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

The Taste of Thanksgiving

5176608082I took a sip of sugary Coke and was struck by a hideous intense blast of aluminum. I rushed to the sink and spit out the tainted drink. Poison! What’s wrong with this Coke! I took another tentative sip. I was slammed again by the overwhelming metallic taste. I spat out the poison by rapid reflex. This can of Coke must have been contaminated during manufacturing! Or, had the likes of the Tylenol Killer switched to soft drinks? Then I remembered. . . the taste of Thanksgiving and mountain climbing!

An hour earlier I had taken a pill to help me combat the effects of high altitude in preparation for climbing Cotopaxi, a 19,347 foot active volcano in Ecuador. The pill works by resetting the pH (acidity) in the blood to offset the effects of panting at high altitude in the body’s struggle to extract oxygen from the thin atmosphere. At high altitude, a mountain climber pants breathlessly as if running a marathon, but the effort only collects enough oxygen molecules to fuel muscles sufficiently to lug one leg a step forward. Then the climber pants some more–three quick breaths– and heaves the other leaden leg one step forward. It is pure misery–and ecstasy!

The problem with this is that when we exhale, we release carbon dioxide from our blood stream, but all that huffing and puffing in high altitude eliminates too much CO2 from the body. This drops the acidity in the blood sharply (making it alkaline), because CO2 dissolves into solution to make carbonic acid. The proper amount of carbonic acid in the blood is crucial to keep the acidity in our blood at the level needed for hemoglobin in our red blood cells to extract oxygen. Part of the acclimatization process that mountain climbers undergo by taking days or weeks to slowly ascend a mountain to avoid getting altitude sickness involves changes in the body’s chemistry to restore normal levels of acidity in the blood. (Stick with me here–this will soon come back to Thanksgiving dinner!)

Within minutes of our blood becoming alkaline, our kidneys respond by increasing excretion of bicarbonate in urine until this offsets the low CO2 levels in our blood. (Bicarbonate is the same stuff used as an over-the-counter antacid to treat indigestion. Dumping the body’s natural antacid restores acidity in the blood stream to normal levels.) There are many other bodily responses in acclimatization to high altitude, but this one is vital, and it is quite obvious and annoying as climbers find themselves suffering frequent and urgent exits from the warmth of a down sleeping bag to let their kidneys do their work overtime throughout the freezing cold night.

Acetazolamide (the trade name is Diamox), is a carbonic anhydrase inhibitor. Inhibiting carbonic anhydrase in the kidney stimulates excretion of bicarbonate in the urine. By taking the pill before climbing, a mountaineer can jump start the process of acclimatization and help prevent high-altitude illness. This is important because high altitude illness can be far more serious than a pounding headache–it can be deadly. One of the effects of low oxygen is to make blood capillaries in the brain leaky. As fluid oozes out of capillaries the brain swells inside the bony skull, causing brain damage and death.

That’s when I suddenly remembered that one of the side effects of acetazolamide is to disrupt the sense of taste in a very specific way. Our sense of taste comes from five main categories, sweet, salty, bitter, sour, and umami; each of which is the result of a specific set of taste receptors in our tongue that respond selective to one of these tastes. Umami is the taste that we associate with savory flavor, but sour is the body’s pH meter–it is a sensor for acid. In a paper published in the journal Science in 2009, researchers reported that they had identified a class of taste-receptor cells in the tongue that respond to carbon dioxide (carbonic acid). This is the gas that gives sodas, beer, champagne, and other carbonated beverages their distinct tang. The molecular sensor in these taste cells was found to be an enzyme called carbonic anhydrase-4, and here’s the punchline–acetazolamide (Diamox) quashes that enzyme in these taste buds, as a side effect of its action on the kidneys. So as I enjoyed my salty salami sandwich for lunch, I had no idea that the Diamox I had taken earlier had temporarily killed my ability to taste the acid of CO2, until I took a sip of Coke and found the flavor horribly wrong and off-putting. All the other taste receptors in my tongue were working just fine, but not the ones that savor the fizz of carbonated drinks.

More amazing to me than this fascinating bit of neuroscience in taste reception was that it did not matter a whit that I understood completely–down to the chemical equations involved–that there was absolutely nothing wrong with my Coke. It was utterly impossible for me to drink it. So powerful is our sense of taste, it overrides our conscious reasoning and force of will in controlling our eating behavior. (The same is true for the sense of smell. Can you eat anything with the smell of vomit in the air?) These are deeply embedded life-saving neurocircuits that protect us from poisoning.

So as we savor the distinct and wonderful flavors of Thanksgiving dinner, the sweet potatoes, the salty gravy, umami of turkey breast, the tartness of cranberries, the sweetness and spice of apple pie, the bitter bite of beer, and the tang of sparkling wine; give a moment to reflect on the festival of amazing sensory reception going on in our nervous system.

Keep in mind too that everyone has different likes and dislikes when it comes to flavor, and that is in part because things do not always taste the same to everyone. The bitter taste of Brussel sprouts on a child’s tongue may have taste buds screaming, “Poison!” in shock from the strong bitter flavor, while the parent’s taste buds might not even detect the bitterness. An analysis of my personal genome, for example, revealed that I have a gene variant that reduces my ability to detect bitter flavor. This explains why I love a hoppy IPA, but my wife can’t stand the taste of a sip of beer. Children and adults have a different sense of taste because the human tongue and taste buds do not develop into the adult form until about 11-12 years of age. This makes sense because the nutritional needs of rapidly growing children are different from those of adults. A child’s sweet tooth fuels the active young body. Taste buds last only about 8-12 days and they are renewed constantly. As we age, our ability to replace taste buds declines and our sense of taste becomes less acute. Females tend to have greater taste sensitivity than males because they have more and larger fungiform papillae (the bumps on the tongue where taste buds reside). This sex-specific difference may relate to differences in behavioral roles of males and females throughout the course of evolution, where women needed to gather high-quality foods, detect potential toxins, and prepare food in their maternal role of caring for their offspring.

Differences in taste reception have important consequences. Eating disorders are associated with differences in taste reception. Many diseases alter the sense of taste, and conversely, changes in taste perception can be diagnostic of certain diseases. The bacterium that causes stomach ulcers, H. pylori, results in a poor ability to distinguish between bitter and acid tastes, for example. Interestingly, the same receptor that senses bitterness, T2Rs, is also found in our airway. It turns out that these bitter sensing cells in our sinus can detect a bitter molecule, acetyl-homoserine lactone, which is secreted by gram-negative bacteria, including the very nasty Pseudomonas. Upon sensing the bitter secretions of bacteria in our nasal cavities, these taste receptors stimulate cells in our nasal cavity to sweep away and kill the bacteria. Research is underway to determine if people with chronic sinus infection may lack the gene for T2R bitterness detection.

The last example shows that taste receptors are hardly limited only to the surface of our tongue. People have long realized that the sense of smell and taste are closely linked, but only in the last few years have researchers discovered that we also have taste receptors in our gut! Yes, even after we have swallowed and started digesting our meal, our brain is still sensing the content of what we have consumed through taste receptors in our gut. Presumably this unconscious monitoring can give us pleasure of a satisfying meal or alarm as what we have eaten “turns on us.” Taste is a vital protective system that is essential for our health and survival, and these remote sensors have powerful effects in the brain that alter mood and control behavior through neurotransmitter systems that include serotonin, norepinephrine, ATP, acetylcholine, and GABA.
However, if you were taught in school that the tongue is divided up into different territories to detect the different tastes in different spots, that bit of “science” has been debunked. Amazing that this myth persisted so long, given that anyone could easily taste the truth simply by touching the tip of the tongue to salt and finding that the flavor briny and not sweet. Happy Thanksgiving!


