A well-known psychology trick called the "rubber hand illusion" could be useful for treating patients with obsessive-compulsive disorder.
- It is easy to trick your brain into believing that a rubber hand belongs to your body.
- OCD is a crippling condition afflicting 1 in 50 people.
- The "rubber hand illusion" could offer a novel strategy to treat this condition.
I feel anchored "here and now" in my body. But this sense of embodiment which we take for granted is an illusion created by the brain. In fact, in just five minutes, I can make you feel like a rubber hand is yours!
I simply ask you to place both your hands flat on a table in between a piece of cardboard serving as a "little wall." You can't see your real right hand. And left to the "cardboard screen" you see a rubber hand, which looks like your own. Now, when you look down on the table you see two hands in front of you. But only one is yours — that is, the left one. Sitting across from you, I stroke the fake hand and the hidden right hand in perfect synchrony with a paintbrush. Astonishingly, after just a few minutes you'll most likely feel touch sensations arising from the rubber hand as if it were yours!
This compelling illusion illustrates the fragility of the sense of self and how your brain creates this feeling based on statistical correlations. It's extremely unlikely for such stroking seen on the rubber hand and felt on the hidden real right hand to occur by random chance. So, your brain concludes, however illogical, that the rubber hand is yours. This famous psychology trick — the "rubber hand illusion" — has been known for decades, but no one had examined how it could be used to treat obsessive-compulsive disorder (OCD) until my colleagues and I hit upon a novel technique: "multisensory stimulation therapy."
Treating OCD with a rubber hand
OCD is a crippling condition afflicting 1 in 50 people. A common type of OCD involves repetitive handwashing sometimes for hours until they bleed. These patients are petrified of trivial things like touching a garbage bin. Unsurprisingly, OCD patients suffer immensely. Yet there are few treatment options for them.
The most widely used "talking therapy" — dubbed "exposure and response prevention" — entails instructing patients to touch things they consider "disgusting" like a toilet seat and not washing their hands afterward. The aim is to make them feel anxious initially but then showing that nothing horrible occurs when they refrain from handwashing. However, a substantial limitation of this therapy is that patients fear touching things they consider contaminated. As many as 25 percent of patients outright refuse this treatment and 20 percent drop out before completion. But what if a rubber hand were to touch the disgusting objects instead — I thought to myself — one that feels like the patient's hand? Then one could create a less fear-provoking yet realistic therapy for OCD.
To show if this could work, V.S. Ramachandran, D. Krishnakumar, and I explored if healthy volunteers (without OCD) would experience disgust if we were to contaminate the fake hand during the aforementioned rubber hand illusion. So, we first induced the illusion, and after a few minutes, we put disgusting things like fake feces on the rubber hand. Curiously, participants experienced disgust, as if the sensation was emanating from the fake hand. In other words, when they felt like the fake hand was theirs, they were grossed out by what it was touching. These findings were later replicated in a large study from Japan, suggesting that these results are reliable even across cultures.
Therefore, my colleagues at Harvard and I (in collaboration with McLean Hospital and V.S. Ramachandran) later tested this trick in OCD patients and found the same result: that is, after stroking the rubber hand for 10 minutes, OCD patients displayed disgust reactions, just as if their real hand had been contaminated.
These results are striking because they show that OCD patients can experience contamination feelings, even from a rubber hand. Such contamination feelings are, as noted above, the basis for treating OCD. Over time, by repeating this rubber hand trick, patients should build up disgust tolerance — just like standard OCD therapy — and this could therefore represent a new way of treating the disorder that keeps so many souls hostage.
OCD is a strange disorder that blurs the boundary between mind and body, reality and illusion. It may just be that one has to trick the brain to tackle OCD, combating one illusion with another.
