Nicotine May Compensate for Brain Deficits in Schizophrenia

Regular use of nicotine may normalize brain activity impairments linked with schizophrenia, according to a study using a mouse model, published online in Nature Medicine. The finding may explain why up to 90% of people with schizophrenia smoke—most of them heavily.

“Basically the nicotine is compensating for a genetically determined impairment,” said researcher Jerry Stitzel, PhD, of the University of Colorado Boulder. “No one has ever shown that before.”

Dr. Stitzel is part of an international research team that investigated whether a variant in the CHRNA5 gene, which is believed to increase schizophrenia risk, is associated with a reduction of neural firing in the brain’s prefrontal cortex, or hypofrontality. Researchers also examined whether nicotine could interrupt the effect.

In mice with the CHRNA5 gene variant, brain images confirmed hypofrontality, researchers reported. Behavioral tests further revealed that the mice shared key characteristics of people with schizophrenia, such as an inability to suppress a startle response and aversion to social interaction. The findings, they explained, suggest the CHRNA5 gene variant plays a role in schizophrenia by causing hypofrontality.

Nicotine, however, seemed to reverse hypofrontality. When researchers gave the mice daily nicotine, their sluggish brain activity improved within 2 days. Within a week, it was normal.

Researchers believe the nicotine corrected the impaired brain activity by acting on nicotinic receptors in regions important for healthy cognitive function.

Noting that hypofrontality is also linked with addiction, attention deficit hyperactivity disorder, bipolar disorder, and other psychiatric conditions, researchers believe the discovery could lead to new nonaddictive, nicotine-based medications.

“This defines a completely novel strategy for medication development,” said lead author Uwe Maskos, PhD, of Institut Pasteur, Paris, France.

—Jolynn Tumolo


Koukouli F, Rooy M, Tziotis D, et al. Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nature Medicine. 2017 January 23;[Epub ahead of print].

Nicotine normalizes brain deficits key to schizophrenia [press release]. Boulder, CO: University of Colorado Boulder; January 23, 2017.

Taurine, a common additive to energy drinks, may help lessen the symptoms in first episode psychosis.

Supplementation with taurine, the additive found in many energy drinks, may improve the symptoms in young people suffering a first episode of psychosis (FEP), according to a new study presented at the International Early Psychosis Association (IEPA) meeting.

Taurine, an amino acid naturally occurring in the body, exhibits an inhibitory neuro-modulatory effect in the nervous system and also functions as a neuroprotective agent. The authors devised a study to analyze the efficacy of taurine supplementation in improving symptoms and cognition in patients with FEP.

The study included 86 individuals with FEP between the ages of 18 and 25 years. It was conducted by Dr. Colin O’Donnell, Donegal Mental Health Service, Co. Donegal, Ireland, and Professor Patrick McGorry and Dr. Kelly Allott, Orygen, The National Centre of Excellence in Youth Mental Health, Australia, and colleagues. Each participant was taking a low dose antipsychotic medication and was attending Orygen.

Forty-seven participants received 4g of taurine daily, while 39 received placebo. Symptoms were assessed Using the scoring system called BPRS (Brief Psychiatric Rating Scale) and cognition was assessed with the MCCB tool (MATRICS consensus cognitive battery).

Results showed that taurine significantly improved symptoms on the BPRS scale, in overall score and in psychosis specific analysis, however, there was no difference between the treatment and placebo group regarding cognition. Depression symptoms (rated by the Calgary Depression Scale for Schizophrenia) and general overall functioning also improved in the taurine group.

“The use of taurine warrants further investigation in larger randomised studies, particularly early in the course of psychosis,” concluded the authors, who themselves, are planning to conduct further studies into the potential benefits of taurine in the treatment of psychosis.

Small RNA identified that offers clues for quieting the “voices” of schizophrenia

St. Jude Children’s Research Hospital scientists have linked disruption of a brain circuit associated with schizophrenia to an age-related decline in levels of a single microRNA in one brain region

St. Jude Children’s Research Hospital scientists have identified a small RNA (microRNA) that may be essential to restoring normal function in a brain circuit associated with the “voices” and other hallucinations of schizophrenia. The microRNA provides a possible focus for antipsychotic drug development. The findings appear today in the journal Nature Medicine.

