Posted by: R. Douglas Fields | June 26, 2015

To Flee or Freeze? Neural Circuits of Threat Detection Identified

jack-nicholson-shelley-duvall-shiningSuddenly something streaks into your peripheral vision. Instantly, you jump back and raise your arms defensively. “What was that!” You exclaim in shock. Only then do you realize that the blurred streak you just dodged was a wayward basketball zinging like a missile on a collision course for your face. A rush of adrenaline flushes through your blood setting your heart pounding and muscles twitching, but there is nothing left to do. Your brain’s rapid response defense system has already detected the threat and avoided it before your conscious mind is even engaged. How is that possible, scientist, Peng Cao and colleagues of the Chinese Academy of Sciences wondered?

The mystery runs deeper. The sight of a sudden threat can trigger the completely opposite response–you may freeze like a deer in the headlights. Sometimes freezing is the best move. Spotting a rattlesnake in the bush, perhaps, is best handled by freezing. Running away could provoke the reptile to strike. But neither response–freezing nor fleeing–is a deliberate, conscious reaction to a threat that looms so quickly you can scarcely perceive what it is. These familiar facts must mean that all of the neural processing for this life-saving reaction takes place in neural circuits that are not located in the cerebral cortex where consciousness arises. These neural circuits that suddenly grip control of your behavior, known as the “fight-or-flight” response, must reside in deeper layers of the brain.

Previous research has shown that there is a high-speed pathway from the retinas in our eyes to the center of the brain’s threat detection region, which includes the amygdala and related structures comprising the limbic system. The majority of visual information detected by the retinas is transmitted to the cerebral cortex at the back of the brain, where complex analysis enables us to interpret the shifting patterns of light and shows cast on our retinas as objects in space, with color, dimension, motion, and identity. This sophisticated visual processing takes time. The subcortical pathway from the eyes to the amygdala is fast, but we are not able to actually see what the object is, because the necessary analysis for vision requires the cerebral cortex. But that route through the visual cortex takes far too long to dodge something like an opponent’s right hook. This high-speed, subcortical threat detection pathway is like a motion detector in a home security system. A moving object in the environment sets off an alarm that there is an intruder. Whatever it is, we can’t say for sure, but it should not be there!

Cao and colleagues traced out this circuitry in detail and they have identified the specific neurons that control whether we flee or freeze when an object suddenly looms in our visual field. The first relay point for high-speed information transmission from the retina to the brain is a region called the superior colliculus. There are three different types of neurons in the superior colliculus that can be identified by the different types of proteins that are contained in them. One set of neurons contains a protein called parvalbumin (PV). Mixed in with these, are neurons that contain either the protein somatostatin (SST) or vasoactive intestinal peptide (VIP). The researchers found that when they stimulated the PV neurons, the mouse immediately bolted or froze.

To stimulate these neurons selectively, the researchers used genetic manipulation to insert light-sensitive ion channels specifically into the PV neurons. These channels will activate when stimulated by light delivered through a fiber optic cable surgically implanted into the mouse’s brain, thereby causing the PV neurons to fire electrical impulses. When researchers flipped on the fiber optic light, the mouse fled away, and then it cowered after they stopped stimulating the PV neurons. This suggests that the PV neurons are a vital part of a threat detection circuit in the visual pathway. This function of PV neurons was further supported by monitoring the electrical activity in these neurons in anesthetized mice. The researchers found that when a virtual object on a computer screen that resembled a soccer ball came flying directly toward the animal’s head, the PV neurons began firing electrical impulses vigorously. The mouse’s heart rate accelerated and the stress hormone corticosterone increased in the blood stream–the bodily responses we experience as fear in the fight-or-flight reaction. But if the ball moved through the visual field in any other direction except on a collision course, the PV neurons remained silent. The mouse’s heartrate remained calm.

But what determines whether the animal flees or freezes? Interestingly the researchers found that the same neurons controlled both behaviors. Strong stimulation of the PV neurons caused the animal to escape rather than freeze. Either a brighter laser beam, or longer pulses of light, or higher frequency of flashes, would cause the animal to escape rather than freeze.

An interesting observation was that male and female mice responded somewhat differently. Females tended to escape, whereas males tended to freeze–stand their ground, perhaps, in the face of a sudden visual threat that stimulated these PV neurons. Further research will be required to uncover the additional factors that predispose males and females to respond differently to the same visual threat. The researchers then traced the circuit from these neurons and found that they did indeed connect to the amygdala, via a relay neuron in a part of the brain called the PBGN (parabigeminal nucleus). Further analysis showed that PV neurons stimulated neurons to fire by using the excitatory neurotransmitter glutamate. This is unusual because PV neurons elsewhere in the brain use a different neurotransmitter (GABA) to inhibit firing of the neurons they connect to.

This work advances our understanding of how visual threats trigger a fight-or-flight response, but there is much more to be discovered. “What are the functions of the other two pathways?” Peng Cao asks in response to my question about the next step in his research. (He is referring to the function of the SST and VIP neurons in the superior colliculus.)

“Do human beings share a similar pathway with rodents?” He wonders. Cao’s hunch is that these neurons are relevant to fear disorders. “We speculate that this pathway in mice may be genetically defined and subject to environmental modifications.” If humans have the same circuitry from their retina to the amygdala via PV neurons in the superior colliculus, Cao suspects that, “this pathway may be involved in fear disorders such as PTSD.” The amygdala is involved in fear and in learning to avoid dangers, but in addition to this anatomical evidence suggesting that PV neurons may be involved in fear disorders, Cao and his colleagues noticed something interesting. When they stimulated this pathway in the superior colliculus of mice repeatedly, the mice began to show depression and avoidance-like behaviors, much as people do who develop PTSD after surviving an extremely traumatic event.

Note: Readers who are interested in this subject may be interested in my new book Why We Snap, to be published this year by Dutton and available for pre-order now. The unconscious neural circuitry of the fight-or-flight response is involved in many other responses to threats, fear, and when they misfire: snapping in rage.

WWS cover low res

http://www.penguinrandomhouse.com/books/316682/why-we-snap-by-r-douglas-fields/

Reference
Shang, C., et al., (2015) A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice. Today’s edition of Science, June 26, 2015.

Photo credit: https://filmjamblog.wordpress.com/2012/11/11/the-light-house-cinema-book-club-the-shining/

Posted by: R. Douglas Fields | June 20, 2015

Bruce Jenner and Changing Your Brain’s Sex

Bruce Jenner after his sex change.  Did the treatment affect his brain?

Bruce Jenner after his sex change. Did the treatment affect his brain?

The debut of Bruce Jenner’s sex change on the cover of Vanity Fair was stunning, but superficial. A deeper question than her new-found beauty is: What about her brain?

Just like the anatomy of nearly every other part of the human body, the brains of guys and gals are slightly different. The biggest differences are in the part of the brain controlling automated behaviors and urges–hunger, thirst, sexual behavior and reproductive physiology–the hypothalamus. In fact, one part of the hypothalamus, the preoptic nucleus which is important in sexual reproduction, is twice as big in males as in females. But receptors for sex hormones are found on neurons and glia throughout the adult human brain. It is fascinating to wonder why. But the fact is that cells throughout the brain are acutely keyed into the amount of male and female sex hormones circulating in the body. From this alone it should not be too surprising to learn that sex differences in the brain are hardly limited to the hypothalamus.

