Tag Archives: schizophrenia

Schizophrenia patients show fewer brain connections than healthy people

New research confirms that schizophrenia’s cognitive symptoms are correlated with lower synaptic density in certain parts of the brain.

Image credits Ellis Chika Onwordi / MRC London Institute of Medical Sciences.

Researchers have hypothesized that there is a link between schizophrenia and malfunctioning synapses since the early 1980s but lacked proper tools needed to investigate this in living brains. However, it was confirmed in post-mortem brain samples and animal cells in the lab.

But there’s no better proof of something than seeing it in action. New research at the Medical Research Council (MRC) London Institute of Medical Sciences did just that by using advanced brain-imaging techniques to peer into the synapses of living schizophrenia patients.

Instant synapses, just add protein

“Our current treatments for schizophrenia only target one aspect of the disease—the psychotic symptoms—but the debilitating cognitive symptoms, such as loss of abilities to plan and remember, often cause much more long-term disability and there’s no treatment for them at the moment. Synaptic loss is thought to underlie these symptoms,” says Professor Oliver Howes from the MRC London Institute of Medical Sciences, Imperial College London and King’s College London, the paper’s lead author.

For the study, the team enlisted the help of 18 adults with schizophrenia and 18 people without (these were the controls). The research was made possible by a tracer molecule that emits a signal that can be picked up by a PET (positron emission tomography) brain scan. This tracer is injected into the bloodstream of a subject and binds to SV2A, a specific protein found in brain synapses. Animal and post-mortem human studies have shown that SV2A is a reliable marker for synaptic density in the brain.

The team reports that patients with schizophrenia showed lower levels of SV2A in the frontal and anterior cingulate cortices of the brain, which are involved in planning and other high-level functions. In essence, the lower levels of SV2A proteins seen here suggest a lower number of synapses (and thus, brain functionality) in the area.

“Our lab at the MRC London Institute of Medical Sciences is one of the few places in the world with this new tracer, which means we’ve been able for the first time to show there are lower levels of a synaptic protein in people with schizophrenia,” Professor Howes adds.

“This suggests that loss of synapses could underlie the development of schizophrenia.”

The schizophrenia patients that participated in this study had all received antipsychotic medication, which could affect the results. To address this, the team gave haloperidol and olanzapine, two antipsychotic drugs, to lab rats for 28 days, then analyzed their brains using the same method. Such medication had no effect on SV2A protein levels, they found, which helped to validate their results. This step also indicated that the antipsychotic medication currently in use doesn’t lead to a loss of synaptic density or function, which is always nice to know.

Therapeutic options for schizophrenia remain few and far between. The condition is a highly debilitating one, and any effective avenue of treatment would dramatically improve the quality of life for patients. Studies such as this one serve as a launching pad for developing future treatments, according to Dr. Ellis Onwordi from the MRC London Institute of Medical Sciences, lead author of the paper. The findings can also help guide brain research into other similar conditions by showcasing “how the extraordinarily complex wiring of the human brain is altered by this disease.”

“Having scans that can characterise the distribution of the approximately 100 trillion synapses in the living brain, and find differences in their distribution between people with and without schizophrenia, represents a significant advance in our ability to study schizophrenia,” he adds.

“We need to develop new treatments for schizophrenia. This protein SV2A could be a target for new treatments to restore synaptic function.”

In the future, the team hopes to scan the brains of younger people during the early stages of schizophrenia, to better understand how it develops in the brain. Do all the changes seen in this study happen suddenly, or do they develop over time as the condition progresses? Such data could help us better treat the condition, and maybe even stop it altogether.

The paper “Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats” has been published in the journal Nature Communications.

Your hairs hide secrets — some subsets of schizophrenia can be detected by biomarkers in our hair

A certain subtype of schizophrenia could be diagnosed based on biomarkers in a patient’s hair, a new study found.

Image credits Ryan McGuire.

The team at the RIKEN Center for Brain Science (CBS) in Japan reports that a certain subtype of schizophrenia is related to very high levels of hydrogen sulfide in the brain. This mutation, caused by a DNA-modifying reaction during development, can also be detected by analyzing biomarkers in a patient’s hair.

A headful of markers

“Nobody has ever thought about a causal link between hydrogen sulfide and schizophrenia,” says team leader Takeo Yoshikawa, the paper’s corresponding author.

“Once we discovered this, we had to figure out how it happens and if these findings in mice would hold true for people with schizophrenia.”

The best way to diagnose a condition is to have a reliable, objective marker you can look for or compare a patient against. For schizophrenia, the most reliable such marker in use is an abnormal startle response test (the link between schizophrenia and abnormal startle responses has been documented since around 30 years ago).

Humans aren’t normally startled by a random burst of noise if it’s preceded by a smaller one — this latter one is called a prepulse. The whole phenomenon is known as prepulse inhibition (PPI); in people with schizophrenia, PPI is lowered, meaning such patients don’t experience a dampened startle response after the prepulse (or experience much lower dampening than normal). Because it’s pretty reliable and consistent, the PPI test is a strong tool used in diagnosing schizophrenia, even if it doesn’t tell us very much about the biology behind the condition.

The RIKEN CBS team set out to look for differences in protein expression between strains of mice that had either very low or very high PPI. They found that one protein (Mpst) was expressed much more in the brains of mice with low PPI than in those with high PPI. Knowing that this enzyme is involved in the synthesis of hydrogen sulfide, the team measured the concentration of this compound in the hairs of low-PPI mice — they found elevated levels.

