An early feasibility study finds a potential new treatment for Alzheimer's disease.
For the past few years, Annabelle Singer and her collaborators have been using flickering lights and sound to treat mouse models of Alzheimer's disease, and they've seen some dramatic results.
Now they have results from the first human feasibility study of the flicker treatment, and they're promising.
"We looked at safety, tolerance, and adherence, and several different biological outcomes, and the results were excellent—better than we expected," says Singer, assistant professor in the biomedical engineering department at Georgia Institute of Technology and Emory University.
Singer shared preliminary results of the feasibility study in October at the American Neurological Association annual meeting. Now she is a corresponding author with Emory neurology researcher James Lah of a paper outlining their findings in the journal Alzheimer's & Dementia: Translational Research & Clinical Interventions.
The flicker treatment stimulates gamma waves, manipulating neural activity, recruiting the brain's immune system, and clearing pathogens—in short, waging a successful fight against a progressive disease that still has no cure.
Previous research already had shown that sensory areas in the human brain will entrain to flickering stimuli for seconds to hours. But this was the first time Singer and her team were able to test gamma sensory stimulation over an extended period of time.
The study included 10 patients with Alzheimer's-associated mild cognitive impairment, which required them to wear an experimental visor and headphones that exposed one group to light and sound at 40 hertz for an hour a day over eight weeks, and another group for four weeks after a delayed start.
"We were able to tune the devices to a level of light and sound that was not only tolerable, but it also successfully provoked an underlying brain response," Lah says.
As they hoped and expected, Singer says, "there was widespread entrainment." That is, brain activity—in this case, gamma waves—synchronized to the external stimulation.
Gamma waves are associated with high-level cognitive functions, like perception and memory. Disruptions to these waves have been found in various neurological disorders, not just Alzheimer's.
The human feasibility study showed that the gamma flicker treatment was safe and tolerable. And perhaps most surprising, patients followed the full treatment schedule.
"Adherence was one of our major concerns," Singer says. "When we sent the device home with the participants, would they use it? Would they use it for a couple of days, and that would be it? We were pleasantly surprised that this wasn't the case."
Adherence rates hovered around 90%, with no severe adverse effects reported during the study or the 10-month open label extension (some patients even volunteered to continue being monitored and assessed after the study, though this data wasn't part of the published research).
Some participants reported mild discomfort that could have been flicker related—dizziness, ringing in the ears, and headaches. But overall, Singer says, the device's safety profile was excellent. She also reported some positive biological outcomes.
"We looked at default mode network connectivity, which is basically how different brain regions that are particularly active during wakeful rest and memory, interact with each other," Singer says.
"There are deficits in this network in Alzheimer's, but after eight weeks [of treatment], we found strengthening in that connectivity." This may indicate stronger interactions and therefore better communication between these regions.
In previous animal studies, the 40Hz of flicker stimulated mouse gamma waves, significantly reducing some Alzheimer's pathogenic hallmarks and recruited microglia to the cause—these are the primary immune cells in the brain. But in the human study, there were no clear changes in the presence of pathogens amyloid beta or p-Tau.
However, as with the mouse studies, "we are getting immune engagement in humans," Singer says. The flicker treatment sparked the activity of cytokines, proteins used in cell signaling—a sign that flicker had engaged the brain's immune system.
"That is something we want to see, because microglia do things like clear out pathogens. Some people think that part of what's going wrong in Alzheimer's is a failure of this clearance mechanism," Singer says.
She and Lah have wondered if a longer human trial would make a difference—would there be reduced amyloid activity, for example.
"So far, this is very preliminary, and we're nowhere close to drawing conclusions about the clinical benefit of this treatment," Lah says. "But we now have some very good arguments for a larger, longer study with more people."
Funding for the study came from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, the Packard Foundation, the Friends and Alumni of Georgia Tech, the Lane Family, the Wright Family, and Cognito Therapeutics. Any findings, conclusions, and recommendations are those of the researchers and not necessarily of the sponsors.
Annabelle Singer owns shares in Cognito Therapeutics, which funded the human study at Emory Brain Health Center. Cognito aims to develop gamma stimulation-related products. These conflicts are managed by Georgia Tech's Office of Research Integrity Assurance.
Source: Georgia Tech
Original Study DOI: 10.1002/trc2.12178
Engineered immune cells have prevented Type 1 diabetes in mice.
This article was originally published on our sister site, Freethink.
Nearly 2 million Americans suffer from type 1 diabetes — a condition that causes drastic spikes or drops in sugar levels and, in turn, dizziness, nausea, and fatigue. It's a condition that must constantly be monitored, something that a lot of diabetics find mentally exhausting.