His and her differences can be found throughout the brain. Parts of the limbic system, which is involved in arousal and other emotional responses; the basal ganglia, which is part of the brain’s reward system giving us that elated sensation of satisfaction; portions of the prefrontal cerebral cortex, notably the insula, as well as many other brain regions are slightly enlarged in one sex and diminished in the other. Overall, men’s brains have slightly more white matter than women’s, and men’s brains are bigger. So, what happens when a person undergoes a sex change procedure to correct an accident of birth in which a person’s mind is mismatched to the sex of their body?

A study performed in the Netherlands by Hilleke Hulshoff Pol and colleagues used MRI brain imaging to compare the anatomy of the brains of transsexual men and women before and after treatment to reassign their sex. In all, eight men changing their bodies into female, as in Bruce Jenner’s transformation into Caitlyn, and six transgender females becoming male were studied. In addition to surgery, male-to-female transsexuals are treated with “female sex hormones” (estrogens) and blockers of “male sex hormones” (anti-androgens) to suppress the production and physiological effects of androgens. In fact, estrogen and testosterone are normally present in both males and females, but the amount of each hormone differs by sex. Female-to-male transsexuals undergoing sex reassignment are treated with testosterone. The study found that after only four months of hormonal therapy there were widespread changes in the brains of transsexuals that align the brain’s anatomy with their body’s new sex.

The hypothalamus increased in size in transsexual women undergoing reassignment to men, and it shrank in transsexual men undergoing reassignment to women. Most striking was a dramatic decrease in total brain volume in male-to-female subjects. The opposite effect was seen in female-to-male subjects. The change in brain volume was not subtle. Total brain volume decreased by 31 ml (about the size of a shot glass) in male-to-female subjects after only four months of treatment. On the basis of this research one would expect that Jenner’s body would have lost not only muscle, but also lost brain tissue to adapt her body appropriately to the innate differences between sexes in their body and brain.

Appearances can be misleading. Are the anatomical changes taking place in the brains of transsexuals accompanied by functional differences? Another study used functional magnetic resonance imaging (fMRI) to investigate brain activity that was provoked by sexual arousal. In this study, male-to-female transsexuals were shown erotic nude pictures of either male or female bodies after their sex reassignment surgery. Sexual arousal stimulates activity throughout the brain, and the neural circuits that are involved are well documented. As one would expect, these include parts of the limbic system, hypothalamus, and prefrontal cortex. Electrical stimulation of the anterior cingulate gyrus in animal studies, for example, provokes autonomic and endocrine responses, including erection of the penis and secretion of hormones from the gonads. The study on transsexuals found that seeing nude pictures of men activated wide-spread areas of the brain of male-to-female transsexuals. Pictures of nude men caused a surge in brain activity that swept through the cerebellum, hippocampus, the amygdala and other parts of the limbic system, the brain’s reward center (caudate nucleus), and the insula. These changes in brain activity reflect brain function that is associated with sexual arousal being provoked by viewing the male nude body. All of these brain areas cooperate in the powerful sensation of sexual arousal, which involves many components, including cognitive, emotional, motivational, and autonomic physiological processes.

On the other hand, viewing female nudes activated predominantly the hypothalamus and septal areas. The hypothalamus is the most powerful control center of sexual behavior in animals, and the strong activation of the hypothalamus and septal area in male-to-female transsexuals viewing female nudes is perplexing. Other studies show that neither heterosexual individuals viewing videos of the same sex nor homosexual individuals viewing images of the opposite sex show activation of the hypothalamus. Although the reasons are unclear, activation of these areas triggering sexual responses in male-to-female transsexuals when viewing female nude pictures, which is opposite to the sexual orientation of these individuals, suggests that it is overly simplistic to regard transsexuals as homosexuals or heterosexuals who self-identify with the opposite sex.

Will these anatomical and functional changes in the brain of transsexuals also change behavior? In animal studies, it is well established that hormonal treatment alters both the brain and behavior. For example, treating adult female canaries with testosterone triggers changes in brain areas that control singing and this in turn changes the female signing behavior into that of a male canary. In studies of male-to-female transsexuals receiving estrogen treatment and testosterone suppression for three months, there is a measurable decline in anger, aggression, sexual arousal, sexual desire, spatial ability (usually males outperform females), and an increase in verbal fluency (usually females outperform males). The opposite behavioral and cognitive responses were found in female-to-male transsexuals.

Being born into the body of the wrong gender from your mind’s point of view is one of many accidents of birth that modern science can now help to alleviate. As the cover of Vanity Fair shows, the effects of hormonal treatment on the former Olympic gold medalist’s body were profound, but the treatment must also have changed Jenner’s brain. And so it must be. Otherwise, sex reassignment treatment would be a superficial failure.

References
Pol, H.E.H., et al., (2006) Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure. Europ. J. Endocrinology 155:S107-114.

Oh, S.-K., et al., (2012) Brain activation in response to visually evoked sexual arousal in male-to-female transsexuals: 3.0 Tesla functional magnetic resonance imaging. Korean J. Radiology 13:257-264.

Photo credit: “VanityFairJuly2015″ by Source (WP:NFCC#4). Licensed under Fair use via Wikipedia – https://en.wikipedia.org/wiki/File:VanityFairJuly2015.jpg#/media/File:VanityFairJuly2015.jpg

Posted by: R. Douglas Fields | May 5, 2015

Watching TV Alters Children’s Brain Structure and Lowers IQ

TV viewing changes brain structure and lowers IQ of children

TV viewing changes brain structure and lowers IQ of children

From the black-and-white days of I Love Lucy to the blue-ray lasers of today’s Game of Thrones in dazzling 3D, parents have worried that television might harm their child’s brain development. Now the answer is plain to see. Brain imaging (MRI) shows anatomical changes inside children’s brains after prolonged TV viewing that would lower verbal IQ.

Neuroscientists in Japan imaged the brains of 290 children between the ages of 5 and 18 years and sorted the data according to how many hours of TV each child had watched. The results showed significant anatomical differences in several brain regions that correlated with the number of hours of TV viewed. These findings were strengthened when the researchers re-examined the same children several years later and were able to see many of these anatomical changes taking place in the children’s brain over time. The more hours of TV children watched, the greater the changes were in brain structure.

The parts of the brain affected are involved in emotional responses, arousal, aggression, and vision. The brain regions that bulked up in children watching more television include gray matter increases in the hypothalamus, septum, sensory motor areas and visual cortex, but also in a frontal lobe region (frontopolar cortex), which is known to lower verbal IQ. Tests confirmed that the children’s verbal IQ had lowered in proportion to the hours of TV watched, ranging from 0 to more than 4 hrs/day. Changes were also observed beneath the cerebral cortex in the brain’s wiring network “white matter regions.” The changes in brain tissue were evident regardless of the sex of the child, age, family income, and many other factors.

The increase in visual cortex is likely caused by exercising vision in TV viewing, but changes in hypothalamus are characteristic of patients with borderline personality disorder, increased aggressiveness and mood disorders. The frontopolar region is active in monitoring and regulating internal mental states, and enlargements in frontopolar cortex are known to be associated with lower verbal IQ. Several previous studies have found lower verbal IQ and increased aggressiveness in proportion to the amount of television children watch. This new research uncovers the biological mechanism for these changes in behavior and drop in intelligence.

The brain alterations could be caused directly by TV viewing, or indirectly by the different life experiences gained through physical and virtual activities while the young brain is maturing. The more time spent sitting on the couch, the less time spent in physical activity, reading, and interacting with friends. Consider that children who watch 4 or more hours of TV a day, spend more than half of their free time watching the tube, assuming they devote 8 hrs for sleep and 8 hours for school. “Guardians of children should consider these effects when children view TV for long periods of time,” the researchers conclude.