To validate the findings so far, the team engineered some of the low-PPI mice in order to reduce the expression of the MPST gene (which governs the Mpst protein) — this helped make the mice behave more closely like their healthy kin. Next, the team established that MPST gene expression was higher (postmortem) in the brains of people with schizophrenia compared to healthy controls. The level of MPST protein seen in the brains also correlated well with the severity of the symptoms each patient experienced, they add.

After establishing that MPST expression can be used as a biomarker for schizophrenia, the team examined hair follicles from over 150 schizophrenia patients. The findings so far held firm: all of them had much higher expression of MPST mRNA than people without the condition. The results weren’t perfect, the team explains — which indicates that sulfide stress does not account for all cases of schizophrenia — but they did show that MPST levels in hair are a reliable biomarker for the disease, and can be tested before other symptoms become apparent.

Testing on postmortem mice’s brains showed that the high MPST levels were associated with changes in DNA that lead to permanently altered gene expression. The team hypothesized that inflammatory stress during early development might be the root cause (hydrogen sulfide can protect against inflammatory stress).

“We found that anti-oxidative markers—including the production of hydrogen sulfide—that compensate against oxidative stress and neuroinflammation during brain development were correlated with MPST levels in the brains of people with schizophrenia,” says Yoshikawa.

“Currently, about 30 percent of patients with schizophrenia are resistant to dopamine D2-receptor antagonist therapy. Our results provide a new principle or paradigm for designing drugs, and we are currently testing whether inhibiting the synthesis of hydrogen sulfide can alleviate symptoms in mouse models of schizophrenia.”

The paper “Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology” has been published in the journal EMBO Molecular Medicine.

Blind people don’t suffer from schizophrenia — and the reason could help us find a treatment

In February 2019, an intriguing study made the rounds. Researchers from the University of Western Australia found conclusive evidence that congenital blindness is protective against schizophrenia.

The unusual discovery offered new insights into the inner workings of schizophrenia, a condition which still has many unknowns, despite decades of research.

“This leads us to think there is a link that must be explored,” said Professor Vera Morgan from the UWA Neuropsychiatric Epidemiology Research Unit, lead author of the study.

Now, a new study sheds new light on that phenomenon and could help us better understand how schizophrenia works — as well as how we build a mental model of the world around us.

The mind’s eyes

The relationship between vision and psychosis is complex. While congenital visual loss appears to be protective against psychotic disorders, gradual visual loss can give rise to hallucinations or even psychotic episodes.

The age at which vision loss happens appears to be a crucial factor. The absence of vision at birth or very early in life appears to have a protective effect, whereas later-life visual loss appears to predispose one to the development of psychotic symptoms. This is particularly unusual as there are very few medical disorders that may be protective against psychosis (the already-notorious example is rheumatoid arthritis).

Researchers suspect that it’s not just the loss of sight that is at work here — it’s also the way the other senses and the brain are rearranged after vision loss. For instance, the brains of blind people adapt to sharpen the other senses, which they are also better at processing.

When something interferes with a person’s vision, it can also send all kinds of confusing signals to the brain. If a person with functioning eyesight is blinded, the auditory and tactile information that he or she receives will be chaotic, confusing, and potentially overwhelming. For a blind person, that just doesn’t happen, as the brain is used to processing this sort of information. Simply stated, their internal model of the world is simpler and more resilient to malfunctions.

“In simple terms, we argue that when people cannot see from birth, they rely more heavily on the context they extract from the other senses,” the researchers write. They also add that this can also explain the
relationship between later visual loss and other psychotic
symptoms, as well as the effects of visual deprivation and
hallucinogenic drugs on psychosis and schizophrenia.

While this is still somewhat speculative, this hypothesis would explain the effect. If this is true, then it would mean that congenitally blind people have overall lower psychosis susceptibility than the sighted population. There are also ways to test this, researchers say.

Congenitally blind individuals will show fMRI prediction error responses during causal learning, unlike people with psychosis whose prediction error is aberrant. In addition, they will experience reduced psychoactive effects from drugs such as ketamine

The study has been published in Schizophrenia Bulletin.

Credit: Public Domain.

Targeted cognitive training improves symptoms in patients with severe schizophrenia

Credit: Public Domain.

Credit: Public Domain.

Living with schizophrenia can be a real struggle. Treating the mental disorder is no piece of cake either, especially when 50% of schizophrenia patients don’t actually believe they are sick (it’s one of the symptoms). This is why a new study may be particularly important in this context.

Researchers at the University of California San Diego found that targeted cognitive training (TCT) improved auditory and verbal outcomes among the most difficult of schizophrenia patients. Previously, this kind of therapy was shown to be effective in mild to moderate forms of schizophrenia, but it was unclear whether the most severe cases would benefit from the therapy.

TCT uses sophisticated brain grames and other interactive exercises on a computer or virtual reality simulation in order to target specific neural pathways, such as memory, learning, and auditory-based senses.

“Chronic, treatment-refractory patients mandated to locked residential care facilities make up just a small subgroup of persons with schizophrenia, but they consume a disproportionately large share of mental health care resources,” Gregory A. Light, professor of psychiatry at UC San Diego School of Medicine, said in a statement. “Finding an effective therapy for them is critical.”

The researchers recruited 46 patients with acute symptoms of schizophrenia — the kind that is very difficult to treat because they often don’t respond to therapy and do not cooperate with caretakers. The participants were randomized to either standard psychiatric treatment or standard treatment plus TCT.

Those who completed three months of TCT improved their verbal learning and auditory perception scores, and had fewer episodes of auditory hallucinations.

