How studying damage to the prefrontal lobe has helped unlock the brain’s mysteries

Until the last few decades, the frontal lobes of the brain were shrouded in mystery and erroneously thought of as nonessential for normal function—hence the frequent use of lobotomies in the early 20th century to treat psychiatric disorders. Now a review publishing August 28 in the Cell Press journal Neuron highlights groundbreaking studies of patients with brain damage that reveal how distinct areas of the frontal lobes are critical for a person’s ability to learn, multitask, control their emotions, socialize, and make real-life decisions. The findings have helped experts rehabilitate patients experiencing damage to this region of the brain.

Although fairly common, damage to the prefrontal lobes (also called the prefrontal cortex) is often overlooked and undiagnosed because patients do not manifest obvious deficits. For example, patients with prefrontal brain damage do not lose any of their senses and often have preserved motor and language abilities, but they may manifest social abnormalities or difficulties with high-level planning in everyday life situations.

"In this review, we aimed to highlight a blend of new studies using cutting edge research techniques to investigate brain damage, but also to relate these new studies to original studies, some of which were published more than a century ago," said lead author Dr. Sara Szczepanski, of the University of California, Berkeley. "There is currently a large push to better understand the functions of the prefrontal cortex, and we believe that our review will make an important contribution to this understanding."

In addition to revealing the functions of different areas within the prefrontal cortex, studies have also demonstrated the flexibility of the region, which has helped experts optimize cognitive therapy techniques to enable patients with brain damage to learn new skills and compensate for their impairments.

The review indicates that by studying patients with damage to the prefrontal cortex, investigators can gain insights into this still-mysterious region of the brain that is critical for complex human skills and behavior.

Train your heart to protect your mind

Exercising to improve our cardiovascular strength may protect us from cognitive impairment as we age, according to a new study by researchers at the University of Montreal and its affiliated Institut universitaire de gératrie de Montréal Research Centre. “Our body’s arteries stiffen with age, and the vessel hardening is believed to begin in the aorta, the main vessel coming out of the heart, before reaching the brain. Indeed, the hardening may contribute to cognitive changes that occur during a similar time frame,” explained Claudine Gauthier, first author of the study. “We found that older adults whose aortas were in a better condition and who had greater aerobic fitness performed better on a cognitive test. We therefore think that the preservation of vessel elasticity may be one of the mechanisms that enables exercise to slow cognitive aging.”

The researchers worked with 31 young people between the ages of 18 and 30 and 54 older participants aged between 55 and 75. This enabled the team to compare the older participants within their peer group and against the younger group who obviously have not begun the aging processes in question. None of the participants had physical or mental health issues that might influence the study outcome. Their fitness was tested by exhausting the participants on a workout machine and determining their maximum oxygen intake over a 30 second period. Their cognitive abilities were assessed with the Stroop task. The Stroop task is a scientifically validated test that involves asking someone to identify the ink colour of a colour word that is printed in a different colour (e.g. the word red could be printed in blue ink and the correct answer would be blue). A person who is able to correctly name the colour of the word without being distracted by the reflex to read it has greater cognitive agility.

The participants undertook three MRI scans: one to evaluate the blood flow to the brain, one to measure their brain activity as they performed the Stroop task, and one to actually look at the physical state of their aorta. The researchers were interested in the brain’s blood flow, as poorer cardiovascular health is associated with a faster pulse wave,at each heartbeat which in turn could cause damage to the brain’s smaller blood vessels. “This is first study to use MRI to examine participants in this way,” Gauthier said. “It enabled us to find even subtle effects in this healthy population, which suggests that other researchers could adapt our test to study vascular-cognitive associations within less healthy and clinical populations.”

The results demonstrated age-related declines in executive function, aortic elasticity and cardiorespiratory fitness, a link between vascular health and brain function, and a positive association between aerobic fitness and brain function. “The link between fitness and brain function may be mediated through preserved cerebrovascular reactivity in periventricular watershed areas that are also associated with cardiorespiratory fitness,” Gauthier said. “Although the impact of fitness on cerebral vasculature may however involve other, more complex mechanisms, overall these results support the hypothesis that lifestyle helps maintain the elasticity of arteries, thereby preventing downstream cerebrovascular damage and resulting in preserved cognitive abilities in later life.”

Musical Training Offsets Some Academic Achievement Gaps

Learning to play a musical instrument or to sing can help disadvantaged children strengthen their reading and language skills, according to research presented at the American Psychological Association’s 122nd Annual Convention.

