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
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."
Can the main psychoactive ingredient of magic mushrooms help treat the world's sixth most debilitating illness?
- Migraines afflict more than ten percent of the U.S. population, yet treatments are often unreliable and there is no cure.
- The new study involves giving migraine sufferers a placebo and, two weeks later, a single dose of pure synthetic psilocybin.
- The results showed that participants reported significantly fewer migraines in the two weeks after the study.
Psychedelics research is enjoying a renaissance. In recent years, studies have shown that hallucinogenic drugs like LSD, psilocybin, and MDMA seem to have powerful therapeutic effects on conditions including major depression, anxiety, and addiction disorders.
One unique aspect of psychedelics is that taking a single moderate dose can yield long-lasting therapeutic benefits for people with certain conditions, such as cancer patients with depression and anxiety.
Now, new research published in Neurotherapeutics suggests these outsized benefits may also apply to people with migraines. The evidence is preliminary but promising, and it could open up new areas of research for treating migraines, which are often chronic and debilitating.
A painful, debilitating condition
Migraine affects more than 10 percent of the U.S. population and it's ranked as the world's sixth most debilitating illness. Treatments can alleviate migraine symptoms, but efficacy varies from person to person, and even treatments that do work sometimes produce unpleasant side effects. There's currently no cure for the condition.
What's a migraine like?
"Put your finger on your temple and imagine drilling it inside your head," a 29-year-old woman named Heather once told Prevention. "My migraines feel like a screwdriver in there, in that one spot, always on my left side and in my left eye. I get a burning sensation throughout my body and in my jaw. Everything becomes sensitive to the touch, like my muscles are on fire."
Migraine treatments can be either preventive or abortive, and they range from prescription drugs, to over-the-counter medications like Advil Migraine, to home remedies like yoga or taking a hot shower. Psychedelics are another sort of home remedy. For decades, anecdotal evidence has suggested that drugs like LSD and psilocybin may help prevent or alleviate migraines, possibly because they're pharmacologically similar to migraine medications like dihydroergotamine, noted the researchers behind the new study.
To put that anecdotal evidence to the test, the researchers designed a placebo-controlled study in which they gave migraine sufferers a moderate dose of pure synthetic psilocybin. The participants included seven women and three men, all adults, who regularly suffered at least two migraines per week. All participants were free of any serious psychiatric or medical diseases and hadn't abused drugs within three months prior to the study.
To track migraine activity, the participants documented their headache attacks in a journal for six weeks, starting two weeks before the study and stopping two weeks after. The study was divided into two sessions, one of which involved taking a small dose of pure synthetic psilocybin.
"In the first experimental session, all subjects received an oral placebo capsule, and in the second experimental session, all subjects received an identically appearing oral psilocybin capsule," the researchers wrote. "In this design, each subject acted as his own control and placebo was given first so that the potential long-term effects of psilocybin, if given first, would not interfere with placebo treatment, if given second."
Schindler et al.
In the hours after each session, the participants answered questions about any psychedelic effects they might have been experiencing. No participants reported any adverse effects.
In the two weeks after taking the psilocybin, most participants did report significant decreases in migraines compared to baseline and the placebo session.
"The percentages of subjects who had at least 25%, 50%, and 75% reductions in weekly migraine days were as follows: 80%, 50%, 30% after psilocybin, and 20%, 20%, 0% after placebo, respectively," the researchers wrote. "Psilocybin and placebo significantly differed at the level of at least 25% reduction."
Interestingly, these reductions weren't correlated with how strongly the participants felt the psychedelic effects of psilocybin. That suggests migraine sufferers don't need to take a large dose of psilocybin and therefore experience its intense and potentially unpleasant hallucinogenic effects to reap the benefits from it.