One diabetic, Naomi, told the BBC that she couldn't handle "the physical or mental challenges of diabetes anymore," and struggled to monitor her blood sugar levels multiple times a day. Naomi's struggle isn't unique — it's called diabetes burnout.
There's no cure for type 1 diabetes. However, researchers at the University of Arizona have adapted a cancer immunotherapy technique that has produced promising results in treating diabetes (in mice). The researchers engineered immune cells to fight off rogue T cells (immune cells that go haywire and attack the body) that can damage the pancreas, causing type 1 diabetes.
This new technique would prevent that from happening — and if it works in humans, it could be an exciting first step for diabetics like Naomi.
T cells and diabetes
Type 1 diabetes is a kind of autoimmune disorder, which is hypothesized to occur when rogue T cells attack the pancreas's insulin-producing beta cells. As a result, a patient with type 1 diabetes is unable to regulate their blood sugar levels effectively.
Patients must take artificial insulin daily to avoid all this. If they don't, they run the risk of amputation, coma, or even death.
To prevent the development of this disease, scientists behind the new research, published this November in the Proceedings of the National Academy of Sciences, planned to stop the attack at its source — the rogue, pathogenic T cell.
The research team bioengineered a T cell that looks and behaves just like the rogue T cell they're trying to eliminate, which they named 5MCAR.
This bioengineered T cell can target and kill the pathogenic T cells on its own or order natural T cells to do it. Both approaches are designed to prevent healthy pancreas cells from being attacked.
Michael Kuhns, the study's lead author and an associate professor of immunobiology at the University of Arizona, says that this design was a way to take advantage of evolution's natural process instead of reinventing the wheel.
"We engineered a 5MCAR that would direct killer T cells to target autoimmune T cells that mediate type 1 diabetes. So now, a killer T cell will actually recognize another T cell. We flipped T cell-mediated immunity on its head," said Kuhns.
Essentially, the idea is that the engineered T cells would target the rogue T cells and turn the rest of the immune system against them, too — thus, stopping the damage that causes type 1 diabetes.
To see how well this worked in practice, researchers tested their engineered T cells in a rodent model of type 1 diabetes and found that the engineered T cells were incredibly effective at finding and attacking rogue T cells.
"When we saw that the 5MCAR T cells completely eliminated the harmful T cells that invaded the pancreas, we were blown away," says Thomas Serwold, co-author of the study and assistant professor of medicine at Harvard Medical School.
"It was like they hunted them down. That ability is why we think that 5MCAR T cells have tremendous potential for treating diseases like type 1 diabetes."
The human question
Of course, success in mice models does not necessarily mean that this treatment will be effective in humans. Similar CAR T cell therapies have been approved by the FDA to treat blood cancers, but while they have shown early success, there have also been several deaths during clinical trials.
All and all, targeted T cell therapies may have a promising future for fighting these diseases and disorders, but further research will need to be done before these can confidently and effectively be brought to humans.
This discovery could lead to better treatments for PTSD, borderline personality disorder, and epilepsy.
This article was originally published on our sister site, Freethink.
Feeling centered and in control of your body is a part of being human that we take for granted in our daily lives. But for millions of people suffering from post-traumatic stress, epilepsy, or another neuropsychiatric condition, this sense of self can slip out their hands in moments of "dissociation."
These dissociated states, which are often described as out-of-body experiences, are not inherently harmful in themselves, but they can be extremely disorienting and affect a person's quality of life. And even stranger than these moments is that scientists do not have a good understanding of how or why these states occur.
But new research published this September in the journal Nature may have just gotten closer to figuring it out than ever before — using mice, a human, and some advanced brain-scanning technology. This new knowledge could bring us closer to targeted treatments for PTSD and epilepsy.
The "God Helmet" Can Give You Near-Death and Out-of-Body Experiences www.youtube.com
Starting With What We Know
While scientists did not know exactly what in the brain causes dissociative states, they did know that certain drugs, like ketamine, could also induce these states. So, to start, the researchers wanted to look into the brains of mice to see what was happening when ketamine sent them into the mouse-equivalent of a dissociative state.
To determine whether ketamine was in fact eliciting a unique brain state, researchers gave the mice a sampling of different sedative or hallucinogenic drugs, including two other drugs like ketamine known to cause dissociation.
The brain activity of these drugged mice showed electric oscillations in a part of the brain called the retrosplenial cortex — an area of the brain responsible for memory and navigation. Importantly these oscillations did not occur in response to other types of drugs, like LSD.