Dr. Baland S. Jalal is a researcher at Harvard University, Department of Psychology and visiting researcher at Cambridge University, Department of Psychiatry. He obtained his PhD at Cambridge University in the School of Clinical Medicine (Trinity College Cambridge) and was a Fellow at Harvard University (2016, 2018). He is a close collaborator and co-author on ten papers with the renowned neuroscientist V.S. Ramachandran (2011 TIME magazine 100 most influential people in the world).
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."
A lithium imbalance appears linked to suicide.
- Lithium appears essential to brain activity, but how it works remains a mystery.
- A team of researchers analyzed where in the brain lithium tends to accumulate in two healthy controls and one suicide victim.
- The healthy controls had more lithium in their white matter than gray matter.
Lithium is known to students of chemistry as the lightest solid element, to electronics enthusiasts as a fine material to make a battery out of, and to millions of others as an effective medication. It was initially used as a medicine against a variety of conditions, including "brain gout" and "general nervousness," to some success in the 19th century. It was briefly an ingredient in the soda 7 Up, much like how Coca-Cola once included cocaine. In 1948, the government banned the use of lithium in this way.
Ironically, it was a year after these bans took place that the use of lithium got a dose of science. Its safe use in treating a number of conditions, most notably mania, was demonstrated. It is now widely used to treat bipolar disorder and depression, though it can be toxic in high doses.
Exactly how lithium works in the body isn't known. How the trace amounts of lithium in our bodies, acquired naturally from sources like food and water, affect us is also poorly studied. A new study published in Scientific Reports hopes to fill that gap in the literature. Its findings suggest that lithium is even more important than previously thought, with the body regulating where it is distributed in the brain.
Lithium in the brain of a suicide victim
The researchers used a new technique called neutron-induced coincidence (NIK), which involves shooting neutrons at brain sections and measuring the decay products that form after lithium absorbs a neutron. In this way, they can determine where and how much lithium is in the sample.
This was used to examine a total of 139 samples from the brains of three deceased individuals: the first died a natural death and never took lithium as a medication; the second also never took lithium and died of suicide; and the third took lithium but died a natural death.
The brains of the two subjects who died a natural death contained much more lithium in the white matter than in the gray matter. (Gray matter is involved in higher thought, while white matter is involved in information transfer.) For the suicide victim, there was much less lithium in the white matter compared to the gray matter. The authors concluded that the distribution was "almost diametral to the control collective, where the ratio was well > 1, so that an acute lithium depletion in suicide could be considered."
It appears, therefore, that lithium distribution is controlled in the brain.
What are the implications?
Lead author Jutta Schöpfer explained:
"Our results are fairly groundbreaking, because we were able for the first time to ascertain the distribution of lithium under physiological conditions. Since we were able to ascertain trace quantities of the element in the brain without first administering medication and because the distribution is so clearly different, we assume that lithium indeed has an important function in the body."
The authors note that "our results accordingly support the thesis that lithium may be of essential relevance not only in animal, but also in man." They also mesh well with recent findings suggesting people receiving greater concentrations of lithium in their drinking water are less likely to commit suicide. Additionally, other studies suggest that lithium levels in the water relate to local crime rates and occurrences of neurodegenerative disease.
There is much more to learn about that element in the upper-left corner of the Periodic Table.
A small percentage of people who consume psychedelics experience strange lingering effects, sometimes years after they took the drug.
- LSD flashbacks have been studied for decades, though scientists still aren't quite sure why some people experience them.
- A subset of people who take psychedelics and then experience flashbacks develop hallucinogen persisting perception disorder (HPPD), a rare condition in which people experience regular or near-constant psychedelic symptoms.
- There's currently no cure for the disorder, though some studies suggest medications may alleviate symptoms.
In February 2021, Conor was in his room and looking at his phone when he was struck by a strange feeling.
"The room looked normal, nothing was moving, but I felt as though I was under the influence of a psychedelic," he told Big Think.
As a teenager, Conor had experimented with LSD, mushrooms, and other psychedelics a couple dozen times. Now 25, he had been sober for about a year. He brushed off the incident.
But soon, Conor was struck again by the same strange feeling.
