Excerpted with permission from Reaching Down the Rabbit Hole: A Renowned Neurologist Explains the Mystery and Drama of Brain Disease, by Dr. Allan H. Ropper and Brian David Burrell. Available from Saint Martin’s Press, LLC. Copyright © 2014.

It was a bad omen when my beeper went off one morning at 6:10 as I warmed up my car in the garage. Trey, my senior ICU fellow, asked me to meet him in the emergency room to save time on an admission. “A guy fell on Comm Ave this morning and cracked his head,” he informed me when I rang him back. “He’s got a big subdural, but the neurosurgeons don’t want him because he may be too far gone.”

A subdural is short for a subdural hematoma, a brain hemorrhage typical of traumatic brain injuries, caused in this case when the skull hit the sidewalk and the brain caromed off the inside of the skull, in the process tearing veins that run across its surface.

When I arrived at the Emergency Department, I found the poor guy—a very thin, elfin-looking man, with pallid skin and short, whitish, sparse hair—breathing on a ventilator. According to his driver’s license, his name was Mike Kavanagh, and he was an organ donor. A huge gash decorated his scalp, with dry-crusted blood cascading onto the bedsheets like a frozen brackish waterfall.

Knowing when someone’s alive and knowing when someone’s dead: it’s one of the most important jobs that doctors do. If we can’t do that, we can’t do anything.

The person must have an apnea test. Then you can prove to yourself that the whole brain, including the brainstem, is gone. Just remember, when you take a patient off a ventilator, either for an apnea test or after a declaration of death, make sure that family members are out of sight, and forewarn the nurses. Many brain dead patients, once the ventilator is removed, exhibit the so-called Lazarus sign, where their arms spontaneously contract and their hands come up to their chest as though they’re grasping for the endotracheal tube. It’s creepy no matter how many times you’ve seen it.

This test is the big one. It grew out of Moses Maimonides’ practice of holding up a glass to see if the breath fogs it. The object is to see whether the patient will breathe on his own. We sent 100 percent oxygen through Mike Kavanagh’s lungs for two minutes, enough to sustain his heart and blood pressure without a ventilator for the next ten minutes, then shut off the ventilator.

Silence. I could hear my pocket watch ticking. As Trey and I watched closely, we could see a few arching movements in Mike’s back, definitely not Lazarus signs, but something not entirely compatible with brain death. We waited. With the palm of my hand acting as Maimonides’ mirror, I felt air moving almost imperceptibly in and out of the ventilator tube. Was he breathing? It was important to be sure.

Ten minutes were up, and the result was conclusive. Mike Kavanagh had failed the apnea test.

“That’s a wrap,” Trey said, snapping off his gloves.

“Is it? If he’s dead, in what sense is he dead?”

“In the dead sense,” Trey replied.

“Well, his brain may be dead, but his other organs are alive. They can be transplanted.”

“But they’re just organs. Organs can be sustained, even grown outside of a body, independent of a body.”

“The gash on his neck where the transplant surgeon cuts out a lymph node would heal.”

“Those are just cells,” Trey countered. “They’re on automatic pilot. You provide them with blood, they keep going, but there’s nothing meaningful going on.”

“But if Mike Kavanagh were a pregnant woman,” I said, “we could keep him alive in order to bring the baby to term. What could be more meaningful than that? My point is that we just engaged in an operational decision, not a biological one. The end result is still correct, but we shouldn’t pat ourselves on the back and say that we have come to an ontological certainty. We need to be honest about what we’re doing. His brain may be dead, but the rest of him is not dead, and we can use the rest of him. I have no problem with what we’re doing, but we should think it through more carefully.”

Trey paused, and said, “And that’s what we just did, right?”

“You’re not buying it, are you?”

“No,” he replied.

Trey and I knew very well what would happen when I signed the death certificate. Brain death is a firm, unambiguous, and operationally solid determination, an absolute point of no return for the brain. Any two competent neurologists or neurosurgeons who examine a brain-dead patient will come to the same conclusion, just as we had: this entire brain will never recover, and all the king’s horses and men can’t do a damn thing about it.