Reference
Takeuchi, H., et al., The impact of television viewing on brain structures: Cross-sectional and longitudinal analyses. Cerebral Cortex, May, 2015; 25: 1188-1197.

Posted by: R. Douglas Fields | May 2, 2015

Heisenberg Uncertainty and the Baltimore Riots

tvtruck

Yesterday I encountered a colleague outside the elevator. He was profoundly troubled, as are many, anguished by the violence in Baltimore this week. The looting, burning, and scores of injured from angry youths hurling bricks at police were sparked by the violent death of a black man, Freddie Gray, in police custody.

“I was there yesterday,” I told my concerned colleague.

“What? Where?”

“I went to the CVS Drugstore that was looted and burned,” I replied.

In disbelief he asked, “What was it like?”

“I was too late. All of the DVR’s and other good stuff were already gone,” I said.

My reply can be taken as a crass, inappropriate outburst of dark humor, but there is a deeper message. It is a message that every scientist knows well and grapples with every day–the Heisenberg uncertainty principle. Fundamentally, reporters and scientists are driven by the same passion. Both are engaged in the challenging process of trying to find truth from primary evidence. Thus science and reporting, subject to the same types of errors, sometimes fail for similar reasons.

The facts are that a young black man died a violent cruel death while in police custody. His spine was snapped. He was restrained by handcuffs and leg irons and mortally injured while being transported inside a police wagon in the custody of six police officers. Angry riots erupted in rage against police brutality.

We watched it all live on TV. Hordes of angry black men armed with clubs and stones, facing off against a phalanx of police in black riot gear, wearing modern armor, helmets and shields that harken back to medieval battles between knights of the kingdom and oppressed peasants. We have seen this angry scene thousands of times through thousands of years of human history. As the city of Baltimore burned those of us who remember the horror of the summer of violence that plunged the country into chaos in 1968, were sickened.

“Can’t we all get along?” Rodney King pleaded during riots in Los Angeles in 1992. The black taxi driver was brutally beaten by Los Angeles Police officers after a high-speed chase in 1991. That beating by police was videotaped by a citizen appalled by the brutality erupting on the street beneath his balcony. After a trial that acquitted the police of serious charges, Los Angeles was consumed by riots in which 53 people were killed, 2000 were injured, and the neighborhoods were looted and burned. The military was dispatched to restore order, but many neighborhoods never fully recovered and the violence spread to other cities.

Rodney King’s plea echoed the bewilderment of everyone, and unfortunately the answer to his vexing question cannot be more obvious or more disheartening. Such turmoil and brutality are a deadly consequence of the human mind that within milliseconds of observing another person categorizes the individual into either “us or them.” It happens as quickly and as automatically as the brain attaches the color red or green to an apple. Paradoxically, those automated brain circuits are the essence of human success. They enabled our species to coalesce spontaneously into groups for mutual protection and common purpose, and often to do so through violence. This is the double-edged sword of the human brain. There can be no patriotism without a foreign adversary; no maternal bonding without seeing other babies differently.

The heavy thumping of helicopter blades circling overhead, the smell of charred wood, sirens squealing from every direction, echoing hysterically through the alleyways and streets it is impossible for me to tell where they originate. In a flash a fire truck, police car, or ambulance streaks past, ablaze with flashing red lights, racing toward the violence or away from it to hospitals or police stations.

Stepping into the neighborhood surrounding the CVS drugstore triggers screeching alarms in your brain that raise hair on the back of your neck and make your spine shiver. Groups of men loiter on street corners, drinking oversized cans of malt liquor from rumpled paper bags and smoking. Others pass the day sitting on the stoops of red brick row houses as if discarded. The windows of buildings are boarded with plywood weathered into a furry gray, warped and pealing, the homes and businesses have been abandoned for ages. It is a neighborhood of pawn shops, discount liquor stores, mom and pop corner markets with bars on the doors and windows, of bail bonds and check cashing establishments. Faded tent cities rot under an overpass, cluttered with shopping carts and scavenged junk. It is a perilous place of danger, crime, and drugs. 25 percent of the men are unemployed. They have nothing to do. Nowhere to go. Trapped, they have no way out. Children grow up in squalor and poverty.

All eyes follow me. They are the eyes of black men. I am white. There is not a thing in the world that either of us can do about that. Ours is the biological legacy of genetics; mine following a line of descent from northern Europe, theirs from Africa. It shouldn’t make much difference, but it does.

The violence, though, is not exactly the result of racism; it is the result of tribalism, a human trait that divides the world into us vs them. I suspected as much when I visited the boarded up drugstore, but today we learned that three of the six police officers charged with assaulting Freddie Gray are black. The driver of the police wagon now facing murder charges was a black officer. An unfortunate result of tribalism can be festering pockets of poverty, neglect, hopelessness, divisions between the haves and the have not’s, and instantaneous violence unleashed by brain circuits designed for herding, defense, and mutual cooperation in groups.

But this is not what I wish to explore in this article, which is targeted to those with an interest in science. As we watched the looting streamed live into our homes on TV, what we did not see was the view from the opposite direction. When I visited the burned and boarded up CVS store this week, in the midst of the protests and before the police were charged with the crime, I saw the streets lined with TV vans, satellite dishes, cameramen, soundmen, reporters interviewing men in suits and residents gathered around ogling and curious. Reporters, some of them from foreign countries, positioned carefully so that the camera angle would capture the person being interviewed with a snippet of boarded storefront in frame as the backdrop, carefully avoiding the throngs of other reporters and gawkers loitering around.

A good example is the large photograph on the front page of today’s Washington Post (May 2, 2015). It shows a black woman with orange blond hair standing up through the moon roof of her vehicle jubilantly cheering with her arms outstretched in the air. In her hand, partially cropped from the frame she holds not stones, but rather a cell phone. She is surrounded by others mugging for the camera. I was at that same spot on Wednesday. Look past her and you see not a crowd, but rather people milling about, eyes fixed on their cell phones, and two other cameramen caught in the frame trying to snap the same image that would carry the day’s narrative.

People do not behave the same in private and in public. If a reporter does not block them off, people will jump into the scene and clown for the camera. Morning news shows exploit this human phenomenon by shooting live weather reports on the streets outside the TV studio in Manhattan so people will mug for the camera and liven up the otherwise boring announcement of temperature and rain fall.

What effect did the media circus have on the youths watching the looting of stores or of protestors assembling, or of youthful gangs collecting into peer groups intent on confrontation with police? The situation sets up a sort of street theater in which people assume roles and act out in the way they see others doing or in the way that aligns them with others to which they aspire to be. The act of trying to capture the events runs the risk of altering them–the Heisenberg uncertainty principle.

Freedom of the press is essential. It is the only real means to find truth in public affairs. It is the only way to shed light on shady dealings, and to counter the inevitable corruption and abuses of power that otherwise overtake government and industry. Without the videos broadcast by the media of Rodney King being beaten and of the violent protests this week in Baltimore, there is no question that injustice and abuse of power would have gone unchecked. But the same conundrum that perplexes scientists applies to reporters.

Heisenberg’s principle cannot be overcome. It can only be recognized. The laser scanning confocal microscope in my laboratory has revealed wonderful insights for me into how living brain cells operate and communicate, but I know and must always be mindful of the fact that the laser beam that illuminates the cell is also stimulating it and changing it. The light illuminating the cell also heats it, blanches it, drives chemical reactions that generate toxic products, and so do the lights of TV cameras on a crowd.