Chandrashekar et al., (2009) The Taste of Carbonation, Science 326, : 443-445.

Fields, R. D. (2009) Outside Magazine, September, 2009,

Fields, R. D. (2008) Into thin air: Mountain climbing kills brain cells. Scientific American, April 3, 2008

O’Connor, A. (2008) The Claim: Tongue is mapped into four areas of taste. The New York Times, November 10, 2008.

Photo credit: Tongue taste map: “Taste buds” by Messer Woland – own work created in Inkscape. Licensed under CC BY-SA 3.0 via Commons –

Turkey dinner: Steve A. Johnson

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

Toxin in Dungeness Crab Causes Brain Damage

livecrabsCropCommercial Crab Fishermen, Pillar Point, CA

The California Fish and Game Commission has banned crab fishing until further notice after detecting high levels of a neurotoxin in Dungeness and rock crabs. The toxin, domoic acid, is produced by certain types of planktonic algae, and it becomes concentrated in tissue of crabs and other marine organisms during plankton blooms. People who consume sufficient quantities of the toxin develop amnesic shellfish poisoning, so named because it kills neurons in a part of the brain that is critical for memory. Here’s how it works.

To most of us it comes as a surprise that crabs can be toxic, but we are all familiar with the rule that oysters should not be eaten except in months that contain the letter “R.” The mnemonic is a clever way to remember not to eat wild oysters and other shellfish during summer months, because the warm water fuels blooms of phytoplankton that contain toxins. Since the toxins are not broken down readily or rapidly eliminated from the body, they become concentrated in tissue as the shellfish filter feed on microorganisms suspended in the water.

Paralytic shellfish poisoning results from eating mussels, clams, oysters, or scallops that contain high levels of saxitoxin, a natural substance produced by certain types of plankton (dinoflagellates and diatoms). Paralysis is caused by the toxin blocking the mechanism by which neural impulses are generated in our nerve fibers (axons). The extremely potent toxin prevents sodium channels in neuronal membranes from functioning. To generate an electrical impulse, voltage-sensitive sodium channels open briefly to allow positively charged sodium ions to rush into the neuron, raising the voltage transiently and producing a voltage spike called an action potential. These voltage spikes are the fundamental mechanism by which our nervous system communicates.

A different type of marine toxin, domoic acid, from a different family of diatoms (Pseudo-nitzschia) is responsible for amnesic shellfish toxin, and this is what closed crab fishing in California. This toxin poisons the brain in a different way. A celebrated outbreak of mass domoic acid poisoning of seabirds in August, 1961 in Capitola, California was the inspiration for Alfred Hitchcock’s horror movie, The Birds (1963). Baitfish (sardines and anchovies, for example) accumulate domoic acid during algal blooms and the fish become toxic to seabirds and marine mammals feeding on them. The_Birds_original_poster (2)The neurotoxin causes bizarre behavior, seizures, and mass deaths of marine mammals and birds. As sensationalized in the movie, seabirds in the Capitola outbreak of domoic acid poisoning were observed screaming, flying erratically, and smashing through glass windows and crashing into other objects.

In people, consumption of domoic acid causes nausea, diarrhea, and abdominal cramps shortly after eating tainted shellfish. Within 48 hours this can develop into headache, dizziness, confusion, motor weakness, and in severe cases, short-term memory loss, coma, and death. In 1987 three people died in Prince Edward Island, Canada, from eating mussels contaminated with domoic acid. Clearly, domoic acid does not block action potentials–the frenzied activity of birds and marine mammals suffering domoic acid poisoning is the opposite of paralysis.

In fact, domoic acid works much like nerve gas used in chemical warfare–it causes intense firing of synapses. The uncontrolled firing of synapses sends the nervous system into a frenzy of uncontrolled activity, seizure, and kills neurons by over stimulation. Nerve gas works by overstimulating synapses that use the neurotransmitter acetylcholine for signaling at synapses, so the effects are quite different. Acetylcholine is the transmitter used to contract our muscles, for example. Sarin nerve gas results in rapid, gruesome death through respiratory failure caused by paralysis of the diaphragm (in addition other horrible and painful effects on the body that depend on synapses signaling by using the neurotransmitter acetylcholine).

Domoic acid acts by mimicking the neurotransmitter glutamate, which is the most common type of neurotransmitter in the brain used by synapses that excite neurons. (Other neurtransmitters, for example GABA, work by inhibiting neurons from firing.) A closely related compound, kainic acid, also originally derived from algae, works in a similar manner to domoic acid. Kainic acid is frequently used in laboratory studies of epilepsy (including in my laboratory), because it overexcites neurons that receive input from excitatory synapses that use glutamate as the neurotransmitter. A part of the brain critical for short-term memory, and also frequently the focus for initiating seizures, is the hippocampus. Kainic acid or domoic acid cause seizures and kill hippocampal neurons through over stimulation. Thus, the crazed birds in Capitola, and the loss of short-term memory in people who consume shellfish with high levels of domoic acid, are caused by over-excitation and death of neurons in the brain that respond to the neurotransmitter glutamate. Nasty stuff indeed!

But why crabs? The answer has to do with how the toxin is ingested and eliminated by different types of organisms. Muscles and oysters, for example, eliminate domoic acid from their body within hours or a few days, but razor clams are poor at eliminating the toxin. Several months to years after ingesting domoic acid, only half the initial dose is gone from razor clam tissue. This June levels of domoic acid in razor clams in Washington State reached record levels. Studies on Dungeness crabs show that within two hours of ingesting domoic acid, the toxin is deposited in the hepatopancreas, while other tasty tissues retain extraordinarily low levels of toxin, 100 to 1000 times lower than in the hepatopancreas. Crabs are not very efficient in excreting the toxin, so crabs feeding on contaminated shellfish absorb domoic acid very efficiently and eliminate it slowly in urine.

If you are not familiar with crab anatomy and would like to be able to identify the hepatopancreas where domoic acid accumulates, look up the episode of Parts Unknown by TV personality and former chef, Anthony Bordain in the recent program about restaurants in San Francisco, and you will see him slurping up what is yellowish crab innards, sometimes called the mustard, with a slice of sour dough bread and raving about the flavor while poking fun at folks who are too persnickety to enjoy the rich taste of crab guts. (Possibly he now has no memory of doing this.)

Domoic acid is tough stuff, and dangerous. It can’t be broken down by cooking or freezing or by digestion and it latches on to glutamate receptors with a vengeance. But let’s not get hysterical and freak out like people in the fictional movie The Birds. Fatal poisoning caused by consuming shellfish contaminated with domoic acid is rare. The example of the three unfortunate people who died on Prince Edward Island in 1987, illustrates how far back we must go to find cases. I venture to say that countless more unfortunate people have choked to death on a steak dinner during the same interval.

Crabs and shellfish contaminated with domoic acid are to be avoided. They will make you sick and in high levels cause serious harm to your brain, but the key is dosage. Marine mammals and birds eat essentially nothing but fish and so they receive high dosages of the toxin when it is present in their prey. Unlike invertebrates, vertebrates are quite good at eliminating domoic acid. (But domoic acid also causes kidney damage.) In low doses, the effects of domoic acid are not much different from half an asprine, which is to say nonexistent. Domoic acid and kainic acid are even used as drugs in low concentrations to treat people suffering from intestinal worms, because the vermin succumb to doses far below those that have any negative effects on the human body.