The work was done in a mouse model of a human disorder that is one of the genetic causes of schizophrenia. Building on previous St. Jude research, the results offer important new details about the molecular mechanism that disrupts the flow of information along a neural circuit connecting two brain regions involved in processing auditory information. The findings also provide clues about why psychotic symptoms of schizophrenia are often delayed until late adolescence or early adulthood.

“In 2014, we identified the specific circuit in the brain that is targeted by antipsychotic drugs. However, the existing antipsychotics also cause devastating side effects,” said corresponding author Stanislav Zakharenko, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. “In this study, we identified the microRNA that is a key player in disruption of that circuit and showed that depletion of the microRNA was necessary and sufficient to inhibit normal functioning of the circuit in the mouse models.

“We also found evidence suggesting that the microRNA, named miR-338-3p, could be targeted for development of a new class of antipsychotic drugs with fewer side effects.”

There are more than 2,000 microRNAs whose function is to silence expression of particular genes and regulate the supply of the corresponding proteins. Working in a mouse model of 22q11 deletion syndrome, researchers identified miR-338-3p as the microRNA that regulates production of the protein D2 dopamine receptor (Drd2), which is the prime target of antipsychotics.

Individuals with the deletion syndrome are at risk for behavior problems as children. Between 23 and 43 percent develop schizophrenia, a severe chronic disorder that affects thinking, memory and behavior. Researchers at St. Jude are studying schizophrenia and other brain disorders to improve understanding of how normal brains develop, which provides insights into the origins of diseases like cancer.

The scientists reported that Drd2 increased in the brain’s auditory thalamus when levels of the microRNA declined. Previous research from Zakharenko’s laboratory linked elevated levels of Drd2 in the auditory thalamus to brain-circuit disruptions in the mutant mice. Investigators also reported that the protein was elevated in the same brain region of individuals with schizophrenia, but not healthy adults.

Individuals with the deletion syndrome are missing part of chromosome 22, which leaves them with one rather than the normal two copies of more than 25 genes. The missing genes included Dgcr8, which facilitates production of microRNAs.

Working in mice, researchers have now linked the 22q11 deletion syndrome and deletion of a single Dgcr8 gene to age-related declines in miR-338-3p in the auditory thalamus. The decline was associated with an increase in Drd2 and reduced signaling in the circuit that links the thalamus and auditory cortex, a brain region implicated in auditory hallucination. Levels of miR-338-3p were lower in the thalamus of individuals with schizophrenia compared to individuals of the same age and sex without the diagnosis.

The miR-338-3p depletion did not disrupt other brain circuits in the mutant mice, and the findings offer a possible explanation. Researchers found that miR-338-3p levels were higher in the thalamus than in other brain regions. In addition, miR-338-3p was one of the most abundant microRNAs present in the thalamus.

Replenishing levels of the microRNA in the auditory thalamus of mutant mice reduced Drd2 protein and restored the circuit to normal functioning. That suggests that the microRNA could be the basis for a new class of antipsychotic drugs that act in a more targeted manner with fewer side effects. Antipsychotic drugs, which target Drd2, also restored circuit function.

The findings provide insight into the age-related delay in the onset of schizophrenia symptoms. Researchers noted that microRNA levels declined with age in all mice, but that mutant mice began with lower levels of miR-338-3p. “A minimum level of the microRNA may be necessary to prevent excessive production of the Drd2 that disrupts the circuit,” Zakharenko said. “While miR-338-3p levels decline as normal mice age, levels may remain above the threshold necessary to prevent overexpression of the protein. In contrast, the deletion syndrome may leave mice at risk for dropping below that threshold.”

The study’s first authors are Sungkun Chun, Fei Du and Joby Westmoreland, all formerly of St. Jude. The other authors are Seung Baek Han, Yong-Dong Wang, Donnie Eddins, Ildar Bayazitov, Prakash Devaraju, Jing Yu, Marcia Mellado Lagarde and Kara Anderson, all of St. Jude.

Cat ownership linked to schizophrenia and other mental illness

A pair of new studies links childhood cat ownership and infection with the parasite Toxoplasma gondii (T. gondii) with later onset schizophrenia and other mental illness. Researchers published their findings in the online Schizophrenia Research and Acta Psychiatrica Scandinavica.

In the Schizophrenia Research study, investigators compared two previous studies that suggested childhood cat ownership could be a possible risk factor for schizophrenia or another serious mental illness with a third, even earlier survey on mental health to see if the finding could be replicated.