“These findings indicate that even highly symptomatic, functionally
disabled patients with chronic illness benefit from this emerging treatment.,” the authors wrote in the journal Schizophrenia Research

Most severe cases of schizophrenia involved auditory hallucinations — internal words or noises that have no real origin in the outside world and are perceived to be separate from the person’s mental processes. The voice — sometimes multiple voices — sound like whispering or murmuring and may seem angry or urgent. Often, the voices are demanding of the hallucinating person.

“Our results suggest that chronically ill, highly disabled patients can benefit from TCT,” said Light. “That contradicts current assumptions.”

Computers: the therapists of the future for mental disorders

There has been much progress in the past two decades as far as understanding schizophrenia goes. However, treatment outcomes and standard therapy targetting the disorder have only improved marginally because schizophrenia is extremely complex and challenging to treat.

Research such as this shows that cognitive training may soon become an important part of schizophrenia treatment. Therapists, such as those you can find on BetterHelp, may want to look closely into this.

Previously, other studies showed that playing a simple computer game relaxed the part of the brain responsible for verbal communication, thus reducing hallucinations. Another study showed that voices could be silenced when schizophrenic patients interacted with an ‘avatar’ — a digital rendition of the imaginary person responsible for the auditory hallucinations.

“We’re somewhere between the Wild West and golden age of cognitive training for schizophrenia patients. There is much still to be learned and done,” Light said.  “We need to do a lot more research.”

Schizophrenia patients can calm down their brain by playing a computer game

In an innovative pilot, researchers have shown that using a computer game can help patients relax the part of the brain responsible for verbal communication, thus reducing hallucinations.

Participants had to land a rocket by controlling their brain. Credits: King’s College London.

The study involved 12 patients, all of which had near-daily hallucinatory events. They were asked to play a simple computer game while their brains were hooked to an fMRI focusing on an area called the auditory cortex, which is sensitive to speech and human voices.

The patients were able to monitor their own activity in the auditory cortex and in turn, this activity was represented by a computerized space rocket. They were instructed to safely land the rocket but were not given any additional instructions. Instead, they had to come up with their own strategies.

Essentially, through the game, they were learning to control their own symptoms. Dr. Natasza Orlov, from King’s College London, lead author of the study, said:

“The patients know when the voices are about to start – they can feel it, so we want them to immediately put this aid into effect to lessen them, or stop the voices completely.”

The auditory cortex (in yellow). Credits: King’s College London.

After four sessions, patients were able to handle the symptoms much better. The hallucinatory voices had become much more internalized, which means that they were more manageable and less stressful. Patients were also able to take the strategies they developed for the study and bring them back to their day to day life. In other words, the patients gained a long-term ability to control their brains and significantly reduce the impact of schizophrenic hallucinations.

Corresponding author Paul Allen added:

“The results of this pilot are astonishing as almost everyone in the patient group was able to control the space rocket, successfully bringing the rocket in the game back down to the ground. What this means is that by using this technique, patients learnt to control brain activity in the area of the brain that responds to voices – an area we know is hyperactive in people whom experience auditory verbal hallucinations.”

It isn’t the first study to conclude something like this. In November last year, a study found that people also gained similar abilities by confronting an avatar on a computer screen. Two years ago, a different review also reported that computer games can be used to improve cognitive function in schizophrenia patients.

The main downside of this study is its small sample size. Researchers plan on confirming the findings in a much broader study.

“Although the study sample size is small and we lacked a control group, these results are promising. We are now planning to conduct a randomised controlled study to test this technique in a larger sample,” Orlov concluded.

Journal Reference: Natasza D. Orlov et al. Real-time fMRI neurofeedback to down-regulate superior temporal gyrus activity in patients with schizophrenia and auditory hallucinations: a proof-of-concept study.

Credit: Youtube.

Digital avatars for schizophrenic auditory hallucinations make the voices go away

If you can’t beat them, join them. This is the crux of a novel therapeutic approach in which psychiatrists took over digital avatars of a schizophrenic patient’s auditory hallucinations — the ‘voice’ in their heads. Instead of a dominant and hostile imaginary antagonist, the patients were now greeted by a reconciling voice, controlled by the therapist, which helped them feel less persecuted. Remarkably, some participants stopped hearing voices entirely.

A face for the persecuting voice

Credit: Youtube.

Credit: Youtube.

The most common type of auditory hallucinations in psychiatric illnesses consists of voices. Voices may be male or female, and with intonations and accents that typically differ from those of the patient. Studies suggest that about half of schizophrenia patients experience auditory hallucinations consisting of a voice which comments on or discusses the individual’s behavior, and which usually refer to the patient in the third person.

While what the voices say can vary between individuals, most often it’s negative and malicious. The voices speak in a derogatory and insulting manner, sometimes commanding the patient to perform unacceptable behavior. This causes great distress in the patient. Roughly a quarter of people with such psychotic conditions don’t respond to treatment.

The AVATAR

Audio Visual Assisted Therapy Aid for Refractory, or AVATAR for short, was first tested between 2009 and 2011 by researchers at the National Institute for Health Research, UK. Patients had to create a visual representation of the source of their perceived auditory hallucinations — a face for the “persecutor”, as they imagined it must look like. Researchers also created a voice for the avatar that closely matched the pitch and tone of the persecutor.

The therapist, who switches between speaking as a ‘therapist’ and as the ‘avatar’, facilitates a dialogue between the two, helping the patient gain more power and control. The seemingly omnipotent voice gradually loses its grip over the patient since it now sounds conciliatory rather than hostile.