Capt. John Hurwitz and crew unloading their catch of Dungeness crab, Pillar Point Harbor, California

Capt. John Hurwitz and crew unloading their catch of Dungeness crab, Pillar Point Harbor, California

The point is, all things shall pass. Sometimes fishing is good, sometimes it is not. Nature works in fits and cycles. Some years, such as right now, the complex mixture of favorable weather, currents, and nutrients, all come together to cause a population explosion of particular types of algae, but thanks to the biologists who work for the California Department of Fish and Game and other agencies who constantly monitor levels of toxins, heavy metals, and other poisons in our seafood, we can eliminate the risk. These scientists will let us all know when it’s time to dine on something else–a far better way to go than trusting in the old “month with and R in it” rule. Let’s also remember that many hard working California crab fishermen are going to have a very difficult time for a while, but when the coast is clear and the algal populations drop to where domoic acid levels are normal in seafood again, that famous California Dungeness crab of is going to taste all the sweeter!

(Disclaimer: I once worked as a biologist for the California Department of Fish and Game. I absolutely love Dungeness crab. I don’t eat the guts. I watch Anthony Bourdain’s show almost every Sunday night. The skipper of the crab boat in the photo is a friend, John Hurwitz. He’s a long-time crab fisherman and writer. I once traded him an article I wrote about sharks published in Scientific American in exchange for live crabs fresh off his boat–a windfall compared to the usual rate of a dollar/word.)

Domoic acid: A major concern to Washington state’s shellfish

Fields, R.D. (2007) The Shark’s Electric Sense. Scientific American, August, 2007

Pelley Scott (2015) A crime against humanity. Scott Pelley reports on the 2013 sarin gas attack in Syria that U.S. intelligence estimates killed more than 1,400 civilians. CBS News 60 Minutes, August 23, 2015,

Schultz, I.R., Skillman, A., Sloan-Evans, S., and Woodruff, D. (2013) Domoic acid toxicokinetics in Dungeness crabs: New insights into mechanisms that regulate bioaccumulation. Aquatic Toxicology, 140-141, 15 September, 77-88.

Sabalow, R., and Kasler, D. California delays opening of crab season amid toxic scare. The Sacramento Bee, November 5, 2015.

Tuder, Stefanie, Everywhere Anthony Bourdain Eats in San Francisco ‘Parts Unknown’, October 18, 2015, 7:00 pm, CNN.

Photo credits: Crab boats, Douglas Fields. “The Birds original poster” by Copyrighted by Universal Pictures Co., Inc.. – IMP. Licensed under Public Domain via Commons -

U.S. Army Sgt. Andrew Mahoney (left) of Laingsburg, Mich., with then-1st Lt. Florent Groberg serving on a personal security detail with the 4th Infantry Brigade Combat Team, 4th Infantry Division, during a deployment to Regional Command-East, Afghanistan. (Photo courtesy of Retired U.S. Army Capt. Florent Groberg)

U.S. Army Sgt. Andrew Mahoney (left) of Laingsburg, Mich., with then-1st Lt. Florent Groberg serving on a personal security detail with the 4th Infantry Brigade Combat Team, 4th Infantry Division, during a deployment to Regional Command-East, Afghanistan. (Photo courtesy of Retired U.S. Army Capt. Florent Groberg)

Today it was announced that Army Capt. Florent Groberg will receive the Medal of Honor for instantly tackling a suicide bomber in a split-second reaction of self-sacrifice to save the lives of his comrades. “You don’t have time to think. You react,” he explains. But how is that possible?

As we honor Capt. Groberg with the nation’s highest award for military valor, and we set aside one day, Veteran’s Day, to reflect on all the men and women who served their country in the armed forces, let’s take a moment to examine the most astonishing and noble characteristic of our species–unhesitating self-sacrifice for others.

As recounted in an article in today’s Washington Post, Army Capt. Florent Groberg had a weird feeling about the mission as their helicopter touched down on August 8, 2012 in Kunar province in Afghanistan. “Something seemed out of place,” he said explaining the eerie sense of alarm that welled up inside him for no specific reason that he could pinpoint.

Suddenly he spotted a man in dark baggy clothing approaching Groberg’s squad. Gut instinct wrested control over conscious deliberation and Groberg instantly dashed toward the man and tackled him, sensing somehow that the stranger might be a suicide bomber. “I hit him, grabbed him, tried to push him as far away and throw him to the ground,” Groberg said. Sgt. Andrew Mahoney, who would later receive the Silver Star for Valor, immediately joined Groberg in trying to subdue the man. The bomb detonated as Groberg’s body took the ferocious impact and shrapnel of the fiery explosion. The lives of many in the squad were saved by Groberg who used his body to shield others from the bomb blast, but the explosion killed four men in the squad and several others were severely wounded. Groberg suffered grievous injuries that required 33 surgeries to treat. The wounds have left him with life-altering disability and physical pain.

Groberg’s treatment and rehabilitation too place over three years since the bomb blast at the Walter Reed National Military Medical Center in Bethesda, Maryland. Looking out the window of my office I see the towering concrete skyscraper of the Naval Hospital, which was built during the Roosevelt administration, projecting into the sky like a giant obelisk at the center of what is now Walter Reed Medical Center. I see it every day. Knowing the trauma, sacrifice, healing, and loss of life taking place inside that tower brings profound gratitude every day. Capt. Groberg and the men and women like him represent the best in human nature.

Naval Medical Hospital, Walter Reed National Military Medical Center

Naval Medical Hospital, Walter Reed National Military Medical Center

All bodily actions are the result of brain circuits controlling behavior in response to constant assessment of environmental and internal conditions. What such heroism illustrates is how much of the human brain is devoted to threat detection and rapid response operating automatically without any deliberation. The human brain can hold only a tiny fraction of the information in our conscious mind that our senses are taking in constantly and evaluating for threats. The capacity of our conscious brain is horribly limited. Long division, for example, is difficult to perform without pencil and paper because the capacity of the brain’s working memory is so feeble, it can’t retain the intermediate result of one simple arithmetic step long enough to perform the next. The unconscious brain, in contrast, is constantly monitoring and evaluating enormous volumes of data and situational information, which it conveys to our consciousness in the only way it can, by multicolored emotions–gut feelings.

People in combat, secret service agents, and others who must act aggressively to confront a threat in situations where a split-second hesitation could have monumental consequences, develop these unconscious abilities to the highest level, and they learn to rely upon them. So do elite athletes who must respond instantly to sudden situations, be it on the football field, backcountry ski slopes, the race track, and many other dangerous or fast moving sports.

This is the neuroscience behind Capt. Groberg’s gut reaction that warned him that something was amiss. There were too many subtle factors to bring to his conscious mind to alert him to the deadly threat that was approaching, but working feverishly beneath the level of conscious, his brain “knew” he was in danger and it signaled that conclusion with the gut twisting emotion of alarm.

In many threatening situations, conscious deliberation would be too slow. This is why the human brain and the brains of other animals have a rapid response threat detection circuit that can react to a sudden danger in a flash and without conscious deliberation. This high-speed circuitry races beneath the cerebral cortex where consciousness arises. If your purse is snatched on the street, it is this subcortical circuitry that will dictate your immediate response to fight back, freeze, or flee.

Using new methods to study these circuits of threat detection, which span the brain from the hypothalamus to the amygdala to the prefrontal cortex, these circuits are being traced out in fine detail. This research is showing that different types of threats activate different specific circuits that launch an aggressive response to a specific type of trigger. The circuit that propels a mother to protect her young in jeopardy is distinct from the circuit that controls our instantaneous response to defend ourselves in a physical attack, for example, or to act, as Capt. Groberg did, to defend someone else.