The problem is the word dead. It muddies the important issue, as does diagnosis. Brain death is not a diagnosis—a word that suggests probability—but rather a determination. A diagnosis raises the specter of false positives, of fallibility, of someone being buried alive. That can only happen if someone does the test incorrectly, and we hadn’t.

“Look, Trey,” I said, “it’s fine to have an operational definition to work with. We couldn’t get through the day without that. But you are in a position, because you are a doctor of the brain, to think about these things more broadly, and you should, because if you don’t, nobody will.”

In The Wizard of Oz, after the tragedy of the tornado and the falling house, the medical examiner of Munchkinland was called upon to check under the front porch for the remains of Evanora, the Wicked Witch of the East. After due consideration, he solemnly pronounced to the mayor:

As Coroner I must aver,
I thoroughly examined her,
And she’s not only merely dead,
She’s really most sincerely dead.

In the case of Mike Kavanagh, Trey was satisfied with “merely dead,” as was the Presidential Commission, the Commonwealth of Massachusetts, and the Vatican. I’m not entirely sure.

Itty-bitty seeds of human stomachs can now bud in plastic dishes.

By bathing stem cells in a brew of growth-boosting chemicals, scientists have kick-started the construction of crude organs about as big as the head of a pin. These primitive balls of gastric tissue — the first to be cooked up in the lab — resemble the stomachs of developing fetuses. The lab-grown bellies represent the latest in a line of do-it-yourself organlike cell clumps, including livers, brains and guts (SN: 12/28/13, p. 20).

Three years after figuring out how to transform stem cells into human intestinal tissue, and more recently, how to make that tissue grow in mice (SN Online: 10/19/14), developmental biologist James Wells of Cincinnati Children’s Hospital Medical Center  and colleagues have monkeyed with their method to make 3-D stomachlike organs.

Like human stomachs, the lab-grown globs contain both mucus-making and hormone-pumping cells. The tissue also mimics a stomach’s response to infection with Helicobacter pylori. The ulcer-causing bacteria cue the globs to switch on the same molecular signals that real stomach cells use, Wells and his team report October 29 in Nature.

The mini stomachs hand researchers a new tool for studying gastric human disease, including cancer, the researchers suggest.

What we see in the mirror

As part of the ERC’s IdeasLab session in Tianjin (China) on Wednesday 10 September, Dr Fotopoulou will be addressing the question of the embodied self. Her presentation will focus on the relationship between how we see our bodies and how we protect ourselves against an uncritical internalisation of these images. “By giving so much significance to outside images, we forget about what happens inside – how we process these images, how we filter these perceptions and what this does to our sense of self”, she says.

Dr Fotopoulou’s ERC project ranges beyond questions of body image into the role of primary body signals. Signals from the body are known to be processed in hierarchically organised re-mappings in the brain. However, it remains unknown how the brain integrates them to give rise to our awareness of ourselves as embodied beings. These signals can be roughly divided into three areas – signals from inside the body, from outside and those we receive from others. They are, perhaps inevitably, interrelated. How the inside of the body makes us feel, for example when our heart is racing, is inextricably linked to what we see in the mirror as well as to the perceptions we have absorbed from others.

Bodily signals continuously condition our sense of self, but we are only really aware of them when something goes wrong: “when you are walking somewhere, you are concentrating not on your sense of the bodily self moving through space but on reaching your destination. But if you trip, then you are suddenly jolted into a sense of your self failing to negotiate a pavement“, Dr Fotopoulou says.

Processing pain 

One particularly interesting aspect of this research is the group’s investigation of the experience of pain. “The link between stimulus and damage when we feel pain, the perception of pain is not a category in the brain. Instead, our response to pain is based on our previous experience of it,” Dr Fotopoulou explains. “When a child falls over, there is a delay. The child stops and watches its mother. If the mother reacts dramatically, the child will start to cry. If the mother’s response is more practical, the child is much more likely to pick themselves up and carry on. In other words, the child’s experience of pain is conditioned by their mother’s sense of how much danger they are in.”