The pilot trial proved successful beyond expectations, with patients undergoing AVATAR therapy showing a significant reduction in auditory hallucinations across multiple standard scores, whereas the control group experienced no change.

A participant in the trial created this avatar. Credit: King’s College London.

One of the participants created this avatar. Credit: King’s College London.

Scientists think the therapy mainly works its magic in two ways. First and foremost, AVATAR is a desensitization therapy which allows patients to feel less frightened by their voices since these now have a face. Secondly, AVATAR can boost self-esteem by helping some participants confront real trauma in cases when that’s the source of their persecuting auditory hallucinations.

“Voices often echoed earlier lived experience of humiliation and abuse,” Tom Craig, a professor at King’s College London and the study’s lead author, told The Smithsonian. “The conversation with the avatar, that was chosen to represent these former bullies or abusers, allowed the person to say things to the avatar that they were never able to say to the person at the time, to correct misconceptions and to demonstrate positive aspects of themselves.”

Now, researchers report in The Lancet replicating the results across a much larger, randomized controlled trial. The psychiatrists at King’s College London enlisted 150 patients, aged 18 to 65, who had endured auditory verbal hallucinations during the previous 12 months, despite continued treatment. The patients were divided into two equal groups: one to receive AVATAR therapy, the other to receive supportive counseling.

About 83% of the participants from the AVATAR group showed a reduction in auditory-verbal hallucinations after 12 weeks. In some cases, the voices stopped entirely. These are outstanding results, considering that many of the patients involved in the AVATAR group didn’t respond to regular supervision and pharmacological treatment.

“The participants were all people who had suffered for many years with troubling auditory hallucinations and all had diagnoses of major psychoses (schizophrenia spectrum disorders mainly, but also psychotic depression). The auditory hallucinations were just one symptom among the several that make up these diagnoses. All were taking medication,” the study’s lead author Tom K J Craig told MD Mag. “So using that to put AVATAR into perspective, I would say we have a promising add on treatment.”

Craig and colleagues stress that their study doesn’t mean AVATAR therapy should replace medication or a broader cognitive-behavioral treatment for psychosis. Instead, AVATAR could form an integral part of a wider therapy. Follow-up research will tell us more, showing whether or not these results can be replicated across different social and cultural settings. What’s more, both the AVATAR group and the control group showed no significant differences after six months. Perhaps the therapy needs to continue more for the therapeutic effects to last for a longer period of time.

Secondly, this kind of therapy might not be for everyone. Many participants involved in this trial said they were absolutely terrified by the experience. As such, for some people, this kind of therapy might end up doing more harm than good if the experience proves traumatizing.

“I found the avatar sessions intimidating at times,” says “Joe,” a 49-year-old participant, in an interview with researchers. “It was like bringing my voices out into the open. Sitting in front of a computer, which seemed to know my every thought. In some ways it allows me to share my experience, which can only be helpful.”

Schizophrenia is not a single disease but multiple genetically distinct disorders

Cloth embroidered by a schizophrenia sufferer. Image via Wiki Commons

A new study concluded that schizophrenia isn’t a single disease, but rather a group of eight genetically distinct disorders, each with its own set of symptoms, and likely, its own treatment. The study could be the first step in finally understanding the condition and how it can be dealt with.

Currently, schizophrenia is thought of as a complex mental disorder, often associated with abnormal social behavior and failure to recognize what is real. Common symptoms include false beliefs, unclear or confused thinking, auditory hallucinations, reduced social engagement and emotional expression, and inactivity. The main difficulty in treating it is the huge variety in symptoms. If we’d be dealing with eight distinct diseases as opposed to just one, that would make a lot more sense.

Igor Zwir, PhD, one of the senior investigators, helped match precise DNA variations in people with and without schizophrenia to symptoms in individual patients. Image: Robert Boston.

This recent study, conducted at the University of Washington concludes just that: distinct gene clusters that contribute to eight different classes of schizophrenia. They analyzed the genes of over 4,000 people with schizophrenia:

“Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.”

Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms; in total, they analyzed over 700,000 genetic places where changes had occurred. The results were pretty clear.

For example, patients with symptoms such as hallucinations or delusions had a different type of genetic modification than those with impaired speech and behavior. The first group genetic variations interacted to create a 95 percent certainty of schizophrenia, while in the second group, there was a 100 percent change of genetic interaction leading to schizophrenia.

“What we’ve done here, after a decade of frustration in the field of psychiatric genetics, is identify the way genes interact with each other, how the ‘orchestra’ is either harmonious and leads to health, or disorganized in ways that lead to distinct classes of schizophrenia,” Cloninger said.

Most individual genes can’t be associated with schizophrenia at all, but when you start to think at a larger scale and analyzed gene clusters, you end up with a certainty between 70 and 100 percent.

“In the past, scientists had been looking for associations between individual genes and schizophrenia,” explained Dragan Svrakic, PhD, MD, a co-investigator and a professor of psychiatry at Washington University. “When one study would identify an association, no one else could replicate it. What was missing was the idea that these genes don’t act independently. They work in concert to disrupt the brain’s structure and function, and that results in the illness.”

By identifying different groups of genetic variation and classifying them in a genetic database, we can enter a new age of schizophrenia treatment, directly treating the pathogens which cause schizophrenia in the first place.