This circuitry, however, can misfire. When it does we call this behavior “snapping.” Whether it is the aggressive behavior of snapping in road rage, or aggressive behavior to defend your property, it is this same neural circuitry of threat response that is involved. This is the double-edged sword of this rapid threat detection and response circuit deep inside the human brain. Like any brain function, this one is subject to malfunctioning. For this reason, it is especially important that neuroscience is now exploring this unconscious realm of the brain that triggers sudden aggression.

The point here is to provide some illumination into how, at the level of brain function, such instant and selfless heroism as Capt. Groberg displayed occurs from the perspective of neuroscience. This “dissection” should amplify our respect and appreciation of such heroism, not in any way diminish it. Just as understanding how the genius of Albert Einstein can be traced to particular highly developed functions in specific cortical regions involving abstract thought, mathematical ability, and imagination, new research to analyze the neurobiological underpinnings of threat response illuminates our understanding of this vital aspect of the human brain.

Clearly different individuals differ in various aspects of cognitive and other brain functions. Not everyone with Capt. Groberg that day sensed the same threat. Others would have missed or ignored the danger. In the face of a perceived life-or-death threat some people will freeze while others will fight. Different types of threats and different types of triggers will provoke different responses in different individuals, because of individual differences in the neuro circuitry of their brain’s threat detection and response mechanism. These differences have their roots in both genetics and environment, and thus different people will be more highly sensitive to different triggers of sudden aggression. A mother may respond passively to a purse snatcher, but violently defend her child, for example.

In Capt. Groberg, we see and honor the most noble of all human behaviors–self-sacrifice for another person. “People are asking me, ‘What were you thinking?’” Groberg says about his split-second response to save other people’s lives in exchange for his own. The answer is that unlike someone else, Groberg did not think–he reacted. There is no higher honor a nation can give in recognition of such a person than the Medal of Honor that the President of the United States will drape around his neck on behalf of us all.


Lamothe, D. Army Captain to get Medal of Honor. The Washington Post, p. A10, November 11, 2015.

Fields, R.D. Why We Snap, Dutton Press.

Posted by: R. Douglas Fields | October 30, 2015

The Neuroscience of Witches

witch2Toads, spells, potions, flying brooms, and witch’s brews–witchcraft is all about neuroscience.

Witches have thrived through the centuries, and today many women still practice witchcraft. I’ve met a few. Peering by flickering candle light at dimly lit Tarot cards a self-proclaimed witch read my fortune one foggy night in New Orleans years ago. She predicted that one day I would write for Huffington Post. No, just kidding about the Huffington Post part, but she and her fellow Wiccans were an intriguing group of right-brained ladies. Cloaked in a cloud of patchouli vapor, adorned with crystal pendants and clutching strange totems, these sensitive women fully embrace the supernatural mysteries of the natural world. Witches worship and harness the mysterious power that is unique to the female sex (and brain). But listening to her divine my fate that night, it was clear to me that neuroscience, not the supernatural, are what witches, witchcraft, and witch hunts are all about.

To begin with the obvious, witches are women. Male and female brains differ in interesting ways to carry out the traditionally different roles of men and women throughout the course of evolution, which has given us the brain we have today. While prehistoric men roamed in bands armed with stone weapons to battle wild beasts, bring home raw meat, and to brutalize and plunder other tribes; women, saddled with pregnancy and the demands of child care, were confined to the vital domestic chores of gathering, gardening, grooming, cooking, and babysitting. Superior spatial analysis and memory, for example, was essential for the caveman to hunt and then find his way back home. Neuroimaging shows that the female brain is better at instantly divining social cues and threats from facial expressions. The impulsive, warring and confrontational male brain gave us tribes and nations, protection, and production of grand architectural marvels and cities. The patient and intuitive female brain gave us weaving, clothing, pottery, family, agriculture, and witches. Witchcraft is very much about the mysterious powers of the female sex and about an approach to understanding the supernatural by embracing nature.

Caveat: It is important to emphasize that we are speaking here of the evolution of the human brain over eons, which is the product of the traditional roles of males and females in a struggle for survival in the wild, and we are speaking of population averages. Today human beings enjoy diverse varieties of interpersonal relationships in a very different environment. Technology has given women control over their reproductive ability and expanded opportunities for women. While drawing these general conclusions, it is important to remember that everyone’s brain is different. However, every biologist knows well that sex is the hub of animal behavior and the driving force for evolution. Now back to witches and broom sticks. . .

The sexual bond between men and women was a powerful draw that pulled the roving male back home from his exploits. (It still is.) This invisible magic works on males (and similarly bonds infants and females) by activating release of neurotransmitters in the brain (dopamine, serotonin, endorphin, and oxytocin) to infuse us with the emotions of pleasure, reward, and attraction. The neurocircuitry of sexual attraction also gave us love and empathy. The same neural circuitry for these powerful emotions is engaged in spiritual belief, something that is unique to Homo sapiens. Likewise, Paganism, Voodoo, and witchcraft all arise from these unique human neural circuits that allow us to perceive our transient existence in a vast and mysterious universe.

Obviously, direct physical combat between a petite female and a larger male would likely end badly for the female. So females tend to utilize indirect forms of aggression–gossip, sabotage, revenge, and poisoning. Superstitious curses, incantations, Voodoo dolls, black magic, and potions are a safer way for the fairer sex to do battle. In centuries past, females were the healers, midwives, gardeners and gathers of herbs and berries. In this role women developed an intricate knowledge of medicinal properties of plants, including the mind-bending properties of some of them. These women were early neuropharmacologists.

The two most iconic features of witches are the broom and the cauldron. These items in witchcraft can be traced to sex and neuropharmacology. In past centuries, most witches were widows or unmarried girls, living relatively isolated in a patriarchal society. Riding the broom handle was a mode of sexual self-gratification. Often the pole or broom handle would be greased with potions, and many of these lubricants included herbs that had stimulating, psychotic, or hallucinogenic properties. Ingesting these neuroactive substances extracted from plants caused nausea, but topical application to the mucous membrane, much like snorting cocaine, bypassed the gut and delivered the drugs into the blood stream and to the brain. Now you know why witches ride brooms and not a sleigh like Santa.

In their book, A Witches’ Bible, Janet and Stewart Farrar explain the origin of the broomstick in witchcraft. “It was originally a riding- and dancing-pole disguised as an ordinary household besom for security reasons. . . Women would ride them around the fields, leaping as high as they could. . . . The higher the leap, the higher the crop would grow. And the fertility theme would be dramatized, in those less prudish days, by the way in which the women used the phallic poles during their ‘riding’. . . It is hardly necessary to add that the broomstick is a masculine symbol.”

It is neuroscience that explains this broomstick behavior, as many neurotransmitters are released in the powerful state of orgasm. A newsworthy example is serotonin, which is the basis for the newly approved drug, Filbanserin, “female Viagra,” which works by increasing serotonin signaling. Long before drug companies got into the game, people who grew and collected herbs had a vast knowledge of the medicinal properties of different plants. Serotonin levels can be increased by the 5-HTP (5-hydroxytroptophan) which is contained in the woody shrub Griffonia simplificola and other plants. Carcumin, from the spice turmeric, also boosts serotonin and dopamine. St. John’s wart lifts depression by modulating neurotransmitters that influence mood.

frogThe cauldron was where alcoholic brews and herbal extracts were concocted by women from exotic plants and animals. The frogs, newts, and other exotic components of witch’s brews contain compounds that have powerful effects on the heart and nervous system, including psychotropic and hallucinogenic properties. For example, scopolamine, hyoscyamine, and atropine are powerful prescription drugs, but all three of these anticholinergics are readily available in the seeds and flowers of Datura (Jimsonweed) which was used for centuries to treat various illnesses, induce hallucinations, to intoxicate, or poison people. There is a long list of such neurotoxic and psychotropic herbals used by caregivers through the centuries, often by women, and applied in witchcraft. Tetrodotoxin, which is contained in newts and certain other animals, is a potent neurotoxin that blocks sodium channels. The electrical impulses in our nerves are generated by activating sodium channels, and tetrodotoxin blocks this fundamental mechanism by which our nervous system operates. In Haiti, zombies–the living dead–were created by tetrodotoxin extracted from puffer fish and used in Voodoo practices.