Posted by: R. Douglas Fields | April 26, 2015

The Kathmandu earthquake will alter brain structure of survivors

Brain structure was altered in survivors of Wenchuan earthquake

Brain structure was altered in survivors of Wenchuan earthquake

The disastrous earthquake in Kathmandu has killed hundreds of people and brought grievous tragedy to thousands. Even among the survivors, the earthquake will leave its mark in the form of altered brain structure, according to neuroimaging research performed on survivors of the Wenchuan earthquake of 2008.

Studies by Lui and colleagues on survivors of the 2008 Wenchuan earthquake in China report changes in brain structure that can be seen by MRI. The 7.9 magnitude Wenchuan earthquake (also called Sichuan earthquake) rocked the mountainous central region of Sichuan province in southwestern China on May 12, 2008. 90,000 people died. 375,000 people were injured. Millions of people were rendered homeless.

A 2013 study was performed on 44 survivors, male and female, 25 days after the earthquake and compared to 38 matched controls who had their brains scanned for other reasons prior to the earthquake. The results showed a decrease in gray matter in the insula, hippocampus, and caudate, and an increase in the orpitofrontal cortex (OFC) and parietal cortex.

The OFC is important in modulating emotional responses in the hippocampus, amygdala, ventral striatum and insula. The increase in gray matter is consistent with elevated demands for top-down (that is executive functioning of the cerebral cortex) regulation of threat, fear, and stress circuitry in the limbic system. The increase in parietal cortex has been reported previously in other types of trauma survivors, and this may reflect enhanced neural activity related to the hyper-vigilant state.

The authors suggest that the lower grey matter volume in the insula, striatum, and hippocampus may result from decreased neurogenesis and increased synapse elimination that are seen in studies of experimental animals subjected to chronically elevated stress hormone levels. Acute stress elevates corticotropin-releasing hormone to activate the hypothalamic-pituitary-adrenal axis that is engaged in the “fight-or-flight” response, but prolonged elevation of this stress response is damaging to the brain and body in many respects.

Scientific data on the effects of stress on the human brain are difficult to obtain for ethical reasons, and extrapolating complex cognitive processes of human stresses from animal research is problematic. Studies of people who have survived natural disasters or traumatic events can provide important insights into the effect of stress on human brain structure.

Similar brain changes have been observed in people who have experienced other major life stresses. Studies have reported altered brain structure in patients with PTSD involving regions that function in threat detection and fear, notably the amygdala, hippocampus, and prefrontal cortex (anterior cingulate and medial frontal gyrus). The altered gray matter volume in the prefrontal to limbic and striatal systems found in earthquake survivors are recognized to be involved in emotional and conscious decision making. The striatum and parietal regions are activated in making decisions under time pressure. These regions also undergo changes in people with anxiety disorders, and these brain regions are engaged when processing fear and pain.

The authors conclude that survivors of severe emotional trauma may experience substantial change in brain function and also in the structural anatomy of the prefrontal-limbic, parietal and striatal brain system. These changes are not necessarily pathological. Rather they reflect in part the brain’s remarkable capacity to modify its structure and function rapidly in response to environmental experience. The changes found in earthquake survivor’s brains likely increase the ability of survivors to respond rapidly and appropriately to the danger and trauma. However, if these brain modifications do not return to normal after the threat has passed, this can result in dysfunction. This is well demonstrated by brave military men and women who suffer post-traumatic stress disorder after returning to a safe environment. Similar changes in the brains of people under stress that helped them survive in combat, can become debilitating after returning to civilian life.

References
Cohen, R.A. et al., (2006) Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei. Biol. Psychiatry 59: 975-82.
Davidson, R.J. (2000) Dysfunction in the neural circuitry of emotion regulation — a possible prelude to violence. Science 289: 591.
Lui, S. (2009) High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China. Proc. Natl. Acad. Sci. USA 106; 15412-7.
Lui, S., et al., Bran structural plasticity in survivors of a major earthquake. J Psychiatry Neurosci. 2013 Nov;38(6):381-7
McEwen, B.S. (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87:873-904.

Posted by: R. Douglas Fields | April 5, 2015

Snakes on the Brain

Pit vipers have infrared vision.  (Photo by author.)

Pit vipers have infrared vision. (Photo by author.)

After repeated encounters with a friendly rattlesnake last week I have snakes on the brain. Serpents are a storehouse of fascinating neuroscience. Infrared vision, venom, fast-twitch muscles to energize its “warning buzzer,” and more…

The western diamondback rattlesnake can rattle its tail at frequencies of 90 Hz and do this continuously for hours. This is about the frequency of sound handled by the subwoofer in your fancy home theater system. Even a piano virtuoso can’t begin to approach this feat of turbocharged muscle contraction executed with ease by the lowly cold-blooded viper. Try it. You’ll find you can tap your finger at a feeble maximum rate of about five taps/sec (5 Hz), and you’ll quickly poop out.

Hi speed rattling

High speed rattling


You may not know that the simple test of finger tapping rate provides revealing insight into your brain function. The maximum rate of finger tapping correlates with IQ. The finger tapping rate also declines with age in parallel with cognitive decline. So how does the rattler shake its tail into a fuzzy blur, you, and envious surf rock guitarist Dick Dale, might ask?

Dick Dale

Dick Dale


The tailshaker muscle is absolutely packed with energy producing mitochondria. This enables the tailshaker muscle to use oxygen at a much faster rate than muscles of other warm or cold-blooded animals. Hummingbirds have shared this design principle to flutter their wings so fast they can hover in place.

Infrared night-vision cameras are the ultimate imaging technological that can peer through walls and see clearly in complete darkness. Recall the ghostly glowing image of the Boston Bomber hidden inside the fiberglass boat shot from a police helicopter’s infrared camera as the SWAT team closed in? Cool technology, but snakes have had this stealthy equipment for eons.

Boston Bomber seen by infrared camera

Boston Bomber seen by infrared camera

Have a look at the lovely face of the rattler who greeted us repeatedly last week in the backcountry of Nevada. Notice those tiny openings below the eyes? Snakes do have nostrils, but snakes “smell” with their tongues (that’s another story). They flick their tongue in the direction of a warm blooded prey item just before striking–something I observed, but my trigger finger was too slow to catch it on camera. The second set of pits on the reptile’s face are unique sense organs that give pit vipers infrared vision and also give them their name “pit vipers.”

In 1937 Noble and Schmidt put blindfolds on rattlesnakes and found that the blindfolded snakes could magically strike at moving objects very accurately, such as a dead rat or a cloth-wrapped light bulb. Moreover, the snakes had the ability to distinguish between identical warm and cold objects. In 1952, Bullock and Cowles took an electrophysiological approach to understand the function of these pits and uncover how they worked. The scientists surgically exposed the superficial branch of the superior maxillary division of the trigeminal nerve that connects the pit organs to the brain. They suspended the slender nerve on a pair of wire electrodes that were connected to an electronic amplifier powering a loudspeaker. (Try that sometime. I’m leaving out some thrilling procedural details.) What they heard on the loud speaker was a constant barrage of nerve impulses shooting from the sense organ to the brain. The researchers found that when a warm or cold object was held in front of the snake’s face, the firing rate of nerve impulses either suddenly increased or decreased depending on whether the object was slightly warmer or colder than room temperature. An ice cube, for example, held in front of the snake caused the firing rate to instantaneously slow–within 50 ms (5/100s of a second). This response was much too fast to be explained by actual heating or cooling of tissue in the snake’s sense organ. They concluded that these sense organs had to be detecting infrared radiation emitted by warm objects– but how?

