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An Inflammatory Theory of Brain Disease

<p>
 Beginning in March, 2010, 882 men and women who had suffered traumatic brain injury were enrolled in a clinical trial to test whether administering the human hormone progesterone within four hours would improve their outcome. While it’s often thought of as a one-time event, traumatic brain injury is better described as a disease: it’s irreversible, sometimes progressive, and often affects people for the rest of their lives. More than 5 million Americans—ranging from professional football players to Iraq war veterans and victims of car accidents—live with disabilities caused by traumatic brain injury.
</p>
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<p>
 Traumatic brain injury is irreversible, sometimes progressive, and often affects people for the rest of their lives.
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<p>
 One striking hallmark of traumatic brain injury is inflammation in the brain, which occurs shortly after the trauma and can cause swelling, tissue breakdown, and cell death. Because it can be so debilitating, a lot of research has gone into finding ways to limit the damage in the hours immediately following injury. Progesterone can interfere with inflammation and is also thought to stimulate repair, so it was considered a promising candidate for reducing brain damage. Plus, the hormone is cheap and widely available.
</p>
<p>
 Experimental animal models and two early, small clinical trials had all shown positive results. After years of failing to find effective medications, hopes were high for this new approach.
</p>
<h2>
 The Role of Inflammation
</h2>
<p>
 While inflammation is harmful in the case of traumatic brain injury, it is also critical for our survival. When our immune system encounters a microbe or when we bruise our knees, the inflammation that results rushes key cells and proteins to the site to fight the infection or to encourage healing. But there are times when inflammation doesn’t know when to quit, and many doctors and researchers believe it plays a role in many chronic diseases. The growing list goes beyond autoimmune diseases, such as arthritis, diabetes, or multiple sclerosis, to include cardiovascular disease and possibly even brain diseases such as Alzheimer’s, Parkinson’s, epilepsy, or depression.
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<p>
 Here’s how the immune system is supposed to work. Let’s say you slam a car door on your finger. That causes tissue damage and possibly infection—stuff that doesn’t belong there and looks foreign to the body. White blood cells and other molecules swarm in, wall off the damaged area, and attack the invaders and the damaged tissue. The area gets hot, red, swollen, and painful. Clean-up cells like macrophages—which means “big eaters” in Greek—gobble up the garbage. Once the damage has been contained, other immune molecules begin the repair process and the inflammation subsides.
</p>
<p>
 But inflammation also causes collateral damage, a sort of friendly fire. The same processes that get rid of foreign agents can damage good cells as well. The death of those cells can in turn trigger further inflammation. For reasons that remain unclear, sometimes this creates a vicious cycle that becomes self-sustaining. Steven Meier, a neuroscientist at the University of Colorado who researches how the brain regulates immune responses points out that, “like many, many other adaptive mechanisms that are adaptive when they’re activated briefly, they may not be so adaptive when they’re activated chronically.”
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<p>
 “Inflammation is an important element, and maybe at the heart of a variety of disorders.”
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<p>
 For decades, researchers have noticed a link between ongoing inflammation and cardiovascular disease. Today it’s widely accepted that the immune system’s response to plaques of low-density lipoproteins, or LDL, on blood vessel walls plays a pivotal role in the progression of the disease. Sensing these plaques as foreign invaders, white blood cells and other molecules that are meant to protect the body turn into its own worst enemy. Instead of healing the body, white blood cells become trapped inside the plaques, provoking further inflammation and allowing the plaques to continue to grow. Eventually one of those plaques can break off and cause a clot, with potentially disastrous results.
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<p>
 Though it may be going too far to call inflammation a grand unifying theory of chronic disease, the link between the two is a focus of labs around the world. “I do think inflammation is an important element, and maybe at the heart of a variety of disorders,” Meier says, “and does account for a lot of the comorbidity that occurs between disorders. Why on earth is there comorbidity between depression and heart disease? But once you start thinking about inflammation, you realize they may be both inflammatory disorders or at least involve an inflammatory element.”
</p>
<p>
 In the last decade, interest in the relationship between inflammation and brain disease in particular has exploded. Tantalizing associations abound. For example, some population-based studies of Alzheimer’s patients suggested that people who took non-steroidal anti-inflammatories—so-called NSAIDs like aspirin or ibuprofen—for long periods have a reduced risk of developing Alzheimer’s. Low-grade systemic inflammation, as measured by higher than normal levels of certain inflammatory molecules in the blood, have been found in people with depression. And in children with severe epilepsy, techniques to reduce inflammation have succeeded in stopping their seizures in cases where all other attempts had failed.
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<h2>
 The Brain’s Immune System
</h2>
<p>
 The key is the brain’s unique immune system, which is slightly different from the rest of the body. For starters, it’s less heavy-handed. “The immune system, during evolution, learned that, ‘This is the brain, this is the nervous system. I cannot really live without it, so I have to be very, very, careful,’” says Bibiana Bielekova, chief of the Neuroimmunological Diseases Unit at the NIH.
</p>
<p>
 The first line of defense for the central nervous system is the blood brain barrier, which lines the thousands of miles of blood vessels in your brain. It is largely impermeable, for the most part letting in only glucose, oxygen, and other nutrients that brain cells need to function. This prevents most of the toxins and infectious agents we encounter daily from coming into contact with our brain’s delicate neurons and fragile microenvironment, preserving the brain’s balance of electrolytes—such as potassium—which if disturbed can wreak havoc on the electrical signaling required for normal brain function. Normally the blood brain barrier is very selective about what it invites inside the brain, but when the barrier gets damaged, for example because of a traumatic brain injury, dangerous molecules and immune cells that aren’t supposed to be there can slip inside.
</p>
<p>
 The second line of defense are microglia, the brain’s specialized macrophages, which migrate into the brain and take up permanent residence. Typically, microglia have a spindly, tree-like structure. Their branches are in constant motion, which allows them to scan the environment, but also delicate enough to do so without damaging neural circuits. However, when they’re activated by injury or infection, microglia multiply, shape-shift into blobby, amoeba-like structures, release inflammatory chemicals, and engulf damaged cells, tissue debris, or microbes.
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<h2>
 Mounting Failures in Clinical Trials
</h2>
<p>
 Late last year, the results of the progesterone-traumatic brain injury study with 882 patients were announced. Despite the apparent promise, patients who took progesterone following the initial brain injury fared no better than those on placebo. In fact, those who took placebo had slightly better outcomes. Women who took progesterone fared slightly worse. And episodes of phlebitis, or blood clots, were significantly more frequent in patients taking progesterone. A second study that enrolled 1,195 patients was also shut down when it showed no benefit.
</p>
<p>
 These two efforts are far from the only disappointing clinical trials that have tested anti-inflammatory treatments to intervene in brain diseases. A trial that used the antibiotic minocycline in ALS patients to reduce inflammation and cell death wound up harming more than helping. Alzheimer’s trials that attempted to reproduce the population effect that had been seen using NSAIDs also failed. In fact, in older patients the drugs appeared to make their symptoms worse.
</p>
<p>
 Another trial that attempted to circumvent inflammation by “vaccinating” with amyloid beta, the plaques that are one of the hallmarks of the disease, had to be discontinued after it caused inflammation of the brain and the membranes surrounding it in some patients. “Any time you intervene in any of these complicated biological processes that involve multiple proteins, multiple pathways, multiple loops, it’s going to be very complicated,” Meier notes.
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<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/microglia_and_neurons.width-990_itH1mv2.jpg"/>
<figcaption>Microglia, seen here stained green, are part of the brain's specialized immune system.
        