Ergot, a fungus of rye, has been implicated by some researchers in the mass hallucinations and hysteria surrounding the Salem witch hunts. Accused of witchcraft, 24 early settlers to America were tortured, hanged, died in prison, or crushed under rocks in a frenzy of mass hysteria in the year 1692. Three centuries later scientists Albert Hofmann and Arthur Stoll would isolate a compound from this fungus which stimulated dopamine receptors in the brain. They called it LSD (Lysergic acid diethylamide), and found that it had rather potent hallucinogenic properties, somewhat consistent with the delirious fits and visions of the teenage girls who sparked the witch hunts in Salem.

Witch Hunts
A sorry intersection between neuroscience, witches, and witch hunts, derives from ignorance about mental illness, and the fright that is evoked by seeing a person possessed by an overpowering hallucination or convulsion. Throughout history, mental illness and neurological illness, such as epilepsy, have been attributed to supernatural causes and to witchcraft. Among those burned at the stake or hanged as witches were people afflicted by mental and neurological illnesses because they were thought to be possessed by demons.

Fundamentally, the witch hunts of Salem were the result of a neural circuit in the insula, amygdala, striatum, orbital and ventromedial frontal cortex, which within a fraction of a second of seeing another person, categorizes the individual into either “us” or “them.” Brain imaging shows that these neural circuits become activated in response to seeing another person suffering pain, but they do not become activated when seeing a member of another race or outgroup suffering pain. This explains how the unspeakable cruelty that took place against the “witches” of Salem was possible. Witches were members of an outgroup, especially in a highly religious and patriarchal society, and thus they were dehumanized and subjected to brutality. Burning at the stake, crucifixion, horrendous acts of war all stem from this circuit of discrimination imbedded in our brain. This brain circuit has separated “us from them” throughout human history and it continues to do so today. Recently a Hindu man accused of eating beef was murdered by a mob, and many others in the Middle East who are deemed to be acting outside the beliefs of the local community are stoned to death for transgressions–modern day witch hunts.

Sex, bias, and mind-bending properties of natural products are at the core of witchcraft. The Tarot cards and highly intuitive witches who read them in New Orleans were fun, but all of this natural and supernatural human behavior–witch’s brews, witchcraft, and witch hunts–is neuroscience.

Bucciarelli, G.M., Li, A., Zimmer, R.K., Kats, L.B., Green, D.B. (2014) Quantifying tetrodotoxin levels in the California newt using non-destructive sampling method. Toxicon 80: 87-93.
Cahill, L. (2006) Why sex matters for neuroscience. Nature Reviews Neuroscience, 7: 477-84.
Davis, E.W. (1983) The ethnobiology of the Haitian zombie. J. Ethnopharmacol. 9: 85-104.
FDA approves first treatment for sexual desire disorder. FDA Press announcement August 18, 2015
Farrar, J. and Farr Stewart, A Witches’ Bible, Phoenix Publishing, Inc. Custer, Washington, 1984
Fields, R.D. (2013) Ladies out of Luck: FDA Blocks “Female Viagra” December 15, 2013
Fields, R. D. Why We Snap, Dutton Press, January 2016 (Includes information on the neurocircuitry of fear and threat detection and gender differences in the brain.)
Guerre, P., (2015) Ergot alkaloids produced by endophytic fungi of the genus Epichloe. Toxins (Basel) 7: 773-90.
Harris, L.T., and Fiske, S. T. (2006) Dehumanizing and the lowest of the low: neuroimaging responses to extreme out-groups. Psychological Science 17: 847-53.
Kapogiannis D. et al., (2014) Brain networks shaping religious belief. Brain Connect. 4: 70-9.
Kulkarni, S.K., Bhutani, M.K., and Bishnoi, M. (2008) Antidepressant activity of curcumin: involvement of serotonin and dopamine system. Psychopharmacology 201: 435-442.
Lee, M.R. (2010) The history of ergot of rye (Claviceps purpurea) III: 1940-80. J. R. Coll. Physicians Edinb. 40: 77-80.
Megan Garber, Oct. 31, 2013 Why Do Witches Ride Brooms? (NSFW) The Atlantic October 31, 2013
Michale E. Miller, A mob in India just dragged a man from his home and beat him to death — for eating beef September 30, 2015 The Washington Post
Rimar, Y. and Rimar, D. (2003) Witches saints and other diseases. Harefuah 142:383-6.
Salem Witch Trials Documentary Archive and Transcription Project, The University of Virginia
Schmidt, M., Butterweck, V., (2015) The mechanisms of action of St. John’s wort: an update. Wien. Med. Wochenschr. 165: 229-35.
The 1692 Salem Witch Trials, The Salem Witch Museum

Photo credits: Photos by the author

First published in Huffington Post Science

Perineuronal nets forming on neurons in the insular cortex after binge drinking

Perineuronal nets forming on neurons in the insular cortex after binge drinking

“Why can’t you stop drinking?” This week at the Annual Meeting of the Society for Neuroscience in Chicago, researchers from the University of Illinois at Chicago announced a new finding that provides a fresh answer to this persistent question that plagues people addicted to alcohol. The discovery offers an entirely new approach to treatment.

Neuroscientist, Amy Lasek, at the Department of Psychiatry at the University of Illinois at Chicago, and colleagues, report that after binge drinking, neurons in brain circuits responsible for alcohol addiction become encased in a protein material, called a perineuronal net. The impenetrable coating cements neurons involved in alcohol addiction into a circuit that is extremely difficult to break. Current drugs for treating alcohol dependence work by modifying neurotransmitter signaling between neurons, but for many people these treatments cannot break the overwhelming compulsion to drink. Drugs that can break down the glue-like cement in perineuronal nets could offer a new approach to treatment.

Lasek’s unusual approach into addiction research stems from her background as a molecular and cell biologist working in the field of cancer research. The root of cancer is changes in specific genes. Small molecules designed to target these aberrant genes is the approach used in cancer therapy. Lasek’s background made her think of finding molecularly targeted therapies for psychiatric disorders.

Lasek and her colleagues began by studying fruit flies to search for gene variations that altered the fly’s behavior toward alcohol. She found several genes that had this effect, including an obscure one called ALK (anaplastic lymphoma kinase). Then she suppressed these genes in mice to see if the animal’s response to alcohol was altered. “I got hooked,” she says, “because to me the fact that you can manipulate a single gene in a single brain region and change behavior—like drinking or cocaine reward—was fascinating from a biological point of view!”

She and her colleagues examined the genome of families who had a history of alcohol dependence. They found that ALK—the gene they had identified in fruit flies, which altered the insects’ responses to alcohol—was also associated with people in families with a history of alcohol dependence. Lasek found several variations in the ALK gene (polymorphisms) that were strongly associated with differences in the immediate reaction individuals had to drinking alcohol, such as the subjective high or the amount of motor uncoordination experienced after having a drink. This correlation was a strong clue that ALK and alcohol abuse were somehow linked.

