Posts tagged schizophrenia
Articles and news from the latest research reports.
What Is the Brain Telling Us About the Diagnoses of Schizophrenia and Bipolar Disorder?
We live in the most exciting and unsettling period in the history of psychiatry since Freud started talking about sex in public.
On the one hand, the American Psychiatric Association has introduced the fifth iteration of the psychiatric diagnostic manual, DSM-V, representing the current best effort of the brightest clinical minds in psychiatry to categorize the enormously complex pattern of human emotional, cognitive, and behavioral problems. On the other hand, in new and profound ways, neuroscience and genetics research in psychiatry are yielding insights that challenge the traditional diagnostic schema that have long been at the core of the field.
“Our current diagnostic system, DSM-V represents a very reasonable attempt to classify patients by their symptoms. Symptoms are an extremely important part of all medical diagnoses, but imagine how limited we would be if we categorized all forms of pneumonia as ‘coughing disease,” commented Dr. John Krystal, Editor of Biological Psychiatry.
A paper by Sabin Khadka and colleagues that appears in the September 15th issue of Biological Psychiatry advances the discussion of one of these roiling psychiatric diagnostic dilemmas.
One of the core hypotheses is that schizophrenia and bipolar disorder are distinct scientific entities. Emil Kraepelin, credited by many as the father of modern scientific psychiatry, was the first to draw a distinction between dementia praecox (schizophrenia) and manic depression (bipolar disorder) in the late 19th century based on the behavioral profiles of these syndromes. Yet, patients within each diagnosis can have a wide variation of symptoms, some symptoms appear to be in common across these diagnoses, and antipsychotic medications used to treat schizophrenia are very commonly prescribed to patients with bipolar disorder.
But at the level of brain circuit function, do schizophrenia and bipolar differ primarily by degree or are there clear categorical differences? To answer this question, researchers from a large collaborative project called BSNIP looked at a large sample of patients diagnosed with schizophrenia or bipolar disorder, their healthy relatives, and healthy people without a family history of psychiatric disorder.
They used a specialized analysis technique to evaluate the data from their multi-site study, which revealed abnormalities within seven different brain networks. Generally speaking, they found that schizophrenia and bipolar disorder showed similar disturbances in cortical circuit function. When differences emerged between these two disorders, it was usually because schizophrenia appeared to be a more severe disease. In other words, individuals with schizophrenia had abnormalities that were larger or affected more brain regions. Their healthy relatives showed subtle alterations that fell between the healthy comparison group and the patient groups.
The authors highlight the possibility that there is a continuous spectrum of circuit dysfunction, spanning from individuals without any familial association with schizophrenia or bipolar to patients carrying these diagnoses. “These findings might serve as useful biological markers of psychotic illnesses in general,” said Khadka.
Krystal agreed, adding, “It is evident that neither our genomes nor our brains have read DSM-V in that there are links across disorders that we had not previously imagined. These links suggest that new ways of organizing patients will emerge once we understand both the genetics and neural circuitry of psychiatric disorders sufficiently.”
(Image: ALAMY)
Video: The animation describes the paths of traveling performed by an OCD patient who is about to leave his apartment (left) and by a co-morbid OCD and schizophrenia patient performing the same behavior (right). Black circles indicate the number of acts performed in each location. As shown, the COD patient is mostly stationary, while the schizo-OCD patient travels all over the apartment.
The Difference Between Obsession and Delusion
TAU researchers use a zoological method to classify symptoms of OCD and schizophrenia in humans
Because animals can’t talk, researchers need to study their behavior patterns to make sense of their activities. Now researchers at Tel Aviv University are using these zoological methods to study people with serious mental disorders.
Prof. David Eilam of TAU’s Zoology Department at The George S. Wise Faculty of Life Sciences recorded patients with obsessive-compulsive disorder and “schizo-OCD” — which combines symptoms of schizophrenia and OCD — as they performed basic tasks. By analyzing the patients’ movements, they were able to identify similarities and differences between two frequently confused disorders.
