When she woke up after a procedure involving drilling small holes in her skull, a woman suffering from chronic depression reported feeling “euphoric”. The holes were made to fit the wires that connected her brain with a matchbox-sized electrical implant; this would deliver up to 300 short-lived electricity bursts per day to specific parts of her brain.
Over a year later, Sarah, 36, says the brain implant has turned her life around. A sense of alertness and energy have replaced suicidal thoughts and feelings of despair, which had persisted despite antidepressants and electroconvulsive therapy. Sarah is the first person to have received a brain implant to treat depression, a breakthrough that happened during an experimental study published recently in Nature Medicine.
“What we did was use deep-brain stimulation (DBS), a technique used in the treatment of epilepsy,” says Andrew Krystal, professor of psychiatry at University of California, San Francisco (UCSF), and one of the study’s researchers. DBS typically involves implanting electrodes into specific areas of the brain to reduce seizures not controlled with medication or to remove the part of the brain that causes the seizures. Instead of choosing and stimulating a single brain site though, the UCSF team took a different approach.
They first used 10 electrodes to map Sarah’s brain activity, a phase that lasted 10 days, during which they developed a neural biomarker, a specific pattern of brain activity that indicated the onset of depression symptoms (in Sarah, this was detected in her amygdala, an almondlike structure located near the base of the brain). But they also saw that delivering a tiny burst of electricity to the patient’s ventral striatum, an area of the brain that sits in the center, above and behind the ears, dramatically improved these symptoms. What they had to do was outfit Sara’s brain with a DBS-device programmed to propagate small waves of electricity to the ventral striatum only when it discerned the pattern.
“We are not trying to take away normal responses to the world. We are just trying to eliminate this one thing, which is depression, which impedes patients’ ability to function and deal with normal stuff.”
“It was a personalized treatment not only in where to stimulate, but when to stimulate,” Krystal says. Sarah’s depression translated to low amounts of energy, loss of pleasure and interest in life, and feelings of sluggishness. Those symptoms went away when scientists stimulated her ventral capsule area. When the same area was manipulated by electricity when Sarah’s symptoms “were not there” though, she was feeling more energetic, but this sudden flush of energy soon gave way to feelings of overstimulation and anxiety. “This is a very tangible illustration of why it's best to simulate only when you need it,” says Krystal.
We have the tendency to lump together depression symptoms, but, in reality, they are quite diverse; some people feel sad and lethargic, others stay up all night; some overeat, others don’t eat at all. “This happens because people have different underlying dysfunctions in different parts of their brain. Our approach is targeting the specific brain circuit that modulates different kinds of symptoms. Simply, where we stimulate depends on the specific set of problems a person has,” Krystal says. Such tailormade brain stimulation for patients with long-term, drug-resistant depression, which would be easy to use at home, could be transformative, the UCSF researcher concludes.
In the U.S., 12.7 percent of the population is on antidepressants. Almost exactly the same percentage of Australians–12.5–take similar drugs every day. With 13 percent of its population being on antidepressants, Iceland is the world’s highest antidepressant consumer. And quite away from Scandinavia, the Southern European country of Portugal is the world’s third strongest market for corresponding medication.
By 2020, nearly 15.5 million people had been consuming antidepressants for a time period exceeding five years. Between 40 and 60 percent of them saw improvements. “For those people, it was absolutely what they needed, whether that was increased serotonin, or increased norepinephrine or increased dopamine, ” says Frank Anderson, a psychiatrist who has been administering antidepressants in his private practice “for a long time”, and author of Transcending Trauma, a book about resolving complex and dissociative trauma.
Yet the UCSF study brings to the mental health field a specificity it has long lacked. “A lot of the traditional medications only really work on six neurotransmitters, when there are over 100 neurotransmitters in the brain,” Anderson says. Drugs are changing the chemistry of a single system in the brain, but brain stimulation is essentially changing the very architecture of the brain, says James Giordano, professor of neurology and biochemistry at Georgetown University Medical Center in Washington and a neuroethicist. It is a far more elegant approach to treating brain disorders, with the potential to prove a lifesaver for the 40 to 50 percent of patients who see no benefits at all with antidepressants, Giordano says. It is neurofeedback, on steroids, adds Anderson. But it comes with certain risks.
Even if the device generating the brain stimulation sits outside the skull and could be easily used at home, the whole process still involves neurosurgery. While the sophistication and precision of brain surgeries has significantly improved over the last years, says Giordano, they always carry risks, such as an allergic reaction to anesthesia, bleeding in the brain, infection at the wound site, blood clots, even coma. Non-invasive brain stimulation (NIBS), a technology currently being developed by the Defense Advanced Research Projects Agency (DARPA), could potentially tackle this. Patients could wear a cap, helmet, or visor that transmits electrical signals from the brain to a computer system and back, in a brain-computer interface that would not need surgery.