"I had no idea what was going on in my brain at that time and the anxiety and paranoia grew so intense that I became fearful I had developed everything from brain cancer to schizophrenia," he said.
The physical and psychological symptoms he began suffering were "devastating."
"The world [looked] crooked and out of focus, pictures had an eerie quality to them, things would go in and out of focus, at night while falling asleep I would experience vivid and terrifying hypnagogic hallucinations that made rest impossible."
After three weeks, Conor said his visual symptoms amplified with "unbelievable intensity."
"The floors would [breathe], paint on the walls looked wet, visual snow was so intense [that] pure black looked like it was glowing, at night I would see tracers everywhere, halos appeared around text. [...] I did not sleep, my thoughts were anxious and at times deranged, I had unbelievably intense dereliction that made the world seem fake."
What Conor experienced is commonly called an LSD flashback. It's a mysterious phenomenon in which someone who's previously taken a hallucinogenic drug suddenly and temporarily experiences the effects of that drug days, weeks, or even years after consuming it.
Flashbacks can occur after taking a wide range of psychedelic drugs. But compared to other hallucinogens, flashbacks seem to be most common among people who have consumed LSD, according to studies.
Credit Newwup via Adobe Stock
People have reported acid flashbacks for decades. The earliest recorded case may be
Havelock Ellis' 1898 report of taking mescaline and then experiencing sustained heightened sensitization to "the more delicate phenomena of light and shade and color."
But it wasn't until the 1950s, little more than a decade after Albert Hoffman first synthesized LSD, that scientists started researching LSD and its potential long-term effects. While studies have illuminated some aspects of how psychedelics affect the brain, scientists still have much to learn about the nature of LSD flashbacks, what causes them, and how to treat them.
What's certain, however, is that a small percentage of people who consume psychedelics report bizarre and sometimes debilitating effects that emerge long after taking hallucinogens.
Symptoms of LSD flashbacks
Among the most common symptoms of LSD flashbacks are visual distortions. In a 1983 study titled " Visual Phenomenology of the LSD Flashback," the psychiatrist and LSD researcher Dr. Henry David Abraham described 16 common visual disturbances reported by people with LSD flashbacks. To name a few:
- Acquired color confusion: The color of objects changed or presented a newly discovered problem of color confusion.
- Difficulty reading: Text may appear jumbled or leave afterimages of the type against the background of the page.
- Geometric phosphenes: Phosphenes, or eigengrau, are non-specific luminous perceptions that occur when the eyes are closed and may originate from entopic (i.e., arising from within the eye itself) stimuli in normal persons. They also may be induced by gentle pressure on the closed eyelid.
- Pareidolias: This is literally an image within an image. These were described when a subject gazed into a finely reticulated design in linoleum, veneer, or a cloud formation. Besides the abstract pattern of the linoleum, subjects often would be able to see a series of concrete images as well, such as "a fish," "a face," and "a little boy."
- Macropsia: Macropsia is the perception of an object larger than it really is. A characteristic description of this phenomenon came from a subject who noticed that his hand was enormous and then of normal size a few seconds later.
- Micropsia: Micropsia is the perception of an object smaller than reality. One subject said, "My feet looked so tiny, like they were a million miles away."
The effects of LSD flashbacks aren't limited to visual distortions. In a 1970 study called "Analysis of the LSD Flashback," researchers sorted LSD flashbacks into three broad categories: perceptual, somatic (meaning of the body), and emotional.
The emotional flashback is "far more distressing" than the other two, the researchers wrote, providing a case study of a 21-year-old woman who was suffering from LSD flashbacks:
"The patient had these frightening flashbacks during the day, while walking down the street, after smoking marijuana or drinking wine, during the night, and occasionally even while asleep. In one situation she awoke during the middle of the night with a feeling of panic and began running around her house fleeing an imagined threat she could not identify or comprehend. She had taken LSD a number of times, but her last few trips were bad ones with panic and fright followed by loneliness to the point of suicidal despair when she 'came down.' The combination of bad trips and emotional flashbacks made her seek professional help because of her fear that she would harm herself."