But perhaps most promising was that the therapeutic effects lasted at least two weeks after a single dose, differentiating psilocybin from other migraine medications that need to be taken regularly. Still, the researchers noted more research is needed:
"While encouraged by the findings in this exploratory study, before this approach could be used clinically, it is imperative that additional controlled investigations be completed in order to understand psilocybin's full capacity to suppress migraine, as well as its long-term safety and tolerability. To verify the present findings, it will be necessary to replicate the results of this study in a larger sample under a fully randomized design. Studies with a dose range will inform on whether the effects of psilocybin in migraine are dose dependent."
Who needs steroids when you have the placebo effect?
- A study suggests that the effectiveness of sports drinks may depend in part on their color.
- Runners who rinsed with a pink liquid ran better than those who consumed the same but colorless drink.
- Improvement in their performance is likely due to a placebo effect.
The "placebo effect" is real. It's the name for a strange phenomenon that most notably occurs during clinical trials. People who are given an inactive substance, like a sugar pill, often experience the same therapeutic benefit as those who are given actual medicine. It's not their imagination — it really happens. (Even better, recent research suggests that therapeutic benefits occur even when the person knows that they were given a placebo.)
Now, a new study from the University of Westminster (UOW) Centre for Nutraceuticals in London and published in Frontiers in Nutrition suggests that the placebo effect may explain yet another phenomenon: Athletic performance.
The research showed that treadmill runners who rinsed their mouths with a pink liquid increased their performance over runners who swished with exactly the same liquid but without the coloring. Why pink? The color is generally linked to sweetness, and the researchers wondered if that association would subconsciously trick the runners into an expectation of more carbohydrates and thus energy.
Author Sanjoy Deb explains:
"The influence of color on athletic performance has received interest previously, from its effect on a sportsperson's kit to its impact on testosterone and muscular power. Similarly, the role of color in gastronomy has received widespread interest, with research published on how visual cues or color can affect subsequent flavor perception when eating and drinking."
Running for science
Credit: Ryan De Hamer / Unsplash
For the study, the researchers recruited ten healthy adults — six men, four women. All were regular exercisers, with an average age of 30. The participants were told that they would be testing the relative benefits of two commercial sports drinks after watching a brief video explaining the value of such beverages. Previous research found that mid-exercise rinsing with such drinks can reduce the perceived intensity of exercise.
The drinks consisted of 0.12 grams of sucralose dissolved in 500 mL of plain water — an artificially sweetened rinse low in calories. The liquids contained no other additives common to sports drinks such as caffeine. The pink version had non-caloric coloring added but was otherwise identical.
After a 12-minute warmup phase of jogging followed by running, the athletes ran at a difficult pace for 30 minutes, rinsing with their drinks as they ran. Following a brief cool-down, they were interviewed to capture their impressions of the exercise session. (Each runner tested both drinks.)
The researchers found that when the volunteers used the pink rinse, they ran an average of 212 meters farther and 4.4 percent faster. They also enjoyed the exercise more.
Deb said, "The findings from our study combine the art of gastronomy with performance nutrition, as adding a pink colorant to an artificially sweetened solution not only enhanced the perception of sweetness, but also enhanced feelings of pleasure, self-selected running speed, and distance covered during a run."
The researchers also plan to dig deeper into the phenomenon by investigating the possibility that the pinkness of the beverage is somehow directly activating the brain's reward areas.
A new study used functional near-infrared spectroscopy (fNIRS) to measure brain activity as inexperienced and experienced soccer players took penalty kicks.
- The new study is the first to use in-the-field imaging technology to measure brain activity as people delivered penalty kicks.
- Participants were asked to kick a total of 15 penalty shots under three different scenarios, each designed to be increasingly stressful.
- Kickers who missed shots showed higher activity in brain areas that were irrelevant to kicking a soccer ball, suggesting they were overthinking.
In a 2019 soccer match, Swansea City was down 1-0 against West Brom late in the first half. A penalty was called against West Brom. Swansea midfielder Bersant Celina was preparing to deliver a penalty kick. He scuttled up to the ball, but his foot only made partial contact, lobbing it weakly to the right.
Was it a simple mistake? Maybe. But there might be deeper explanations for why professional athletes choke under high-pressure situations.