How mind–body processes can affect healing 

The awareness of the relationship between the body and the self is significant when studying the experiences of brain damaged patients. Dr Fotopoulou and her team are particularly interested in patients who deny their conditions, or who are unaware of them – who believe that they retain motion in a paralysed side after a stroke for example. This kind of self-deception can inhibit treatment: it is difficult to treat a patient who does not believe that there is anything wrong with them.

“Brain damaged patients are traditionally treated as broken-down machines in neurological terms,” Dr Fotopoulou explains. “But their problems are psychological as well as physical. By applying cognitive neuroscience methods when treating a small number of patients we have demonstrated that disorders that were previously thought to be intractable can be treated. Studies of this kind are vital: working with patients whose sense of self is fractured can teach us not only about their disorders but also tell us something about how these mechanisms function in healthy individuals.”

The hope is that these findings can be fed into future policy decisions about the treatment of brain damaged patients: particularly in terms of the importance of psychotherapy as part of the rehabilitation process.

ERC funding has enabled Dr Fotopoulou and her team to set up a truly interdisciplinary project. “We have been given the luxury of time to apply a wide range of methods and tools from disciplines as diverse as philosophy and psychology. We have the freedom to pursue the best science without any external pressures – to develop ideas and to publish only when the science is ready.” Dr Fotopoulou and her team are based at University College London (UCL), UK.

Researchers have discovered a link between prenatal enamel growth rates in teeth and weaning in human babies. The research found that incisor teeth grow quickly in the early stages of the second trimester of a baby’s development, while molars grow at a slower rate in the third trimester. This is so incisors are ready to erupt after birth, at approximately six months of age, when a baby makes the transition from breast-feeding to weaning.

Weaning in humans takes place relatively early compared to some primates, such as chimpanzees. As a result, there is less time available for human incisors to form, so the enamel grows rapidly to compensate.

This research can increase our understanding of weaning in our fossil ancestors and could also help dentists as dental problems do not register in all teeth in the same way. Enamel cells deposit new tissue at different times and different rates, depending on the tooth type.

Exactly when early weaning in humans first began is a hotly debated topic amongst anthropologists. Current dental approaches rely on finding fossil skulls with teeth that are still erupting — which is an extremely rare find. Anthropologists will now be able to explore the start of weaning in an entirely new way because ‘milk teeth’ preserve a record of prenatal enamel growth after they have erupted and for millennia after death.

The research, funded by a Royal Society equipment grant, was conducted by Dr Patrick Mahoney from the Human Osteology Research Lab in the University’s School of Anthropology and Conservation.

WASHINGTON — The recreational drugs known as bath salts reduce communication between different areas of the brain in rats, new research finds. This decline may be tied to the depression and aggressive behavior that some users feel after taking the drugs.

Compared with control animals, rats dosed with one bath salt variant had less synchronized activity, or “functional connectivity,” among the 86 brain areas that the researchers examined.

“The higher the dose, the less connectivity you get in the brain,” says neuroscientist Marcelo Febo, who presented the research November 15 at the annual meeting of the Society for Neuroscience. “It causes a pretty global reduction.”

Bath salts are a group of stimulants that boost levels of dopamine, a messenger molecule related to reward and pleasure, as well as norepinephrine and serotonin, which play roles in attentiveness and mood. They are chemically similar to methamphetamine, cocaine and ecstasy, and take their name from their similar appearance to the Epsom salt crystals sprinkled in bathwater.

 M. FEBO ET AL

Initially marketed as “legal highs,” the most common bath salt variants were banned in 2011. One of them,  MDPV (short for 3,4-methylenedioxypyrovalerone), is much more potent than cocaine, says Michael Baumann, a neuroscientist at the National Institute on Drug Abuse in Baltimore. “For people experimenting with this drug, if they’re used to doing a line of cocaine and they do the same-sized line of this drug, it’s essentially like they just did 10 lines of cocaine.”

Low doses of bath salts can make users feel euphoric and alert. Within hours of taking MDPV, however, some users experience a powerful crash that can make them delirious, suicidal or violent.