“The results were the same,” researchers reported, “suggesting that cat ownership in childhood is significantly more common in families in which the child later becomes seriously mentally ill.”

If accurate, the researchers expect the culprit to be infection with T. gondii, a parasite commonly carried by cats. At this point, though, they are urging others to conduct further studies to clarify the apparent link between cat ownership and schizophrenia.

The Acta Psychiatrica Scandinavica study was a meta-analysis of 50 previously published studies to investigate the prevalence of t. gondii infection in people diagnosed with psychiatric disorders compared with healthy controls.

In cases of schizophrenia, researchers said evidence of an association with T. gondii was “overwhelming,” CBS News reported. Specifically, people infected with T. gondii were nearly twice as likely to be diagnosed with schizophrenia as people never infected with the parasite, according to the report.

The meta-analysis also suggested associations between T. gondii infection and bipolar disorder, obsessive-compulsive disorder, and addiction. No association, however, was found for major depression.

—Jolynn Tumolo


1. Fuller Torrey E, Simmons W, Yolken RH. Is childhood cat ownership a risk factor for schizophrenia later in life? Schizophrenia Research. 2015 April 18. [Epub ahead of print].

2. Sutterland AL, Fond G, Kuin A, et al. Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis. Acta Psychiatrica Scandinavica. 2015 April 15. [Epub ahead of print].

New discovery on brain chemistry of patients with schizophrenia and their relatives


People with schizophrenia have different levels of the neurotransmitters glutamate and gamma-aminobutyric acidergic (GABA) than healthy people do, and their relatives also have lower glutamate levels, according to a study published online in Biological Psychiatry.

Using magnetic resonance spectroscopy, researchers discovered reduced levels of glutamate — which promotes the firing of brain cells — in both patients with schizophrenia and healthy relatives. Patients also showed reduced levels of GABA, which inhibits neural firing. Healthy relatives, however, did not.

Researchers are unsure why healthy relatives with altered glutamate do not show symptoms of schizophrenia or how they maintain normal GABA levels despite a predisposition to the illness.

“This finding is what’s most exciting about our study,” said lead investigator Katharine Thakkar, PhD, assistant professor of clinical psychology at Michigan State University, East Lansing. “It hints at what kinds of things have to go wrong for someone to express this vulnerability toward schizophrenia. The study gives us more specific clues into what kinds of systems we want to tackle when we’re developing new treatments for this very devastating illness.”

The study included 21 patients with chronic schizophrenia, 23 healthy relatives of other people with schizophrenia not involved in the study, and 24 healthy nonrelatives who served as controls.

Many experts believe there are multiple risk factors for schizophrenia, including dopamine and glutamate-GABA imbalance. Drugs that regulate dopamine do not work for all patients with schizophrenia. Dr. Thakkar believes magnetic resonance spectroscopy may help clinicians target effective treatments for specific patients.

“There are likely different causes of the different symptoms and possibly different mechanisms of the illness across individuals,” said Dr. Thakkar.

“In the future, as this imaging technique becomes more refined, it could conceivably be used to guide individual treatment recommendations. That is, this technique might indicate that one individual would benefit more from treatment A and another individual would benefit more from treatment B, when these different treatments have different mechanisms of action.”

—Jolynn Tumolo


Thakkar KN, Rösler L, Wijnen JP, et al. 7T proton magnetic resonance spectroscopy of GABA, glutamate, and glutamine reveals altered concentrations in schizophrenia patients and healthy siblings [publisehd online ahead of print April 19, 2016]. Biological Psychiatry.
Study uncovers clue to deciphering schizophrenia [press release]. Washington, DC: EurekAlert!; June 7, 2016.

Computers can now accurately predict future development of schizophrenia based on how a person talks

A new study finds an algorithmic word analysis is flawless at determining whether a person will have a psychotic episode.


Although the language of thinking is deliberate—let me think, I have to do some thinking—the actual experience of having thoughts is often passive. Ideas pop up like dandelions; thoughts occur suddenly and escape without warning. People swim in and out of pools of thought in a way that can feel, paradoxically, mindless.

Most of the time, people don’t actively track the way one thought flows into the next. But in psychiatry, much attention is paid to such intricacies of thinking. For instance, disorganized thought, evidenced by disjointed patterns in speech, is considered a hallmark characteristic of schizophrenia. Several studies of at-risk youths have found that doctors are able to guess with impressive accuracy—the best predictive models hover around 79 percent—whether a person will develop psychosis based on tracking that person’s speech patterns in interviews.