    </figcaption>
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<p>
 One reason why ongoing inflammation is assumed to be driving—if not instigating—brain diseases is that activated microglia are seen in the brains of these patients. However, activated microglia are not always bad. They also help protect it by shielding damaged areas from healthy regions, clearing debris from the brain, and initiating other complex anti-inflammatory processes that are far from fully understood. Bielekova points out that, “if you just see immune cells in the tissue, it’s very hard to say if they are playing bad guys or good guys.” In fact, a recent study published by the Yale School of Medicine in
 <i>
  Nature Communications
 </i>
 shows that microglia, at least in mice, appear to protect the brain by walling off the plaques from the surrounding environment. It’s possible, then, that tamping down microglia activation could actually make things worse.
</p>
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<p>
 “It can be very hard to say if immune cells are playing bad guys or good guys."
</p>
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<p>
 The difficulty of figuring out how to intervene in an immune response without turning off necessary functions may be just one reason why we haven’t seen major successes yet. Experts have pointed out a number of other reasons why so many trials have failed, from animal models that don’t translate well to humans and clinical trials that some would argue were poorly designed to the fact that once an inflammatory immune response has been well established, it becomes much harder to resolve.
</p>
<p>
 “Once you have this fully established chronic inflammation, it’s much, much more difficult to deliver effective treatments to those areas,” Bielekova says. “In multiple sclerosis, it is very clear that whichever drug you take that is efficacious, the efficacy decreases as you delay the treatment. So if you use the treatment very, very early on, every drug looks like a winner. But you wait just a couple of years and you take patients that are now three four years longer in the disease duration you may lose 50% efficacy of your drug.”
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<h2>
 Glimmers of Hope
</h2>
<p>
 Disappointing results aside, there are hints that intervening early to tamp down inflammation can be helpful. The same data analysis that showed NSAIDs can actually speed up the progression of Alzheimer’s in patients in the advanced stages of the disease also revealed that those who started taking NSAIDs regularly in midlife, when their brains were healthier, had slower cognitive decline.
</p>
<p>
 Other approaches built around intervening early have yielded similar results. For example, last summer Genentech
 <a href="http://www.pbs.org/wgbh/nova/next/body/alzheimers-treatments/">
  announced the results
 </a>
 of a phase II trial testing the efficacy of crenezumab to treat Alzheimer’s disease. Crenezumab is an antibody that binds to amyloid beta, the protein that makes up the plaques scattered throughout the brain that are one of the main visible features of Alzheimer’s. The theory behind this choice of antibody was that it would stimulate microglia just enough to begin clearing the plaques, but not so much so that these immune cells would launch a major inflammatory response. While this phase II trial failed to meet its targets, patients in the early stages of the disease who had been given large doses showed slower cognitive decline.
</p>
<p>
 Damir Janigro, a blood brain barrier researcher at Cleveland Clinic who studies traumatic brain injury and epilepsy, has a very different take on how to approach brain diseases linked with inflammation. He considers both of these diseases to be “blood brain barrier” diseases because repeated seizures and traumatic brain injury can damage the blood brain barrier, making it leakier. That means that not only can substances that don’t belong inside the brain slip through, materials from inside the brain can travel to the rest of the body.
</p>
<p>
 “The blood brain barrier shields your brain, which is good for you. But then it’s bad for you if you leak a piece of your brain and this is considered an enemy” by the rest of your immune system, he says. Janigro is part of what he calls a “vocal minority” of researchers who look at inflammation outside the brain as being another cause of inflammation inside the brain—and potentially even a better target for treatment. “Neuroinflammation is probably bad for you. But it’s a very hard target to go after. Everybody who does is surprised that it fails, like the Alzheimer’s trial in pulling amyloid from the brain.”
</p>
<p>
 We’re still early in our understanding of how the brain’s immune system works, when it is damaging, and when it is protective. If inflammation is the common element in brain diseases, it may turn out that understanding how to intervene successfully in one disease will make it possible to use similar therapeutic approaches across many. But, because we don’t fully understand how the unfathomably complex immune system works, it is likely to be a long and difficult journey before we find ways to intervene safely and effectively.
</p>
<p>
 “If you look at the range of disorders and diseases there’s probably a continuum where in some it plays little or no role, with some it’s in between,” Meier says. “You can go too far with any of these unifying themes. There’s a natural tendency to want to do so. But I do think the inflammation story is not going away. I think it’s real.”
</p>
<p>
 Image credit:
 <a href="http://commons.wikimedia.org/wiki/File:Microglia_and_neurons.jpg">
  GerryShaw/Wikimedia Commons (CC-BY)
 </a>
</p>

<p>Neuroscientists are torn over whether inflammation—a natural immune response—is causing a vast number of brain diseases.</p>

Will Surgery and Anesthesia Harm Your Memory?

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<p>
</p>
<p>
 Dr. H. had a struggling heart and a consequential decision to make. He needed an operation to fix a faulty valve but postponed it, afraid that the surgery and anesthesia would irrevocably damage his brain. The man made this decision more than a decade ago based on a phenomenon that was reported in an alarming article all the way back in 1955—one that many doctors still see first hand—of older patients who deteriorate cognitively after surgery.
</p>
<p>
 “When patients are asked, ‘what is the thing that you fear the most?’ it’s being disabled,” says Mervyn Maze, an anesthesiologist and researcher at the University of San Francisco. “It’s not dying. It’s living with a cognitive disability. And that becomes even more scary the older that you get.”
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<img alt="" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/eeg-3-months-after-surgery.width-990_rewrdBN.jpg"/>
<figcaption>PET scans show profound changes in the brain's immune response three months after major abdominal surgery.
        
    </figcaption>
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<p>
 The author of the 1955
 <i>
  The Lancet
 </i>
 article was a surgeon and consulting physician in England who reviewed thousands of charts and zeroed in on 18 “extreme” cases of people who appeared to be cognitively normal before the operation but became severely demented afterwards. He concluded that “operations on elderly people should be confined to unequivocally necessary cases.”
</p>
<p>
 It was a bold statement, and one that likely overstated the risk. Today, you would be unlikely to find a surgeon who would advise against surgery that could significantly improve your quality of life. But the potential for damage remains. Dallas Seitz is a young geriatric psychiatrist at Queen’s University in Ontario, Canada, who says his colleagues are familiar with memory or cognitive problems after surgery, what’s been known as postoperative cognitive dysfunction, or POCD. “I would be hard pressed to find a colleague who said I’ve never heard of it or I don’t think that that exists,” he says, though he’s quick to acknowledge that such anecdotes are not scientific evidence. “It’s not an experimental study. But I think we can’t discount what our patients tell us and what our experience tells us as well.”
</p>
<p>
 Because some 60,000 people undergo surgery daily in the U.S., and the numbers continue to climb, quantifying the risk is essential. It hasn’t helped that the term “POCD” is vague. “We’re talking about things that happen immediately after operations, like delirium, to things that happen perhaps a decade after an operation like dementia or Alzheimer’s,” notes Roderic Eckenhoff, an anesthesiologist and researcher at the University of Pennsylvania. New, more precise terms will soon be announced, and even though the picture is muddled, there is hope that the tools of modern science—from animal models to well-designed clinical trials—will bring more clarity.
</p>
<div class="pullquote">
<p>
 “I think we can’t discount what our patients tell us and what our experience tells us as well.”
</p>
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<p>
 Delirium is the most likely complication of surgery in older adults, with a risk as high as 60%. Patients with delirium are in a temporary and sometimes fluctuating type of acute brain failure: they can be confused, sometimes hallucinatory, aggressive, agitated, or sleepy and passive. Some small subset have mild cognitive impairment that can last for months before they recover. Their memory is not as clear and they describe themselves as being in a fog. They are generally less competent at planning or making decisions. And, worryingly, some remain permanently impaired or even descend into dementia, with studies suggesting that this outcome is more likely in patients who experience delirium compared to those who don’t.
</p>
<p>
 But it turns out that many older people were already on the road to dementia before their surgery. “It’s a standard sort of thing that we hear, that we are contacted by people who say, ‘you know, Mom was perfectly fine or Dad was perfectly fine until they had their knee replacement,’ says Lis Evered, an anesthesiologist and researcher at St. Vincent’s Hospital Melbourne in Australia. “But when you drill down on the ‘perfectly fine,’ they weren’t perfectly fine. It’s just that they were coping. And people develop strategies that can cover a decline quite markedly.”
</p>
<p>
 Between 10–34% percent of people over the age of 65 are already in a state of mental decline ranging from mild cognitive impairment—problems that go beyond what you would expect in normal aging—to dementia, including the most common form, Alzheimer’s disease. Evaluating someone’s mental status can be tricky, and not just because they’ve developed coping strategies. A visit to the surgeon before the operation occurs at a particular moment in time, but patients have good and bad days, and cognitive decline doesn’t always follow a smooth trajectory. It’s only after surgery that an underlying vulnerability may be unmasked. A recent study published in
 <i>
  The Neurobiology of Aging
 </i>
 showed that in apparently normal adults undergoing elective surgery with general anesthesia, a particular brain signature associated with the development of Alzheimer’s disease was tied to how severe the postoperative delirium was.
</p>
<p>
 “Patients are saying, ‘look this is my husband, he has cognitive impairment, and I’m really worried about conversion to Alzheimer’s,’” says Dr. Charles Brown, a cardiac anesthesiologist and researcher at Johns Hopkins University, “‘How does this particular procedure affect that? Should I get it? Should I not? If I do get it, how are you going to manage me differently?’ “
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<h2>
 Quantifying the Risk
</h2>
<p>
 “It’s very important to really be careful about what we know, about what we don’t know, and what we anticipate or hypothesize,” cautions Lars Eriksson, an anesthesiologist and clinical researcher at Karolinska University Hospital in Sweden. Many studies have significant weaknesses, adds Michael Avidan, an anesthesiologist and researcher at Washington University in St. Louis, and that includes overlooking shared risk factors.
</p>
<p>
 “If you have a cohort of people who have a disease that is known to be associated with cognitive decline,” Avidan says, “like hypertension, people who are heavy smokers, who are obese, who have diabetes, who have peripheral vascular disease, who have arthritis—whether or not they undergo surgery I can predict that those people are going to decline cognitively more than people who are marathon runners who are fit and all the rest of it.” Moreover, hospitalization itself, with or without surgery, has been shown to be a risk factor for cognitive decline, for reasons that are not entirely clear.
</p>
<div class="pullquote">
<p>
 “People develop strategies that can cover a decline quite markedly.”
</p>
</div>
<p>
 Avidan believes the evidence for the idea that anesthesia and surgery cause long term cognitive decline is “incredibly flimsy,” and points to a 2013 randomized controlled clinical trial published in
 <i>
  The Annals of Thoracic Surgery
 </i>
 as strong support for the idea that the risk is overblown, or perhaps even non-existent. The study found that patients who had open heart coronary artery bypass surgery with general anesthesia were better off cognitively 7.5 years after surgery than those who were treated with a less invasive non-surgical procedure that used only regional anesthesia. (Because regional or local anesthesia does not enter the brain, it’s assumed that it has no impact on brain function.)
</p>
<p>
 In contrast, a 2017 study in
 <i>
  Alzheimer Disease and Associated Disorders
 </i>
 reached the opposite conclusion, finding an association between coronary artery bypass graft surgery and long-term dementia risk. The researchers controlled for many typical risk factors but the study was not randomized.
</p>
<p>
 These are just two studies out of hundreds of others published over the past decade, each with different groups of patients or types of operations. That makes it difficult to reach a definitive conclusion on whether surgery and anesthesia cause permanent cognitive decline.
</p>
<h2>
 Managing the Immune Response
</h2>
<p>
 Perhaps it shouldn’t be so surprising that some elderly patients experience profound changes to their mental capacities after an operation. Surgery is a violent assault on the whole body, of which the brain is a part. Anesthesiologists administer drugs that push the brain into a reversible state of amnesia, immobility, loss of consciousness, and freedom from pain. Surgeons cut open bodies, stop hearts, replace hips or knees with titanium, and stitch stomachs smaller and tighter. In response, the traumatized tissues release substances that engage the immune system, activating a host of key cells and proteins that encourage healing. A mere 12 hours after surgery, signs of inflammation can also be detected in the cerebrospinal fluid. This is actually a good thing.
</p>
<p>
 “There is a signal within the body after peripheral injury that’s purposeful, that reaches the brain,” Eriksson says. “And that contributes to a condition that you could call sickness behavior, or the injured phenotype. It’s time to rest—to not be out hunting for food—and to heal. But, of course, when the injury becomes so large and big and it goes over the top, the situation can be different.”
</p>
<div class="pullquote">
<p>
 “The more unregulated your immune system was at three months, the worse was the cognitive function.”
</p>
</div>
<p>
 An immune response that doesn’t know when to quit is likely to be dangerous. In the elderly, the blood brain barrier is weaker, giving immune cells easier access to the brain. In aged rodents, scientists have found inflammatory molecules crossing the blood brain barrier and setting up shop in areas that are essential for learning and memory, such as the hippocampus. In human patients, researchers also found amyloid beta and tau—two proteins associated with Alzheimer’s disease—went from normal levels before cardiac surgery to levels associated with mild cognitive impairment six months after the operation. Other studies have shown similar changes as soon as 48 hours after surgery.
</p>
<p>
 This year, an international study by Eriksson and his colleagues pulled off a pioneering feat—using PET scans to image the immune response in patients before surgery, three to four days afterwards, and again at three months. In four of the eight patients, they saw profound and global changes in the brain’s immune system three months after surgery, long after the patients were home and going about their daily lives.“There was an association between the amount of immune activity and the decline in cognitive capacity,” Ericsson says. “The more unregulated your immune system was at three months, the worse was the cognitive function.”
</p>
<p>
 But finding a way to safely and effectively intervene in the immune response is notoriously difficult. In the case of surgical patients, extinguishing the initial inflammation could disrupt important processes like wound healing. “I suppose until we actually understand the mechanisms that are occurring in the perioperative period, trying to address what interventions might have an impact is very difficult,” says Evered, the Melbourne-based anesthesiologist. Many experts underscore the importance of using animal models to suggest possible mechanisms for the disease process so as to develop treatments. But a key interim step is to make sure that that same mechanism translates in humans. This is what makes Eriksson’s recent PET imaging study so important—it makes the connection between what we see in rodent models and what we see in us.
</p>
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<h2>
 Optimizing Anesthesia
</h2>
<p>
 Regardless of the actual mechanism, doctors and researchers are hard at work to find anesthetics and postoperative practices that will minimize the risk of any sort of cognitive decline. “If you are going to have a procedure, what are the ways that we can protect the brain the most?” asks Dr. Brown, who is investigating whether optimizing blood flow to the brain during surgery can make a difference. “Maybe you’re someone with mild cognitive impairment—and that is such a strong predictor of further cognitive decline—maybe you need to take that into account a lot more.”
</p>
<div class="pullquote">
<p>
 “We could never say, what effect does anesthesia have on the surgical effect?”
</p>
</div>
<p>
 Optimizing anesthesia could be one way to mitigate risk. Anesthesia was the original leading contender for cognitive decline, but while studies in rodents have shown toxic effects, the data for human trials has not. In a 2014 study of more than 12,000 patients, Dallas Seitz from Ontario found that the risk of dementia in patients who had an operation under general anesthesia versus regional, or local pain control, was “almost identical in the two groups. There was no statistical difference.” This is but one of many studies that lead anesthesiologists like Eckenhoff to believe that “the anesthetic is a minor player.”
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<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/eeg-display.width-990_uPgOVH1.jpg"/>
<figcaption>This anesthesia monitor combines EEG brain wave monitoring with other measurements such as heart rate.
        
