Toward an early diagnostic tool for Alzheimer’s disease

Despite all the research done on Alzheimer’s, there is still no early diagnostic tool for the disease. By looking at the brain wave components of individuals with the disease, Professor Tiago H. Falk of INRS’s Centre Énergie Matériaux Télécommunications has identified a promising avenue of research that may not only help diagnose the disease, but also assess its severity. This non-invasive, objective method is the subject of an article in the journal PLOS ONE.

Patients with Alzheimer’s disease currently undergo neuropsychological testing to detect signs of the disease. The test results are difficult to interpret and are insufficient for making a definitive diagnosis. But as scientists have already discovered, activity in certain areas of the cerebral cortex is affected even in the early stages of the disease. Professor Falk, who specialises in biological signal acquisition, examined this phenomenon and compared the electroencephalograms (EEGs) of healthy individuals (27), individuals with mild Alzheimer’s (27), and individuals with moderate cases of the disease (22). He found statistically significant differences across the three groups.

In collaboration with neurologists and Francisco J. Fraga, an INRS visiting professor specializing in biological signals, Professor Falk used an algorithm that dissects brain waves of varying frequencies. “What makes this algorithm innovative is that it characterizes the changes in temporal dynamics of the patients’ brain waves,” explains Professor Falk. “The findings show that healthy individuals have different patterns than those with mild Alzheimer’s disease. We also found a difference between patients with mild levels of the disease and those with moderate Alzheimer’s.”

To validate the model in order to eventually develop an early diagnostic tool for Alzheimer’s disease, Professor Falk’s team is sharing their algorithm on the NeuroAccelerator.org online data analysis portal. It is the first open source algorithm posted on the portal and may be used by researchers around the world to produce additional research findings.

Alzheimer’s disease accounts for 60% to 80% of all dementia cases in North America and is skyrocketing. This step toward the development of an early diagnostic tool that is non-invasive, objective, and relatively inexpensive is therefore welcome news for the research community.

Long-term memory in the cortex

Game changing results: Brain uses the cortex for making sensory associations, not the hippocampus

‘Where’ and ‘how’ memories are encoded in a nervous system is one of the most challenging questions in biological research. The formation and recall of associative memories is essential for an independent life. The hippocampus has long been considered a centre in the brain for the long-term storage of spatial associations. Now, Mazahir T. Hasan at the Max Planck Institute for Medical Research and José Maria Delgado-Garcìa at the University Pablo de Olavide of Seville, Spain, were able to provide first experimental evidence that a specific form of memory associations is encoded in the cerebral cortex and is not localized in the hippocampus as described in most Neuroscience textbooks. The new study is a game changer since it strongly suggests that the motor cortical circuits itself, and not the hippocampus, is used as memory storage.

Henry Molaison, known widely as H.M., is a famous name in memory research. Large parts of the American‘s hippocampus – the region of the brain that is a major element in learning and memory processes – were removed in the 1950s in an attempt to cure his epileptic seizures. He subsequently suffered severe memory lapses and was no longer able to remember virtually anything new he had learned. Most scientists thereby concluded that the hippocampus is the site of long-term memory.

However, the extent of H.M.’s brain damage was obviously underestimated, because other regions in addition to the hippocampus were also removed or damaged in the surgical procedure. The researchers from Heidelberg and Seville have therefore investigated the learning behaviour of genetically modified mice in which NMDA receptors are turned off only in the motor cerebral cortex. NMDA receptors bind the neurotransmitter glutamate to the synapses and become active when several signals feed into one synapse at the same time. They are the central molecular elements of learning processes, being involved in increasing or decreasing transmission of the signals to synapses.

As the new study shows, in the motor cortex this so-called synaptic plasticity no longer functions without the NMDA receptors. The scientists were thus able to rule out the hippocampus or other regions as the cause for their observations. Based on the new findings, it is the cerebral cortex, not the hippocampus that is the storage site for some forms of memory.