A computer, it seems, can do better.

That’s according to a researchers at Columbia University, the New York State Psychiatric Institute, and the IBM T. J. Watson Research Center. They used an automated speech-analysis program to correctly differentiate—with 100-percent accuracy—between at-risk young people who developed psychosis over a two-and-a-half year period and those who did not. The computer model also outperformed other advanced screening technologies, like biomarkers from neuroimaging and EEG recordings of brain activity.

“In our study, we found that minimal semantic coherence—the flow of meaning from one sentence to the next—was characteristic of those young people at risk who later developed psychosis,” said Guillermo Cecchi, a biometaphorical-computing researcher for IBM Research, in an email. “It was not the average. What this means is that over 45 minutes of interviewing, these young people had at least one occasion of a jarring disruption in meaning from one sentence to the next. As an interviewer, if my mind wandered briefly, I might miss it. But a computer would pick it up.”

Researchers used an algorithm to root out such “jarring disruptions” in otherwise ordinary speech. Their semantic analysis measured coherence and two syntactic markers of speech complexity—including the length of a sentence and how many clauses it entailed. “When people speak, they can speak in short, simple sentences. Or they can speak in longer, more complex sentences, that have clauses added that further elaborate and describe the main idea,” Cecchi said. “The measures of complexity and coherence are separate and are not correlated with one another. However, simple syntax and semantic incoherence do tend to aggregate together in schizophrenia.”

Here’s an example of a sentence, provided by Cecchi and revised for patient confidentiality, from one of the study’s participants who later developed psychosis:

I was always into video games. I mean, I don’t feel the urge to do that with this, but it would be fun. You know, so the one block thing is okay. I kind of lied though and I’m nervous about going back.

While the researchers conclude that language processing appears to reveal “subtle, clinically relevant mental-state changes in emergent psychosis,” their work poses several outstanding questions. For one thing, their sample size of 34 patients was tiny. Researchers are planning to attempt to replicate their findings using transcripts from a larger cohort of at-risk youths.

They’re also working to contextualize what their findings might mean more broadly. “We know that thought disorder is an early core feature of schizophrenia evident before psychosis onset,” said Cheryl Corcoran, an assistant professor of clinical psychiatry at Columbia University. “The main question then is: What are the brain mechanisms underlying this abnormality in language? And how might we intervene to address it and possibly improve prognosis? Could we improve the concurrent language problems and function of children and teenagers at risk, and either prevent psychosis or at least modify its course?”

Intervention has long been the goal. And so far it has been an elusive one. Clinicians are already quite good at identifying people who are at increased risk of developing schizophrenia, but taking that one step farther and determining which of those people will actually end up having the illness remains a huge challenge.

“Better characterizing a behavioral component of schizophrenia may lead to a clearer understanding of the alterations to neural circuitry underlying the development of these symptoms,” said Gillinder Bedi, an assistant professor of clinical psychology at Columbia University. “If speech analyses could identify those people most likely to develop schizophrenia, this could allow for more targeted preventive treatment before the onset of psychosis, potentially delaying onset or reducing the severity of the symptoms which do develop.”

All this raises another question about the nature of human language. If the way a person speaks can be a window into how that person is thinking, and further, a means of assessing how they’re doing, which mechanisms of language are really most meaningful? It isn’t what you say, the aphorism goes, it’s how you say it. Actually, though, it’s both.

As Cecchi points out, the computer analysis at the center of the study didn’t include any acoustic features like intonation, cadence, volume—all characteristics which could be meaningful in interpreting a person’s pattern of speaking and, by extension, thinking. “There is a deeper limitation, related to our current understanding of language and how to measure the full extent of what is being expressed and communicated when people speak to each other, or write,” Cecchi said. “The discriminative features that we identified are still a very simplified description of language. Finally, while language provides a unique window into the mind, it is still just one aspect of human behavior and cannot fully substitute for a close observation and interaction with the patient.”

Viral and Bacterial Links to the Brain’s Decline

Herpes simplex viruses pass through the outer protein coat of a nucleus, magnified 40,000 times. Dr. Ruth Itzhak’s research published in 1997 revealed a potential link to the presence of HSV-1 (one specific variety of Herpes simplex) and the onset of Alzheimer’s in 60 percent of the cases they studied. However, she has only been able to study a low number of cases since the work has received only a cursory nod from the greater research world and little funding.