“This could counter the implantation of hardware into the brain and body, around which there is also a lot of public hesitance,” says Giordano, who is working on such techniques at DARPA.
Embedding a chip in your head is one of the finest examples of biohacking, an umbrella word for all the practices aimed at hacking one’s body and brain to enhance performance –a citizen do-it-yourself biology. It is also a word charged enough to set off a public backlash. Large segments of the population will simply refuse to allow that level of invasiveness in their heads, says Laura Cabrera, an associate professor of neuroethics at the Center for Neural Engineering, Department of Engineering Science and Mechanics at Penn State University. Cabrera urges caution when it comes to DBS’s potential.
“We've been using it for Parkinson's for over two decades, hoping that now that they get DBS, patients will get off medications. But people have continued taking their drugs, even increasing them,” she says. What the UCSF found is a proof of concept that DBS worked in one depressed person, but there’s a long way ahead until we can confidently say this finding is generalizable to a large group of patients. Besides, as a society, we are not there yet, says Cabrera. “Most people, at least in my research, say they don't want to have things in their brain,” she says. But what could really go wrong if we biohacked our own brains anyway?
In 2014, a man who had received a deep brain implant for a movement disorder started developing an affection for Johnny Cash’s music when he had previously been an avid country music fan. Many protested that the chip had tampered with his personality. Could sparking the brain with electricity generated by a chip outside it put an end to our individuality, messing with our musical preferences, unique quirks, our deeper sense of ego?
“What we found is that when you stimulate a region, you affect people’s moods, their energies,” says Krystal. You are neither changing their personality nor creating creatures of eternal happiness, he says. “’Being on a phone call would generally be a setting that would normally trigger symptoms of depression in me,’” Krystal reports his patient telling him. ‘I now know bad things happen, but am not affected by them in the same way. They don’t trigger the depression.’” Of the research, Krystal continues: “We are not trying to take away normal responses to the world. We are just trying to eliminate this one thing, which is depression, which impedes patients’ ability to function and deal with normal stuff.”
Yet even change itself shouldn't be seen as threatening, especially if the patient had probably desired it in the first place. “The intent of therapy in psychiatric disorders is to change the personality, because a psychiatric disorder by definition is a disorder of personality,” says Cabrera. A person in therapy wants to restore the lost sense of “normal self”. And as for this restoration altering your original taste in music, Cabrera says we are talking about rarities, extremely scarce phenomena that are possible with medication as well.
Maybe it is the allure of dystopian sci-fi films: people have a tendency to worry about dark forces that will spread malice across the world when the line between human and machine has blurred. Such mind-control through DBS would probably require a decent leap of logic with the tools science has--at least to this day. “This would require an understanding of the parameters of brain stimulation we still don't have,” says Cabrera. Still, brain implants are not fully corrupt-proof.
“Hackers could shut off the device or change the parameters of the patient's neurological function enhancing symptoms or creating harmful side-effects,” says Giordano.
There are risks, but also failsafe ways to tackle them, adds Anderson. “Just like medications are not permanent, we could ensure the implants are used for a specific period of time,” he says. And just like people go in for checkups when they are under medication, they could periodically get their personal brain implants checked to see if they have been altered or not, he continues. “It is what my research group refers to as biosecurity by design,” says Giordano. “It is important that we proactively design systems that cannot be corrupted.”
Two weeks after receiving the implant, Sarah scored 14 out of 54 on the Montgomery-Åsberg Depression Rating Scale, a ten-item questionnaire psychiatrists use to measure the severity of depressive episodes. She had initially scored 36. Today she scores under 10. She would have had to wait between four and eight weeks to see positive results had she taken the antidepressant road, says Krystal.
He and his team have enrolled two other patients in the trials and hope to add nine more. They already have some preliminary evidence that there's another place that works better in the brain of another patient, because that specific patient had been experiencing more anxiety as opposed to despondency. Almost certainly, we will have different biomarkers for different people, and brain stimulation will be tailored to a person’s unique situation, says Krystal. “Each brain is different, just like each face is different.”
Lori Tipton's life was a cascade of trauma that even a soap opera would not dare inflict upon a character: a mentally unstable family; a brother who died of a drug overdose; the shocking discovery of the bodies of two persons her mother had killed before turning the gun on herself; the devastation of Hurricane Katrina that savaged her hometown of New Orleans; being raped by someone she trusted; and having an abortion. She suffered from severe PTSD.