On a closer look, the researchers saw that these low-frequency oscillations were restricted to just a small part of the retrosplenial cortex. For a drug like ketamine, which causes activity across a wide swath of the brain, it was unexpected to see activity like this in such a concentrated area.
A Stimulating Time
To determine if these specific brain patterns and the dissociative states were actually connected, the researchers tried to elicit this response in the mice without ketamine, using neural stimulation. (Since mice can't actually express to scientists whether they're experiencing a dissociative state, the researchers went off their responses to physical indicators, like feeling their paws touch a hot plate but not licking them to cool down, instead.)
In these undrugged mice, scientists modified two proteins in the retrosplenial cortex to be sensitive to light and exposed them to alternating blue and yellow light as stimulation. When exposed to these lights, the mice displayed the same blunted responses to stimuli as they had when under the ketamine-induced state.
But what does this mean for humans? In a patient with pre-existing electrode implants in their brain, the research team stimulated an analogous part of the human brain and found they were able to reliably stimulate a dissociative state.
In addition to being an exciting discovery in itself, the researchers are also hopeful that further exploration of dissociative experiences in humans could lead to new targeted treatments for disorders that cause them, including PTSD, borderline personality disorder, and epilepsy.
Less tangible — but just as interesting — the study's senior author, Karl Deisseroth, said that this could help scientists better understand what chemical reactions in our brain create our sense of self.
"This study has identified brain circuitry that plays a role in a well-defined subjective experience," Deisseroth, a professor of bioengineering and psychiatry and behavioral sciences at Stanford University, said. "Beyond its potential medical implications, it gets at the question, 'What is the self?' That's a big one in law and literature, and important even for our own introspections."
Hippocrates overturned conventional wisdom and invented modern medicine.
- Ancient "medicine" once consisted of sacrificial offerings and divine petition. Disease was a supernatural infliction; health was a gift.
- Hippocrates invented medical science, and his theory of the humors and holistic health dominated Western medical thought for more than two thousand years.
- Today, medicine is much more disease centred, and perhaps something has been lost from the Hippocratic doctor-patient relationship.
You're feeling sick — so sick you can barely walk — and so you visit a professional. You wait outside, feverish and exhausted, hoping they can help. Your name is called. You start to explain your symptoms but are interrupted before you can get going.
"Let me stop you there", he says, "it's obvious what's happened. You've been cursed by the god Hermes. You must sacrifice two young goats and pray to him every day. I hope he takes pity on you. NEXT!"
You leave, still sick.
The doctor will see you now
This was the standard medical model of the ancient world. Priests and prayer cured diseases. That is, until Hippocrates reinvented the entire practice and defined medicine as a profession.
All we know of Hippocrates comes from a series of writings from the library at Alexandria, collected around 250 BCE. It's a mishmash of collected wisdom, case notes, and philosophy, composed by multiple authors over many years. But Hippocrates is the master and name that binds it all.
Hippocrates argued that sickness and disease can be understood by rational enquiry and had natural explanations (as opposed to gods or the supernatural). Man was just as much part of nature as chickens or cows and could be treated or cured in much the same way.
Because the Greeks had strict rules against dissecting or cutting a dead body, Hippocrates and the early physicians knew very little about human physiology. Most anatomical learning had to come from the gruesome mess of the battlefield — people (literally) carrying their arms or returning with gaping puncture wounds in their stomach. The only other way was by drawing parallels with the animal world. For instance, the Hippocratics believed human pregnancy was similar to how a hen nurtured her eggs.
Man was just as much part of nature as chickens or cows and could be treated or cured in much the same way.
Without microscopes or medical experimentation, Greek physicians were much more limited and took a holistic view of the body. Today, medicine is pretty heavily disease centered, in that it focuses on pathology, such as dysfunctional organs or microbial infections. For Hippocrates, sickness was a whole body thing — caused only when the natural balance and equilibrium of the body was disturbed.
A sense of humor
The humors blood (red) and phlegm (blue) are depicted in this document at Raeapteek pharmacy in Tallinn, Estonia.Credit: Alex Berezow
Hippocrates believed that the body was made up of various fluids, called humors, and different organs were responsible for their creation and regulation.
There were four humors: blood, phlegm, yellow bile, and black bile. These all existed in the body, and when present in moderation or in balance with the other humors, a person was considered healthy. (It should be noted that black bile was often seen as being uniformly negative). It was believed disease resulted when one or more of the humors was overproduced or located in an incorrect part of the body. So, if you have too much phlegm, you will get a cough. Too much blood, and you would vomit. Too much black bile, and you would become depressed.