(I am fortunate to have had Ted Bullock as one of my mentors when I was a graduate student. His stories of delivery men and secretaries unwittingly walking into the lab and being perplexed by the sudden cacophony of buzzing surrounding them, emanating from burlap bags suspended from the ceiling, are precious. “Rattlesnakes,” he would explain offhandedly to the wide-eyed visitors who immediately departed, propelled by a jolting primal response embedded in the amygdala of human brains by evolution.)

It is difficult to imagine a sensory ability that we humans do not have, but these pit organs likely give the viper a visual sense. The neural pathways from the pit organs connect to the same brain structure as pathways from the snake’s eyes, the optic tectum. Behavioral studies by Bakken and Krochmal in 2007 indicate that the pit organ must be able to respond to temperature changes as minute as 0.001 degree C or less! This is sensitive enough to provide a detailed gray-scale image of objects from the emitted infrared radiation.

In 2002 Terashima and Ogawa reported that capsaicin, the fiery ingredient in hot peppers, caused the nerve terminals in the infrared receptors of snakes to degenerate. This is a clue that the molecular mechanism of detecting warmth somehow shares affinity with how we sense the burn of hot sauce. Indeed, in 2010, Grachevia et al., reported that the molecular basis of infrared detection by pit vipers was provided by an ion channel TRPA1 (transient receptor potential channels). This is a member of a large family of ion channels that give our own heat-sensing neurons the ability to respond to temperature changes and also give us the painful sensation of heat from hot sauce. The researchers discovered this by analyzing the genes expressed in sensory cells in the pit organs. There are many members of the TRP channel family, but more recent studies show that the same TRPA1 ion channel operates as a thermoreceptor in a wide range of animals from mosquitos to rats.

Countermeasures to heat seeking missiles--not news to squirrels

Countermeasures to heat seeking missiles–not news to squirrels


Fighter jets use thermal decoys to confuse heat seeking missiles, but ground squirrels have been using the same cleaver decoy against their venomous predators long before the DoD stumbled upon the same countermeasure. Rundus et al, found that California ground squirrels add an infrared component to their shaking tail when confronted by infrared-sensitive rattlesnakes, but squirrels don’t emit strong infrared signals from their wagging tails when confronted by gopher snakes, which lack the infrared receptors. Using a robotic squirrel to test the rattle snake’s response, the researchers found that when an infrared component was added to the flagging robotic tail, the rattlesnakes shifted from predatory to defensive behavior. This did not happen when the tail was flagged without the added infrared component. That behavior provoked the snake to strike.

Infrared emissions from squirrel tail only when encountering pit vipers, a countermeasure to rattlesnake infrared imaging.  PNAS 2007 104:14382-6.  Fig. 2.

Infrared emissions from squirrel tail only when encountering pit vipers, a countermeasure to rattlesnake infrared imaging. PNAS 2007 104:14382-6. Fig. 2.

Gees, already 1000 words and I’ve hardly gotten started. This story will have to be continued as a sequel–“Snakes on the Brain, Part II.”

Bonus Question: Can someone tell me what species of rattler it is in the photo above?

References

Bakkens, G.S. and Krochmal, A.R. (2007) The imaging properties and sensitivity of the facial pits of pitvipers as determined by optical and heat-transfer analysis. J. Exp. Biol. 210: 2801-10.

Bullock, T.H. and Cowles, R.B. (1952) Physiology of an infrared receptor: The facial pit of pit vipers.

Gracheva E.O., et al., (2010) Molecular basis of infrared detection by snakes. Nature 464: 1006-11.

Nobel, G.K., and Schmidt, A. (1937) Physiology of an infrared receptor: The facial pit of pit vipers. Proc. Am. Phil. Soc. 77: 263.

Rundus, A.S. et al., (2007) Ground squirrels use an infrared signal to deter rattlesnake predation. Proc. Natl. Acad. Sci. USA 104:14372-6.

Schaeffer, P., et al., (1996) Structural correlates of speed and endurance in skeletal muscle: the rattlesnake tailshaker muscle. J. Exp. Biol. 199: 351-8.

Terashima, S. and Ogawa, K., (2002) Degeneration of infrared receptor terminals of snakes caused by capsaicin. Brain Res. 958: 468-71.

Tomoko Aoki, Yoshiyuki Fukuoka (2010) Finger Tapping Ability in Healthy Elderly and Young Adults. Med Sci Sports Exerc. 2010;42(3):449-455

Warner MH, et al., (1987) Relationships between IQ and neuropsychological measures in neuropsychiatric populations: within-laboratory and cross-cultural replications using WAIS and WAIS-R. Clin Exp Neuropsychol. 1987 Oct;9(5):545-62.

Posted by: R. Douglas Fields | March 17, 2015

Big Brains/Little Brain: Whale Brains Provide Clues to Cognition

The cerebellum of whales suggest its role in higher level cognition.  Photo by the author

The cerebellum of whales suggest its role in higher level cognition. Photo by the author

A fascinating report on NPR by science correspondent Jonathan Hamilton yesterday (March 16, 2015) tells the story of Jonathan Keleher, a rare individual born with a major portion of his brain missing: the cerebellum. The name in Latin means “little brain,” because the cerebellum sits separately from the rest of the brain looking something like a woman’s hair bun. Neuroscientists have long understood that the cerebellum is important for controlling bodily movements, by making them more fluid and coordinated, but researchers have also long appreciated that cerebellum does much more. Exactly what these other functions are, have always been a bit mysterious. It is difficult to pinpoint the more hidden functions of the cerebellum, because some of them seem not to involve straight-forward actions that can be easily observed, for example controlling breathing or vision. But this suggests that the little brain is doing something far more complex and interesting.

Whale brains provide interesting insight into the possible functions of the cerebellum beyond its important role in regulating movement. A comparison of cetacean brains supports the growing body of research indicating that the cerebellum contributes to higher level cognitive function. A study by Sam Ridgway and Alicia Hanson compares the brains of two animals with the largest brains on earth: sperm whales and killer whales. (Pause for a minute and consider that last sentence. Having done some anatomical studies on whales as a graduate student, I can say that doing neuroanatomy on an animal that can reach 60 feet in length and 60 tons in weight, is not easy. This is not a job for a scalpel. Electric saws, chisels, and hatchets are the surgical instruments required.) Killer whales are well known from marine aquarium shows, and sperm whales are the enormous beasts harpooned in Herman Melville’s tale of Captain Ahab’s quest. What this study found is that the animal with the biggest brain on the planet (sperm whale) has a smaller cerebellum (proportionately) than a killer whale. In fact, in proportion to the size of the cerebrum, sperm whales have the smallest cerebellum of any mammal on land or sea. Why?

Both killer whales and sperm whales swim in the same way, by undulating their enormous tail (flukes). Both of these whales echolocate. They both have long gestational periods and live long lives. They are closely related animals evolutionarily; both being members of the toothed whales (odontocete). The mass of the killer whale’s cerebellum is 13.7% of its entire brain mass, but the cerebellum of sperm whales is only 7% of its brain mass.