By Ed Cara

As recently as the 1970s, doctors stubbornly treated complaints of festering open sores in the stomach as a failing of diet or an inability to manage stress. Though we had long accepted the basic premise of Louis Pasteur’s germ theory—that flittering short bursts of disease and death are often caused by microscopic beings that could be stopped by sanitary food, water and specially crafted drugs—many researchers ardently resisted the idea that they could also trigger more complicated, chronic illnesses.

When it came to ulcers, no one believed that any microorganisms could endure in the acidic cauldron of our digestive system. It took the gumshoe work of Australian doctors and medical researchers Barry Marshall and Robin Warren in the 1980s to debunk that belief and discover the specific bug responsible for most chronic stomach ulcers, Helicobacter pylori. Marshall even went so far as to swallow the germ to prove the link was real and, obviously, became sick soon after. Thankfully, his self-sacrifice was eventually validated when he and Warren were awarded a Nobel Prize in 2005.

But while modern medicine has grown comfortable with the idea that even chronic physical ailments can be sparked by the living infinitesimal, there is an even bolder, more controversial proposition from a growing number of researchers. It’s the idea that certain germs, bugs and microbes can lie hidden in the body for decades, all the while slowly damaging our brains, even to the point of dementia, depression and schizophrenia.

In January 2016, a team led by Shawn Gale, an associate professor in psychology at Brigham Young University, looked at the infection history of 5,662 young to middle-aged adults alongside the results of tests intended to measure cognition. Gale’s rogues’ gallery included both parasites (the roundworm and Toxoplasma gondii ) and viruses (the hepatitis clan, cytomegalovirus, and herpes simplex virus Types 1 and 2). The team created an index of infectious disease —the more bugs a participant had been exposed to, the higher the person’s index score. It turned out that those with a higher score were more likely to have worse learning and memory skills, as well as slower information-processing speed than those with a lower score, even after controlling for other factors, like age, sex and financial status.

Aside from their shared ability to stay rooted inside us, the ways these pathogens might influence our noggins are as varied as their biology is from one another. Some, like T. gondii (often transmitted to humans via contaminated cats and infected dirt), can discreetly infest the brain and cause subtle changes to our brain chemistry, altering levels of neurotransmitters like dopamine while causing no overt signs of disease. Others, like hepatitis C, are suspected of hitching a ride onto infected white blood cells that cross the brain-blood barrier and, once inside, deplete our supply of white brain matter, the myelin-coated axons that help neurons communicate with each other and seem to actively shape how we learn. And still others, like H. pylori, could trigger a low-level but chronic inflammatory response that gradually wears down our body and mind alike.

Gale’s team found only fairly small deficits in cognition connected to infection. But other researchers, like Ruth Itzhaki, professor emeritus of molecular neurobiology at Britain’s University of Manchester, believe microbes may play an outsized role in one of the most devastating neurodegenerative disorders around: Alzheimer’s disease, which afflicted 47 million people worldwide in 2015. Last March, Itzhaki and a globe-spanning group of researchers penned an editorial in the Journal of Alzheimer’s Disease, imploring the scientific community to more seriously pursue a proposed link between Alzheimer’s and particular germs, namely herpes simplex virus Type 1 (HSV-1), Chlamydia pneumoniae and spirochetes—a diverse group of bacteria that include those responsible for syphilis and Lyme disease. The unusually direct plea, for scientists at least, was the culmination of decades of frustration.

“There’s great hostility to the microbial concept amongst certain influential people in the field, and they are the ones who usually determine whether or not one’s research grant application is successful,” says Itzhaki. “The irony is that they never provide scientific objections to the concepts—they just belittle them, so there’s nothing to rebut!”

It’s a frustration Itzhaki knows too well; in 1991, her lab published the first paper finding a clear HSV-1 link to Alzheimer’s. Since then, according to Itzhaki, over 100 published studies, from her lab and elsewhere, have been supportive of the same link. Nevertheless, Itzhaki says, the work has received only a cursory nod from the greater research world and little funding. Out of the $589 million allocated to Alzheimer’s research by the National Institutes of Health in 2015, exactly zero appeared to be spent on studying the proposed HSV-1 connection.