“My life was filled with anxiety and hypervigilance,” she says. “I was constantly afraid and had mood swings, panic attacks, insomnia, intrusive thoughts and suicidal ideation. I tried to take my life more than once.” She was fortunate to be able to access multiple mental health services, “And while at times some of these modalities would relieve the symptoms, nothing really lasted and nothing really address the core trauma.”
Then in 2018 Tipton enrolled in a clinical trial that combined intense sessions of psychotherapy with limited use of Methylenedioxymethamphetamine, or MDMA, a drug classified as a psychedelic and commonly known as ecstasy or Molly. The regimen was arduous; 1-2 hour preparation sessions, three sessions where MDMA was used, which lasted 6-8 hours, and lengthy sessions afterward to process and integrate the experiences. Two therapists were with her every moment of the three-month program that totaled more than 40 hours.
“It was clear to me that [the therapists] weren't going to heal me, that I was going to have to do the work for myself, but that they were there to completely support my process,” she says. “But the effects of MDMA were really undeniable for me. I felt embodied in a way that I hadn't in years. PTSD had robbed me of the ability to feel safe in my own body.”
Tipton doesn’t think the therapy completely cured her PTSD. “But when I completed the trial in 2018, I no longer qualified for the diagnosis, and I still don't qualify for the diagnosis today,” she told an April workshop on psychedelics as mental health treatment by the National Academies of Sciences, Engineering and Medicine, or NASEM.
Rick Doblin has been a catalyst behind much of the contemporary research into psychedelics. Prior to the DEA clamp down, the Boston psychotherapist had seen that MDMA and other psychedelics could benefit some of his patients where other measures had failed. He immediately organized efforts to question the drug rescheduling but to little avail. In 1986, he created the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), which slowly laid the scientific foundation for clinical trials, including the one that Tipton joined, using psychedelics to treat mental health conditions.
Now, only slowly, have researchers been able to explore the power of these drugs to treat a broad spectrum of severely debilitating mental health conditions, including trauma, depression, and PTSD, where other available treatments proved inadequate.
“Psychedelic psychotherapy is an attempt to go after the root causes of the problems with just a relatively few administrations, as contrasted to most of the psychiatric drugs used today that are mostly just reducing symptoms and are meant to be taken on a daily basis,” Doblin said in a 2019 TED Talk. Most of these drugs can have broad effect but “some are probably more effective than others for certain conditions,” he added in a recent interview with Leaps.org. Comparative head-to-head studies of psychedelic therapies simply have not been conducted.
Their mechanisms of action are poorly understood and can vary between drugs, but it is generally believed that psychedelics change the activity of neurons so that the brain processes information differently, says Katrin Preller, a neuropsychologist at the University of Zurich. A recent important study in Nature Medicine by Richard Daws and colleagues used functional magnetic resonance imaging (fMRI) of the brain and found that “functional networks became more functionally interconnected and flexible after psilocybin treatment…implying that psilocybin's antidepressant action may depend on a global increase in brain network integration.”
Rosalind Watts, a clinical investigator at the Imperial College in London, believes there is “an overestimation of the importance of the drug and an underestimation of the importance of the [therapeutic] context” in psychedelic research. “It is unethical to provide the drug without the other,” she says. Doblin notes that “psychotherapy outcomes research demonstrates that the therapeutic alliance between the therapist and the patients is the single most predictive factor of outcomes. [It is] trust and the sense of safety, the willingness to go into difficult spaces” that makes clinical breakthroughs possible with the drug.
Excitement and Challenges
Recurrent themes expressed at the NASEM workshop were exciting glimpses of the potential for psychedelics to treat mental health conditions combined with the challenges of realizing those potentials. A recent review paper found evidence that using psychedelics can help with treating a variety of common mental illnesses, but the paper could identify only 14 clinical trials of classic psychedelics published since 1991. Much of the reason is that the drugs are not patentable and so the pharmaceutical industry has no interest in investing in expensive clinical trials to bring them to market. MAPS has raised about $135 million over its 36-year history to conduct such research, says Doblin, the vast majority of it from individual donors and none from foundations.
The workshop participants’ views also were colored by the history of drug crackdowns and a fear that research might easily be shut down in the future. There was great concern that use of psychedelics should be confined to clinical trials with high safety and ethical standards, instead of doctors and patients experimenting on their own. “We need to get it right this time,” says Charles Grob, a psychiatrist at the UCLA School of Medicine. But restricting access to psychedelics will become even more difficult now that Oregon and several cities have acted to decriminalize possession and use of many of these drugs.