Killer whales are much different from sperm whales in their behavior. Killer whales are the ocean’s top predator, working in organized groups to hunt down a large variety of different fish, birds, and marine mammals, whereas sperm whales graze in the deep ocean on primarily one food source: giant squid and some fish. The authors conclude that the group coordination during hunting by killer whales on a variety of elusive prey requires higher level cognition and creativity to outfox their prey, to communicate and cooperate with other members of their group. This could explain why they have a larger cerebellum proportionately than sperm whales.

The researchers cite other evidence in support of the function of the cerebellum in higher level cognition. The cerebellum increases in size going up the evolutionary tree from monkeys to great apes. Increased cerebellar size is also seen in hominoid evolution. Fossils show that early hominids had a relatively small cerebellum.

Mr. Kehler’s remarkable brain is giving similar insights into the function of this poorly understood part of the brain, but also more. His inspirational story shows how adaptable the human brain can be in some people who are fiercely determined to develop their abilities to the highest level possible.

References:
Hamilton, J (2014) A man’s incomplete brain reveals cerebellum’s role in thought and emotion. NPR, March 16, 2015 http://www.npr.org/templates/transcript/transcript.php?storyid=392789753.

Ridgway, S.H. and Hanson, A.C. (2013) Sperm whales and killer whales with the largest brains of all toothed whales show extreme differences in cerebellum. Brain Behavior and Evolution, 83;266-274.

Posted by: R. Douglas Fields | February 5, 2015

Brian Williams ‘False Memory’–a Neuroscience Perspective

Brian WilliamsNBC News anchor Brian Williams apologized for his erroneous account of being aboard a helicopter forced to make an emergency landing after being hit by enemy fire while reporting on the Iraq war in 2003. Williams blames the fallibility of human recall for the error. How can the neuroscience of memory (and false memory) provide insight?

“I would not have chosen to make this mistake,” Williams told the Washington Post. “I don’t know what screwed up in my mind that caused me to conflate one aircraft with another.”

Williams’ bewilderment is perhaps understandable. We all know that memory is fallible. Eye witness testimony has been shown often to be false, even though the witness firmly believes his or her account of what they personally experienced. Rapists sent to prison on the basis of a victim identifying the attacker without any doubt, have been found to be innocent through DNA evidence years later.

“I spent much of the weekend thinking I’d gone crazy, Williams says in the Washington Post article. “I feel terrible about making this mistake.” This is the same remorse and disbelief that shakes the victim of a rape who is forced by facts to accept that her memory was false.

To understand false memories one must first understand what a memory is and what it is not in terms of brain function. Memory is not a recording. A recording of our day-to-day experiences would be worse than useless; it would be counterproductive. Memories are fabrications, and they have to be.

“That hole [in the helicopter] was made by a rocket-grenade, or RPG. It punched cleanly through the skin of the ship, but amazingly it didn’t detonate.” This account by Williams we now know is entirely false, but consider for a moment the following. What if this picture of the helicopter with a hole pierced through it was indeed a snapshot of a true experience embossed in the mind’s ‘memory bank.” Even if it were accurate, this picture is not a memory. This picture would be much like a single frame snipped out of a movie reel. Without context, sequence, and significance in relation to other experiences, there is no memory of what had transpired.

Consider all the various sights, sounds, tastes, smells, emotions, that must be combined together to form a coherent memory, and assembled in the proper temporal sequence and in meaningful relationships between these new experience and past experiences that are essential to form a coherent memory. These multiple sensory inputs and the other aspects of mental processing required to associate emotions and other events with the new experience, must somehow tie together multiple mental functions taking place all over the brain into one scene, which we call a memory. Memory researchers call this a schema. How this assembly is accomplished is still poorly understood, but this stitching together of a mental scene is the essence of what a memory is.

One of the brain’s remarkable abilities is that it can fill in missing information to connect the dots and form a coherent memory. We can recognize a specific individual from a skilled cartoonist’s squiggly line. This mental filling in is where false memories can begin to form.

Secondly, a memory needs to be continually updated. Of what use is an outdated image of a person in our memory in recognizing that individual now or in the future? Even a picture of a loved one from years ago surprises us because we have completely forgotten that they once looked that way. That memory has been erased. We constantly update memories according to new information, and much of this happens while we sleep. Memories are not recordings; they are fabrications.

Can Williams’ false report be understood in the context of a false memory? Consider that Williams is a reporter. His function and purpose while on the scene in Iraq was to record facts and to do so accurately. There is no opportunity for false memory in this situation. Just as a scientist would never falsify data, because doing so would completely undermine their objective, neither would a reporter. Researchers do sometimes fudge data, but scientists do not. Likewise, there is not and cannot be any false memory in the mind of a reporter.

Reference
Paul Farhi February 4, 2015. Brian Williams admits that his story of coming under fire while in Iraq was false. The Washington Post

http://www.washingtonpost.com/lifestyle/style/brian-williams-admits-that-his-story-of-coming-under-fire-while-in-iraq-was-false/2015/02/04/d7fe32d0-acc0-11e4-9c91-e9d2f9fde644_story.html

Posted by: R. Douglas Fields | January 27, 2015

Synapse Poisons in Croc Bile Beer the Likely Killer in Mozambique

aleOn January 11, 2015 news swept the globe reporting that scores of people died and 200 were sickened by drinking beer poisoned with crocodile bile in Mozambique. Thinking is now shifting to the possibility of poisoned synapses, not reptilian bile as the cause of these deaths.

A horribly tragic incident occurred at a funeral on January 9, 2015 in Mozambique, when people who had come to pay their last respects suffered poisoning from consuming the traditional home-made beer that was served. The mass fatalities of over 70 people devastated families, leaving many children orphans overnight. The toxic substance in the beer is still not known, but the media frenzy is astonishing. Is crocodile bile a deadly poison? How much bile can a person drink anyway? What is it in croc bile that could be so potent, trace amounts too weak to taste could kill and sicken hundreds of people?

Science writer for Forbes, David Kroll, traced the story back to the source. What he found was rumor and superstition, and what is more important, a likely cause of all this death. I refer you to his article for the details of his investigation and the suspicion that croc bile was not likely the poison in this brew.

The cause of these deaths is not yet known, but if it wasn’t croc bile that killed the beer drinkers, let’s have a look at the alternatives being suggested–all of them are related to nervous system function, and along the way delve a bit into the science of homebrew.

Not what made Milwaukee famous

The beverage brewed in Mozambique is a far cry from the Bud Light that most Americans associate with beer. Called pombe, the brew is a mixture of corn, bran, sorghum, and sugar, fermented with a different species of yeast (Schizosaccharomyces pombe) from the Saccharomyces cerevisiae used for making beer and wine. Beer as we know it is made from malted barley and hops. The fermented drink in Mozambique appears to somewhat resemble the corn-based traditional beverage, called chicha, which has been made in South America for centuries.

Professor Javier Carvajal Barriga, a microbiologist at Pontificia Universidad Católica del Ecuador in Quito, Ecuador, has resurrected yeasts from ancient fermentation vessels and other sources all over the world, including fermentation pottery from a pre-Incan tomb. From a fermentation vessel dating from 650 AD, Professor Carvajal Barriga resurrected dormant yeast and discovered an entirely new species, which he named Candida theae. This discovery also provided clues to how the ancient brew was made. Human spit was used to break down the corn starch into sugar that yeast can ferment into alcohol. (Saliva contains the starch digesting enzyme, amylase). His microbiological research also supported what conquistadores recorded about the traditional chicha recipe: that human feces were added to start the pot fermenting.