The findings, which involved hundreds of kids participating in musical training programs in Chicago and Los Angeles public schools, highlight the role learning music can have on the brains of youth in impoverished areas, according to presenter Nina Kraus, PhD, a neurobiologist at Northwestern University.

“Research has shown that there are differences in the brains of children raised in impoverished environments that affect their ability to learn,” said Kraus. “While more affluent students do better in school than children from lower income backgrounds, we are finding that musical training can alter the nervous system to create a better learner and help offset this academic gap.” Up until now, research on the impact of musical training has been primarily conducted on middle- to upper-income music students participating in private music lessons, she said.

Kraus’s lab research has concluded that musical training appears to enhance the way children’s nervous systems process sounds in a busy environment, such as a classroom or a playground. This improved neural function may lead to enhanced memory and attention spans which, in turn, allow kids to focus better in the classroom and improve their communication skills, she said.

Many of Kraus’s study participants are part of the Harmony Project in Los Angeles, which was founded by fellow presenter Margaret Martin, DrPH. In her most recent research, Kraus studied children beginning when they were in first and second grade. Half participated in musical training and the other half were randomly selected from the program’s lengthy waiting list and received no musical training during the first year of the study. Children who had no musical training had diminished reading scores while Harmony Project participants’ reading scores remained unchanged over the same time span. 

Kraus’s lab also found that, after two years, neural responses to sound in adolescent music students were faster and more precise than in students in another type of enrichment class. The researchers tested the auditory abilities in adolescents from lower economic backgrounds at three public high schools in Chicago. Over two years, half of the students participated in either band or choir during each school day while the other half were enrolled in Junior Reserve Officer’s Training Corps classes, which teaches character education, achievement, wellness, leadership and diversity. All participants had comparable reading ability and IQs at the start of the study. The researchers recorded the children’s brain waves as they listened to a repeated syllable against soft background sound, which made it harder for the brain to process. The researchers repeated measures after one year and again at the two-year mark. They found music students’ neural responses had strengthened while the JROTC students’ responses had remained the same. Interestingly, the differences in the music students’ brain waves in response to sounds as described above occurred after two years but not at one year, which showed that these programs cannot be used as quick fixes, Kraus said. This is the strongest evidence to date that public school music education in lower-income students can lead to better sound processing in the brain when compared to other types of enrichment education, she added.

Even after the lessons stop, the brain still reaps benefits, according to studies on the long-term benefits of music lessons. In one study, Kraus’s team surveyed college students and asked them how many years they had music training. As they found with the elementary school students, college students who had more than five years of musical training in elementary school or high school had improved neural responses to sound when compared to college students who had had no musical training.

The Harmony Project provides instruments for the students who participate five or more hours a week in musical instruction and ensemble rehearsals. The project is year-round and tuition-free based on income, said Martin. Many of the programs build full-time bands in neighborhoods where the students live and the students agree to commit to the program from elementary school through high school, she said.

“We’re spending millions of dollars on drugs to help kids focus and here we have a non-pharmacologic intervention that thousands of disadvantaged kids devote themselves to in their non-school hours — that works,” Martin said. “Learning to make music appears to remodel our kids’ brains in ways that facilitates and improves their ability to learn.”

The Harmony Project has launched programs in other urban school districts, including Miami, New Orleans, Tulsa, Oklahoma, Kansas City, Missouri and Ventura, California.

(Image: Shutterstock)

Do we really only use 10% of our brain?

As the new film Lucy, starring Scarlett Johansson and Morgan Freeman is set to be released in the cinemas this week, I feel I should attempt to dispel the unfounded premise of the film – that we only use 10% of our brains. Let me state that there is no scientific evidence that supports this statement, it is simply a myth.

The concept behind the film is that through the administration of a new cognitive enhancing drug, our female lead character, Lucy, becomes able to harness powerful mental capabilities and enhanced physical abilities. These include telekinesis, mental time travel and being able to absorb information instantaneously. Viewed as such, the human brain should be essentially capable of these feats, we just fail to push our capacity. So if we can unlock the “unused” 90% of the brain we too could be geniuses with super powers?

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(Image credit: The insular cortex of an autism mouse model is already so strongly activated by a single sensory modality (here a sound), that it is unable to perform its role in integrating information from multiple sources. Credit: © MPI of Neurobiology / Gogolla)

Insular cortex alterations in mouse models of autism

The insular cortex is an integral “hub”, combining sensory, emotional and cognitive content. Not surprisingly, alterations in insular structure and function have been reported in many psychiatric disorders, such as anxiety disorders, depression, addiction and autism spectrum disorders (ASD). Scientists from Harvard University and the Max-Planck Institute of Neurobiology in Martinsried now describe consistent alterations in integrative processing of the insular cortex across autism mouse models of diverse etiologies. In particular, the delicate balance between excitation and inhibition in the autistic brains was disturbed, but could be pharmacologically re-adjusted. The results could help the development of novel diagnostic and therapeutic strategies.