To be sure, LSD flashbacks aren't always emotionally distressing. A 2010 survey of 600 hallucinogen users found that, of the minority of users who reported experiencing at least one flashback, only 3 percent described it as a negative experience. In fact, some people enjoyed their flashbacks. On the website Erowid, which promotes research of psychedelic drugs, one user wrote:
"After 2 years of my last acid trip, while on vacation in a very nice wilderness place I was sitting on a rock and then I experienced a clear acid high. I was looking at a very steep hill and suddenly it started moving in nice patterns, exactly as one sees patterns while on acid. It wasn't something uncomfortable. In fact it was really pleasant and there was absolutely no trace of the nasty anxiousness after effects common to LSD. It lasted approximately 2 minutes and I enjoyed it very much."
But some LSD flashbacks are neither brief nor pleasant. A subset of people who use psychedelics develop hallucinogen persisting perception disorder (HPPD), a rare and poorly understood condition in which people experience omnipresent or recurring flashbacks. While the symptoms of HPPD vary, the condition can cause intense pain, irreversible perceptual distortions, emotional and psychological distress, and even suicidal thoughts.
HPPD: The never-ending trip
HPPD is estimated to affect between one to five percent of LSD users, though the actual figure is impossible to determine without better data. The disorder was first described formally in 1986 by the American Psychiatric Association's Diagnostic & Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R). The current edition of the manual (DSM-5) says patients need to meet several criteria to be diagnosed with HPPD:
- Patients must reexperience perceptual symptoms they experienced while intoxicated with the hallucinogen.
- These symptoms must cause "significant distress or impairment in social, occupational, or other important areas of functioning."
- These symptoms aren't due to a separate medical condition or mental disorder.
So, what's the difference between a flashback and HPPD? Mainly frequency and duration. A 2017 review published in Frontiers in Psychiatry noted that while "a flashback is usually reported to be infrequent and episodic, HPPD is usually persisting and long-lasting."
A 2014 review published in the Israel Journal of Psychiatry and Related Sciences outlined two types of HPPD. The first, HPPD I, is the "flashback type," which is a generally short-term, non-distressing, benign and reversible state accompanied by a pleasant affect. The severity of HPPD I varies, with some people describing their mild flashbacks as annoying, while others say it's like getting "free trips."
But HPPD II is a different beast. The condition can be permanent, with perceptual distortions and other symptoms manifesting irregularly or almost constantly.
"The symptoms usually include palinopsia (afterimages effects), the occurrence of haloes, trails, akinetopsia, visual snows, etc.," according to the aforementioned 2017 review. "Sounds and other perceptions are usually not affected. Visual phenomena have been reported to be uncontrollable and disturbing. Symptomatology may be accompanied by depersonalization, derealization, anxiety, and depression."
What causes flashbacks and HPPD?
When asked what causes flashbacks and HPPD, Dr. Abraham told Popular Science, "I've spent my life studying this problem and I don't know, is the short answer."
But researchers have proposed explanations. One centers on memory. Because psychedelics can cause extremely powerful and emotional experiences, it's theoretically possible that certain environmental stimuli can remind people of those experiences, and then memory "transports" them back into that subjective mindset — similar to how a soldier with post-traumatic stress disorder might suffer an episode after hearing a loud, sudden noise.
Another hypothesis involves how LSD interacts with the brain's visual processing center. Dr. Abraham proposed that HPPD may arise due to "disinhibition of visual processing related to a loss of serotonin receptors on inhibitory interneurons," which may be caused by consuming LSD.
The basic idea is that LSD somehow changes the way the brain interprets visual stimuli. That might explain why people with HPPD have difficulty properly "disengaging" from the things they see around them. For example, a red stoplight might appear not as a discrete red circle but as a streak of red light painted across their field of vision; or a strobe light might not appear as a flickering light but a light that's constantly on.