The experience with ketamine also troubled Grob. He is hoping to “mitigate the rush of rapid commercialization” that occurred with that drug. Ketamine technically is not a psychedelic though it does share some of their potentially euphoric properties. In 2019, soon after the FDA approved a form of ketamine with a limited label indication to treat depression, for profit clinics sprang up promoting off label use of the drug for psychiatric conditions where there was little clinical evidence of efficacy. He fears the same thing will happen when true psychedelics are made available.
If these therapies are approved, access to them is likely to be a problem. The drugs themselves are cheap but the accompanying therapy is not, and there is a shortage of trained psychotherapists. Mental health services often are not adequately covered by health insurance, while the poor and people of color suffer additional burdens of inadequate access. Doblin is committed to health care equity by training additional providers and by investigating whether some of the preparatory and integration sessions might be handled in a group setting. He says it is important that the legal aspects of psychedelics also be addressed so that patients “don't have to go underground” in order to receive this care.
As a type 2 diabetic, Michael Snyder has long been interested in how blood sugar levels vary from one person to another in response to the same food, and whether a more personalized approach to nutrition could help tackle the rapidly cascading levels of diabetes and obesity in much of the western world.
Eight years ago, Snyder, who directs the Center for Genomics and Personalized Medicine at Stanford University, decided to put his theories to the test. In the 2000s continuous glucose monitoring, or CGM, had begun to revolutionize the lives of diabetics, both type 1 and type 2. Using spherical sensors which sit on the upper arm or abdomen – with tiny wires that pierce the skin – the technology allowed patients to gain real-time updates on their blood sugar levels, transmitted directly to their phone.
It gave Snyder an idea for his research at Stanford. Applying the same technology to a group of apparently healthy people, and looking for ‘spikes’ or sudden surges in blood sugar known as hyperglycemia, could provide a means of observing how their bodies reacted to an array of foods.
“We discovered that different foods spike people differently,” he says. “Some people spike to pasta, others to bread, others to bananas, and so on. It’s very personalized and our feeling was that building programs around these devices could be extremely powerful for better managing people’s glucose.”
Unbeknown to Snyder at the time, thousands of miles away, a group of Israeli scientists at the Weizmann Institute of Science were doing exactly the same experiments. In 2015, they published a landmark paper which used CGM to track the blood sugar levels of 800 people over several days, showing that the biological response to identical foods can vary wildly. Like Snyder, they theorized that giving people a greater understanding of their own glucose responses, so they spend more time in the normal range, may reduce the prevalence of type 2 diabetes.
The commercial potential of such apps is clear, but the underlying science continues to generate intriguing findings.
“At the moment 33 percent of the U.S. population is pre-diabetic, and 70 percent of those pre-diabetics will become diabetic,” says Snyder. “Those numbers are going up, so it’s pretty clear we need to do something about it.”
Fast forward to 2022,and both teams have converted their ideas into subscription-based dietary apps which use artificial intelligence to offer data-informed nutritional and lifestyle recommendations. Snyder’s spinoff, January AI, combines CGM information with heart rate, sleep, and activity data to advise on foods to avoid and the best times to exercise. DayTwo–a start-up which utilizes the findings of Weizmann Institute of Science–obtains microbiome information by sequencing stool samples, and combines this with blood glucose data to rate ‘good’ and ‘bad’ foods for a particular person.
“CGMs can be used to devise personalized diets,” says Eran Elinav, an immunology professor and microbiota researcher at the Weizmann Institute of Science in addition to serving as a scientific consultant for DayTwo. “However, this process can be cumbersome. Therefore, in our lab we created an algorithm, based on data acquired from a big cohort of people, which can accurately predict post-meal glucose responses on a personal basis.”
The commercial potential of such apps is clear. DayTwo, who market their product to corporate employers and health insurers rather than individual consumers, recently raised $37 million in funding. But the underlying science continues to generate intriguing findings.
Last year, Elinav and colleagues published a study on 225 individuals with pre-diabetes which found that they achieved better blood sugar control when they followed a personalized diet based on DayTwo’s recommendations, compared to a Mediterranean diet. The journal Cell just released a new paper from Snyder’s group which shows that different types of fibre benefit people in different ways.
“The idea is you hear different fibres are good for you,” says Snyder. “But if you look at fibres they’re all over the map—it’s like saying all animals are the same. The responses are very individual. For a lot of people [a type of fibre called] arabinoxylan clearly reduced cholesterol while the fibre inulin had no effect. But in some people, it was the complete opposite.”