A new study published in Frontiers in Computer Science used functional near-infrared spectroscopy (fNIRS) to analyze the brain activity of inexperienced and experienced soccer players as they missed penalty shots. Although past research has explored why soccer players miss penalty shots, the recent study is the first to do so using in-the-field fNIRS measurement.
The results showed that kickers who choked were activating parts of their brain associated with long-term thinking, self-instruction, and self-reflection. The chokers, in other words, were overthinking it.
The psychology of penalty kicks
Penalty shots offer an interesting case study of how mental pressure affects physical performance. After all, there's a lot at stake, not only because the kick can sometimes render a win or loss, but also because there are sometimes millions of people anxiously watching, some of whom might have a financial interest in the outcome.
That pressure is no joke. For example, research on Men's World Cup penalty shoot-outs has shown that when the score is tied and a goal means an immediate win, players score 92 percent of kicks. But when teams are facing elimination in a shootout, and the kick determines an immediate tie or loss, players only score 60 percent of the time.
"How can it be that football players with a near perfect control over the ball (they can very precisely kick a ball over more than 50 meters) fail to score a penalty kick from only 11 meters?" study co-author Max Slutter, of the University of Twente in the Netherlands, said in a press release.
"Obviously, huge psychological pressure plays a role, but why does this pressure cause a missed penalty? We tried to answer this by measuring the brain activity of football players during the physical execution of a penalty kick."
In the new study, the researchers aimed to answer two key questions about choking under pressure among both experienced and inexperienced players: (1) What is the difference in brain activity between success (scoring) and failure (missing) when taking a penalty kick? (2) What brain activity is associated with performing under pressure during a penalty kick situation?
To find out, the researchers asked ten experienced soccer players and twelve inexperienced players to participate in a penalty-kicking task. The task was divided into three rounds, each of which was designed to be increasingly stressful:
- Round 1 had no goalkeeper and was labeled as a practice round.
- Round 2 had a friendly goalkeeper who wasn't allowed to distract the kicker.
- Round 3 had a competitive goalkeeper who was allowed to distract the kicker, and kickers were also competing for a prize.
Participants kicked five shots in each round. They wore a fNIRS-equipped headset during the task that measured activity in various parts of the brain.
All participants performed worse in the second and third rounds and reported experiencing the most pressure in the third round. Inexperienced players performed worse than experienced players, which might suggest that they were less able to deal with the mental stress.
The locations in which experienced and inexperienced players kicked the ball in each round. Red dots represent missed penalties and green dots represent scored penalties.Slutter et al., Frontiers in Computer Science, 2021.
The neuroscience of choke artists
So, what types of brain activity were associated with missed shots?
The most noticeable result was that kickers missed more shots when they showed higher activity in their prefrontal cortex (PFC), an area of the brain associated with long-term planning. This was especially true among participants who reported higher levels of anxiety. More specifically, experienced soccer players who missed shots showed high activity in the left temporal cortex, which is related to self-instruction and self-reflection.
"By activating the left temporal cortex more, experienced players neglect their automated skills and start to overthink the situation," the researchers wrote. "This increase can be seen as a distracting factor."
Also, when players of all experience levels felt anxious and missed shots, they showed less activity in the motor cortex, which is the brain area most directly associated with kicking a penalty shot.
Don't overthink it
The results suggest that mental pressure can activate parts of the brain that are irrelevant to the task at hand. In general, expert athletes show more efficient brain activity — that is, more activity in relevant areas, and less activity in irrelevant areas — and therefore experience fewer distractions. This is likely one reason why they were more successful at penalties than inexperienced players in high-stress situations.
This principle is described by neural efficiency theory, and it applies not only to athletes but experts in any field. As you gain mastery over something, you can rely more on automatic brain processes rather than deliberate thinking, which can lead to distractions. The authors of the study concluded that their results provide supporting evidence for neural efficiency theory.
Still, as long our experts are human, it seems that high-pressure situations can turn anyone into a choke artist.