    </figcaption>
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<p>
 While we don’t know if anesthesia can hurt the human brain, what if certain types of anesthetic drugs could help protect it? Until recently, investigating this idea has been hamstrung by the simple fact that it would be unethical to perform surgery—whether on people or lab animals—without any anesthesia. But a discovery by Maze and colleagues provided a neat workaround. They showed that a protein called HMGB1, which launches the immune response to trauma, can simulate the inflammatory effect of surgery. “We now don’t have to do surgery to cause the surgical effect,” Maze says. “We can just provide an injection of HMGB1 and start the process that way.” Maze is a co-founder of a start-up company called NeuroproteXeon that is in a phase 3 clinical trial of xenon. Xenon is not the only drug or class of drugs being investigated for neuroprotective qualities. For example, in small clinical trials, the anesthetic agent ketamine has been shown to reduce postoperative cognitive impairments, perhaps by modulating the immune response.
</p>
<div class="pullquote">
<p>
 “We’re trying to prevent or to avoid a pattern called EEG suppression during general anesthesia, where the EEG looks like it’s flatlined.”
</p>
</div>
<p>
 Another way to optimize anesthesia could be to fine-tune the amount a patient receives. Typically anesthesiologists track heart rate and blood pressure as their guide for deciding whether the patient has the right amount of drugs on board. But Avidan and others are investigating whether monitoring brain waves during surgery using an EEG can identify a “goldilocks” amount of general anesthesia that could decrease the risk of delirium. It’s easy to give more drugs than necessary, particularly in the elderly. “We’re trying to prevent or to avoid a pattern called EEG suppression during general anesthesia, where the EEG looks like it’s flatlined, and to see if that decreases postoperative delirium,” says Avidan.
</p>
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<h2>
 Optimizing Patient Care
</h2>
<p>
 Other measures could include making sure sleep and nutrition are optimal and that patients are given the right antibiotics at the right time to decrease the likelihood of surgical wound infections.
</p>
<p>
 And then there’s a decidedly low-tech approach: reorienting patients quickly. This includes having friends or family nearby as soon as possible after the operation, giving back their glasses, dentures, and hearing aids, or putting clocks and calendars on the wall. While it’s unproven whether this reduces delirium, “there’s no downside to doing these things,” Avidan says. “And it’s kind. If nothing else it’s respecting people’s humanity and dignity, and making their surgery experience more pleasant. So you have enough reason to do that regardless of whether or not you think it’ll improve short or long term outcomes.“
</p>
<p>
 None of these approaches are likely to tackle the problem on their own, though. Robert Whittington, an anesthesiologist and researcher at Columbia University Medical Center, addressed this question at the 2017 meeting of the American Society of Anesthesiologists, pointing out that given the complexity of the brain, rather than trying to find the magic bullet therapy, there should be a multi-pronged approach similar to treatment strategies for HIV.
</p>
<div class="pullquote">
<p>
 “There could be vulnerability out there that we need to define.”
</p>
</div>
<p>
 As with many medical procedures, and as with Dr. H., who chose not to get heart surgery, making tough decisions goes back to looking at risk and benefit. Surgery is a powerful stress test that can unmask underlying cognitive problems. But by the same token, surgeries that repair your heart or your hip, that allow you to exercise, or that reduce pain can improve your cognition.
</p>
<p>
 Older people should be aware that their brains may still be healing long after they go home. But there is still an unanswered question: can surgery and anesthesia accelerate or even cause a permanent cognitive decline, even if the surgery and aftercare are optimal? On top of all the vulnerabilities that elderly patients may enter the operating room with—from previous risk factors for cognitive decline, to leaky blood brain barriers, to the mere fact of being in a hospital—is there a specific surgical vulnerability for permanent cognitive decline that has yet to be nailed down?
</p>
<p>
 “There can be a little subgroup, perhaps not very big, that has a very unfavorable outcome,” says Eriksson. “And if you don’t do standard studies, using standard designs, those people may go undetected. The biological signal might be very small. There might be vulnerable individuals out there where a particular trigger—in this case surgery—where the pathways are very important. We might not be able to detect them. There could be vulnerability out there that we need to define.”
</p>
<p>
 Image credits: Forsberg et al. 2017,
 <a href="https://commons.wikimedia.org/wiki/File:Cardiac_surgery_operating_room.jpg">
  Pfree2014 / Wikimedia Commons (CC BY-SA 4.0)
 </a>
 , Wildes et al 2016 (CC BY-NC)
</p>

<p>Doctors aren&#x27;t ready to discount the possibility that surgery could have lasting cognitive effects.</p>

Fentanyl can be used as a painkiller in addition to an anesthetic.