Surprisingly, it turned out that the protein made by the ALK gene was not controlling neurotransmitter signaling; it was on the surface of neurons where it controlled deposition of proteins called the extracellular matrix, which binds cells together into tissue. Some neurons are heavily encased in a special meshwork of extracellular matrix, called the perineuronal net. “It’s something like collagen,” she says. A very tough and slippery material that is resistant to change after it is deposited. But how could “brain glue” be related to alcoholism?

Research in other labs has shown that perineuronal nets are a specialized form of extracellular matrix that regulate synaptic plasticity—the ability of neurons to make and break connections between neurons. “You only get synapses [formed] where there are holes in the nets,” Lasek explains. When a neuron becomes heavily encased in a perineuronal net, new synapses cannot form and existing synapses become cemented in place.

Addiction is thought to be an aberrant learning process. Fundamentally, learning is connecting different events or environmental stimuli together to direct a specific behavior, such as Pavolv’s dogs learning to associate the sound of a bell with food to follow. At a cellular level, synaptic connections are formed and strengthened, weakened and broken, to encode the learning into a neural circuit that controls behavior. Likewise in addiction, a person learns to associate certain environmental stimuli or internal mental states, with an overpowering compulsion to drink alcohol. Quitting time, perhaps, may trigger an overpowering urge to have a cocktail, and then another, and another. “It may be that perineuronal nets are locking in that learning process that occurred, where you have this aberrant memory for the drug.”

Neurologist Varda Lev-Ram and colleagues, working at the University of California, San Diego, reported at the same meeting that perineuronal nets are extremely long lasting. She and her team discovered this by spiking mouse chow with traces of the isotope of nitrogen 15N, which would become incorporated into newly synthesized proteins in the animal’s body. Using this method of biological dating, the researchers found that some of the most long-lasting proteins in the body are components of the perineuronal nets.

These nets can be broken down and when this is done, long-term memory is eroded. When Lev-Ram and colleagues treated mice with compounds that inhibit enzymes that remodel components in the perineuronal nets (enzymes called matrix metalloproteinases), mice trained to fear a tone that signaled an electric shock, soon forgot the association between the warning tone and the electric shock. This is significant, because fear memories, as in PTSD, are some of the most difficult memories to break, but interfering with formation of the perineuronal net allows these traumatic memories to slip away.

Lasek’s team devised an experiment in which young adult mice were provided water tainted with alcohol in a manner similar to binge drinking in college-age students. When they examined brains of mice after six weeks of binge drinking they found that perineuronal nets formed and thickened around neurons in the insula, a part of the cerebral cortex that is known to be involved in compulsive alcohol use. These deposits did not develop around neurons in other regions of cerebral cortex, for example motor cortex, which controls bodily movement, suggesting a specific effect targeted on neurons involved in alcohol dependence. “These nets are accumulating in response to drugs of abuse. It may be locking in that learning process that occurred, where you have this aberrant memory for the drug,” she says.

This new finding suggests that to conquer addiction, “You have to get rid of the nets,” Lasek says. In her lab she is treating mice with inhibitors of ALK and other proteins in the perineuronal nets, and the unpublished results thus far show that these mice voluntarily decrease their binge drinking. “This would be an entirely new avenue of treatment,” she says. However, drug treatments are not the only way to take advantage of this new finding, because many other factors will influence how the perineuronal nets form and how quickly they can break down, including exercise and diet, she suggests. “I think these kind of things can ameliorate whatever risk you have with your genetics,” Lasek says. “I don’t always think that drugs are the solution; sometimes you need both [medicine and lifestyle changes].” Perineuronal nets are a new part of the puzzle explaining why it is so difficult to overcome alcohol addiction, and this new insight offers fresh hope for people whose lives are destroyed by addiction.


Chen, H., He, D., Lasek, A.W. (2015) Repeated binge drinking increases perineuronal nets in the insular cortex. Alcohol Clin. Exp. Res. October, 39:1930-8.

Chen, H., He, D., Lasek, A.W. (2015) Repeated binge drinking increases perineuronal nets in the insular cortex. Society for Neuroscience Meeting Abstract 695.01/N12

Lev-Ram, V., Bushong, E.A., Deerinck, T.J., Poczatek, C.J., Lechene, C.P., Palida, S.F., Taliman, K.M., Savas, J.N., Yates, J.R., Ellisman, M.H., Tsien, R.Y. (2015) Are very long-term memories stored in the pattern of holes in the perineuronal net? Society for Neuroscience Meeting Abstract 391.03/C27

Palida, S., Lev-Ram, V., Bushong, E.A., Ellisman, M.H., Tisen, R.Y. (2015) Visualizing structure and activity-dependent changes in the perineuronal net, a putative substrate for very long-term memory. Society for Neuroscience Meeting Abstract 391.04/C28

Modified from Scientific American:

Posted by: R. Douglas Fields | September 29, 2015

What’s in Your Nightmares? The Top 5 Recurring Dreams of Adults and Kids

dreams-skull-lowresWe spend a third of our life in a completely altered state of consciousness, indeed madness. Dreaming is a descent into what would otherwise be a severe form of psychosis, and often these hallucinations are terrifying. Dreams that reoccur are especially disturbing, and nearly everyone has experienced them. A new study reveals the most common content of recurring dreams and finds very different hallucinations in the dreaming minds of adults and children.

What’s in your dreams — especially dreams that revisit night after night? Are you flying high above the heads of other people in gleeful euphoria? Are you sharing a tender moment with a loved one in a beautiful surrounding? Or are you terror struck, running for your life from a monster or murderer, immobilized by paralysis or rendered mute as an intruder breaks into your bedroom. Maybe you are tumbling through the air helplessly or badly injured?

The first finding of this study of several hundred boys and girls between the ages of 11 and 15, by Aline Gauchat, Psychologist at the Université de Montréal and colleagues, is that most reoccurring dreams are not pleasant. They are most often terrifying confrontations with deadly threats of some sort. But the reoccurring dreams of kids, adolescents, and adults differ in interesting ways.

There is a long history of research on dreams of adults, but according to Gauchat, their new study published in the journal of Consciousness and Cognition is the first to investigate the content of recurrent dreams reported directly by children. Up to now, insight into recurrent dreams of children was gleaned by questioning adults about their personal memories of their childhood dreams. Such recollections are likely to be unreliable, as memory fades and can be very selective.

Here are the most common themes of recurrent dreams categorized in the present study:

Common themes in recurrent dreams

Being chased (Dreamer is chased but not physically attacked)

Physical aggression (Threat or direct attack on one’s person or character, including sexual aggression, murder, being kidnapped or sequestered)

Falling (Feeling of falling in mid-air, off cliffs or from another elevated object)

Car accidents (The dreamer or another character is involved in a car accident)

Contact with strangers

Death of the dreamer

Death in the family

Confrontation (Dreamer is confronted by monsters, animals, zombies, or similar creatures)

The dreamer is injured or ill

Stranger entering the dreamer’s house (A stranger is breaking into the dreamer’s house or trying to enter it)

Being stuck or trapped

Others (Dreams including flying or of control and facing natural forces as well as other idiosyncratic themes)

The first finding was that only 9% of the recurrent dreams of children between the ages of 11 and 15 were positive experiences. Most recurrent dreams involved serious threats, with confrontations with monsters, animals or zombies, being the most frequently reported category. The next most common theme in recurrent dreams of children involved threats of physical aggression, falling, and being chased. In 87.9% of the children’s dreams, the dreamer is the target of the threat. Themes involving car accidents occurred in 6.9% of boys and girls, but the threats to girls were twice as likely to be related to being chased (11.3% vs. 6.5%). All the other common themes reported in recurrent dreams comprised only 6% of the narratives children reported.