Published in the journal CNS Spectrums, the research represents a step toward resolving a longstanding question about the nature of schizo-OCD: Is it a combination of OCD and schizophrenia, or a variation of just one of the disorders?
The researchers concluded that schizo-OCD is a combination of the two disorders. They noted that the behavioral differences identified in the study could be used to help diagnose patients with OCD and other obsessive-compulsive disorders, including schizo-OCD.
The taxonomy of mental disorders
"I realized my methodology for studying rat models could be directly applied to work with humans with mental disorders," Prof. Eilam said. "Behavior is the ultimate output of the nervous system, and my team and I are experts in the fine-grained analysis of behavior, be it of humans or of other animals."
The main features of OCD are, of course, obsessions and compulsions. Obsessions are recurring and persistent thoughts, impulses, or images that are experienced as intrusive and unwanted and cause marked distress or anxiety. In contrast, compulsions are repetitive motor behaviors, such as counting, that occur in response to obsessions and are performed according to strictly applied rules. Schizophrenia is marked by delusions, hallucinations, disorganized speech, abnormal motor behavior, and diminished emotional expression, among other symptoms.
Eilam and graduate student Anat Gershoni of the Zoology Department and Prof. Haggai Hermesh of TAU’s Sackler Faculty of Medicine set out with Dr. Naomi Fineberg of the Queen Elizabeth II Hospital in England to resolve the controversy. To this end, they recorded and compared videos of diagnosed OCD and schizo-OCD patients performing 10 different mundane tasks, like leaving home, making tea, or cleaning a table. The patients met the criteria of the widely used Diagnostic and Statistical Manual of Mental Disorders.
A matter of space
The researchers found that both OCD and schizo-OCD patients exhibited OCD-like behavior in performing the tasks, excessively repeating and adding actions. But schizo-OCD patients additionally acted like schizophrenics.
For a typical OCD patient in the study, the task of leaving home involved standing in one place and repeatedly checking the contents of his pockets before finally taking his keys and cell phone and going to the door. In contrast, a typical schizo-OCD patient traveled around the apartment — switching the lights in the bathroom on and off, then taking his keys and phone to the door, going to scan the bedroom, then taking his keys and phone to the door, going to empty the ashtray, then taking his keys and phone to the door and so on. A typical healthy person would simply pick up his keys and phone and walk out.
Overall, the researchers found that the level of obsessive-compulsive behavior was the same in OCD and schizo-OCD patients. This suggests that both types of patients had the difficulty shifting attention from one task to another that helps define OCD. The schizo-OCD patients, though, did more divergent activity over a larger area than did OCD patients. This suggests that the schizo-OCD patients were continuously shifting attention, which happens in schizophrenia but not OCD.
"While the obsessive compulsive is obsessed with one idea; the schizophrenic’s mind is drifting," said Eilam. "We found that this is reflected in their paths of locomotion. So instead of tracking the thoughts of the patients, we can simply trace their paths of locomotion."
Eilam plans to conduct research comparing repetitive behavior in OCD and autism patients.
Brain Wiring Quiets the Voice Inside Your Head
Researchers find nerve circuits connecting motion and hearing
During a normal conversation, your brain is constantly adjusting the volume to soften the sound of your own voice and boost the voices of others in the room. This ability to distinguish between the sounds generated from your own movements and those coming from the outside world is important not only for catching up on water cooler gossip, but also for learning how to speak or play a musical instrument.
Now, researchers have developed the first diagram of the brain circuitry that enables this complex interplay between the motor system and the auditory system to occur.
The research, which appears Sept. 4 in The Journal of Neuroscience, could lend insight into schizophrenia and mood disorders that arise when this circuitry goes awry and individuals hear voices other people do not hear.
"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."
Researchers have long surmised that the neuronal circuitry conveying movement — to voice an opinion or hit a piano key — also feeds into the wiring that senses sound. But the nature of the nerve cells that provided that input, and how they functionally interacted to help the brain anticipate the impending sound, was not known.