Rare Form of Amnesia Linked to Fentanyl Overdoses is Spreading

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<p>
 A rare and frightening form of overdose-induced amnesia continues to spread in Massachusetts, with 18 confirmed cases, according to a New England Journal of Medicine report
 <a href="http://www.nejm.org/doi/full/10.1056/NEJMc1716355">
  published yesterday
 </a>
 .
</p>
<p>
 The hallmarks of the syndrome are severe anterograde amnesia—the inability to form new memories—and a distinctive pattern of damage to the hippocampi. The hippocampi are twin, c-shaped structures close to the center of the brain that are the epicenter of initial learning and memory.
</p>
<p>
 The first patient appeared at a Boston area hospital in 2012 following what was presumed to be a heroin overdose. By late 2016, doctors had identified 14 patients with this syndrome, and all but one had a known history of opioid use or had tested positive for opioids.
</p>
<p>
 Because the appearance of this syndrome parallels the rise of fentanyl overdose deaths, clinicians who have investigated the syndrome from the beginning suspected fentanyl, even though there was no evidence that anyone in this cluster had used fentanyl. “We know fentanyl is out there, we know that people are using it, we know it’s driving a lot of the phenomena that we see,” said Dr. Alfred DeMaria, the state epidemiologist for Massachusetts. “But we don’t have that documentation of fentanyl.”
</p>
<p>
 That’s because it’s rarely screened for when someone comes into the emergency room after an overdose, despite the fact that fentanyl was responsible for about three quarters of all opioid overdose deaths in the state of Massachusetts in the first half of 2016. In fact, the only time fentanyl screening is routinely performed is for autopsies to determine the precise cause of death after an overdose.
</p>
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<h2>
 A Potent Drug
</h2>
<p>
 Ironically, fentanyl was originally designed in 1960 as a safer form of anesthesia than morphine. But the same qualities that make it ideal for surgery make it addictive and deadly when used illegally and difficult to detect in blood or urine samples.
</p>
<p>
 The designer, a Belgian chemist named Paul Janssen, tweaked the structure of a molecule similar to morphine so that it could slip quickly past the blood brain barrier, making it extremely fast-acting. He also tinkered with its design to make it bind more tightly to the brain’s opioid receptors, which makes it more potent. In surgeries, doctors usually use far less of the drug, and can induce pain relief within one to two minutes. It’s effect is short-lived, generally lasting just a few hours or even less. This fast-in and fast-out mechanism gives anesthesiologists much better control during an operation.
</p>
<p>
 The flip side is that it’s easier for someone to overdose outside the controlled setting of a surgery and harder to detect when they do. “Fentanyl and fentanyl analogs are very potent,” said Nicholas Manicke, a chemist at Indiana University-Purdue University Indianapolis who has helped develop a rapid test for new synthetic cannabinoids and fentanyl and its analogues. “The amount of drug that a person would take is less than they might take with heroin. And that also translates to a smaller concentration in the blood.” Because fentanyl clears the body so quickly, blood samples have to be taken as soon as a patient comes into the hospital.
</p>
<p>
 Manicke’s rapid drug test consists of a small, square, inexpensive cartridge into which a few drops of blood plasma can be loaded. Any drugs in the cartridge are run through a mass spectrometer, which matches the suspect molecule to a database of about 20 synthetic drugs, all within five minutes. The product is still in development, but a screening method like this is orders of magnitude faster than sending blood or urine samples out to a toxicology lab, which is expensive and can take weeks to deliver results.
</p>
<p>
 To find out whether fentanyl is responsible for the syndrome, last May the Massachusetts Department of Health made this new form of amnesia a so-called “Reportable Disease Syndrome,” encouraging clinicians who saw patients that fit this pattern to send out for advanced toxicology screens that could detect the presence of fentanyl. That alert resulted in the four new patients from 2017 that are described in yesterday’s report in the New England Journal of Medicine. All four patients’ drug tests were positive for fentanyl, and two of them had no other drugs detectable.
</p>
<p>
 Despite this new evidence, the jury is still out as to whether fentanyl is truly the culprit. It now seems far less likely that a contaminant in the drugs is behind the outbreak, but proof that someone developed this syndrome after using pure, pharmaceutical grade fentanyl would help rule that out.
</p>
<p>
 The report’s authors note that one plausible cause of the unique pattern of brain damage is excitotoxicity, a kind of storm in the brain caused by excessive stimulation of neurons. They point to studies that showed severe damage to neurons in the hippocampus of rats who were given fentanyl. It’s likely that insufficient oxygen caused by slowed breathing during an overdose makes matters worse.
</p>
<p>
 The fact that only a tiny percentage of opioid overdose survivors develop this syndrome leads investigators to believe that genetics is also likely to play a role.
</p>
<p>
 As to whether any other drug is responsible, Dr. DeMaria said, “Nothing else has emerged. You have scientific plausibility and consistency. What we don’t have is proof of cause and effect.”
</p>
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<p>
 Photo credit:
 <a href="https://www.flickr.com/photos/nilswommelsdorf/34268050184">
  Nils Wommelsdorf
 </a>
</p>

<p>A rare and frightening form of overdose-induced amnesia continues to spread in Massachusetts, with 18 confirmed cases, according to a recently-published New England Journal of Medicine report.</p>