HSV-1 is more often known as the version of herpes that causes cold sores. Nearly all of us carry the virus from infancy; our peripheral nervous system serves as its dormant nesting ground. From there, HSV-1 can reactivate and occasionally cause mild flare-ups of disease, typically when our immune system is overwhelmed due to stress or other infections. Itzhaki’s lab, however, found that by the time we reach our golden years, the virus often migrates to the brain, where it remains capable of resurrecting itself and wreaking a new sort of havoc when opportunity presents, such as when our immune system wavers in old age.

Her team has also discovered the presence of HSV-1 in the telltale plaques—clumps of proteins in the nerve cells of the brain—used to diagnose Alzheimer’s. In mice and cell cultures infected with HSV-1, they’ve found accumulation of two proteins, beta-amyloid and tau, that form the main components of, respectively, plaques and tangles—twisted protein fibers that form inside dying cells and are another defining characteristic of Alzheimer’s. Plaques and tangles, while sometimes found in normal aging brains, have been found to overflow in the brains of deceased Alzheimer’s sufferers; neuroscientists believe these protein accumulations can cause neuron death and tissue loss. Itzhaki speculates that herpes-infected cells may either produce the proteins in an attempt to fend off HSV-1 or, because the virus itself commands them to, the proteins somehow needed to jump-start the virus’s replication.

Itzhaki, Gale and their colleagues emphasize that rather than being the sole cause of memory loss, slower reaction time or depression, viral and bacterial infections are likely just one ingredient in a soup of risk factors. But for Alzheimer’s, HSV-1 could be especially significant. Itzhaki has found that elderly people who carried both HSV-1 in the brain and the e-4 subtype of the APOE gene (responsible for creating a protein that helps transport cholesterol throughout the body) were 12 times more likely to develop Alzheimer’s than people without either.

APOE-e4, already considered a significant risk factor for Alzheimer’s and thought to make us more vulnerable to viral infection, has also been linked to a greater risk of dementia in HIV-infected patients. In a 1997 Lancet paper, Itzhaki’s group concluded that HSV-1 infection, in conjunction with APOE-e4, could account for about 60 percent of the Alzheimer’s cases they studied. Due to limited funds, however, her group was able to study only a relatively low number of cases.

“I think the proposed theory is certainly reasonable given the supporting evidence,” says Iain Campbell, a professor of molecular biology at the University of Sydney. “What is difficult to establish here is actual causality.”

It might be the case that HSV-1 and other suspects aren’t responsible for the emergence of Alzheimer’s but are simply given free rein to worsen its symptoms as the neurodegenerative disorder weakens both the immune and nervous systems. Deciphering the relationship between these latent infections and Alzheimer’s will take more dedicated research, an effort that Itzhaki feels has been stymied by the persistent lack of resources available to her and her like-minded colleagues.

As things stand, though, she believes there is enough evidence to go ahead with treatment trials; for instance, giving Alzheimer’s patients HSV-1-targeted antivirals in hopes of slowing down or stopping the progression of the disease. She and a team of clinicians are trying to obtain a grant for such a pilot clinical trial to do just that.

Exasperated as Itzhaki has been, the headwinds against her and those who share her beliefs about the brain are slowly dying down. In some cases, once-derided and obscure scientists studying how infections affect the brain are now getting some financial support. There’s Jaroslav Flegr, for example, who has for decades theorized that T. gondii could alter human behavior and even cause certain forms of schizophrenia. In the wake of increased media attention, Flegr’s volume of work on T. gondii has noticeably stepped up as well. From 2014 to 2015, he co-authored 13 papers on T. gondii, nearly twice the number he published the previous two years; the trend of increased T. gondii papers holds across all of PubMed, the largest database of published biomedical research available. “ I have no serious problem with funding of my Toxo research now,” Flegr says.

As of now, though, there have been no ulcer-related Sherlock moments to prove a link between mental dysfunction and latent infections—only indirect correlations clumping together to form a blurry snapshot of a potential crime scene. Which is why Gale and others recommend a wait-and-see approach for the public, even as they acknowledge the potentially vast implications of their research. “I wouldn’t want someone to go out tomorrow and get a whole battery of tests,” he says. “There’s still a lot we need to understand.”

New study may explain gene’s role in major psychiatric disorders

A new study shows the death of newborn brain cells may be linked to a genetic risk factor for five major psychiatric diseases, and at the same time shows a compound currently being developed for use in humans may have therapeutic value for these diseases by preventing the cells from dying.