Credit Yurok Aleksandrovich via Adobe Stock
"Such a locking of visual circuitry into an 'on' position following perception of a visual stimulus would explain such diverse complaints as trailing, color intensification, positive afterimages, phosphenes, and color confusions, each of which may represent a failure of the respective visual function to turn off the brain's response to the stimulus once the stimulus is gone," Dr. Abraham
It's also possible that people are genetically predisposed to HPPD and that ingesting LSD is the key that unlocks the disorder. This hypothesis would help explain why people have reportedly developed HPPD after taking a single, moderate dose of LSD.
Ultimately, the exact causes of HPPD are unclear. Partially as a result, there's currently no cure for the disorder, though studies show that people with HPPD have reported improvements in symptomatology after taking benzodiazepines. There's also anecdotal evidence that fasting can alleviate the disorder.
Despite uncertainty over the causes of HPPD, researchers do have a good idea of what can trigger "flare-ups" of HPPD. Dr. Abraham's 1983 study listed the most common triggers, some of which include:
- Emergence into a dark environment
- Intention (intentionally inducing visual aberrations by, say, staring at a blank wall)
People with HPPD describe the condition
To get a better understanding of HPPD, Big Think posted a questionnaire to the HPPD community on Reddit. Here are some of the responses:
How did HPPD first manifest for you?
"First I noticed highly enhanced creativity and intense visuals when [high on] weed and I really enjoyed that part. The realization that this is not going to go away soured the whole experience tho."
"My enhanced creativity left me after about a week and what I was left with was mild visual snow. I hardly knew anything about HPPD at the time and just didn't really care about my symptoms and still thought they were just going to vanish at some point, which they didn't. I kept taking drugs simply because I was addicted and felt like life is no fun without them. My HPPD got gradually worse over time and more symptoms appeared. First, I noticed mild tracers, which got worse over time (again due to continued drug use) and then tinnitus and brain fog. But primarily my symptoms are visual."
Are your symptoms episodic or constant?
"Both constant and episodic," wrote user LotsOfShungite. "A stressful event can trigger my symptoms off into the deep end."
"Except the brain fog and head pressure that varies, my visual disturbances are constant. The most debilitating ones are the visual snow, especially when I'm inside except if I watch the TV since it filters some of it out. It's also VERY frustrating that I no longer can focus on objects/details (can't stare) and the astigmatism-like symptoms that I got, like blurriness, especially in the distance and ghosting (double vision) plus starbursts from strong light sources. When I'm outside, the pattern glare is really annoying, same with the excessive amount of floaters that came with this. I also see halos from light sources."
"My symptoms are mostly constant and only change through rather obvious outside influences, such as certain drugs (almost all drugs), stress, lack of sleep, etc. Although my HPPD is quite pronounced, I have learned to accept it and almost only notice it when I pay attention to it. I always [know] it's there and it somewhat bugs me but I get along."
What are some common misconceptions about HPPD?
"I think the most common misconception about hppd is when people refer to it as "tripping permanently". There is a massive distinction between those two things. Generally with hppd, your vision may be altered, but to call it "tripping" is incredibly misleading. Tripping entails a massively altered state of mind and visual perception that is not seen with hppd. There are psychological symptoms like panic attacks, anxiety and dpdr, but those stem from the stress of dealing with the condition. Not because you have trapped lsd molecules flying around your brain for decades (another common myth) A person with hppd is capable of thinking clearly and acting the same as any other sober minded person. A lot of us have jobs, can hold conversations, are capable of being productive members of society. The "burnt out acid junkie" stuck in a "permanent trip" is an extremely toxic trope that creates stigmas around people who already feel intense regret and emotional distress caused by a poorly understood condition. We are not the drugs that we took, and are capable of growing past the mistakes we made in life."
"One of if not the biggest 'misconception' is that many people believe that HPPD does not exist. But I guess there is no way to prove to another person that it does, so this is gonna stay the case until HPPD enters the public consciousness of the psychedelic community."