Journal Reference: Arnedo J, Svrakic DM, del Val C, Romero-Zaliz R, Hernandez-Cuervo H, Fanous AH, Pato MT, Pato CN, de Erausquin GA, Cloninger CR, Zwir I. Uncovering the hidden risk architecture of the schizophrenias: Confirmation in three independent genome-wide association studies. The American Journal of Psychiatry. vol. 172 (2), 2014. Published online Sept. 15, 2014. www.ajp.psychiatryonline.org

Heavy marijuana use causes poor memory and abnormal brain structure, study concludes

We’ve written a number of times about the advantages that cannabinoids can bring – how they can become effective pain killers even without the high, how they don’t harm the lungs when smoked, and many more. But marijuana is definitely not a substance you want to abuse, just like tobacco and alcohol. In many cases, it can prolong and spread pain, and when consumed in significant quantities, on a regular basis, it has important negative effects on the brain.

Photo by Dean J. Koepfler/Tacoma News Tribune/MCT via Getty Images.

Teenagers and youngsters who smoked marijuana daily (or several times a week) for three years or more performed poorly on memory tasks and showed abnormal changes in their brain structure, according to a Northwestern Medicine study. Furthermore, the brain abnormalities were observed 2 years after the individuals stopped smoking, apparently indicating long lasting, chronic effects of smoking marijuana. Memory-related structures in their brains appeared to have a strange development shrinking and collapsing inward, potentially indicating a decrease in neurons and/or neural paths.

“The study links the chronic use of marijuana to these concerning brain abnormalities that appear to last for at least a few years after people stop using it,” said lead study author Matthew Smith, an assistant research professor in psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. “With the movement to decriminalize marijuana, we need more research to understand its effect on the brain.”

The study also highlighted the similar poor memory performance in marijuana smokers and schizophrenics. This isn’t to say that they experience the same symptoms or anything like this, just that there are similarities in terms of memory performance; the point they make here is that since both the substance and schizophrenia affect the same areas of the brain, people suffering from this disease should really avoid smoking weed.

The main downside of this study, as I see it, is that it only analyzes a single point in time. Sure, it seems to indicate long lasting (if not permanent) damage to the brain caused by marijuana, but a study with a bigger time frame is needed in order to better understand the effects of the substance on the brain. This study is one of the first to analyze these effects on the deep regions in the brain, and it is actually the first one to focus on the working memory.

“A tremendous amount of addiction research has focused on brain regions traditionally connected with reward/aversion function, and thus motivation,” noted co-senior study author Hans Breiter, M.D., professor of psychiatry and behavioral sciences and director of the Warren Wright Adolescent Center at Feinberg and Northwestern Memorial. “This study very nicely extends the set of regions of concern to include those involved with working memory and higher level cognitive functions necessary for how well you organize your life and can work in society.”

Personally, I wish both the positive and the negative effects of marijuana would have been studied long ago, but sadly, this is very hard to do for scientists from a legislative point of view… for whatever reason.

Via Northwestern University.

A mouse brain's motor cortex shows a subset of neurons, labeled in orange, that have long axons extending to the auditory cortex. These neurons convey movement-related signals that can alter hearing. Blue dots in the background show brain cells that do not send axons to the auditory cortex. (Credit: Richard Mooney Lab, Duke University.)

Brain circuit that silences the voice inside your head discovered

Every time we’re engaged in a certain action, the sounds we produce while walking, eating, even playing music are tuned down a notch in volume by the brain. For instance, during a conversation your voice will be perceived as quieter than it actually is in reality, since our brain want to receive clearer  the information relayed by the other person. This mechanism is a very important function of the brain, since this distinguishing between the sounds we make and those coming from our environment is paramount to anything from learning how to speak, to survival (is that sound made by me or some predator lurking in the dark?). Recently, scientists at Duke University made a big breakthrough after they uncovered the brain circuitry that governs this ability of the brain. The findings are important since they might help in the future explain how a malfunction in this motor-auditory system interplay causes psychotic diseases, like schizophrenia.

“Our finding is important because it provides the blueprint for understanding how the brain communicates with itself, and how that communication can break down to cause disease,” said Richard Mooney, Ph.D., senior author of the study and professor of neurobiology at Duke University School of Medicine. “Normally, motor regions would warn auditory regions that they are making a command to speak, so be prepared for a sound. But in psychosis, you can no longer distinguish between the activity in your motor system and somebody else’s, and you think the sounds coming from within your own brain are external.”

A mouse brain's motor cortex shows a subset of neurons, labeled in orange, that have long axons extending to the auditory cortex. These neurons convey movement-related signals that can alter hearing. Blue dots in the background show brain cells that do not send axons to the auditory cortex. (Credit: Richard Mooney Lab, Duke University.)

A mouse brain’s motor cortex shows a subset of neurons, labeled in orange, that have long axons extending to the auditory cortex. These neurons convey movement-related signals that can alter hearing. Blue dots in the background show brain cells that do not send axons to the auditory cortex. (Credit: Richard Mooney Lab, Duke University.)

For a long time, the researchers hypothesized that the same neuronal circuitry used to convey movement (stroke a piano key, pick up an item etc) is shared by the wiring that senses sound. The exact nerve cells that provide this function, however, remained unknown until recently. Mooney and colleagues used a Duke University patented technology to  trace all of the inputs into the auditory cortex — the sound-interpreting region of the brain. A number of regions of the brain feed information into the auditory cortex, but the researchers focused their attention on the secondary motor cortex (M2), responsible for relaying motor signals directly into the brain stem and spinal cord.