Autism is a neurodevelopmental disorder characterized by impaired social interaction, verbal and non-verbal communication, and by restricted and repetitive behaviors. Diagnosis is solely based on behavioral analysis as biological markers and neurological underpinnings remain unknown. This makes the development of novel therapeutic strategies extremely difficult. 

As the cellular basis of autism spectrum disorders cannot be addressed in human patients, scientists have developed a number of mouse models for the disease. Similar to humans, mice are social animals and communicate through species-specific vocalizations. The mouse models harbor all diagnostic hallmark criteria of autism, such as repetitive, stereotypic behaviors and deficits in social interactions and communication.

Nadine Gogolla and her colleagues in the laboratory of Takao Hensch at Harvard University have now searched for common neural circuit alterations in mouse models of autism. They concentrated on the insular cortex, a brain structure that contributes to social, emotional and cognitive functions. ‘We wanted to know whether we can detect differences in the way the insular cortex processes information in healthy or autism-like mice’, says Nadine Gogolla, who was recently appointed Leader of a Research Group at the Max Planck Institute of Neurobiology.

As the researchers now report, the insular cortex of healthy mice integrates stimuli from different sensory modalities and reacts more strongly when two different stimuli are presented concomitantly (e.g. a sound and a touch). ‘We recognize a rose more easily when we smell and see it rather than when we just see or smell it’ says Nadine Gogolla. This capacity of combining sensory stimuli was consistently affected in all autism models the researchers looked at. Interestingly, often one sense alone elicited such a strong response that adding a second modality did not add further information. This is very reminiscent of the sensory hyper-responsiveness experienced by many autistic patients. The scientist further discovered that the insular cortex of adult autism-model mice resembled the activation patterns observed in very young control mice. ‘It seemed as if the insular cortex of the autism-models did not mature properly after birth’, says Gogolla.

For proper brain function, excitation and inhibition have to be in equilibrium. In the now identified part of the insular cortex, the scientists found that this equilibrium was disturbed. In one of the mouse models, inhibitory contacts between nerve cells were strongly reduced.

To test the influence of this reduction on sensory processing, the researchers gave mice the drug Diazepam, which is also known under the trade name Valium, to boost inhibitory transmission in the brain. Indeed, this treatment transiently rescued the capacity of the insular cortex to combine stimuli of different sensory modalities. The balance between excitation and inhibition in the brain is established after birth. The scientists thus treated young animals over several days with Diazepam. This treatment was efficient in reestablishing the insular cortex capacity for sensory integration permanently, even in adult mice that did not received any further treatment. Interestingly, also the stereotypic grooming of the animals was significantly reduced.

All autism models investigated showed alterations in inhibitory molecules. However, the alterations were very diverse. While in some models certain molecules were reduced, the opposite was true in another model. These results suggest that the disequilibrium between excitation and inhibition may be an important factor in the neuropathology of autism. However, future therapies will need to be carefully tailored to each particular subgroup of autism. For instance, an artificial boost of inhibition through a drug like Diazepam in healthy mice can throw the delicate equilibrium off and create changes in the insular cortex similar to those seen in the autism models. Whether a therapeutic strategy aimed on keeping the brain’s equilibrium between excitation and inhibition could be useful and if so, how to test the individuals’ status of the excitation/inhibition balance and how to implement individually tailored treatments, would need to be established through further studies and pre-clinical tests.

Watching neurons fire from a front-row seat

They are with us every moment of every day, controlling every action we make, from the breath we breathe to the words we speak, and yet there is still a lot we don’t know about the cells that make up our nervous systems. When things go awry and nerve cells don’t communicate as they should, the consequences can be devastating. Speech can be slurred, muscles stop working on command and memories can be lost forever.

Better understanding of how neurons and brains work could lead to new prevention, diagnostic and treatment techniques, but the brain is complex and difficult to study. If you were to hold your brain, you would likely marvel at how much it feels and moves like Jell-O. This tissue is composed of neurons and other supporting cells with tiny cell bodies, which generate electrical signals that determine how the brain and the nervous system function.