In this study, Mooney used a technology created by Fan Wang, Ph.D., associate professor of cell biology at Duke, to trace all of the inputs into the auditory cortex — the sound-interpreting region of the brain. Though the researchers found that a number of different areas of the brain fed into the auditory cortex, they were most interested in one region called the secondary motor cortex, or M2, because it is responsible for sending motor signals directly into the brain stem and the 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 âmove,â but they also send a signal to the auditory system saying ‘I am going to move.’"
Having discovered this connection, the researchers then explored what type of influence this interaction was having on auditory processing or hearing. They took slices of brain tissue from mice and specifically manipulated the neurons that led from the M2 region to the auditory cortex. The researchers found that stimulating those neurons actually 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."
Once the researchers have pinned down the basics of the circuitry, they could begin to investigate whether altering this circuitry could induce auditory hallucinations or perhaps even take them away in models of schizophrenia.
Researchers develop new model to study schizophrenia and other neurological conditions
Schizophrenia is one of the most devastating neurological conditions, with only 30 percent of sufferers ever experiencing full recovery. While current medications can control most psychotic symptoms, their side effects can leave individuals so severely impaired that the disease ranks among the top ten causes of disability in developed countries.
Now, in this week’s issue of the Proceedings of the National Academy of Sciences, Thomas Albright and Ricardo Gil-da-Costa of the Salk Institute for Biological Studies describe a model system that completes the bridge between cellular and human studies of schizophrenia, an advance that should help speed the development of therapeutics for schizophrenia and other neurological disorders.
"Part of the terror of schizophrenia is that the brain can’t properly integrate sensory information, so the world is a disorientating series of unrelated bits of input," says Albright, the Conrad T. Prebys Chair in Vision Research. "We’ve created a model that tests the ability to do sensory integration, which should be extremely useful for pharmaceutical research."
Currently, over 1.1 percent of the world’s population has schizophrenia, with an estimated three million individuals in the United States alone. The economic cost is high: In 2002, Americans spent nearly $63 billion on treatment and managing disability. The emotional cost is higher still: Ten percent of those with schizophrenia are driven to commit suicide by the burden of coping with the disease.
Initially, it was thought that excessive amounts of the neurotransmitter dopamine caused psychotic symptoms, and indeed, current anti-psychotic drugs work by blocking dopamine from entering brain cells. But nearly all of these drugs have severe cognitive side effects, which led researchers to speculate that some other mechanism must also be involved.
A major clue to understanding schizophrenia came with the development of phencyclidine (PCP) in 1956. It was intended to keep patients safely asleep during surgeries, but many woke up with symptoms similar to those experienced by people with schizophrenia, including hallucinations and the disorientation of feeling “dissociated” from their limbs, resulting in PCP being abandoned for clinical purposes. A decade later, it was replaced by a derivative called ketamine. At doses high enough to put patients to sleep, ketamine is an effective anesthetic. At lower doses, it temporarily produces the same schizophrenia-like effects as PCP.
The two drugs are part of a class called N-methyl-D-aspartate receptor antagonists. Essentially, they work by gumming up the mechanism by which glutamate, the main excitatory neurotransmitter, would enter brain cells. Thus, it is clear that dopamine dysfunction accounts for some of the symptoms of psychosis, although that is probably not the full story.
"While dopamine has limited reach in the brain, any dysfunction in glutamate would be expected to have the sort of widespread effects we see in the perceptual disorders associated with schizophrenia," says Albright. "Nevertheless, which neurotransmitter was primary to these disorders—glutamate or dopamine—has been argued about for years."
Standing in the way of a definitive answer was a researcher’s Catch-22: Many experiments designed to understand cognitive disorders such as schizophrenia or Alzheimer’s require a participant’s conscious attention-yet these disorders interfere with attention.
To get around this, scientists turned to electroencephalograms (EEGs), which can be used to detect changes in cases where a subject is not consciously paying attention to a stimulus, by recording the brain’s electrical signals through electrodes placed in a scalp cap. In one test, a series of tones is played, but an “oddball” tone breaks the pattern in the sequence. A healthy brain can still easily spot the differences, even if a participant is concentrating on another task, such as reading a magazine.