In behaviour tests, so called eyeblink conditioning, animals with and without NMDA receptors in the primary motor cortex had to learn to link a tone with a subsequent electrical stimulus of the eyelid. This association of two sensory inputs involves the cerebellum which coordinates the necessary movements, as well as the hippocampus and the cerebral cortex, which are important learning and memory centres. “After a learning phase, the animals’ reflex is to close their eye when they hear just the tone. Without NMDA receptors in the primary motor cerebral cortex, the genetically modified mice on the other hand cannot remember the connection between the tone and electrical stimulus, and therefore they keep their eyes open despite the tone”, explains Mazahir T. Hasan of the Max Planck Institute for Medical Research.

The researchers have thus complemented the findings of their Heidelberg-based colleagues that the hippocampus is not the seat of memory. In July 2012, Rolf Sprengel and Peter Seeburg from the Max Planck Institute for Medical Research discovered that mice without NMDA receptors in the hippocampus are still quite capable of learning. “We now think that the hippocampus provides the necessary environmental cues, which are transmitted to the cortex where learning-dependent associations take place. Memories are thus stored at various sites in the cerebral cortex on a long-term basis”, explains Hasan.

The findings of Hasan and Delgado-Garcìa thus represent a paradigm-shift in memory research as they make clear that the cerebral cortex is the brain region where memory associations are linked and stored – not the hippocampus. An advanced and detailed knowledge of the mechanisms for the acquisition, consolidation, and recall of associations in the brain is the prerequisite for a therapeutic treatment of the devastating effects of memory loss in various neurological diseases, such as amnesia, Alzheimer`s disease and dementia.

Researchers discover a gene’s key role in building the developing brain’s scaffolding

The gene, Arl13b, is necessary for the proper construction of the cerebral cortex. The finding offers new insights on normal brain development and illuminates some of the factors behind Joubert’s syndrome, a rare neurological disorder.

Researchers have pinpointed the role of a gene known as Arl13b in guiding the formation and proper placement of neurons in the early stages of brain development. Mutations in the gene could help explain brain malformations often seen in neurodevelopmental disorders.

The research, led by a team at the University of North Carolina School of Medicine, was published June 30 in the journal Nature Neuroscience.

“We wanted to get a better sense of how the cerebral cortex is constructed,” said senior study author Eva Anton, PhD, a professor in the Department of Cell Biology and Physiology and a member of the UNC Neuroscience Center. “The cells we studied — radial glial cells — provide a scaffolding for the formation of the brain by making neurons and guiding them to where they have to go. This is the first step in the formation of functional neuronal circuitry in the brain. This study gives us new information about the mechanisms involved in that process.”

The researchers became interested in the Arl13b gene because of its expression in a part of the cell called primary cilium and its association with a rare neurological disorder known as Joubert syndrome. The syndrome is characterized by brain malformations and autism like features.

“In addition to helping us understand an important cellular mechanism involved in normal brain development, this study may offer an explanation for some of the malformations seen in Joubert syndrome patients,” said Anton. Although there is no immediate clinical application for these patients, the study does help illuminate the factors behind the disease. “It shows what may have gone wrong in some of those patients that led to the malformations,” said Anton.

The cerebral cortex, the brain’s “gray matter,” is responsible for higher-order functions such as memory and consciousness. Like the scaffolding builders use to move people and materials during construction, radial glial cells provide an instructive matrix to create the basic structural features of the cerebral cortex. Mistakes in the formation and development of radial glial cells can translate into structural problems in the brain as it develops, said Anton.

Both mice and humans have the Arl13b gene. The researchers generated a series of mice with mutations on the Arl13b gene at different developmental stages to track the mutations’ effects on brain development. They discovered that the gene is crucial to the radial glial cells’ ability to sense signals through an appendage called the primary cilium. Without this signaling capability, the radial glia were unable to organize into an instructive scaffold capable of orchestrating the orderly formation of cerebral cortex. “The cilia in these cells play an important role in the initial setup of this scaffolding,” said Anton. “Without a functioning Arl13b gene, the cells were not able to determine polarity and formed haphazardly. As a result, they formed a malformed cerebral cortex with ectopic clusters of neurons, instead of the orderly layers of neurons with appropriate connectivity that would be expected, in the developing brain.

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.

Problem-solving governs how we process sensory stimuli

Various areas of the brain process our sensory experiences. How the areas of the cerebral cortex communicate with each other and process sensory information has long puzzled neuroscientists. Exploring the sense of touch in mice, brain researchers from the University of Zurich now demonstrate that the transmission of sensory information from one cortical area to connected areas depends on the specific task to solve and the goal-directed behavior. These findings can serve as a basis for an improved understanding of cognitive disorders.