To investigate the lingering effects of bath salts on the entire brain, researchers gave 46 rats doses of MDPV or saline, waited an hour, and took functional MRI scans of the rats’ brains. In rats dosed with MDPV, functional connectivity decreased widely.

The findings suggest that bath salts have effects that reach beyond the dopamine reward system. “It can happen with other drugs after chronic use,” says Febo, of the University of Florida in Gainesville. He pointed out that longtime cocaine users can experience panic or anxiety after taking the drug. “But with bath salts it appears to be a much more rapid onset.”

Diminished communication between different areas of the brain may lead to the behavior that accompanies crashes, he says.

His team must still compare the effects of MDPV to those of other stimulants. Attempts to scan the brains of rats dosed with cocaine made the animals too unstable to obtain results.

Without a comparison, the data lack context, says Baumann. “They’re really big findings,” he says. “But the question is, do other stimulants do this? Or is it unique to bath salts?”

In the future, the researchers want to repeat the test with other stimulants, test rats at eight and 24 hours after being dosed with MDPV, and investigate whether the effects on connectivity match up with behavioral changes such as aggression.

The cell biologist Henry Harris, who has died aged 89, made the key discovery that the inactivated form of a virus responsible for a respiratory tract infection in mice could fuse cells together very efficiently, even when they differed widely in type and species of origin. He showed that this remarkable finding could be exploited to reveal how the expression of genes was controlled, how they could be assigned to specific chromosomes and, of central interest to his later research, that some could suppress the growth of cancer cells.

Fusion produces either single large nondividing cells containing multiple separate nuclei of each type or, most interestingly, hybrid cells in which all genes of the participants are encompassed within a single common nucleus. The hybrids are of particular value in showing sustained growth and division, and in tending to shed chromosomes more or less at random. In elegant experiments in which he made such hybrids between cancer cells and their normal counterparts, Henry found that malignancy was consistently suppressed, only to re-emerge later among some of the descendants of the hybrid cells.

He was able to correlate the recrudescence of malignancy with loss of a specific chromosome of the normal partner cell. This provided the first clear evidence for the existence of a class of tumour suppressor genes. By using x-rays and later harnessing DNA technology, he was eventually able to identify a gene capable of suppressing a wide range of malignancies; it produced a type of collagen that is deposited in the material in which many types of cells are embedded. Cell fusion has also proved to be of clinical value, with the development of monoclonal antibodies for treating an increasing number of diseases. Henry’s scientific achievements were recognised by his election as a fellow of the Royal Society in 1968 and the award of a knighthood in 1993.

Born in Russia, Henry was the son of Jewish parents, Sam and Ann. In 1929 the family emigrated to Australia. From Sydney Boys high school, Henry went to the University of Sydney to study modern languages. On graduating in 1944, he embarked on a medical degree inspired, he claimed, by the works of literary doctors, in an attempt to become a latter-day Chekhov. He began to dabble in experiments during his medical training, and this developed into an obsession with basic biomedical research that captivated him for the rest of his life.

When he qualified as a doctor in 1950, he married Alexandra Brodsky, also of Russian Jewish origin, whose family had gone to Australia from Belgium after the second world war. Thereafter, he won a scholarship to take a DPhil degree at the Sir William Dunn School of Pathology, Oxford University, under the supervision of a fellow Australian, Professor Howard Florey, who led the team that had earlier demonstrated the clinical efficacy of penicillin.

Once Henry had gained his DPhil (1954), he became director of research for the British Empire Cancer Campaign at the Dunn School. After a year in the US (1959-60) and three as head of cell biology at the John Innes Institute at Bayfordbury, Hertfordshire (1960-63), he returned to the Dunn School as professor of pathology, in succession to Florey. He continued to head the Dunn School after being appointed regius professor of medicine in 1979, and carried on working in the department for some years after retiring in 1992.

Throughout his career, he undertook much of the experimental work with his own hands, seldom attending conferences and strictly limiting other engagements that would interfere with his research. He also adopted various measures to minimise the burden of other duties on members of staff who were active in research, including recruiting distinguished retirees to help with the preclinical teaching of bacteriology and virology.