This is not how beer is made today. Malted barley is used, making spit unnecessary. Malting is a process whereby the grain is moistened and allowed to start sprouting. When a seed sprouts it generates enzymes to break down the starch to sugar, which is the energy store that will feed the sprouting plant. Beer makers hijack Nature’s intentions by roasting the freshly sprouted barley to stop the germination process right after the enzyme is made. Then the brewer adds water to make a porridge that must be held at a precise sequence of temperature steps to coax the enzymes to make sugar from the starch. Yeast can then convert the sugar to alcohol and carbon dioxide. How early humans figured this all out is baffling, but no less amazing than the ingenuity used to make chicha.

So I when I heard of this mass death in Mozambique from poison pombe, I contacted Professor Carvajal Barriga for his insights.

“I’m really surprised by this news of poisonous beer,” Carvajal Barriga says. In the middle ages they used rats, cats, a number of flowers and other elements like fungi to give magical properties to their brews. Some of those primitive beers would have been poisonous as well.”

When I visited his lab in Quito in 2012, we shared a wonderful Belgian style ale that Carvajal Barriga had brewed from yeast he resurrected from an ancient oak vat that had held the first beer brewed in America. I remember him telling me how plants or mushrooms with psychoactive properties often would be added to the ancient chicha. (He could see this, by identifying species of yeasts in the ancient fermentation vessel that are associated with these other plants.) The ancient brew masters resorted to this because the species of yeast that they had to work with is killed by relatively low alcohol concentrations. So, unable to achieve the alcohol content of the beer we enjoy today, (outside the state of Utah), the bier meisters would toss in other substances to give the brew more of a kick.

“The poisoning in Mozambique may be due to chemicals added to the beer via flowers or even microtoxins produced by molds living on cereals,” he suggests.

This is the same theory considered by Kroll in his Forbes article; specifically, the possibility that the foxglove plant might have been added to the Mozambique brew. Foxglove is the source of digitalis, a drug used for regulating heartbeat. The plant compound acts on the vagus nerve, part of the parasympathetic nervous system regulating heartbeat, and also acts directly on cardiac muscle, by changing the concentration of sodium ions inside these nervous system cells. The cellular voltage produced by neurons and muscle cells results from an imbalance in charged ions across the cell membrane–just as voltage is produced in a battery. Digitalis inhibits a membrane pump (sodium-potassium ATPase) that pushes sodium ions out of the cell and sucks potassium ions into the cell. When the pump is impaired by digitalis, sodium ions seep back in and the cellular voltage drops. This has a number of consequences, most importantly, changing the amount of calcium ions inside the cell. Calcium ions control many vital cellular processes, including the firing of synapses (i.e., release of neurotransmitter).

Poisoning synapses

Mass deaths at social gatherings often result from food poisoning, frequently caused by clostridial toxins made by bacteria found naturally in the soil, for example botulinum toxin. Botulinum toxin is one of the most deadly toxins known to man. The reason for this is that this toxin attacks the fundamental mechanism of communication in the brain–synaptic transmission.

When a nerve impulse reaches a nerve terminal, voltage-sensitive channels in the neuronal membrane open briefly and admit a spurt of calcium ions. These ions activate a protein called synaptotagmin, which is part of a complex machinery of molecules that tether synaptic vesicles next to the cell membrane of the nerve terminal. Synaptic vesicles are like submicroscopic “water balloons” filled with neurotransmitters, small molecules of various types that carry messages between neurons. When stimulated by an electrical impulse, this molecular machinery causes the synaptic vesicles to fuse to the cell membrane and rapidly dump its contents out of the neuron to stimulate receptors on the next neuron in the circuit.

Botulinum toxin (and tetanus toxin), cut the synaptic vesicle release proteins, thereby blocking synaptic transmission. (Either the synaptic proteins synaptobrevin, SNAP-25, or syntaxin can be attacked, depending on the specific type of Botulinum toxin.) The consequences of cutting communication lines in the nervous system are catastrophic, and food poisoning from clostricial toxins can kill quickly.

But beer is not often a source of food poisoning. This is because the process of brewing beer, unlike the process of making wine, requires prolonged boiling. Even a dead rat would become sterilized in the process of brewing beer. The poisoning in Mozambique most likely attacked synapses, but in a different manner.

Organophosphates

The extraordinary potency of clostridial toxins inspired the creation of man-made neurotoxins that work in a similar way for use in warfare against other people (nerve gas) or against insects (pesticides). At this point, this explanation seems the most likely cause of the mass death among the beer drinkers in Mozambique, according to the Forbes article. The brew was concocted in large barrels. If these or other utensils used in brewing, had been recycled from drums with pesticide residue in them, even low levels of organophosphates could have proven fatal.

Organophosphate pesticides work by inhibiting neurotransmission at synapses that use the nerurotransmitter acetylcholine to communicate. This includes the synapses called neuromuscular junctions that control our muscle contractions. Once acetylcholine is released from the nerve terminal and activates the muscle, the chemical signal to contract muscles must be terminated. This is accomplished by an enzyme in the synapse (acetylcholinesterase), which rapidly breaks down acetylcholine. Organophosphate pesticides and Sarin nerve gas prevent this enzyme from working. Unable to control muscles for breathing and other essential bodily functions that are controlled by synapses using acetylcholine, the victim (bug or enemy) dies quickly and quite miserably.

This brings the Mozambique tragedy close to home. An FDA analysis determined that 49% of fruit, 29% of vegetables, and 26% of grain products produced in the United States have pesticide residue. 50% of shallow water wells have pesticide contamination at detectable levels. Children are especially vulnerable to pesticide exposure because their smaller bodies make the same amount of pesticide on one apple a much higher dose than for an adult. Also, children crawl on the floor, play in dirt and put things in their mouths, increasing their exposure to pesticides. Organophosphate pesticide levels in people living in agricultural areas are higher than in people living in urban areas, but in a large sample of children between ages 8-15 in the general population, the level of pesticide residue in urine samples correlates directly with a risk for attention deficit hyperactivity disorder (ADHD).

In a 2012 review article in the journal Pediatrics the authors conclude that organophosphate exposures that are being experience by US children in the general population may have adverse neurodeveopmental consequences. The consequences of organophosphate exposure to the fetus and young children are known to include decreased IQ, ADHD, neurodevelopmental disorders, and cancer. For example, a study of Latino farm worker families from agricultural regions showed that organophosphate levels in urine from pregnant women were associated with lower IQ in their children at 7 years of age. Finally, many veterans of the Gulf War suffered chronic illness, which appears to be related to low-level exposure to Sarin gas and organophosphate pesticides they were exposed to on the battlefield.

We can only hope that the cause of the poisoning in Mozambique can be found, and that we learn from the tragedy.

Figure Caption An ale made by infusion mash of English pale malted barley, crystal and dextrin malt, and Monteuka, Nelson Sauvin and Green Bullet hops from New Zealand and Nottingham Ale yeast.