Eight years ago, Stanford's Michael Snyder began studying how continuous glucose monitors could be used by patients to gain real-time updates on their blood sugar levels, transmitted directly to their phone.
The Snyder Lab, Stanford Medicine
Because of studies like these, interest in precision nutrition approaches has exploded in recent years. In January, the National Institutes of Health announced that they are spending $170 million on a five year, multi-center initiative which aims to develop algorithms based on a whole range of data sources from blood sugar to sleep, exercise, stress, microbiome and even genomic information which can help predict which diets are most suitable for a particular individual.
“There's so many different factors which influence what you put into your mouth but also what happens to different types of nutrients and how that ultimately affects your health, which means you can’t have a one-size-fits-all set of nutritional guidelines for everyone,” says Bruce Y. Lee, professor of health policy and management at the City University of New York Graduate School of Public Health.
With the falling costs of genomic sequencing, other precision nutrition clinical trials are choosing to look at whether our genomes alone can yield key information about what our diets should look like, an emerging field of research known as nutrigenomics.
The ASPIRE-DNA clinical trial at Imperial College London is aiming to see whether particular genetic variants can be used to classify individuals into two groups, those who are more glucose sensitive to fat and those who are more sensitive to carbohydrates. By following a tailored diet based on these sensitivities, the trial aims to see whether it can prevent people with pre-diabetes from developing the disease.
But while much hope is riding on these trials, even precision nutrition advocates caution that the field remains in the very earliest of stages. Lars-Oliver Klotz, professor of nutrigenomics at Friedrich-Schiller-University in Jena, Germany, says that while the overall goal is to identify means of avoiding nutrition-related diseases, genomic data alone is unlikely to be sufficient to prevent obesity and type 2 diabetes.
“Genome data is rather simple to acquire these days as sequencing techniques have dramatically advanced in recent years,” he says. “However, the predictive value of just genome sequencing is too low in the case of obesity and prediabetes.”
Others say that while genomic data can yield useful information in terms of how different people metabolize different types of fat and specific nutrients such as B vitamins, there is a need for more research before it can be utilized in an algorithm for making dietary recommendations.
“I think it’s a little early,” says Eileen Gibney, a professor at University College Dublin. “We’ve identified a limited number of gene-nutrient interactions so far, but we need more randomized control trials of people with different genetic profiles on the same diet, to see whether they respond differently, and if that can be explained by their genetic differences.”
Some start-ups have already come unstuck for promising too much, or pushing recommendations which are not based on scientifically rigorous trials. The world of precision nutrition apps was dubbed a ‘Wild West’ by some commentators after the founders of uBiome – a start-up which offered nutritional recommendations based on information obtained from sequencing stool samples –were charged with fraud last year. The weight-loss app Noom, which was valued at $3.7 billion in May 2021, has been criticized on Twitter by a number of users who claimed that its recommendations have led to them developed eating disorders.
With precision nutrition apps marketing their technology at healthy individuals, question marks have also been raised about the value which can be gained through non-diabetics monitoring their blood sugar through CGM. While some small studies have found that wearing a CGM can make overweight or obese individuals more motivated to exercise, there is still a lack of conclusive evidence showing that this translates to improved health.
However, independent researchers remain intrigued by the technology, and say that the wealth of data generated through such apps could be used to help further stratify the different types of people who become at risk of developing type 2 diabetes.
“CGM not only enables a longer sampling time for capturing glucose levels, but will also capture lifestyle factors,” says Robert Wagner, a diabetes researcher at University Hospital Düsseldorf. “It is probable that it can be used to identify many clusters of prediabetic metabolism and predict the risk of diabetes and its complications, but maybe also specific cardiometabolic risk constellations. However, we still don’t know which forms of diabetes can be prevented by such approaches and how feasible and long-lasting such self-feedback dietary modifications are.”
Snyder himself has now been wearing a CGM for eight years, and he credits the insights it provides with helping him to manage his own diabetes. “My CGM still gives me novel insights into what foods and behaviors affect my glucose levels,” he says.
He is now looking to run clinical trials with his group at Stanford to see whether following a precision nutrition approach based on CGM and microbiome data, combined with other health information, can be used to reverse signs of pre-diabetes. If it proves successful, January AI may look to incorporate microbiome data in future.
“Ultimately, what I want to do is be able take people’s poop samples, maybe a blood draw, and say, ‘Alright, based on these parameters, this is what I think is going to spike you,’ and then have a CGM to test that out,” he says. “Getting very predictive about this, so right from the get go, you can have people better manage their health and then use the glucose monitor to help follow that.”