In the mammalian brain, the cerebral cortex plays a crucial role in processing sensory inputs. The cortex can be subdivided into different areas, each handling distinct aspects of perception, decision-making or action. The somatosensory cortex, for instance, comprises the part of the cerebral cortex that primarily processes haptic sensations. The different areas of the cerebral cortex are interconnected and communicate with each other. A central, unanswered question of neuroscience is how exactly do these brain areas communicate to process sensory stimuli and produce appropriate behavior. A team of researchers headed by Professor Fritjof Helmchen at the University of Zurich’s Brain Research Institute now provides an answer: The processing of sensory information depends on what you want to achieve. The brain researchers observed that nerve cells in the sensory cortex that connect to distinct brain areas are activated differentially depending on the task to be solved.

Goal-directed processing of sensory information

In their publication in Nature, the researchers studied how mice use their facial whiskers to explore their environment, much like we do in the dark with our hands and fingers. One mouse group was trained to distinguish coarse and fine sandpapers using their whiskers in order to obtain a reward. Another group had to work out the angle, at which an object – a metal rod – was located relative to their snout. The neuroscientists measured the activity of neurons in the primary somatosensory cortex using a special microscopy technique. With simultaneous anatomical stainings they also identified which of these neurons sent their projections to the more remote secondary somatosensory area and the motor cortex, respectively.

The primary somatosensory neurons with projections to the secondary somatosensory cortex predominantly became active when the mice had to distinguish the surface texture of the sandpaper. Neurons with projections to the motor cortex, on the other hand, were more involved when mice needed to localize the metal rod. These different activity patterns were not evident when mice passively touched sandpaper or metal rods without having been set a task – in other words, when their actions were not motivated by a reward. Thus, the sensory stimuli alone were not sufficient to explain the different pattern of information transfer to the remote brain areas.

Impaired communication in the brain

According to Fritjof Helmchen, the activity in a cortical area can be transmitted to remote areas in a targeted fashion if we have to extract (‘filter’) specific information from the environment to solve a problem. In cognitive disorders such Alzheimer’s disease, Autism, and Schizophrenia, this communication between brain areas is often disrupted. “A better understanding of how these long-range, interconnected networks in the brain operate might help to develop therapies that re-establish this specific cortical communication,” says Helmchen. The aim would be to thereby improve the impaired cognitive abilities of patients.

Sugar solution makes tissues see-through

Japanese researchers have developed a new sugar and water-based solution that turns tissues transparent in just three days, without disrupting the shape and chemical nature of the samples. Combined with fluorescence microscopy, this technique enabled them to obtain detailed images of a mouse brain at an unprecedented resolution.

The team from the RIKEN Center for Developmental biology reports their finding today in Nature Neuroscience.

Over the past few years, teams in the USA and Japan have reported a number of techniques to make biological samples transparent, that have enabled researchers to look deep down into biological structures like the brain.

“However, these clearing techniques have limitations because they induce chemical and morphological damage to the sample and require time-consuming procedures,” explains Dr. Takeshi Imai, who led the study.

SeeDB, an aqueous fructose solution that Dr. Imai developed with colleagues Drs. Meng-Tsen Ke and Satoshi Fujimoto, overcomes these limitations.

Using SeeDB, the researchers were able to make mouse embryos and brains transparent in just three days, without damaging the fine structures of the samples, or the fluorescent dyes they had injected in them.

They could then visualize the neuronal circuitry inside a mouse brain, at the whole-brain scale, under a customized fluorescence microscope without making mechanical sections through the brain.

They describe the detailed wiring patterns of commissural fibers connecting the right and left hemispheres of the cerebral cortex, in three dimensions, for the first time. They also report that they were able to visualize in three dimensions the wiring of mitral cells in the olfactory bulb, which is involved the detection of smells, at single-fiber resolution.

“Because SeeDB is inexpensive, quick, easy and safe to use, and requires no special equipment, it will prove useful for a broad range of studies, including the study of neuronal circuits in human samples,” explain the authors.