Altering Memories to Treat Addiction

<p>Last fall, a person addicted to cocaine arrived at the Medical University of South Carolina in Charleston. There, he or she watched a video of people using cocaine and was shown a small bag of what appeared to be either crack or powder cocaine, along with other drug-related paraphernalia. These cues were specifically designed to evoke memories of previous cocaine use and trigger intense craving. Shortly afterward, the individual was given a powerful pharmaceutical called propranolol that interferes with the brain’s ability to form memories. All of this may sound like a bad idea, but it’s actually a new and promising experimental treatment for addiction.</p>
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<p>Outside the controlled environment of a hospital, such a procedure would be risky, but this person—the last participant in a trial to test a new approach for preventing relapse—was carefully monitored on site and for six weeks after going home. Recently, much attention has focused on addiction as a chronic disease, but Mike Saladin, the research and clinical psychologist who led the study, explains that addiction is, in part, a disorder of learning and memory. The goal of his study is to reactivate memories of drug use—and then weaken them so they lose their power. The trial is one of 10 or more over the past decade inspired by lab experiments with rodents showing that memory can be manipulated to lessen its influence on addictive behavior. Researchers like Saladin aren’t trying to change the content of people’s memories. Instead, he says, “we’re turning down the volume” so that particular cues “don’t excite drug use the way they used to.”</p><p>Although the approach sounds like science fiction, it’s based on an understanding of learning and memory that goes back to an accidental discovery at the beginning of the last century, when the physiologist Ivan Pavlov, who was studying digestion in dogs, found that by repeatedly pairing a cue such as the tick of a metronome with the provision of food, the dogs would “learn” to salivate when they heard the noise—even before the meal arrived.</p>
<div class="related"></div>
<p>The same associative learning applies to addiction. When you learn that the pop of a wine cork predicts you will soon be enjoying a drink, you’ve created a memory. The more meaningful the experience and the more often you’ve paired those two events, the stronger the memory, even though it may be unconscious. Saladin points out that “people who have long substance use histories are responding to a myriad of cues, some of which they are not really aware of.”</p><p>Ravi Das, a psychologist at University College London, is also testing ways to modify memories in order to treat addiction. “Our brains are great at learning around rewards and what predicts them,” he says, noting that smells, sounds, and even people can serve as cues that promote relapse. This may help explain why 40 to 60 percent of people who have found a way to stop using drugs eventually relapse. Even if they’ve succeeded in staying off drugs for weeks or months or years, the paired association between cues and rewards can reactivate those drug memories, creating an overwhelming desire to use again.</p><p>Although we tend to think of longstanding memories as permanent, learning can be reversed, as Pavlov discovered with his dogs. When he repeatedly stopped providing food after starting the metronome, the dogs no longer salivated when they heard the cue.</p>
<h2>Trial by Exposure</h2><p>Targeting memories in order to treat addiction, as well as anxiety, is not entirely new. The concept is the basis for extinction learning (also called exposure therapy), in which patients in the safe environment of a therapist’s office are exposed to environmental cues that normally trigger maladaptive memories. Because they’re exposed repeatedly to the cues without the response, those cues should gradually lose their power.</p><p>But it’s not that straightforward. It can be hard to transfer that new learning from the lab, to the therapist’s office, to the unpredictable chaos of the real world. “This is the million-dollar question,” says R. Kathryn McHugh, a research and clinical psychologist at McLean Hospital in Belmont, Massachusetts, who treats anxiety and substance use disorders. “People have been looking at this for decades now. In the lab, you absolutely can extinguish these cues. You can decrease craving.” Yet studies to assess the efficacy of incorporating cue exposure with cognitive behavioral therapy to treat alcohol addiction in earlier decades didn’t show much of a benefit, says McHugh. “If the basic research can make that jump more effectively, that would be a tremendous tool for us to have.”</p><p>David Epstein, who heads up the Real-world Assessment, Prediction, and Treatment Unit at the National Institute on Drug Abuse, is at the forefront of trying to make that jump. “We can’t treat addiction just by using extinction, in which someone is repeatedly exposed to drug-related cues until the cues cease to induce craving,” he said via email, “because extinction doesn’t generalize outside the environment where it occurs.”</p><p>Researchers in this nascent field aim to solve that problem by tinkering with how patients are exposed to cues. They were inspired in part by recent advances in treating post-traumatic stress disorder, or PTSD, in which maladaptive memories are triggered by stimuli associated with the original event, like a news report of an assault, or a sudden loud noise.</p>
<div class="pullquote">
<p>“We can’t treat addiction just by using extinction, in which someone is repeatedly exposed to drug-related cues until the cues cease to induce craving.”</p>
</div>
<p>Nearly a decade ago, neuroscientists studying these so-called fear memories discovered what seemed to be a way around the weakness of extinction learning. Their method was based on the idea that when memories are reactivated, they are temporarily unstable. (It makes sense for memories to be fluid and dynamic, capable of incorporating new information, so they can help us make accurate predictions about the future.) “Normally the memory would subsequently re-stabilize,” says Das, who was not involved in these early studies. “But it would be slightly updated and that serves to keep your memories valid and up-to-date.” What if, researchers wondered, that instability provides a temporary window during which to intervene and add new information to the memory?</p><p>The trick was to make sure the behavioral therapy happened while the window of vulnerability was still open. Surprisingly, simply inserting a correctly timed pause between reactivating the memory and providing extinction learning was all that was needed to break the link between the cue and the fear memory, making the new approach more effective in both rodents and humans.</p>
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<p>Epstein helped analyze the results of a clinical trial published in 2012 that sought to reduce heroin craving by inserting these properly timed cues prior to therapy. The research team, based at Peking University in Beijing, worked with hospitalized patients who had detoxified. If the researchers activated the drug-reward memory by showing a video of heroin use, but waited 10 minutes before beginning an hour-long extinction session, they could reduce their patients’ craving. However, if they waited six hours or more, it was too late. The memory had already reconsolidated without the new learning, and the craving for heroin was as strong as before.</p><p>“This is so remarkable on its face that I wouldn’t believe it if it hadn’t been replicated,” says Epstein, who points to follow-up studies in rats and humans.</p>
<h2>Destabilizing Memories</h2><p>Six years later, Epstein is now enrolling patients in the first clinical trial in this country testing a similar approach to treat alcohol misuse, but he’s added a new maneuver to address another weakness of extinction learning. Normally exposure cues that are just images, sounds, smells, or words associated with the drug are only capable of making a subset of drug-reward memories unstable. In Epstein’s trial, the cue for some participants will consist of drinking the alcohol itself. The hope is that this technique will, as Epstein puts it, “get you to the hub of where all learned associations are stored, instead of having to weaken them one by one.” For safety reasons, any test subjects who drink alcohol will stay in the hospital until their blood alcohol levels are very low and will then be taken home. Over the course of the following month, everyone in the trial will use a smartphone to keep track of their drinking and craving.</p><p>At University College London, Das is also testing memory manipulation to prevent relapse, but instead of using extinction learning to modify the memory, he uses drugs to block its reconsolidation. Ninety college graduates who drank heavily at least four times a week participated in a recent trial. They were at risk of transitioning to alcohol addiction and wanted to cut back.</p>
<div class="cove-video">
</div>
<p></p><p>As with the heroin users in the 2012 study, these so-called hazardous drinkers were exposed to visual cues such as pictures of beer and were asked to rate how appealing the images were. This procedure alone should reactivate drinking memories, making them temporarily unstable, but Das added a twist. “It’s harder with these reward memories because they’re really robust,” says Das. “So, you have to get the parameters right during the retrieval in order to destabilize.”</p><p>On the first day of the experiment, participants were allowed to drink a glass of beer at the end of the rating session. When they returned the following day, they began the session assuming that the procedure would be the same. But after rating the pictures and being instructed to pick up the glass and prepare to drink, the beer was withheld at the very last moment. Das’ hope is that this extra element of surprise, which neuroscientists call a prediction error, will destabilize the memory more than just a simple retrieval would. The theory is that if the function of memory is to make accurate predictions, any time your predictions are wrong memories require more updating than usual.</p><p>The coup de grace to the memory occurs five to 10 minutes later with the administration of a drug called ketamine, a safe and widely used anesthetic which, at the low dose used in this trial, causes a psychedelic dissociative experience. Ketamine blocks certain receptors on the surfaces of neurons called NMDA receptors, which Das says have been shown to be key to restabilizing memories once they’ve been destabilized. This blockade makes it difficult for the now-destabilized and weaker alcohol reward memory to reform.</p>
<div class="pullquote">
<p>Das acknowledges that there is some stigma against using a psychedelic drug to treat drug addiction.</p>
</div>
<p>In the trial, which concluded in September, one third of the hazardous drinkers went through this procedure, another third got saline solution instead of ketamine, and the final third received ketamine but only rated pictures of orange juice. All the subjects kept diaries and returned one week, one month, three months, six months, and nine months later to report on their drinking. Das called the preliminary results encouraging and presented a poster session on the trial at a recent conference in Barcelona.</p><p>Das acknowledges that there is some stigma against using a psychedelic drug to treat drug addiction. But he argues that if it proves effective, that concern should be put aside. “If it works, then it works, and you have to weigh up the cost-benefit of giving people a single dose of ketamine versus repeatedly drinking heavily on an almost nightly basis for many years.”</p><h2>The Big Picture</h2><p>In the cocaine cue exposure trial in Charleston, South Carolina, Saladin uses a beta-blocking drug called propranolol—commonly used to treat high blood pressure—which accumulating evidence suggests may be effective in treating anxiety disorders and modulating memory. The five-year study he is now concluding is the follow-up to an earlier trial to treat cravings and reduce relapse in cocaine users. In that first trial, session participants who received propranolol reported less craving the next day, but when they returned for evaluation one week later, there was no significant difference between them and participants who did not receive propranolol.</p><p>In the new trial, Saladin is using two retrieval sessions instead of just one, and testing double the original dose of propranolol to see if drug reward memories will be weakened enough to prevent craving — and cocaine use — for longer than a day. Participants will be evaluated 18 times over the course of six weeks so researchers can document their craving in response to cues both in and out of the hospital, and to find out whether they have used cocaine.</p>
<div class="pullquote">
<p>“There’s no consensus on whether these reconsolidation-targeted treatments really weaken or erase memories at the neural level.”</p>
</div>
<p>Theories about precisely what’s going on are just that—theories. It’s possible that memories are not reconsolidating. “There’s no consensus on whether these reconsolidation-targeted treatments really weaken or erase memories at the neural level. It’s possible that the memories are still physically present, but difficult to access. In practical terms, that might be fine—unless the memories return,” says Epstein.</p><p>And memory manipulation does not address the underlying and complex reasons that lead to substance use disorders in the first place. So it’s not yet clear how effective this approach will be for individuals who struggle with depression, anxiety, or a history of trauma. Finally, it’s often the case that people use multiple drugs and are vulnerable to relapsing on multiple drugs. That could mean having to use separate memory manipulation treatments for each substance.</p><p>For these and other reasons, researchers are treading cautiously while also recognizing the urgent need for better treatment of addiction. “These people are in desperate circumstances and help is necessary,” says Saladin, adding that “reducing suffering is critical.”</p>
<p>This article was originally published on <a href="https://undark.org">Undark</a>. Read the <a href="https://undark.org/article/altering-memory-to-treat-addiction/">original article</a>.</p><img src="https://logs-01.loggly.com/inputs/4a05953f-1607-4284-825e-7df393822342.gif?postid=50744&amp;title=To-Combat-Binge-Drinking,-a-Search-for-Chemical-Solutions"/>

<p>Environmental cues can trigger powerful memories of substance use. What happens when those memories are disrupted?</p>

During a close encounter in November 2006, the Cassini spacecraft captured images of ice geysers erupting on Enceladus, showing that this tiny moon of Saturn is extremely active.

Cassini Imaging Team, SSI, JPL, ESA, NASA

Will We Ever Find ET?

<div class="related"></div>
<p>The discovery in September 2011 of a distant planet that might be hospitable to life made headlines. But a planet on which simple life could arise is a far cry from a planet where alien intelligence could evolve. And not just alien intelligence, but a complex, high-tech, long-lasting civilization with which we could communicate. Yet for now we're stuck here on Earth, with what one scientist has called our carbon chauvinism, hard-pressed to imagine how strange the universe might be.</p>
<p>Is there intelligence elsewhere in the universe? It sounds like a simple question, and for most people there's an obvious answer: Of course. After all, the universe is so big. As the iconic scientist Carl Sagan put it, "there are 100 billion galaxies, each of which contains something like 100 billion stars." That means there's an awful lot of real estate out there.</p><p>In addition to the staggering numbers, the history of science has shown that every time we think we are special in some way, we turn out to be wrong. The sun does not revolve around the Earth, the sun is not the only star, we are not the center of our galaxy, and our galaxy is not the center of the universe. There may even be multiple universes. Like so many important questions for which there are little data but different ways to examine the question, finding an answer can get complicated very quickly.</p><h3>THE SETI PROJECT</h3><p>Aliens have played a part in books and sci-fi movies ever since H.G. Wells' 1897 classic <i>The War of the Worlds</i>, but scientific interest in the topic of extraterrestrial intelligence, or ET, truly soared in the 1960s when space exploration took off. At the time Seth Shostak was a graduate student doing radio astronomy at the Owens Valley Radio Observatory in California, and while there he got hooked on a new book, <i>Intelligent Life in the Universe,</i> by the astronomers I.S. Shklovskii and Carl Sagan. "Reading that late at night, and using the antennas, made me think, gosh, this same technology could be used to hunt for signals," Shostak says.</p>
<div class="pullquote">
<p>"We've been so slow to realize these things. It's kind of been a failure of imagination."</p>
</div>
<p>The idea was that, just as we were broadcasting signals into outer space, the ETs might be doing the same thing. By tuning into the correct frequency, we could eventually hear from someone. Carl Sagan, along with astronomer Frank Drake, began the search for extraterrestrial intelligence, which came to be known as SETI, in the 1960s, and in 1984 the SETI Institute was formed. The organization's mission was to find evidence for alien intelligence using radio astronomy.</p><p></p>
<figure class="richtext-image full-width">
<img alt="The Allen Telescope Array" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/ever-find-et-02.width-990_ffWMUnE.jpg"/>
<figcaption>The Allen Telescope Array represents a new approach not only for SETI but also for observations of the Milky Way, other galaxies, and gamma-ray bursts. The array links together a large number of small dishes rather than relying on the individual large antennas traditionally used to listen to the sky.
        