It is interesting to compare these new results with a 1996 study by Zadra et al., on 110 adults. As with children, most of the recurrent dreams of adults were disturbing (77.3%). In contrast to children where 45.5% of the threats involved recurrent dreams of aggression and violence, this theme dropped to third place in the top 5 themes of content in adult recurrent dreams, with escapes and pursuits being the most commonly experienced recurrent dream of adults (25.9%). Interestingly, dreams of physical anomalies were common in the recurrent dreams of adults, but this terror was absent from the sampling of children reporting their dreams.

Table 1. Most common recurrent dreams of children

1. Aggression and violence (45.5%)

2. Accidents and misfortunes (28.8%)

3. Escapes and pursuits (22.7%)

4. Disasters (4%)

Dreams about failures and physical anomalies were not reported by children.

Table 2. The most common recurrent dreams of adults

1. Escapes and pursuits (25.9%)

2. Accidents and misfortunes (19.7%)

3. Aggression and violence (19.0%)

4. Physical anomalies (17%)

5. Failures (6.9%)

Dreams that the researchers found were absent from interviews with children, were the adult dreams of losing one’s teeth, being unable to find a private toilet, and discovering or exploring new rooms in a house. One striking result was that while friendly interactions were present in almost one third of girls’ recurrent dreams, they occurred in fewer than 3% of boys’ recurrent dreams. In studies of adults, women’s bad dreams are more frequently centered around interpersonal conflicts and women’s dreams are twice as likely to contain friendly interactions as men’s are.

What’s it all mean? The authors speculate that recurrent dreaming is related to life stresses and that imagining these threats in a dream state simulates threatening events of real life, thereby enabling our mind to rehearse strategies to avoid and confront such threats. Since real world threats to boys and girls, men and women, are somewhat different, so too are their threatening recurring dreams. Children are much more likely to experience threats from imaginary creatures and monsters than adults are. Adults, through life experience, have learned that monsters do exist, but they are usually human beings.


Gauchat, A., Seguin, J.R., McSween-Cadieux, E., and Zadra, A. (2015) The content of recurrent dreams in young adolescents. Consciousness and Cognition 37, 103-111.

Photo credit: Photo and video clip by the author, from the catacombs beneath the streets of Paris.

Posted by: R. Douglas Fields | July 25, 2015

Alzheimer’s Disease—America’s Tsunami

us-senate-vote-ipoWASHINGTON, D.C.– Amidst a tempest of election season political turbulence, a wave of bipartisan unity is rising in support of biomedical research, according to two US Senators speaking on Tuesday at an Alzheimer’s disease forum in Washington D.C., organized by AtlanticLIVE. “Every one of us knows how vulnerable we are,” says Senator Dick Durbin, D-IL. The Democratic senator shared the stage with Republican Senator, Susan Collins, R-ME who warns that the nation is facing a “tsunami of cases.” As baby boomers enter old age and people are living longer, one out of two people who reach the age of 85 will develop Alzheimer’s disease. “Alzheimer’s disease is going to bankrupt Medicare and Medicaid,” she says. “We cannot afford not to make this investment [in research].”

Despite the prolonged budget battles in congress, funding for medical research seems to be emerging as a possible exception to the long string of miserly cuts in federal spending. “This is special,” Durbin says of funding research on disease. “I believe this issue covers the spectrum [of political opinion].” Senator Collins is seeing the same support building from her Republican allies. “Constituents resonate to Alzheimer’s disease [as a government priority],” she says. Even ardent critics of the contentious Affordable Care Act (Obama Care), including Sen. Lindsey Graham, R-SC, and former Florida Governor Jeb Bush, are united with liberal Democrats on this issue. Collins cites a recent concrete example, “Republicans are in control of the Senate,” she says, “and they just authorized a 60% increase in Alzheimer’s disease funding.”

Members of congress from both sides of the aisle are calling for a national strategy to defeat Alzheimer’s disease, modeled on the rapid response to the AIDS epidemic or the war on cancer started 40 years ago. Last week Senator Collins proposed new legislation to address the lack of long-term care, for example to provide the custodial in-home care that an Alzheimer patient must have. Senator Durbin has proposed a 5% increase in budget to the NIH per year for 10 years to make the necessary investment for breakthroughs in Alzheimer’s disease and other biomedical research.

From Senator Durbin’s perspective this issue goes beyond improving health and relieving human suffering; he sees biomedical research as a matter of national security. The number of research grants funded by the NIH has declined every year for the past 10 years. Between 1999 and 2009, Asia’s share of worldwide research and development expenditures grew from 24 percent to 32 percent. Meanwhile, American expenditures fell from 38 percent to 31 percent. “America’s place as the world’s innovation leader is at risk as we are falling behind in our investment in biomedical research,” he says.

Biomedical research is a powerful force for economic growth. Senator Durbin cites the Human Genome project as an example where the federal investment has been paid back many times over in technological development and economic gain. This is something that has not escaped notice of leaders in other countries, Senator Durbin observes. “Look at what China is doing. They want to be dominant [in biomedical research and in political leadership in the 21st century]. “We better wake up to this reality,” Durbin warns. “America needs to make a strong commitment to biomedical research in the 21st century,” he says.

But is a cure for Alzheimer’s disease realistic? With the exception of rare genetically-induced forms of early onset Alzheimer’s, no one believes that there will be a silver bullet cure for Alzheimer’s disease. This is because Alzheimer’s disease and dementia are a multifactorial problem, says Richard Mohs, Vice President for Neuroscience Clinical Development at Eli Lilly and Company, who also spoke at the forum. Looking to the future from his perspective in the pharmaceutical industry he predicts, “I don’t think we’ll see the disease disappear–at least not in my lifetime. But the risk will go down, just as it has with heart disease.”

This is far more than a glass-half-full view of the problem, because slowing the progress of the disease may be enough. “It [Alzheimer’s disease] is a slow underlying pathology. . . Slowing the disease is essentially a cure for many,” he says, “because of their advanced age.” Senator Collins adds, “If we can delay onset even five years, it pays for the cost of research,” because the cost of caring for someone with Alzheimer’s disease is so enormous. Mohs predicts that the solution to Alzheimer’s disease will involve a combination of life-style changes (including diet and exercise) and drug treatments, much the way diabetes is managed successfully today.

The key will be early diagnosis. PET (positron emission tomography) scanning is a brain imaging technique that can detect amyloid deposits in the brain 10 to 15 years ahead of the memory loss. These deposits eventually damage brain cells and cause dementia. Drugs that have been developed to attack these deposits of amyloid protein show promise, but they don’t cure the disease. In fact, in some cases these drugs have worsened the disease. The consensus of experts is that drug treatment must be started much earlier, before years of slowly advancing pathology reach a point of no return. This is why identifying risk factors and early signs of Alzheimer’s disease at the pre-symptomatic stage are so important. PET scanning can do this a decade before symptoms begin to appear, but the technique is specialized, expensive, and invasive. Unlike MRI brain imaging, radioactive substances must be injected into patients to reveal the amyloid deposits in the brain using a PET scan. New tests to detect proteins in body fluids, cerebral spinal fluid, and even saliva, hold great promise as early warning signs of the disease that could warrant further testing. If simple tests find evidence for Alzheimer’s disease, then early treatments could be started to knock the amyloid deposits out before the brain becomes severely damaged. “Recovery may be possible,” Mohr says, even in those who now have AD, if the progress of the disease could be slowed or therapies to promote cell regeneration and repair were used, because the brain will repair itself if it can.