References

Fields, RD (2012) Raising the Dead: New Species of Life Resurrected from Ancient Andean Tomb Scientific American on-line February, 19, 2012 http://www.scientificamerican.com/article/new-species-resurrected-ancient-andean-tomb/

Kroll, David, (2015) Did crocodile bile really kill 73 people in Mozambique. Forbes January 12, 2015 http://www.forbes.com/sites/davidkroll/2015/01/12/what-is-crocodile-bile-and-is-it-really-poisonous/

Kroll, David, (2015) Crocodile Bile Expert Suspects Toxic Pesticide In Mozambique Tainted Beer Tragedy Forbes, January 14, 2015

http://www.forbes.com/sites/davidkroll/2015/01/14/crocodile-bile-or-toxic-pesticide-mozambique-death-toll-at-73-from-tainted-beer/

Roberts, JR and Karr CJ Pesticide Exposure in Children Pediatrics 130: e1765, 2012

US FDA Center for Food Safety and Applied Nutrition. Pesticide residue monitoring program http://www.fda.gov/Food/FoodborneIllnessContaminants/Pesticides/UCM2006797.htm

Posted by: R. Douglas Fields | January 14, 2015

Neuroscience of ‘Under the Skin,’ Starring Scarlett Johansson

UnderSkin (2)In the eerie science fiction film, Under the Skin, starring Scarlett Johansson as an alien vixen clothed in human skin, roaming the earth in search of single men for nefarious purposes, a turning point comes when she offers a hooded man on a dark road a ride in her vehicle. When the man takes off his hood we see his shockingly disfigured face. It is not make up. The disfigurement is caused by a genetic condition, neurofibromatosis, affecting actor Adam Pearson. Pearson’s brother has the same disorder, but no disfigurement. Instead he suffers memory problems. The film is a head scratcher–in the best possible way–but neurofibromatosis is not. Let’s have a look.

When Adam Pearson was a school boy he was often taunted as “Elephant Man” by bullies. In fact, one prevailing theory is that the real Elephant Man, Joseph Merrick, suffered from neurofibromatosis. A new paper by Huntley, Hodder and Ramachandran, in the journal Gene, gives a vivid account of the discovery of the Elephant Man in Victorian England, and recounts the scientific sleuthing over the last 125 years to identify the medical condition that caused Merrick to have skin and body features resembling an elephant.

Joseph Merrick was a single-case study presented to the Royal London Hospital in 1884 at the age of 21. Merrick, from Leister England, was discovered at a Freak Show by Sir Frederick Treves, Surgeon to Queen Victoria. The doctor did not routinely seek such entertainment; he went there specifically to see a man on exhibition advertised as having the features of an elephant. Treves paid a shilling to have a private viewing after hours. Sir Treves’ examination documented that Merrick had a large number of disfiguring growths all over his body that made it difficult for the man to speak, sleep or walk. Many of his bones were misshapen and his skull was grossly enlarged, and malformed. Sir Treves described Merrick as “the most disgusting specimen of humanity that I have ever seen.” (Read that with a proper British accent for full effect.)

Soon after the paper describing the case of the Elephant Man was published in 1885 in the journal Trans. Pathol. Soc. London, “A Case of Congenital Deformity,” Freak Shows in Jolly Old London were outlawed. Adding to that tragedy, Merrick was robbed of his life savings by his show manager and he ended up stranded at the Liverpool Street Station, homeless, penniless, and unable to make himself understood because of his speech impediment. The police brought him to Sir Treves, who appealed to the good-hearted public for assistance in a letter to the Times. Within one week he collected enough money to support Merrick the rest of his life at the hospital.

For the rest of the fascinating story of the real Elephant Man, and a recent determination of the medical condition that afflicted Merrick, I highly recommend this new article in the journal Gene. Spoiler alert: the authors conclude that Merrick did not have neurofibromatosis, but instead suffered from a condition called Proteus Syndrome, which is caused by a mutation in the gene PTEN.

Neurofibromatosis is a genetic disorder that causes tumors to grow in the nervous system. I actually published a small paper on neurofibromatosis from research in my lab, which is as close as I expect I will ever get to Scarlett Johansson.

In your dreams, buddy.

In your dreams, buddy.

The tumors in nerves cause disfigurement. As you would expect, they often cause a wide range of neurological problems, from hearing loss to learning impairment, depending on where the tumors grow and interrupt normal communication through nerve axons.

Neurofibromatosis 1 (NF1) causes harmless spots on the skin and tumors under the skin anywhere on the body. Bone growth is often deformed, for example by bowed lower legs or a curved spine. Mild learning disabilities are common, as well as attention-deficit/hyperactivity disorder (ADHD), but not in all cases. The head is typically larger than normal. So there are indeed several similarities to the features exhibited by the Elephant Man, but these are only superficially similar to neurofibromatosis.

Neurofibromatosis 2 (NF2) also causes nerve tumors by unregulated growth of Schwann cells, the glial cell of the peripheral nervous system. Schwann cells form the myelin sheath that is essential for rapid impulse conduction through axons in peripheral nerves. Other Schwann cells encase bundles of slender axons that conduct impulses slowly because they lack the myelin insulation. Hearing loss and balance problems are a common but the tumors can grow in many different nerves causing a wide range of symptoms.

The NF1 gene is on chromosome 17. It normally makes the protein neurofibromin, which helps regulate cell growth. NF2 is caused by the NF2 gene located on chromosome 22. This gene produces the protein merlin, which also controls cell growth.

In either case, you need to inherit only one copy of the mutant gene to get the disorder (autosomal dominant), which means that if you have neurofibromatosis there is a 50:50 probability that your offspring will inherit the disease.

“My kids are going to be genetically awesome anyway,” Pearson says displaying the spunk that has made him a successful actor in a major film. “Now that I’ve appeared nude with Scarlett, I want to be a Bond Villain,” he says. Pearson is also a supporter of the charity Changing Faces which supports people who have medical conditions or injuries that affect their appearance by helping them cope with life. Fundamentally, the coping techniques are to help such people deal with other people’s prejudices and societal reactions to those who are disfigured by burns, injuries, or genetic deformities.

In the movie, the moment when the female alien in human skin meets the character played by Adam Pearson the plot turns, because like the alien herself, the real person who is Adam Pearson, is to be found under the skin.

***Coda***

After my scathing reviews* debunking the inane science fiction movie Lucy, starring Scarlett Johansson, it is nice to have this opportunity to endorse Under the Skin. People either love or hate Under the Skin. This can be explained by the fact that Lucy is a movie, but Under the Skin is a film. A film is a work of art. Art presents captivating and thought-provoking images and performances, left to interpretation by the viewer. Art transcends language in illuminating humankind and the natural world. Under the Skin exposes core issues of sex, gender roles, what it is to be human, and inhuman, but it does it in a way that requires the viewer to bring to the performance their own elusive perceptions, intrinsic beliefs, and fantasies that lie beneath the surface of thought.

For a good review of this film I recommend:

Seitz, M.A. (2014) Under the Skin Movie Review. http://www.rogerebert.como/reviews/under-the-skin-2014

* Fields, R.D. (2014) Cinema Peer Review: Douglas Fields Reviews ‘Lucy’ World Science Festival, July 29, 2014 http://www.worldsciencefestival.com/2014/07/cinema-peer-review-lucy/

*Fields, R.D. Lucy Debunked, Science Friday, August 8, 2014 http://www.sciencefriday.com/guests/r-douglas-fields.html#page/full-width-list/1

References

Changing Faces http://www\changingfaces.org.uk

Day Elizabeth (2014) How Scarlett Johansson helped me challenge disfigurement stigma. The Guardian, April 12, 2014.

Huntley, C., Hodder, A., and Ramachandran (2015) Clinical and historical aspects of the Elephant Man: Exploring the facts and the myths. Gene 555:63-65.

Pearson, A. (2014) ‘Now that I’ve appeared nude with Scarlett, I want to be a Bond villian’: TV’s Beauty and the Beast star hopes to beat prejudice after big-screen debut. Daily Mail, March 29, 2014.

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