        <div class="credit">Seth Shostak/SETI Institute</div>
</figcaption>
</figure>
<h3>THE DRAKE EQUATION</h3><p>To help frame the question and estimate the number of ETs that might be out there, Frank Drake devised an equation that came to be known, perhaps not surprisingly, as the Drake Equation. The equation included a factor for everything that seemed relevant to the question. Thus N—the number of civilizations in our galaxy with which communication might be possible—would be equal to the average rate of star formation per year in our galaxy, times the fraction of those stars that have planets, times the average number of planets that can support life per star that has planets, times the fraction of the above that go on to actually develop life, times the fraction of those that evolve intelligence, times the percentage of those that invent interstellar communication capabilities, times the average length of time that such civilizations release detectable signals into space. (Note that if any one of these factors is zero, then there are no ETs out there.)</p><p>Drake plugged in what he thought were reasonable values and came up with an estimate: 10,000 civilizations in the Milky Way. But at the time, the values he could assign were at best educated guesses, and in some cases little more than speculation.</p><p>Despite how little data existed, excitement about the possibility of finding ET grew during the 1970s as solar system exploration expanded. In 1977, the twin Voyager spacecraft 1 and 2 launched carrying gold-plated copper records inscribed with messages from Earth, including songs, images of our planet, and spoken greetings in 55 languages. The two spacecraft left the solar system in 1990 and are now travelling through interstellar space. It's expected that more than 40,000 years will elapse before they begin to pass other stars.</p><p></p>
<figure class="richtext-image full-width">
<img alt="The Golden Record" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/ever-find-et-03.width-990_b0DPxOK.jpg"/>
<figcaption>The contents of the so-called "Golden Record" were meant to be a selection of meaningful information we could share with alien intelligences, should they ever encounter the Voyager spacecraft. Salutations included, in Armenian, "To all those who exist in the universe, greetings."
        
        <div class="credit">NASA Jet Propulsion Laboratory</div>
</figcaption>
</figure>
<p>Flash forward more than three decades, and today there is greater confidence in the values we can assign to several factors in the Drake Equation. NASA's Kepler spacecraft and telescopes here on Earth have yielded so many discoveries of planets around other stars that some scientists admit they have trouble keeping track. In addition, the estimated value for another factor—the number of planets that might be habitable—keeps going up. Discoveries here on Earth of so-called extremophiles, organisms that can live in conditions previously thought to be inhospitable to life, coupled with discoveries in the solar system of environments not so dissimilar, has fueled optimism that we may find simple extraterrestrial life in our solar system in the not-too-distant future.</p><h3>HABITABLE ZONES</h3><p>Carolyn Porco, a planetary scientist with the Space Science Institute and leader of the Cassini Mission Science Team, confirms that the new findings suggest there are more habitable zones out there than we'd previously thought. "We've been so slow to realize these things," she says. "It's kind of been a failure of imagination. Scientists don't go off and think completely wild and crazy things unless they have some evidence that leads them to do that. It's almost like we have a contract that says we're not supposed to do that." Today, suggesting that life might have taken hold elsewhere in the solar system, even on distant moons, is no longer considered "wild and crazy."</p>
<div class="pullquote">
<p>"Everything you say is slightly inconclusive."</p>
</div>
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<p>Mars, for example, is a barren desert. But life survives in the driest spot of another desert, the Mojave, beneath the shelter of translucent white rocks. Says NASA astrobiologist Chris McKay of NASA's Ames Research Center, "These organisms are photosynthesizing here in the desert where nothing else will grow. They're living in a miniature greenhouse." On Titan, one of Saturn's moons, we now know that there are bodies of liquid as large as one of the Great Lakes that are filled with methane and ethane. While these chemicals might not seem conducive to living things, life may be more flexible than we give it credit for: Icy-cold Europa, one of Jupiter's moons, has cracks on its surface, which has led scientists to suspect that a salty ocean lies beneath the moon's frozen exterior—an ocean that contains its own forms of life.</p><p></p>
<figure class="richtext-image full-width">
<img alt="Mono Lake" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/ever-find-et-04.width-990_H8r4rGI.jpg"/>
<figcaption>The waters of Mono Lake in California are extremely salty and alkaline, and they have high levels of arsenic. Yet bacteria thrive there.
        
        <div class="credit">Lincoln Benedict, 2009</div>
</figcaption>
</figure>
<h3>INGREDIENTS FOR LIFE</h3><p>But if you ask Carolyn Porco, Enceladus ("en-CELL-uh-duss"), another of Saturn's moons, is "the go-to place" in the solar system for examining a potential habitable zone, because it has the three ingredients thought necessary to support it. "It's got liquid water, as far as we know," says Porco. "It definitely has organic compounds. And it has excess heat up the wazoo, more heat than we know what to do with." Porco believes the evidence suggests that liquid water on Enceladus may have persisted indefinitely, a finding that's relevant to one of the factors in the Drake Equation: the number of planets or moons with habitable zones <i>that go on to develop life</i>.</p><p>Here on Earth, life took hold more than half a billion years after our planet formed, but because we only have one example of life arising, there is no way to know if the development of life will always take that length of time. It could take longer, which would reduce the number of planets where life has enough time to evolve, or it could happen more quickly, which would increase that number. "It's so hard," says Shostak. "Everything you say is slightly inconclusive."</p>
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<h3>EVOLUTION AND EXTINCTION</h3><p>Likewise, the evolution of intelligent, communicating civilizations took well over another three billion years. But would it always take that amount of time, and was it even inevitable? Some scientists point out that human intelligence was contingent on numerous things going just right, such as an asteroid hitting the Earth 65 million years ago, simultaneously wiping out the dinosaurs and making our evolution possible. The late evolutionary biologist Stephen Jay Gould questioned whether, if you rewound the tape of life, a creature like us would evolve again. Notes Michael Shermer, author of <i>The Believing Brain</i> and the founding publisher of <i>Skeptic Magazine</i>, "ET is the same question. It's rewinding the tape on another planet and seeing if we end up with something with intelligence."</p>
<div class="pullquote">
<p>"Personally, I don't think they'll ever find a signal anywhere."</p>
</div>
<p>Peter Ward, who studies mass extinctions, has long been doubtful that SETI will ever succeed. He found a kindred spirit in astronomer Donald Brownlee. Over lunch one day at the University of Washington he mentioned to Brownlee, "You know, I'm just sick and tired of all the damn alien shows. [Finding aliens is] hardly likely at all." Brownlee responded, "Really? I think the same thing," and they were off. In 2000, they published a book called <i>Rare Earth: Why Complex Life Is Uncommon in the Universe</i>. While Ward agrees odds are that ET must exist somewhere, he concludes that the universe is so large that, for all intents and purposes, we are alone.</p><p>To drive home the point, Ward and Brownlee came up with a new version of the Drake Equation, to which they added factors they believed had been overlooked, such as the fraction of planets with a large moon, the fraction of planetary systems with Jupiter-sized planets, and the fraction of planets with a critically low number of mass extinctions. They called it the Rare Earth Equation.</p><p>Ward and Brownlee also assigned a very low number to how often intelligence would develop and to the length of time communicating intelligences would last. "There is going to be some fraction of planets with worms, where the worms finally evolve into human being-like equivalents," says Ward. "But the odds against even getting worms is so high." And if you can make it past worms to high-tech life, Ward believes that such intelligent life will be relatively short-lived. "We're going to come to that test here pretty quickly in the next century or the next millennium if we continue to increase carbon dioxide, producing what I think will be a runaway sea-level rise. When you have too many people and no food, and civilization falls into chaos, how much civilization is retained? How long will an intelligent species survive?"</p><h3>INTELLIGENCE</h3><p>Just what we mean by intelligence is a matter of much debate, but SETI has a simple definition. "If you can build a radio transmitter," says Shostak, "then you're intelligent. That's it. It's real simple. It doesn't mean that you're very good at composing rock 'n' roll, for example. But it does mean that we can hear you, and then, suddenly, we define you as intelligent."</p>
<div class="pullquote">
<p>"We're never going to be able to look at every nook and cranny of the universe."</p>
</div>
<p>Despite the doubts of people like Ward and Brownlee, the search goes on. The SETI Institute temporarily lost funding for its Allen Telescope Array—the most advanced instrument for detecting electromagnetic signals from ET—but private funding is bringing it back online. Of the search for ET, Shostak says, "It's a question that people were asking a thousand years ago, but there was nothing they could do about it. We can do something about it. We can actually mount an experiment that looks good on paper. How crazy would it be not to at least try?"</p>
<h3>WHY NOT?</h3><p>Even skeptics like Peter Ward don't argue with that. "Personally, I don't think they'll ever find a signal anywhere," he says. "But as long as there are people willing to fund it and it doesn't cost the public anything, why not?"</p><p>When asked whether the search for ET comes down to a question of beliefs, Michael Shermer had this to say: "It's a provisional belief, given that it could change in a heartbeat if it's confirmed. But it can never be disconfirmed. We're never going to be able to look at every nook and cranny of the universe." Shermer also pointed out that even though we're unlikely to hear from ET, asking the question has value. "Just thinking about how life might start on another planet and evolve into intelligence forces us to think about how that happened here," he says. "And that is legitimate science."</p><p>In the meantime, many scientists believe that finding simple life beyond Earth could well happen in our lifetimes. Says Carolyn Porco of the Cassini mission to Saturn, "If we ever discover that genesis has occurred independently twice in our solar system, that means that no matter where we find it, the spell has been broken. We could infer that life is not a bug but a feature of the universe in which we live, and that means that life has occurred a staggering number of times throughout the 13.7-billion-year history of the universe."</p>
<div class="newsletter"></div>

<p data-block-key="vpmw2">What are the odds that smart aliens exist in the universe?</p>

How Dumb Are Drones?