“That suggests these neurons are providing a copy of the motor command directly to the auditory system,” said David M. Schneider, Ph.D., co-lead author of the study and a postdoctoral fellow in Mooney’s lab. “In other words,they send a signal that says ‘˜move’€™ but they also send a signal to the auditory system saying ‘I am going to move.'”

The brain, sick of hearing itself all the time

It’s basically prepping the brain that the body is going to perform an action, in order to distinguish between sounds. To better understand how this connection works, the researchers cut slices of mice brain and  specifically manipulated the neurons that led from the M2 region to the auditory cortex. Stimulating neurons from this specific regions dampened the activity of the auditory cortex.

“It jibed nicely with our expectations,” said Anders Nelson, co-lead author of the study and a graduate student in Mooney’s lab. “It is the brain’s way of muting or suppressing the sounds that come from our own actions.”

Finally, the researchers tested this circuitry in live animals, artificially turning on the motor neurons in anesthetized mice and then looking to see how the auditory cortex responded. Mice usually sing to each other through a kind of song called ultrasonic vocalizations, which are too high-pitched for a human to hear. The researchers played back these ultrasonic vocalizations to the mice after they had activated the motor cortex and found that the neurons became much less responsive to the sounds.

“It appears that the functional role that these neurons play on hearing is they make sounds we generate seem quieter,” said Mooney. “The question we now want to know is if this is the mechanism that is being used when an animal is actually moving. That is the missing link, and the subject of our ongoing experiments.”

These preliminary findings have uncovered only the basic interplay between the motor and auditory cortex. The next step in the researchers’ work is testing whether altering this circuitry could induce auditory hallucinations or perhaps even take them away in models of schizophrenia.

Findings appeared in The Journal of Neuroscience.

King’s College London’s Institute of Psychiatry (IoP)

Avatar therapy shows great promise in silencing voices in schizophrenics

We’ve written a great deal about schizophrenia in the past, mostly reports about new theories pertaining to the development of the disease or new types of pharmacological treatments. A great deal of interest and efforts are being invested in battling this severe psychological disorder, since it affects so many people (as many as 1 in 100) and its effects make living a normal life nearly impossible. A new alternate therapy was recently reported, with great promise that it might help countless people suffering from the disease, that assigns  avatars to the patients’ tormenting voices. Results so far are looking great, and large scale implementation is scheduled to run shortly.

King’s College London’s Institute of Psychiatry (IoP)

Avatars created by patients in the pilot study. (c) King’s College London’s Institute of Psychiatry (IoP)

The most common symptoms of schizophrenia  are delusions (false beliefs) and auditory hallucinations (hearing voices). The latter are simply devastating, making it impossible for the diseased to concentrate, work or have healthy relationships. Basically, schizophrenia turns you into one big nutcase. To silence voices in peoples head, existing therapy relies on medication, “talking therapy” or a combination of both. Even with the most effective anti-psychotic medication, around one in four people with schizophrenia continue to suffer from persecutory auditory hallucinations, severely impairing their ability to concentrate.

Researchers at King’s College London have developed a novel system that battles the voices inside the schizophrenic diseased individual by creating avatars of these voices so that they may be confronted more easily. Through the computer-based system, people design  computer-based avatar, by choosing the face and voice of the entity they believe is talking to them. The computer then synchronises the avatar’s lips with its speech, enabling a therapist to speak to the patient through the avatar in real time. The therapist encourages the patient to oppose the voice and gradually teaches them to take control of their hallucinations.

“Auditory hallucinations are a very distressing experience that can be extremely difficult to treat successfully, blighting patients’ lives for many years.  I am delighted to be leading the group that will carry out a rigorous randomised study of this intriguing new therapy with 142 people who have experienced distressing voices for many years.

“The beauty of the therapy is its simplicity and brevity. Most other psychological therapies for these conditions are costly and take many months to deliver. If we show that this treatment is effective, we expect it could be widely available in the UK within just a couple of years as the basic technology is well developed and many mental health professionals already have the basic therapy skills that are needed to deliver it.”

An early pilot therapy was conducted with 16 patients using this novel method, most of whom reported dramatic improvements in suppressing the nagging voices inside their heads. Three of the patients stopped hearing voices completely after experiencing  auditory hallucinations for 16, 13 and 3.5 years, respectively.

Professor Julian Leff,  Emeritus Professor, UCL Mental Health Sciences, said: “Even though patients interact with the avatar as though it was a real person, because they have created it, they know that it cannot harm them, as opposed to the voices, which often threaten to kill or harm them and their family. As a result the therapy helps patients gain the confidence and courage to confront the avatar, and their persecutor.

“We record every therapy session on MP3 so that the patient essentially has a therapist in their pocket which they can listen to at any time when harassed by the voices. We’ve found that this helps them to recognise that the voices originate within their own mind and reinforces their control over the hallucinations.”

Its really inspiring to hear of a therapy with such promising results that doesn’t rely on medication, which in my book should be the last course of action. The larger-scale study at the IoP will begin enrolling the first patients in early July. The team are currently training the therapists and research staff to deliver the avatar therapy and finalising the study set-up. The first results of this larger study are expected towards the end of 2015.

source: UCL

Roles of Neuregulin 1 in neural development. NRG1 is released from neurons to promote the formation and maintenance of radial glial cells. Tangential migration of γ-aminobutyric acid-ergic interneurons requires NRG1 in the cortical region. Myelination and ensheathment of peripheral nerves are controlled by the amounts of NRG1 produced in substrate axons. NRG1 from axons might regulate oligodendrocyte development and myelination of axons in the CNS. NRG1 is also necessary for the formation of neuromuscular junctions – NMJs. NRG1 stimulates CNS synapse formation (Lin Mei & Wen-Cheng Xiong, 2008)

Schizophrenia symptoms canceled in mice after gene therapy

A group of international researchers may have reached a breakthrough moment after they successfully eliminated schizophrenia symptoms in mice after they targeted a specific gene and manipulated its expression. Their findings offer hope that similar results might be possible for humans as well.