Alzheimer’s disease affects not only the person afflicted, erasing their memories and leaving them isolated, lost, and dealing with multiple debilitating brain dysfunctions, but it also affects everyone in the family. Senator Collins knows this from “having seen this very close [in her family]. . . Alzheimer’s disease affects even a grandchild whose name is no longer remembered.”

Today there are 5 million Americans with Alzheimer’s disease. There are 43 million family caregivers dealing with the chronic debilitation in loved ones, $450 billion in uncompensated long-term care. Americans aged 85 and older are the fastest growing segment of the population. What we are seeing is only the start of what is certainly a health care tsunami about to roll over American. Making the investment in medical research now will better prepare us to meet that impending crisis.


Alzheimer’s: The Cost of Caring, The AtlanticLIVE

Durbin Introduces The American Cures Act, Press release March 12, 2014

Senator Collins Announces New Legislation in Support of Family Caregivers at National AARP Event. Press Release, July 8, 2015.

Adapted from, Fields, R.D. Burying Political Hatchets to Fight Alzheimer’s Disease. Scientific American Guest Blog, July 23, 2015

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

Why no one helped

KnifeOn Saturday, July 4, 2015, a horrifying bloodbath erupted before the eyes of passengers on the Red Line Metro subway train heading to Fourth of July festivities in Washington, DC. Wide-spread criticism in the press and social media erupted over the “apathetic” response of onlookers who reportedly said or did nothing to help the victim. But from the perspective of brain science, this scornful criticism is misguided.

A man on the Metro train snatched a cell phone from 24-year-old Kevin Joseph Sutherland. In the struggle the robber viciously beat, kicked, and stabbed the life out of the young man, inflicting 30-40 knife wounds. Passengers fled to opposite ends of the car and watched as the recent college graduate was murdered gruesomely. At the next stop the blood-spattered murderer walked casually off the train and escaped into the crowd. Police later identified 18-year-old Jasper Spires from bloody clothing, a knife, and other evidence found in a trash can.

In a commentary in the Washington Post, columnist Petula Dvorak contrasts the apathy of Metro riders with the heroic action of passengers on United Flight 93 who resisted the September 11, 2001 hijackers, and with a local man, Dylan Rawls, 31, who instantly risked his life to save a stranger being violently attacked in a parking lot. Disgusted, some cite the Metro subway tragedy as a sign of society’s moral decay. Others boast with empty bravado in online superhero fantasies about how they would have dispatched the killer. Traumatized witnesses are agonized, second guessing their reaction to the horror.

The finger-pointing reflects a fundamental misunderstanding of the neuroscience of how the brain responds to sudden threats. I know, because like Kevin Sutherland, I was once robbed on a subway, and I reacted the same way he did. I instinctively fought with the robber to get my wallet back. I succeeded, but I was lucky. Had my chance encounter been with a homicidal maniac of the likes that intersected Kevin’s path, I could have been killed just as brutally. But I didn’t think. I just reacted. In a fraction of a second I risked my life in a deadly fight with a criminal without any conscious deliberation. As a neuroscientist, I was driven to understand the threat detection circuits inside my brain.

The actions these threat detection circuits trigger–to fight, freeze, or flee–have momentous consequences. Enormous amounts of data must be evaluated instantaneously. If done consciously this analysis would take too long; moreover, the demands of this complex analysis would overload the feeble capacity of our conscious mind. “I wasn’t thinking,” Rawls said in recalling his heroic act. “Had I stopped, thought about it, weighted the pros or cons, had I had time to react, I might’ve scared myself out of helping.”

It may be comforting to indulge in speculation about how you would have responded to the deadly attack on Kevin, but the fact is that it is difficult to know how anyone will react to a sudden threat. A person’s response depends on a complex set of situational factors, the nature of the treat, and internal states of body and mind at the moment–all assessed in a fraction of a second and acted upon instantly. This must be so. The multiple factors and uncertainties presented means that there is rarely one correct response to a sudden threat. The identical reaction Kevin and I had to being robbed, with opposite outcomes, demonstrate this dramatically.

Some of the factors determining how one will respond to a sudden threat are being identified as neuroscience is beginning to tease apart the complex circuitry of our brain’s threat detection mechanism. This circuitry is largely subcortical; that is, it operates beneath the level of consciousness. Of paramount importance in threat detection and rapid response is the amygdala, located deep in the brain, which alerts us to danger, learns from bad experiences, and engages the body’s automated “fight or flight” response. This response is triggered when the amygdala activates the same region of the brain that controls other powerful unconscious urges including sex, thirst, and hunger: the hypothalamus. The release of adrenalin and other signals set our heart racing, muscles twitching, and body sweating to battle or to flee.

Danger signals shoot through high speed pathways to the brain’s threat detection circuits rather than engage our cerebral cortex. For example, there is a high-speed pathway from the retinas in our eyes to the center of the brain’s threat detection region. Most visual information from our eyes is transmitted to the cerebral cortex at the back of the brain. Here 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. But, this sophisticated visual processing takes time–too much time to dodge a left hook, for example. In bypassing the visual cortex, the rapid subcortical pathway from the eyes to the amygdala alerts our threat detection system like a motion detector in a home security system. No image is formed, but whatever has just intruded into our visual field should not be there!

New research is finding that different types of threats engage different threat detection circuits. A mother rat snapping aggressively to protect her young, for example depends on circuits in the ventral premammilary nucleus (PMv) of the hypothalamus, but a different type of threat, aggression related to social defense for example, passes through a different hippocampal relay point, the dorsal premammillary nucleus. Genetic and environmental factors will also influence the strength of these different circuits in different individuals, as will hormonal fluctuations, chronic stress, and many other factors.

Bystander apathy is a psychological phenomenon in which witnesses to a person being harmed are less likely to intervene the more people there are present. This is thought to be a consequence of the herding instinct of human beings to do as they see others do. But when many people are present it is a much more complex situation. This leads to confusion. Is the person being attacked a victim or are they gang members in combat? But neither apathy nor confusion is what those riders on the Metro train experienced. They experienced terror.

I cannot know what those witnesses lived through on that train, but I am confident from my knowledge of neuroscience that they did exactly the right thing. Their response is not a matter of bravery or cowardice or apathy; it is a matter of deadly strategy. Engaging the homicidal robber physically could have resulted in mass casualties. From all the situational information those people rapidly assimilated, that was their collective conclusion. Instead, the passengers tried to appease the robber with cash. No one else lost their life.

Honed by eons of evolution in a dangerous world of survival of the fittest, the reaction these neural circuits trigger is usually correct; otherwise our species would have gone the way of dinosaurs. This is why rational Monday morning quarterbacking about the passengers’ response on the Metro Red Line is misguided. No fault should be leveled against any individuals on that train. They did as their brain and evolution has equipped them to do.


Dvorak, P., “Hear the roar of armchair Metro heroes, The Washington Post, July 10, 2015, p. 9A.

Hermann, P., “Horrified passengers witnessed brutal July 4 slaying aboard Metro car. The Washington Post, July 7, 2015.

Motta, S.C. et al., (2013) Ventral premammillary nucleus as a critical sensory relay to the maternal aggression network. Proc. Natl. Acad. Sci. USA August 27, 2013 110:14438-43.

Shang, C., et al., (2015) A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice. Science, June 26, 2015, 348:1472-7.

Adapted from: Fields, R.D. Why Nobody Intervened in the July 4 Metro Murder. Scientific American Guest Blog: July 17, 2015

Why We Snap, by R. Douglas Fields

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

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:

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.

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 –

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