Henry had a deep feeling for history, both within the biological sciences and more generally. It gave him great satisfaction that when Henry VIII established the regius chair of medicine he chose to link it with the mastership of the almshouses in the medieval Oxfordshire village of Ewelme, which were founded by Geoffrey Chaucer’s granddaughter, Alice, and her husband, Thomas de la Pole, Duke of Suffolk, and are still in existence. He appreciated the Dunn School for its unusual elegance and setting as a laboratory, and fought successfully against the university’s repeated attempts to destroy its gardens for car parking.

Henry’s writings after retirement included a book offering novel insight into the history of discovery of the cell, The Birth of the Cell (1999), and another, Things Come to Life (2002), which traced the history of the notion that living creatures could arise spontaneously from nonliving material, and described just how difficult it was to design experiments to disprove the idea. He also produced a masterly translation of a book on cancer written a century ago by the great German embryologist Theodor Boveri (2008). Moreover, both before and after retiring, he wrote engaging short stories about academic life for the Oxford Magazine, which were brought together in Remnants of a Quiet Life (2006).

He is survived by Alexandra, his son, Paul, and daughters, Helen and Ann.

• Henry Harris, cell biologist, born 28 January 1925; died 31 October 2014

Americans can take a warning from a University of Florida study of bottled water in China ─ don’t drink the liquid if you’ve left it somewhere warm for a long time.

Our memories are annoyingly glitchy. Names, dates, birthdays, and the locations of car keys fall through the cracks, losses that accelerate at an alarming pace with age and in neurodegenerative diseases. Now, by applying electromagnetic pulses through the skull to carefully targeted brain regions, researchers have found a way to boost memory performance in healthy people. The new study sheds light on the neural networks that support memories and may lead to therapies for people with memory deficits, researchers say.

Transcranial magnetic stimulation, or TMS, is an increasingly popular therapy for psychiatric disorders that involves placing fist-sized coiled magnets on the scalp to stimulate different brain regions. Although researchers aren’t sure why or how it works, it does appear to benefit some patients. Last year, for example, the U.S. Food and Drug Administration approved several TMS devices for treating migraines and depression. Studies have also shown that the technique can improve performance on different types of memory tests, but few researchers have investigated whether benefits persist after stimulation stops or looked at how stimulation affects the brain’s memory circuits, says Joel Voss, a neuroscientist at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois.

To begin answering those questions, Voss and colleagues recruited 16 healthy adults who were between the ages of 21 and 40. Using structural and functional MRI scanners, the researchers made detailed maps of the subjects’ brains, locating the hippocampus, a brain region key to memory, and its connections to another brain region called the parietal cortex. Functional MRI scans of brain activity show greater neuronal traffic between the two areas when people are performing memory-related tasks, and lesions between the areas can result in severe deficits in the ability to remember proper labels for things, such as matching names with faces, Voss says.

After administering a baseline memory test to the participants, the team began the brain stimulation sessions, focusing rapid-fire magnetic pulses on a fingertip-sized area toward the back of the skull for 20 minutes per day. The location of the stimulation differed slightly among individuals, based on brain scans showing their unique connections between the parietal cortex and hippocampus, Voss explains. After 5 days, the participants were given a 24-hour break from stimulation and asked to repeat the memory test. People who had received TMS improved their scores by roughly 20% to 25%, whereas controls who had not received the stimulation showed little to no improvement, Voss and his colleagues report online today in Science. Brain scans also showed increases in the amount of communication between the hippocampus and parietal cortex in subjects who received the stimulation. The more the two regions worked together, the better people performed on the memory test, Voss says.

The study is “very cool” because it supports scientists’ growing understanding of the hippocampus as one vital node in a larger memory network spread throughout the brain, says Alvaro Pascual-Leone, a neurologist at Harvard Medical School in Boston who was not involved in the research. It also “elegantly shows” for the first time that stimulation on the surface of the skull can reach deep brain structures (such as the hippocampus) and increase communication and synchrony throughout the network, ultimately improving performance on a memory test, he says.

