of the thalamus, determined with MRI, can help identify which patients with clinically isolated syndrome (CIS), a patient’s first episode of MS, are at risk for developing clinically definite MS. Such a tool would be immensely helpful to clinicians, Zivadinov notes.

“This study, which included more than 200 patients, shows that thalamic atrophy is one of the most important predictors of clinically definite MS,” says Dana Horakova, MD, PhD, the principal investigator at Charles University.

“Therefore, based on these findings, we think MRI should be used to determine which patients are at highest risk for a second attack,” explains Zivadinov.