Despite schizophrenia being well documented for many years now and it being a somewhat prevailing mental disorder,  schizophrenia continues to confound both health professionals and the public. The hallucinations, peculiar ideas and extremely odd behavior people suffering from schizophrenia exhibit never cease to baffle those of us like to consider themselves normal. In the middle ages, people suffering from the disease were though to be possessed by demons and because of this they were quickly marginalized, tortured, exiled or worse…

Currently, schizophrenia isn’t curable and those suffering from it are forced to live with it for the rest of their days. Treatment exists, of course, which battles one or multiple symptoms. However, while medication helps control the psychosis associated with schizophrenia (e.g., the delusions and hallucinations), it cannot help the person find a job, learn to be effective in social relationships, increase the individual’s coping skills, and help them learn to communicate and work well with others. This is one nasty mental disorder, make no mistake, and scientists have been trying to find means of effectively combating it for many years.

Roles of Neuregulin 1 in neural development. NRG1 is released from neurons to promote the formation and maintenance of radial glial cells. Tangential migration of γ-aminobutyric acid-ergic interneurons requires NRG1 in the cortical region. Myelination and ensheathment of peripheral nerves are controlled by the amounts of NRG1 produced in substrate axons. NRG1 from axons might regulate oligodendrocyte development and myelination of axons in the CNS. NRG1 is also necessary for the formation of neuromuscular junctions – NMJs. NRG1 stimulates CNS synapse formation (Lin Mei & Wen-Cheng Xiong, 2008)

Roles of Neuregulin 1 in neural development. NRG1 is released from neurons to promote the formation and maintenance of radial glial cells. Tangential migration of γ-aminobutyric acid-ergic interneurons requires NRG1 in the cortical region. Myelination and ensheathment of peripheral nerves are controlled by the amounts of NRG1 produced in substrate axons. NRG1 from axons might regulate oligodendrocyte development and myelination of axons in the CNS. NRG1 is also necessary for the formation of neuromuscular junctions – NMJs. NRG1 stimulates CNS synapse formation (Lin Mei & Wen-Cheng Xiong, 2008)

One of the most recent such attempts shines with promise that schizophrenia might be dramatically alleviated, after a team of international researchers reversed schizophrenia-like symptoms in adult mice by restoring normal expression to a gene called Neuregulin-1 (NRG1 for short). The protein is important for brain development, however previous studies have shown that there seem to be a direct correlation between high levels of NRG1 and schizophrenia.

One might ask how does one diagnose a mouse with schizophrenia? Does it think it’s a cat or a dog? Does it start barking? Well, jokes aside, after the scientists bio-engineered mice which expressed higher levels of NRG1, the mice exhibited uncanny schizophrenia characteristics: hyperactivity, poor short-term and long-term memory, poor ability to ignore distracting background or white noise. When they returned NRG1 levels to normal in adult mice, the schizophrenia-like symptoms went away.

Like patients with schizophrenia, adult mice biogenetically-engineered to have higher NRG1 levels showed reduced activity of the brain messenger chemicals glutamate and γ-aminobutyric acid (GABA). The mice also showed behaviors related to aspects of the human illness. To genetically alter the mice, the scientists put a copy of the NRG1 gene into mouse DNA then, to make sure they could control the levels, they put in front of the DNA a binding protein for doxycycline, a stable analogue for the antibiotic tetracycline, which is infamous for staining the teeth of fetuses and babies. The mice are born expressing high levels of NRG1 and giving the antibiotic restores normal levels.

With this in mind, it might be possible for schizophrenia symptoms in humans to be alleviated as well by reducing the expression of the NRG1 gene. Findings were reported in the journal Neuron [source].

Yoga helps reduce symptoms of most major psychiatric diseases

It’s a well known fact that yoga does good to the mind and body, but the extent of that benefit is something still debated. Now, yoga supporters have just gotten a big hand from a study conducted by psychiatrists.

yoga

“Yoga has also become such a cultural phenomenon that it has become difficult for physicians and consumers to differentiate legitimate claims from hype,” researchers from Duke University Medical Center write in their study, published in the journal Frontiers in Psychiatry.

In order to find out what are the facts and what is fiction, they reviewed over 100 studies analyzing yoga effects on the body and mind.

“Most individuals already know that yoga produces some kind of a calming effect. Individually, people feel better after doing the physical exercise,” says lead study author Dr. P. Murali Doraiswamy, a professor of psychiatry and medicine at Duke University Medical Center. “Mentally, people feel calmer, sharper, maybe more content. We thought it’s time to see if we could pull all [the literature] together … to see if there’s enough evidence that the benefits individual people notice can be used to help people with mental illness.”

Ok, so the first thing that struck out was that yoga greatly helps in relatively mild conditions, such as a mild depression, sleep disorders, ADHD, etc. But then, after digging up more and more conclusions, researchers were surprised to see that even with severe diseases such as schizophrenia yoga does patients a great deal of good. In fact, they found positive effects of the mind-and-body practice for all conditions with the exception of eating disorders and cognition.