<div class="related"></div>
<p>For many, the word “drone” summons images of innocent civilians killed in wars conducted from thousands of miles away and raises concerns about invasions of privacy. For others, a drone is simply a next-generation military weapon that saves both lives and money. And for still others, drones are a fascinating backyard hobby for adults and children alike. But no matter what you think about them, drones are here to stay. The Air Force predicts that within a decade nearly 30 percent of its attack and fighter planes will be drones. It’s not just the military that sees their potential, either. Drones are being used for humanitarian purposes such as search and rescue missions, environmental conservation, and forest fire detection.</p>
<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/drone-large.width-990_dS1TviD.jpg"/>
<figcaption>When it becomes operational, the X-47B will be the world's first tailless fighter-sized drone and is expected to be one of the most advanced UAVs in the Navy.
        
    </figcaption>
</figure>
<p>Drones, also known as unmanned aerial vehicles or UAVs, are flying robots that can be as small as a dragonfly or as big as a house. Depending on how you define them, they’ve been around in one form or another since World War I, but what they all have in common is that the living brain—whether it belongs to a fly or a fighter pilot—has been removed from the aircraft. And that means that those smarts have to be recreated from ground control. In fact, it takes considerable support in both equipment and people to operate a military UAV, for example.</p><h2>History to Today</h2><p>The rise of the drone was made possible over the past few decades by a host of technological innovations, including small digital sensors for navigation and flight stabilization, GPS, long-range data links, and lightweight materials. Depending on how you count them, the U.S. military today has between 7,000 and 15,000 UAVs, according to Peter Singer, Director of the 21 st Century Defense Initiative at Brookings. Missy Cummings, a former fighter pilot who is now a professor of aeronautics and astronautics at MIT, considers interest in manned fighters “…old-fashioned. Manned aircraft? Who does that anymore?”</p><p>Smart visual sensors capable of seeing an object on the ground and identifying it are only improving.</p><p>Consistent use of UAVs began during the Korean and Vietnam Wars for targeting and reconnaissance, a role that continued with the so-called Predator, which was used in the 1990s in Bosnia. Beginning in 2001, weapons were added to the Predator. The main advantage of UAVs, weaponized or not, is to save lives by keeping soldiers out of harm’s way. But UAVs also save money. They’re less expensive than comparable aircraft because they don’t have to be as reliable; if they crash or are shot down, no pilots are lost. And the years of training that fighter pilots put in are no longer required. In fact, it turns out that non-pilots are better at controlling UAVs, perhaps because flying a drone requires different skills; untrained officers don’t have to overcome the habits fighter pilots have formed from years of experience.</p><p>While reports of civilians killed during drone strikes continue to make headlines, in theory the use of UAVs should enable more accurate attacks and reduce the number of innocent bystanders who are killed or wounded. As counterintuitive as it may seem, a pilot flying 35,000 feet directly above a target may have a harder time aiming carefully than a UAV operator some 7,000 miles away, in part because the pilot is multitasking. Meanwhile, smart visual sensors capable of seeing an object on the ground and identifying it are only improving.</p><p>An engineer describes the next-generation surveillance sensor for UAVs, called ARGUS. For more on drones, <a href="http://www.pbs.org/wgbh/nova/military/rise-of-the-drones.html">watch the complete program</a> .</p>
<div class="ad"></div>
<h2>Vulnerabilities</h2><p>Advantages aside, the current generation of UAVs suffer from a number of vulnerabilities. Operator boredom is one of them. While backyard drone inventors enthusiastically set aside hours of free time to pilot their craft, a military operator must sit for up to 12 hours at a time trying to maintain attention on a scene where nothing important can happen for days on end. Inevitably, vigilance decreases over time.</p><p>“UAVs sometimes aren’t that smart,” says Bill Sweetman, Chief Editor for Defense Technology at the Aviation Week and Space Technology Group.</p><p>On the flip side, this same operator will often get to know their targets well. They see their patterns—when they get up in the morning, where they go, and who they live with. And, after the operator has hit a target, they continue to monitor the scene, sometimes over the course of several hours. This can provide valuable intelligence, but it also means the operator witnesses death, destruction, and the aftermath, including the reaction of people on the ground.</p><p>“I think the worst part about it,” says Cummings, “is not necessarily that you’re engaged in a fight that led to a death, but then your mission’s over, and then you drive 35 minutes back to north Las Vegas and then you go to church the next day.” In the past, soldiers were surrounded by people who understood and could talk about what they had experienced that day. <a href="http://www.nytimes.com/2013/02/23/us/drone-pilots-found-to-get-stress-disorders-much-as-those-in-combat-do.html?_r=0">Not so with drone operators</a> .</p><p>A UAV pilot describes what it’s like to conduct a drone strike. For more on drones, <a href="http://www.pbs.org/wgbh/nova/military/rise-of-the-drones.html">watch the complete program.</a></p><p>But arguably the greatest vulnerability of the current generation of UAVs is their intelligence, or lack thereof. “UAVs sometimes aren’t that smart,” says Bill Sweetman, Chief Editor for Defense Technology at the Aviation Week and Space Technology Group. “Their self-diagnosis isn’t that smart, and by the time they have a problem, it’s too late. They lose a link, they lose power, and you’re gone.” When that happens, information relayed up to the aircraft, such as changes in direction, altitude, or even whether to terminate the mission, is lost. Information coming back down to the operator—such as real-time streaming images from the aircraft and an understanding of how its systems are performing—is also gone. The data link can go down because of a simple equipment malfunction, but it can also be successfully jammed by enemies, or even “spoofed,” tricking the UAV to do something its operator didn’t intend. In 2012 scientists at the University of Texas at Austin succeeded in doing just that, hacking into a drone and hijacking the flight.</p><h2>What Makes a Drone Smart</h2><p>For the purposes of a UAV, intelligence boils down to how independently the aircraft can operate. What decisions can the machine make on its own, and what requires human intervention? One of the most advanced UAVs is the Navy’s X47-B, which will be capable of taking off and landing on an aircraft carrier on its own. While this requires significant instrumentation so that the aircraft can respond to the environment and be aware of how it’s performing, not everyone sees it as a breakthrough achievement. “It is not a particularly smart aircraft in its current instantiation,” says Cummings. “We’ve been able to take airplanes off and land themselves on the carrier for my entire career in the Navy.”</p><p>The X-47B prototype will be able to land on a flight deck without input from a pilot. For more on drones, <a href="http://www.pbs.org/wgbh/nova/military/rise-of-the-drones.html">watch the complete program</a> .</p><p>Experts make a distinction between automation—the ability of a system to follow a pre-programmed course—and autonomy. Paul Eremenko is the Deputy Director of the Tactical Technology office at DARPA. “Autonomy,” he says, “is the ability of systems to take independent action and reason about the environment, perceive the environment, build some model of the world around them, and adapt to the world around them without human intervention to that environment.”</p><p>Some of the greatest advances are likely to come out of the development of ground robots.</p><p>In practical terms, this would mean, for example, being able to instruct a UAV to go to a region in Iraq, make observations until something noteworthy happens, and then relay that information back to ground control without a human being in the loop at all times. The benefits of autonomy are hardly unique to UAVs. In fact, some of the greatest advances are likely to come out of the development of ground robots, such as driverless cars that must navigate difficult terrain, or from interstellar space probes or rovers on distant planets that must be capable of operating on their own for longer periods of time than a UAV.</p><p>Vijay Kumar’s lab at the University of Pennsylvania is developing tiny drones that sense their environment. For more on drones, <a href="http://www.pbs.org/wgbh/nova/military/rise-of-the-drones.html">watch the complete program</a> .</p><p>Other advances in autonomy come from the world of tiny drones that swarm—just like bees or ants—requiring them to sense and maintain a set distance apart, free of any link to ground control. The ultimate in autonomy would be so called adaptive reasoning, in which the UAV would be able to adapt to an infinite number of possibilities. Chuck Heber, who managed the development of two UAVs for DARPA in the 1990s—Global Hawk and DarkStar—believes that ultimately “UAVs will be able to do just about everything autonomously short of pulling the trigger.” Some argue that an even greater challenge than making UAVs truly autonomous will be in proving that they can operate reliably enough so we can depend on them. As Eremenko puts it, “We really are quite far away from being able to prove that those kinds of systems will always behave in a reasonable manner, in a manner where either the human operator or those around it can depend and trust the system to behave appropriately.”</p><h2>A Partnership</h2><p>Today, almost everyone agrees that autonomous vehicles will require human monitoring and the ability to intervene. As Bill Sweetman describes it, a UAV is a very smart dog running around a lot people with the potential to trip them. Someone has to be responsible.</p><p>A DARPA researcher describes what would constitute a breakthrough in UAV autonomy. For more on drones, <a href="http://www.pbs.org/wgbh/nova/military/rise-of-the-drones.html">watch the complete program</a> .</p><p>Even the UAVs of the future, which will likely be much smarter than a smart dog and better than humans at many things, will be missing human moral judgment, or, as Peter Singer puts it, “a sense on the back of your neck that something’s not right. You don’t know why, but you can react to it. Your moral compass…knowing when and when not to use force.” In essence, the path forward will be to develop UAVs that are good at what machines can be good at, such as planning trajectories and withstanding long trips and high Gs, while leaving such things as judgment, the creative response to the unexpected, and social intelligence, to the humans.</p>
<div class="newsletter"></div>
<p>Interviews conducted by Peter Yost.</p><p>Photo credit: © Bloomberg via Getty Images</p>