"They usually don't understand anything about it since most haven't heard about it, which really is crazy considering how debilitating this disorder is for many. And as Dr. Abraham said: in the medical field it's highly under- and misdiagnosed. Often as psychosis."
Lopyriev via Adobe Stock
Hope for HPPD
Since experiencing his first acid flashback in February, Conor has found a few helpful strategies to minimize symptoms, including seeing a psychologist, staying sober, getting enough sleep, staying productive, and talking regularly with friends.
He's currently training to be in the military.
"The symptoms will lessen with time and sobriety, and HPPD provides an opportunity to improve yourself. That being said, because thoughts of suicide are apparently common with people that have HPPD, the medical community should take the condition seriously. Especially given how many people use psychedelics today."
While the future of HPPD research remains unclear, general psychedelics research is going through something of a renaissance. In recent years, researchers have published a growing body of studies showing how psychedelics like psilocybin, LSD, and MDMA can help treat conditions like depression, anxiety, post-traumatic stress disorder, and existential distress.
But, among people with HPPD, opinions on the utility of psychedelics vary. Conor advised caution:
"I would not recommend [hallucinogenic] drugs be taken for recreational purposes. They are tools to help us treat illnesses and should be treated as such. If someone has depression or other mental health issue, maybe psychedelics administered in a clinical setting by a doctor is appropriate, but otherwise, playing with your brain like it's a chemistry playset is asking for trouble down the road."
A lab identifies which genes are linked to abnormal repetitive behaviors found in addiction and schizophrenia.
These behaviors, termed stereotypies, are also apparent in animal models of drug addiction and autism.
In a new study published in the European Journal of Neuroscience, researchers at the McGovern Institute for Brain Research have identified genes that are activated in the brain prior to the initiation of these severe repetitive behaviors.
"Our lab has found a small set of genes that are regulated in relation to the development of stereotypic behaviors in an animal model of drug addiction," says MIT Institute Professor Ann Graybiel, who is the senior author of the paper. "We were surprised and interested to see that one of these genes is a susceptibility gene for schizophrenia. This finding might help to understand the biological basis of repetitive, stereotypic behaviors as seen in a range of neurologic and neuropsychiatric disorders, and in otherwise 'typical' people under stress."
A shared molecular pathway
In work led by Research Scientist Jill Crittenden, scientists in the Graybiel lab exposed mice to amphetamine, a psychomotor stimulant that drives hyperactivity and confined stereotypies in humans and in laboratory animals and that is used to model symptoms of schizophrenia.
They found that stimulant exposure that drives the most prolonged repetitive behaviors led to activation of genes regulated by Neuregulin 1, a signaling molecule that is important for a variety of cellular functions including neuronal development and plasticity. Neuregulin 1 gene mutations are risk factors for schizophrenia.
The new findings highlight a shared molecular and circuit pathway for stereotypies that are caused by drugs of abuse and in brain disorders, and have implications for why stimulant intoxication is a risk factor for the onset of schizophrenia.
"Experimental treatment with amphetamine has long been used in studies on rodents and other animals in tests to find better treatments for schizophrenia in humans, because there are some behavioral similarities across the two otherwise very different contexts," explains Graybiel, who is also an investigator at the McGovern Institute and a professor of brain and cognitive sciences at MIT. "It was striking to find Neuregulin 1 — potentially one hint to shared mechanisms underlying some of these similarities."
Drug exposure linked to repetitive behaviors
Although many studies have measured gene expression changes in animal models of drug addiction, this study is the first to evaluate genome-wide changes specifically associated with restricted repetitive behaviors.
Stereotypies are difficult to measure without labor-intensive direct observation, because they consist of fine movements and idiosyncratic behaviors. In this study, the authors administered amphetamine (or saline control) to mice and then measured with photobeam-breaks how much they ran around. The researchers identified prolonged periods when the mice were not running around (i.e., were potentially engaged in confined stereotypies), and then they videotaped the mice during these periods to observationally score the severity of restricted repetitive behaviors (e.g., sniffing or licking stereotypies).