Whether TMS will someday be a cure for memory deficits is “a reasonable question to ask, but it’s not answered yet,” Pascual-Leone says. Scientists will need to conduct many studies in people with illnesses such as Alzheimer’s disease to determine whether stimulation is effective for them—the disease might do so much damage that stimulation doesn’t work or even has deleterious effects, Pascual-Leone says.

The fact that the TMS stimulation used in the study had such a targeted effect on memory networks makes Voss optimistic that the technology could counteract memory loss. In an upcoming trial, Voss and colleagues will study the electromagnetic stimulation’s effect on people with early-stage memory loss, he says.

Studies like this one raise the ethical issue of whether it’s a good idea to use such technologies on healthy people to change a normal brain, Pascual-Leone notes. For one thing, it’s unclear how long the improved recall lasts, or if changes to the brain could be permanent. “How long does it take to go back?” he wonders. And although the prospect of memory enhancement may be enticing for those of us who are constantly losing our keys, it’s possible that boosting function in one cognitive skill will take away from another, he says. “The brain may be a zero-sum game in that sense.”

When we search for the seat of humanity, are we looking at the wrong part ofthe brain? Most neuroscientists assume that the neocortex, the brain’s distinctive folded outer layer, is the thing that makes us uniquely human. But a new study suggests that another part of the brain, the cerebellum, grew much faster in our ape ancestors.

“Contrary to traditional wisdom, in the human lineage the cerebellum was the part of the brain that accelerated its expansion most rapidly, rather than the neocortex,” says Rob Barton of Durham University in the UK.

With Chris Venditti of the University of Reading in the UK, Barton examined how the relative sizes of different parts of the brain changed as primates evolved.

During the evolution of monkeys, the neocortex and cerebellum grew in tandem, a change in one being swiftly followed by a change in the other. But starting with the first apes around 25 million years ago through to chimpanzees and humans, the cerebellum grew much faster.

Learning to swing

As a result, the cerebellums of apes and humans contain far more neurons than the cerebellum of a monkey, even if that monkey were scaled up to the size of an ape. “The difference in ape cerebellar volume, relative to a scaled monkey brain, is equal to 16 billion extra neurons,” says Barton. “That’s the number of neurons in the entire human neocortex.”

“That’s not to say the neocortex is boring,” says Barton. But such rapid growth in the cerebellum must have happened for a reason. Since the cerebellum is heavily involved in the control of muscles, particularly in coordination, he suggests the trigger may have been the first apes learning to swing from branch to branch, as modern gibbons do.

The extra coordination skills could then have unleashed other “technical” skills like making tools and fine finger movements. Some researchers, like Richard Byrne of the University of St Andrews in the UK, think that such technical intelligence is a defining feature of apes.

Barton’s data is solid, but he overstates the importance of the cerebellum, saysSusanne Shultz of the University of Manchester, UK. “The cerebellum is important in coordination and synthesis,” she says. “But I don’t think it takes away from the fundamental importance of the neocortex.”

Person skills

Shultz points out that over a century of neuroscience has demonstrated the importance of the neocortex for distinctively human traits like social skills and the ability to plan many years ahead. The famous case of Phineas Gage, a 19th-century railway worker who had a rod driven through the front of his brain in an accident, illustrates this. Before his injury he was clean-living and meticulous, but afterwards he became unable to control his impulses. “All you have to do is knock out the prefrontal area and you start to see all these problems in ‘human’ areas,” says Shultz.

Since the cerebellum pulls together disparate sources of information from all over the brain and uses it to control motor functions such as hand gestures and walking, it may simply have had to grow once the rest of the ape brain ballooned. “As your brain gets increasingly large, it becomes increasingly important to synthesise and coordinate all the information you’re holding,” says Schultz.

Where Shultz and Barton agree is that the neocortex and cerebellum are densely interlinked, so we might mislead ourselves by focusing on one to the exclusion of the other. “We should think about integration in the brain as a whole,” says Shultz.

“The broader part of the story is the way the cortex and cerebellum work together,” says Barton. “It’s hard to damage one without affecting the other.”

So although the rise of the neocortex is probably still the source of our mental prowess, it may be that it would never have worked without the cerebellum outpacing it.