<p>
<figure class="richtext-image full-width">
<img alt="The X-47B" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/how-dumb-are-drones-01.width-990_QHEy1iu.jpg"/>
<figcaption>When it becomes operational, the X-47B will be the world's first tailless fighter-sized drone and is expected to be one of the most advanced UAVs in the Navy.
        
        <div class="credit">© Bloomberg via Getty Images</div>
</figcaption>
</figure>
</p>
<p>
	Drones, also known as unmanned aerial vehicles or UAVs, are flying robots that can be as small as a dragonfly or as big as a house. Depending on how you define them, they've been around in one form or another since World War I, but what they all have in common is that the living brain—whether it belongs to a fly or a fighter pilot—has been removed from the aircraft. And that means that those smarts have to be recreated from ground control. In fact, it takes considerable support in both equipment and people to operate a military UAV, for example.</p>
<h3>
	History to Today</h3>
<p>
	The rise of the drone was made possible over the past few decades by a host of technological innovations, including small digital sensors for navigation and flight stabilization, GPS, long-range data links, and lightweight materials. Depending on how you count them, the U.S. military today has between 7,000 and 15,000 UAVs, according to Peter Singer, Director of the 21<sup>st</sup> Century Defense Initiative at Brookings. Missy Cummings, a former fighter pilot who is now a professor of aeronautics and astronautics at MIT, considers interest in manned fighters ...old-fashioned. Manned aircraft? Who does that anymore?"</p>
<blockquote>
	Smart visual sensors capable of seeing an object on the ground and identifying it are only improving.</blockquote>
<p>
	Consistent use of UAVs began during the Korean and Vietnam Wars for targeting and reconnaissance, a role which continued with the so-called Predator that was used in the 1990s in Bosnia. Beginning in 2001, weapons were added to the Predator. The main advantage of UAVs, weaponized or not, is to save lives by keeping soldiers out of harm's way. But UAVs also save money. They're less expensive than comparable aircraft because they don't have to be as reliable; if they crash or are shot down, no pilots are lost. And the years of training that fighter pilots put in are no longer required. In fact, it turns out that non-pilots are better at controlling UAVs, perhaps because flying a drone requires different skills; untrained officers don't have to overcome the habits fighter pilots have formed from years of experience.</p>
<p>
	While reports of civilians killed during drone strikes continue to make headlines, in theory the use of UAVs should enable more accurate attacks and reduce the number of innocent bystanders who are killed or wounded. As counterintuitive as it may seem, a pilot flying 35,000 feet directly above a target may have a harder time aiming carefully than a UAV operator some 7,000 miles away, in part because the pilot is multitasking. Meanwhile, smart visual sensors capable of seeing an object on the ground and identifying it are only improving.</p>
<p>
	{{cove--2--}}</p>
<h2>
	VULNERABILITIES</h2>
<p>
	Advantages aside, the current generation of UAVs suffer from a number of vulnerabilities. Operator boredom is one of them. While backyard drone inventors enthusiastically set aside hours of free time to pilot their craft, a military operator must maintain attention on a scene where nothing important can happen for days on end. Inevitably, vigilance decreases over time.</p>
<p>
	On the flip side, this same operator will often get to know their targets well. They see their patterns—when they get up in the morning, where they go, and who they live with. And, after the operator has hit a target, they continue to monitor the scene, sometimes over the course of several hours. This can provide valuable intelligence, but it also means the operator witnesses death, destruction, and the aftermath, including the reaction of people on the ground.</p>
<blockquote>
	"UAVs sometimes aren't that smart," says Bill Sweetman, Chief Editor for Defense Technology at the Aviation Week and Space Technology Group.</blockquote>
<p>
	"I think the worst part about it," says Cummings, "is not necessarily that you're engaged in a fight that led to a death, but then your mission's over, and then you drive 35 minutes back to north Las Vegas, and then you go to church the next day." In the past, soldiers were surrounded by people who understood and could talk about what they had experienced that day. Not so with drone operators.</p>
<p>
	{{cove--3--}}</p>
<p>
	But arguably the greatest vulnerability of the current generation of UAVs is their intelligence, or lack thereof. "UAVs sometimes aren't that smart," says Bill Sweetman, Chief Editor for Defense Technology at the Aviation Week and Space Technology Group. "Their self-diagnosis isn't that smart, and by the time they have a problem, it's too late. They lose a link, they lose power, and you're gone." When that happens, information relayed up to the aircraft, such as changes in direction, altitude, or even whether to terminate the mission, is lost. Information coming back down to the operator—such as real-time streaming images from the aircraft and an understanding of how its systems are performing—is also gone. The data link can go down because of a simple equipment malfunction, but it can also be successfully jammed by enemies, or even "spoofed," tricking the UAV to do something its operator didn't intend. In 2012 scientists at the University of Texas at Austin succeeded in doing just that, hacking into a drone and hijacking the flight.</p>
<h2>
	WHAT MAKES A DRONE SMART?</h2>
<p>
	For the purposes of a UAV, intelligence boils down to how independently the aircraft can operate. What decisions can the machine make on its own, and what requires human intervention? One of the most advanced UAVs is the Navy's X47-B, which will be capable of taking off and landing on an aircraft carrier on its own. While this requires significant instrumentation so that the aircraft can respond to the environment and be aware of how it's performing, not everyone sees it as a breakthrough achievement. "It is not a particularly smart aircraft in its current instantiation," says Cummings. "We've been able to take airplanes off and land themselves on the carrier for my entire career in the Navy."</p>
<p>
	{{cove--4--}}</p>
<p>
	Experts make a distinction between automation—the ability of a system to follow a pre-programmed course—and autonomy. Paul Eremenko is the Deputy Director of the Tactical Technology office at DARPA. "Autonomy," he says, "is the ability of systems to take independent action and reason about the environment, perceive the environment, build some model of the world around them, and adapt to the world around them without human intervention to that environment."</p>
<blockquote>
	Some of the greatest advances are likely to come out of the development of ground robots.</blockquote>
<p>
	In practical terms, this would mean, for example, being able to instruct a UAV to go to a region in Iraq, make observations until something noteworthy happens, and then relay that information back to ground control without a human being in the loop at all times. The benefits of autonomy are hardly unique to UAVs. In fact, some of the greatest advances are likely to come out of the development of ground robots, such as driverless cars that must navigate difficult terrain, or from interstellar space probes or rovers on distant planets that must be capable of operating on their own for longer periods of time than a UAV.</p>
<p>
	{{cove--5--}}</p>
<p>
	Other advances in autonomy come from the world of tiny drones that swarm—just like bees or ants—requiring them to sense and maintain a set distance apart, free of any link to ground control. The ultimate in autonomy would be so called adaptive reasoning, in which the UAV would be able to adapt to an infinite number of possibilities. Chuck Heber, who managed the development of two UAVs for DARPA in the 1990s—Global Hawk and DarkStar—believes that ultimately "UAVs will be able to do just about everything autonomously short of pulling the trigger." Some argue that an even greater challenge than making UAVs truly autonomous will be in proving that they can operate reliably enough so we can depend on them. As Eremenko puts it, "We really are quite far away from being able to prove that those kinds of systems will always behave in a reasonable manner, in a manner where either the human operator or those around it can depend and trust the system to behave appropriately."</p>
<h2>
	A PARTNERSHIP</h2>
<p>
	{{cove--6--}}</p>
<p>
	Today, almost everyone agrees that autonomous vehicles will require human monitoring and the ability to intervene. As Bill Sweetman describes it, a UAV is a very smart dog running around a lot of people with the potential to trip them. Someone has to be responsible. Even the UAVs of the future, which will likely be much smarter than a smart dog and better than humans at many things, will be missing human moral judgment, or, as Peter Singer puts it, "a sense on the back of your neck that something's not right. You don't know why, but you can react to it. Your moral compass...knowing when and when not to use force." In essence, the path forward will be to develop UAVs that are good at what machines can be good at, such as planning trajectories and withstanding long trips and high Gs, while leaving such things as judgment, the creative response to the unexpected, and social intelligence, to the humans.</p>

The real questions are, how autonomous are they now and how autonomous can they get?

Lauren Aguirre

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How Dumb Are Drones?

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