Those signals can be recorded and measured if a suitably small electrode is in the vicinity, but that presents challenges. Brain tissue is always moving in response to the body’s movement and breathing patterns. In addition, the nerve tissue is incredibly sensitive. If disrupted by a foreign body, the cells trigger an immune response to encapsulate the intruder and barricade it from the electrical signal it’s trying to capture and understand.

Working to develop intelligent neural interfaces

That challenge led Jit Muthuswamy, an associate professor of biomedical engineering at Arizona State University, Tempe (ASU), to pursue a robotic electrode system that would seek and maintain contact with neurons of interest autonomously in a subject going through normal behavioral routines. That led him to Sandia National Laboratories.

“We are working to develop chronic, reliable, intelligent neural interfaces that will communicate with single neurons in a variety of applications, some of which are emerging and others that are closer to market,” Muthuswamy said. “Applications like brain prostheses are critically dependent on us being able to interface and communicate with single neurons reliably over the course of a patient’s life. Such reliable neural interfaces are also critical to help us understand the dynamic changes in the wiring diagram of the brain.”

Key to the success of that robotic approach are the microscale actuators needed to reposition the electrodes. This led Muthuswamy in 2000 to seek out Sandia engineer Murat Okandan and the unique microsystems engineering capabilities available at Sandia’s Microsystems and Engineering Sciences Applications facility.

“The process flow we use to make these isn’t available anywhere else in the world, so the level of complexity and mechanical design space we had to design and fabricate these was immensely larger than what other researchers might have,” Okandan said. He has been working with Muthuswamy’s research team since that initial contact to find a suitable method to track individual neurons as they fire.

Earlier probes were made of a sharpened metal wire inserted in the tissue. The closer the probe is to the neuron, the stronger the signal, so experimenters ideally try to get as close as possible without disrupting surrounding tissue. The problem is that even a thin wire is too big; such a probe can take measurements around the neuron, but is far too cumbersome to be reliable over time.

Equally important is capturing the signals from an awake animal. Given their size and rigidity, current probes aren’t suited to gather recordings as the animal responds to its environment. Those units aren’t self-contained, so they keep the animals from moving around freely.

Microscale key to capturing signals from awake, moving animals

Microscale actuators and microelectrodes are critical to addressing both of those issues so probes can interact with individual nerve cells while doing minimal damage to surrounding tissue. The microscale actuators and associated packaging system developed at ASU and Sandia let a probe move autonomously in and out of the areas surrounding the cell, collecting measurements while compensating for any movement in the neuron or brain tissue.

About the size of a thumbnail, the self-contained unit has three microelectrodes and associated micro actuators. When a current runs through the thermal actuator, it expands and pushes the microelectrodes outward over the edge of the unit, which is flat to fit against the tissue. Because the actuator is so small, it can be heated to several hundred degrees Celsius and cooled again 1,000 times per second. It takes 540 cycles to fully extend the probe, but that can be done quickly – in a second or less.

The probes were implanted in the somatosensory cortex of rodents and rigorously tested in numerous experiments, both in acute and long-term conditions, Muthuswamy said. Animal procedures were carried out with the approval of ASU’s Institute of Animal Care and Use Committee, and experiments were done in accordance with National Institute of Health guidelines.

Muthuswamy said the neural probes demonstrated significant improvement in the quality and reliability of the signals when the probes were moved with precision using the Sandia microactuators in response to loss of neural signals. Further, he said, adding autonomous closed-loop controls to compensate for microscale perturbations in brain tissue significantly improved the stability of neural recordings from the brain.

Scale of this system is unique

Thermal actuators have been used for years at Sandia and elsewhere, but the scale of this system is unique. “The idea that we could build this system to achieve multiple millimeters of total displacement out of a micron-scaled device was a significant milestone,” said Sandia engineer Michael Baker, who designed the actuator. “We used electrostatic actuators in the past, but the thermal actuator provides much higher force, which is needed to move the probe in tissue.”

The microelectrodes are made of highly conductive polysilicon, which the team discovered has a number of advantages. It is almost metal-like in its conductivity, but durable enough for millions of cycles. It provides a signal-to-noise ratio much greater than previous wire probes and provides high-quality measurement signals.

Muthuswamy and Okandan currently are seeking to produce richer data with resolution in the submicron range to be able to go inside cells and take measurements there. They also are working on stacking the existing neural probe chips and decreasing the spaces between probes. Muthuswamy’s Neural Microsystems lab at ASU has developed a unique stacking approach for creating three-dimensional arrays of actuated microelectrodes.

“By building a three-dimensional array, we would have access to significantly more information, rather than just a slice,” Okandan said. “We’re very encouraged by the progress we have made, and are looking forward to building on that progress.”