While we might find this ridiculous, you can see why the Hippocratics thought this way. Even today, we're often guilty of confusing symptoms with causes, and it's completely logical for someone to think that since the body is expelling phlegm during a cold, that must be the cause of the disease. Or how a nosebleed is caused by excessive blood. Or how diarrhea looks like yellow bile.
Of course, this sometimes meant that Hippocratic medicine offered some absurd treatments. It was thought, for instance, that epilepsy was caused by phlegm blocking the airways — the convulsing was an effort to open them — so warm dry climates were recommended. A regular prescription was for a patient being told to drink Gladiator blood for its potency. If you had a headache, it was suggested that you hold an electric eel to your head to force out the unwanted humors.
Has your doctor ever sniffed your stool?
It's hard to understate just how sick or infirm people would have been in ancient Greece. Thanks to modern medicine and public health, we're very rarely sick, and when we are, medicine is usually effective and easy to get. Antiquity, though, was a world of fever, food poisoning, water-borne infection, animal bites, and frequent, brutal warfare (and the ensuing infections). Today, being healthy is the norm. Back then, it was being sick.
It's not unfair to say that Hippocrates invented both prognosis and diagnosis. For the first time, a physician could say, "I know what's gone wrong, and I can tell you how it'll pan out."
As such, having an empirically minded (if misguided) physician class like the Hippocratics would have had huge success for the patient and physician alike. By seeing disease as an imbalance of the entire body, the Hippocratics took keen interest in their patients. They were frequently bedside and their examinations incredibly thorough. For instance, they would often taste urine or ear wax to check if it was okay. They would eat leg hair and sniff patient's stools. It's not unfair to say that Hippocrates invented both prognosis and diagnosis. For the first time, a physician could say, "I know what's gone wrong, and I can tell you how it'll pan out."
These physicians did not recommend drastic or intense interventions like surgery (not least because anything short of amputation would be fatal, anyway). They would prescribe lifestyle changes such as diet, exercise, hot baths, and sex (which was especially important for older patients). They would constantly ask how patients are doing. They would check that they were taking their medicine.
Though practically none of the Hippocratics' medicine was anywhere near accurate, their bedside manner was quite different from the modern doctor's: "What's wrong with you? Right, here are your drugs. Good luck. So long." Hippocratic medicine used every trick necessary to re-establish harmony to the whole body. The doctor-patient relationship was just that — a relationship, not a transaction.
Hippocrates gave us two great gifts. First, he made medicine a scientific discipline in its own right. Second, he showed us how important it is to pay attention to the whole patient and respond to the totality of their sickness, including their mental state. Medical professionals worldwide still have to swear by the "Hippocratic Oath," which, among many other things, obliges doctors to "remember that I do not treat a fever chart, a cancerous growth, but a sick human being, whose illness may affect the person's family and economic stability."
Voltaire once said, "The art of medicine consists in amusing the patient, while nature cures the disease." This was no doubt true of Hippocrates. Surely, many of his patients recovered, but most often it was likely due less to his medical prowess and more to his patients enjoying a month-long spa with great food and lots of sleep.
The treatment is here, but are we ready?
- Ketamine is the first hallucinogen approved for therapeutic use in the U.S.
- Research has shown ketamine is effective at treating depression.
- Though ketamine infusion therapy is now being offered at hundreds of North American clinics, there are unaddressed dangers in the current ketamine gold rush.
In March 2019, the FDA approved ketamine, under the trade name Spravato (esketamine), for clinical use in treatment-resistant depression therapy. Alongside racemic ketamine, which is commonly used in ketamine infusion therapy, ketamine is the first hallucinogen approved for therapeutic usage in the United States.
Technically, ketamine is not a psychedelic but rather a hallucinogen and dissociative. (While ketamine has psychedelic effects, traditional psychedelics bind to the 5-HT2B receptor.) Still, advocates for psychedelic therapy recognize ketamine as a gateway for traditional psychedelics, such as psilocybin and LSD, to be considered for therapeutic usage.
To understand the proliferation of ketamine clinics across North America, the origins of this peculiar substance — one that went from battlefields to veterinary clinics to dance clubs in the span of two decades — must be discussed.
History of ketamine
In 1962, chemistry professor Calvin Stevens synthesized ketamine while researching alpha-hydroxyimine rearrangements. The first human tests were conducted on prisoners in 1964. Ketamine soon replaced phencyclidine (PCP) as the go-to anesthetic in hospitals. It was initially used on soldiers during the Vietnam War following FDA approval in 1970. Thanks to its success on the battlefield, ketamine was placed on the World Health Organization's List of Essential Medicines.