They gave amphetamine to each mouse once a day for 21 days and found that, on average, mice showed very little stereotypy on the first day of drug exposure but that, by the seventh day of exposure, all of the mice showed a prolonged period of stereotypy that gradually became shorter and shorter over the subsequent two weeks.
"We were surprised to see the stereotypy diminishing after one week of treatment. We had actually planned a study based on our expectation that the repetitive behaviors would become more intense, but then we realized that this was an opportunity to look at what gene changes were unique to that day of high stereotypy," says first author Jill Crittenden.
The authors compared gene expression changes in the brains of mice treated with amphetamine for one day, seven days, or 21 days. They hypothesized that the gene changes associated specifically with high-stereotypy-associated seven days of drug treatment were the most likely to underlie extreme repetitive behaviors and could identify risk-factor genes for such symptoms in disease.
A shared anatomical pathway
Previous work from the Graybiel lab has shown that stereotypy is directly correlated to circumscribed gene activation in the striatum, a forebrain region that is key for habit formation. In animals with the most intense stereotypy, most of the striatum does not show gene activation, but immediate early gene induction remains high in clusters of cells called striosomes. Striosomes have recently been shown to have powerful control over cells that release dopamine, a neuromodulator that is severely disrupted in drug addiction and in schizophrenia. Strikingly, striosomes contain high levels of Neuregulin 1.
"Our new data suggest that the upregulation of Neuregulin-responsive genes in animals with severely repetitive behaviors reflects gene changes in the striosomal neurons that control the release of dopamine," Crittenden explains. "Dopamine can directly impact whether an animal repeats an action or explores new actions, so our study highlights a potential role for a striosomal circuit in controlling action-selection in health and in neuropsychiatric disease."
Patterns of behavior and gene expression
Striatal gene expression levels were measured by sequencing messenger RNAs (mRNAs) in dissected brain tissue. mRNAs are read out from "active" genes to instruct protein-synthesis machinery in how to make the protein that corresponds to the gene's sequence. Proteins are the main constituents of a cell, thereby controlling each cell's function. The number of times a particular mRNA sequence is found reflects the frequency at which the gene was being read out at the time that the cellular material was collected.
To identify genes that were read out into mRNA before the period of prolonged stereotypy, the researchers collected brain tissue 20 minutes after amphetamine injection, which is about 30 minutes before peak stereotypy. They then identified which genes had significantly different levels of corresponding mRNAs in drug-treated mice than in mice treated with saline.
A wide variety of genes showed modest mRNA increases after the first amphetamine exposure, which induced mild hyperactivity and a range of behaviors such as walking, sniffing, and rearing in the mice.
By the seventh day of treatment, all of the mice were engaged for prolonged periods in one specific repetitive behavior, such as sniffing the wall. Likewise, there were fewer genes that were activated by the seventh day relative to the first treatment day, but they were strongly activated in all mice that received the stereotypy-inducing amphetamine treatment.
By the 21st day of treatment, the stereotypy behaviors were less intense, as was the gene upregulation — fewer genes were strongly activated, and more were repressed, relative to the other treatments. "It seemed that the mice had developed tolerance to the drug, both in terms of their behavioral response and in terms of their gene activation response," says Crittenden.
"Trying to seek patterns of gene regulation starting with behavior is correlative work, and we did not prove 'causality' in this first small study," explains Graybiel. "But we hope that the striking parallels between the scope and selectivity of the mRNA and behavioral changes that we detected will help in further work on the tremendously challenging goal of treating addiction."
This work was funded by the National Institute of Child Health and Human Development, the Saks-Kavanaugh Foundation, the Broderick Fund for Phytocannabinoid Research at MIT, the James and Pat Poitras Research Fund, The Simons Foundation, and The Stanley Center for Psychiatric Research at the Broad Institute.