In 2013, the largest genetic study of psychiatric illness to date implicated mutations in the gene called CACNA1C as a risk factor in five major forms of neuropsychiatric disease — schizophrenia, major depression, bipolar disorder, autism, and attention deficit hyperactivity disorder (ADHD). All the conditions also share the common clinical feature of high anxiety. By recognizing an overlap between several lines of research, scientists at the University of Iowa and Weill Cornell Medicine of Cornell University have now discovered a new and unexpected role for CACNA1C that may explain its association with these neuropsychiatric diseases and provide a new therapeutic target.

The new study, recently published in eNeuro, shows that loss of the CACNA1C gene from the forebrain of mice results in decreased survival of newborn neurons in the hippocampus, one of only two regions in the adult brain where new neurons are continually produced – a process known as neurogenesis. Death of these hippocampal neurons has been linked to a number of psychiatric conditions, including schizophrenia, depression, and anxiety.

“We have identified a new function for one of the most important genes in psychiatric illness,” says Andrew Pieper, MD, PhD, co-senior author of the study, professor of psychiatry at the UI Carver College of Medicine and a member of the Pappajohn Biomedical Institute at the UI. “It mediates survival of newborn neurons in the hippocampus, part of the brain that is important in learning and memory, mood and anxiety.”

Moreover, the scientists were able to restore normal neurogenesis in mice lacking the CACNA1C gene using a neuroprotective compound called P7C3-A20, which Pieper’s group discovered and which is currently under development as a potential therapy for neurodegenerative diseases. The finding suggests that the P7C3 compounds may also be of interest as potential therapies for these neuropsychiatric conditions, which affect millions of people worldwide and which often are difficult to treat.

Pieper’s co-lead author, Anjali Rajadhyaksha, associate professor of neuroscience in Pediatrics and the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine and director of the Weill Cornell Autism Research Program, studies the role of the Cav1.2 calcium channel encoded by the CACNA1C gene in reward pathways affected in various neuropsychiatric disorders.

“Genetic risk factors that can disrupt the development and function of brain circuits are believed to contribute to multiple neuropsychiatric disorders. Adult newborn neurons may serve a role in fine-tuning rewarding and environmental experiences, including social cognition, which are disrupted in disorders such as schizophrenia and autism spectrum disorders,” Rajadhyaksha says. “The findings of this study provide a direct link between the CACNA1C risk gene and a key cellular deficit, providing a clue into the potential neurobiological basis of CACNA1C-linked disease symptoms.”

Several years ago, Rajadhyaksha and Pieper created genetically altered mice that are missing the CACNA1C gene in the forebrain. The team discovered that the animals have very high anxiety.

“That was an exciting finding, because all of the neuropsychiatric diseases in which this gene is implicated are associated with symptoms of anxiety,” says Pieper who also holds appointments in the UI Departments of Neurology, Radiation Oncology, Molecular Physiology and Biophysics, the Holden Comprehensive Cancer Center, and the Iowa City VA Health Care System.

By studying neurogenesis in the mice, the research team has now shown that loss of the CACNA1C gene from the forebrain decreases the survival of newborn neurons in the hippocampus – only about half as many hippocampal neurons survive in mice without the gene compared to normal mice. Loss of CACNA1C also reduces production of BDNF, an important brain growth factor that supports neurogenesis.

The findings suggest that loss of the CACNA1C gene disrupts neurogenesis in the hippocampus by lowering the production of BDNF.

Pieper had previously shown that the “P7C3-class” of neuroprotective compounds bolsters neurogenesis in the hippocampus by protecting newborn neurons from cell death. When the team gave the P7C3-A20 compound to mice lacking the CACNA1C gene, neurogenesis was restored back to normal levels. Notably, the cells were protected despite the fact that BDNF levels remained abnormally low, demonstrating that P7C3-A20 bypasses the BDNF deficit and independently rescues hippocampal neurogenesis.

Pieper indicated the next step would be to determine if the P7C3-A20 compound could also ameliorate the anxiety symptoms in the mice. If that proves to be true, it would strengthen the idea that drugs based on this compound might be helpful in treating patients with major forms of psychiatric disease.

“CACNA1C is probably the most important genetic finding in psychiatry. It probably influences a number of psychiatric disorders, most convincingly, bipolar disorder and schizophrenia,” says Jimmy Potash, MD, professor and DEO of psychiatry at the UI who was not involved in the study. “Understanding how these genetic effects are manifested in the brain is among the most exciting challenges in psychiatric neuroscience right now.”