Ketamine has been used broadly as a sedative and anesthetic; to aid in emergency surgeries in war zones; as a bronchodilator for severe asthmatics; to treat certain types of seizures; and in postoperative pain management. Now, ketamine infusions and nasal sprays are being used for depression. Ketamine is also showing potential efficacy in treating chronic pain and suicidal ideation, though more research needs to be done.
Of all of those uses, ketamine has predominantly been used as an anesthetic in humans and animals. While it restricts breathing less than other similar medications, ketamine also produces hallucinations (thus, it's labeled as a dissociative anesthetic). The list of potential side effects from using ketamine is long, including nausea, double vision, breathing problems, impaired memory, liver enzyme abnormalities, urinary tract problems, and even increased depression — an alarming possibility given its growing use as an antidepressant replacement.
Small-scale studies on using ketamine to treat depression were conducted in 2000 and 2006. Further research confirmed its role in alleviating depressive symptoms, including the possibility that the antidepressant effects of a single dose can persist for weeks. In 2016, the FDA fast-tracked ketamine trials for depression.
A chair is seen in a therapy room at Field Trip, a psychedelic therapy clinic in Toronto, Ontario, Canada.Credit: Cole Burston/AFP via Getty Images
Ketamine infusion therapy
There has yet to be a consensus on how ketamine addresses depression. Antidepressants act on the body's serotonin and noradrenaline systems. Ketamine seems to interfere with an amino acid derivative, NMDA. As a 2017 study published in the journal Nature explains:
"Ketamine is responsible for blocking the N-methyl-D-aspartate (NMDA) receptor, which causes an immediate alleviation of depressive effects, while another metabolite in the drug helps the effects last for hours. This blockage is also what causes the hallucinogenic effects."
Small intravenous doses of esketamine — an enantiomer of ketamine and the substance actually approved by the FDA — seem to lift depressed patients out of their funk. So does Spravato, a nasal spray that can only be administered under supervision in a doctor's office or clinic.
Patients that have tried two different antidepressant medications with no success (the definition of treatment-resistant depression) can legally receive ketamine infusions or Spravato at clinics located all over the country. Since the therapy is generally not covered by insurance, treatments range from $300 to $2,000 per session; the Field Trip Treatment Program, which includes psychotherapy and six infusions, runs $4,700.
The process of ketamine infusion therapy is varied depending on which clinic you attend. Companies like Field Trip and organizations such as MAPS require psychotherapy sessions to coincide with infusions.
Unfortunately, therapeutic implementation has not always lived up to federal requirements. Reports of patients quitting antidepressants and psychotherapy to use esketamine as their primary source of treatment abound. Since medical professionals with no mental health training, such as nurse practitioners, anesthesiologists, and pain physicians, can legally administer ketamine, patients are left to process the drug's effects with little to no guidance.
Thus far, efficacy has been mixed. As STAT News editor Megan Thielking writes, people with minor depressive issues are likely better candidates for ketamine therapy than those with treatment-resistant depression, the very cohort the drug is purported to target.
"Studies vary but have found response rates to ketamine as high as 70 percent among people with major depression who have failed a few other antidepressants. But the rate is lower for patients with extremely treatment-resistant depression, and how long any improvement lasts varies from one patient to the next."
Was ketamine approved too quickly?
While ketamine therapy is certainly promising, the FDA-approved trials raise a number of red flags. A recent analysis in The British Journal of Psychiatry concludes that we're moving too fast. Author Mark Horowitz writes:
"Out of the three short-term trials conducted by Janssen only one showed a statistically significant difference between esketamine and placebo. These were even shorter than the 6-8 week trials the FDA usually requires for drug licensing."
Trials usually last three months; the approved ketamine trials only lasted four weeks and barely showed efficacy above placebo. More concerning, the FDA allowed Janssen to submit a discontinuation trial with a study design flaw as evidence of efficacy — side effects were treated as evidence of relapse, not withdrawal symptoms. Even more alarmingly, six people in the esketamine group died during the trials, including three by suicide, two of which had previously shown no signs of suicidal ideation.
When Janssen stated that the problem wasn't esketamine but underlying conditions, the FDA accepted the reasoning even though no conclusive evidence was provided. This doesn't mean ketamine therapy isn't potentially therapeutic, though it does suggest that its approval by the FDA was rushed.
Psychiatrist Lori Calabrese, who offers ketamine infusion for depression and anxiety in her clinic, puts it best when stating, "The pace of ketamine treatment in real-world practices has outstripped what researchers are able to do and publish." Time will tell if this treatment proves more beneficial than dangerous in mental health treatments.
Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."