What’s interesting is that not only did it help improve the condition of medicated patients, but it also greatly improved the state of patients who weren’t taking any meds, suggesting that yoga might affect the body in ways similar to antidepressants and psychotherapy.

schizophrenia yoga

Incorporating yoga as a complementary treatment for mental disorders is not uncommon, and judging by the effects of yoga on mental health, the technique should be implemented in even more treatments.

“Many millions of Americans are doing yoga and many millions of Americans have mental illnesses and are popping psychiatric pills daily. Despite all of this, the vast majority of studies looking at the benefits of yoga are all small studies. We did not come across a single study where there was a coordinated effort done by some large agency to really conduct a large national study,” says Doraiswamy.

However, warn researchers, yoga isn’t a panacea for mental illness, and patients shouldn’t try to replace their treatment with yoga. This should be used only as complementary.

“What we are saying is that we still need to do further, large-scale studies before we are ready to conclude that people with mental illnesses can turn to yoga as a first-line treatment,” says Doraiswamy. ”We are not saying throw away your Prozac and turn to yoga. We’re saying it has the promise and potential. If a large national study were done, it could turn out that yoga is just as good and may be a low cost alternative to people with unmet needs.”

In the meantime, one thing’s for sure: adding yoda as a complement to your treatment, and starting it even if you’re not suffering from any condition is not doing to hurt you – seriously.

A fold in the brain is all that separates reality from imagination

Among your memory’s biggest challenges is remembering what actually happened, versus what you imagined – that’s especially hard with some people I know. That ability, according to a new study, is linked to the presence of a small fold; even more interesting, some people have and some people don’t have this fold – a finding that could help researchers better understand how memory works, as well as treat diseases such as schizophrenia, where the line between reality and imagination is blurred out.

Researchers used MRI scans to look into the brains of a large number of adults; in particular, they looked for the paracingulate sulcus (PCS), a fold located on the front of the brain. There’s a lot of variability in this fold in different people: some have it clearly marked out and distinctive, while in others it is just barely visible.

The participants in the study saw well-known word pairs (“Jekyll and Hyde”) and some half pairs (“Jekyll and ?”). If they only saw a half of pair, they were asked to imagine the other halfAfter each pair or half pair, either the participant or the experimenter said the whole pair aloud. After they saw all the pairs, they were asked some questions, such as ‘Did you see both words of the pair, or just one?’, and the people who didn’t have a clear fold did worse on both questions – remembering if something was real or imgaginary , but they felt just as confident as their counterparts. This is consistent with other studies, which have shown that people with schizophrenia frequently have smaller or no PCS, suggesting a connection between this structure and keeping track of reality.

However, the study only shows clearly that PCS and reality monitoring are linked, not that its absence (for example) meant the total lack of such a capacity. Still, future studies in this direction will definitely point out exactly how tight this bond is.

Via 80 Beats

Scientists give computers schizophrenia to better understand the human brain

Researchers from the University of Texas and Yale infected a computer with schizophrenia in order to find out more about how the human brain behaves and understands things.

Human behaviour from a computer

Computers can show some signs of virtual schizophrenia too, if they can’t ‘forget’ fast enough. So researchers used a virtual computer model, which is also called a ‘neural network’, to simulate the excessive release of dopamine in the brain. The dopamine hypothesis of schizophrenia is a model attributing symptoms of schizophrenia to an increased and unnatural level of dopamine production. They found that the network recalls memories in a distinctly schizophrenic-like fashion.

“The hypothesis is that dopamine encodes the importance-the salience-of experience,” says Uli Grasemann, a graduate student in the Department of Computer Science at The University of Texas at Austin. “When there’s too much dopamine, it leads to exaggerated salience, and the brain ends up learning from things that it shouldn’t be learning from.”

Too much is too much

The results they got sustain the idea that in some people who learn too many things, the brain can lose the ability to forget and ignore as much as it would normally do. Without forgetting to ignore what’s unimportant, the brain would also lack the ability to extract what’s important from the immensity of stimuli that it would receive. Basically, these people start getting lost in a sea of connections, and start making ones that aren’t real, as well as not understanding the ones that are.

This is one of the big theories regarding the development of schizophrenia, and the study could give some valuable directions in understanding, and eventually preventing and treating the disease.

A neural model

They model they used is called DISCERN. It was designed by Professor Risto Miikkulainen, and it is able to do a variety of things, including learning a real language. In this study, DISCERN was used to simulate what happens to language as the result of eight different types of neurological dysfunction. After this, the results were in the hand of Yale professor Ralph Hoffman, professor of psychiatry, who compared them with what he saw when studying schizophreniacs.

“With neural networks, you basically train them by showing them examples, over and over and over again,” says Grasemann. “Every time you show it an example, you say, if this is the input, then this should be your output, and if this is the input, then that should be your output. You do it again and again thousands of times, and every time it adjusts a little bit more towards doing what you want. In the end, if you do it enough, the network has learned.”

In order to modelate the hyperlearning that was needed for this schizophrenia study, they ran the system again and again, but with one key parameter altered. They also increased the system’s learn rate, essentially by telling it to forget so much, thus simulating the excessive release of dopamine.

“It’s an important mechanism to be able to ignore things,” says Grasemann. “What we found is that if you crank up the learning rate in DISCERN high enough, it produces language abnormalities that suggest schizophrenia.”

Questions are still open

The parallel between the computer model and humans isn’t perfect, so this still isn’t definitive proof that the hyperlearning schizophrenia model is correct. However, it does support the hypothesis, and with computer models becoming better and better, scientists can hope to rely on them more and more, especially because you can have much more control over neural networks than you can have on humans.