New research links subgroups of schizophrenia to specific visualized brain anomalies

An international team of researchers has linked specific symptoms of schizophrenia with various anatomical characteristics in the brain, according to research published in NeuroImage.

By analyzing the brain’s anatomy with magnetic resonance imaging (MRI), researchers from the University of Granada, Washington University in St. Louis, and the University of South Florida have demonstrated the existence of distinctive subgroups among patients with schizophrenia who suffer from different symptoms.

These findings could herald a significant step forward in diagnosing and treating schizophrenia.

To perform the study, the researchers conducted the MRI technique “diffusion tensor imaging” on 36 healthy participants and 47 schizophrenic participants.

The researchers found that tests on schizophrenic participants revealed various abnormalities in parts of the corpus callosum, a bundle of neural fibers that connects the left and right cerebral hemispheres and is essential for effective interhemispheric communication.

Different anomalies in the corpus callosum were associated with different symptoms in the schizophrenic participants. An anomaly in one part of the brain structure was associated with strange and disorganized behavior; another anomaly was associated with disorganized thought and speech, as well as negative symptoms such as a lack of emotion; and other anomalies were associated with hallucinations.

In 2014, this same research group proved that schizophrenia is not a single illness. The team demonstrated the existence of 8 genetically distinct disorders, each with its own symptoms. Igor Zwir, PhD, and Javier Arnedo from the University of Granada’s Department of Computer Technology and Artificial Intelligence found that different sets of genes were strongly linked with different clinical symptoms.

“The current study provides further evidence that schizophrenia is a heterogeneous group of disorders, as opposed to a single illness, as was previously thought to be case,” Dr Zwir said in a statement.

While current treatments for schizophrenia tend to be generic regardless of the symptoms exhibited by each patient, the researchers believe that in the future, analyzing how specific gene networks are linked to various brain features and specific symptoms will help develop treatments that are adapted to each patient’s individual disorder.

To conduct the analysis of the gene groups and brain scans, the researchers developed a new, complex analysis of the relationships between different types of data and recommendations regarding new data. The system is similar to that used by companies such as Netflix to determine what movies they want to broadcast.

“To conduct the research, we did not begin by studying individuals who had certain schizophrenic symptoms in order to determine whether they had the corresponding brain anomalies,” said Dr Zwir in a statement. “Instead, we first analyzed the data, and that’s how we discovered these patterns. This type of information, combined with data on the genetics of schizophrenia, will someday be of vital importance in helping doctors treat the disorders in a more precise and effective way.”

Arnedo J, Mamah D, Baranger DA, et al. Decomposition of brain diffusion imaging data uncovers latent schizophrenias with distinct patterns of white matter anisotropy. NeuroImage. 2015; doi:10.1016/j.neuroimage.2015.06.083.

Research uncovers genetic cause underlying schizophrenia

Excessive activity in complement component 4 (C4) genes linked to the development of schizophrenia may explain the excessive pruning and reduced number of synapses in the brains of patients with schizophrenia, according to a study published in Nature.

The study, co-funded by the Office of Genomics Research Coordination at the National Institute of Mental Health and the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts, analyzed various structurally diverse versions of the C4 gene.

Led by Steve McCarroll, PhD, of the Broad Institute of Harvard and MIT, researchers analyzed the genomes of 65 000 study participants and 700 postmortem brains, detecting a link between specific gene versions and the biological process that causes some cases of schizophrenia.

The team—including Beth Stevens, PhD; Michael Carroll, PhD; and Aswin Sekar, BBS— determined that C4 genes generate varying levels of C4A and C4B proteins; the more C4A found in a person, the higher his or her risk of developing schizophrenia. The researchers found that during critical periods of brain maturation, C4 identifies synapses for pruning. Overexpression of C4 results in higher amounts of C4A, which could cause excessive pruning during the late teens and early adulthood, “conspicuously corresponding to the age-of-onset of schizophrenia symptoms,” the researchers noted.

“It has been virtually impossible to model [schizophrenic] disorder in cells or animals,” said Dr McCarroll. “The human genome is providing a powerful new way into this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside, and starting to see actual biological mechanisms.”

Research suggests that future schizophrenia treatments may be developed to target and suppress excessive levels of pruning, halting a process that has the potential to develop into psychotic illness.


Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; doi: 10.1038/nature16549.