"The test works because the brain is a prediction machine-it’s built to anticipate what should come next," says Albright. "If you have healthy working memory, you should be able to perceive a pattern and notice when something violates it, but patients suffering from some mental health disorders lack that basic ability."
In their latest research, Albright’s team detected the difference through two signals, event-related brain potentials called mismatch negativity (MMN) and P3. The MMN reflects differential brain activity to the detected oddball tone, below the level of conscious awareness. P3 picks up the next phase: a subject’s attention orientation to the oddball tone.
Still, a gap in understanding remained. While scientists could do cellular work in animal models on the role of dopamine versus glutamate, and they could do EEGs in human beings, a bridge between the two remained elusive. Such a bridge can help scientists understanding of how healthy and disordered brains work from the cellular level all the way to the multiple interactions between brain areas. Moreover, it can enable pre-clinical and clinical trials linking cellular and systems levels for successful therapeutic avenues.
Gil-da-Costa has at last crossed the bridge by crafting the first non-invasive scalp EEG setup that records accurately from the brains of non-human primates, with the same proportional density of electrodes as a human cap and no distortions in signal caused by an incorrect fit. This setup allows him to get accurate measurements of MMN and P3, with the same protocols that are followed in humans. As a result, the lab has come closer than ever before to untangling the roles of dopamine and glutamate.
"While rodents are essential for understanding mechanisms at a cellular or molecular level, at a higher cognitive level, the best you could do was a sort of rough analogy. Now, finally, we can have a one-to-one correspondence," says Gil-da-Costa. "For sensory integration, our findings with this model support the glutamate hypothesis."
Pharmaceutical companies are interested in the model, because of the potential for more precise testing and the universality of the MMN/P3 assays. “These brain makers are the same across dozens of neurological diseases, as well as brain trauma, so you can test potential therapies not just for schizophrenia, but for conditions such as Parkinson’s, Alzheimer’s, bi-polar disorder, and traumatic brain injuries,” says Gil-da-Costa. “We hope this will help begin a new era in neurological therapeutics.”
(Source: salk.edu)
Schizophrenia symptoms linked to faulty ‘switch’ in brain
Scientists at The University of Nottingham have shown that psychotic symptoms experienced by people with schizophrenia could be caused by a faulty ‘switch’ within the brain.
In a study published today in the leading journal Neuron, they have demonstrated that the severity of symptoms such as delusions and hallucinations which are typical in patients with the psychiatric disorder is caused by a disconnection between two important regions in the brain — the insula and the lateral frontal cortex.
The breakthrough, say the academics, could form the basis for better, more targeted treatments for schizophrenia with fewer side effects.
The four-year study, led by Professor Peter Liddle and Dr Lena Palaniyappan in the University’s Division of Psychiatry and based in the Institute of Mental Health, centred on the insula region, a segregated ‘island’ buried deep within the brain, which is responsible for seamless switching between inner and outer world.
"Powerful explanation"
Dr Lena Palaniyappan, a Wellcome Trust Research Fellow, said: “In our daily life, we constantly switch between our inner, private world and the outer, objective world. This switching action is enabled by the connections between the insula and frontal cortex. This switch process appears to be disrupted in patients with schizophrenia. This could explain why internal thoughts sometime appear as external objective reality, experienced as voices or hallucinations in this condition. This could also explain the difficulties in ‘internalising’ external material pleasures (e.g. enjoying a musical tune or social events) that result in emotional blunting in patients with psychosis. Our observation offers a powerful mechanistic explanation for the formation of psychotic symptoms.”
Several brain regions are engaged when we are lost in thought or, for example, remembering a past event. However, when interrupted by a loud noise or another person speaking we are able to switch to using our frontal cortex area of the brain, which processes this external information. With a disruption in the connections from the insula, such switching may not be possible.
Compromised brain function
The Nottingham scientists used functional MRI (fMRI) imaging to compare the brains of 35 healthy volunteers with those of 38 schizophrenic patients. The results showed that whereas the majority of healthy patients were able to make this switch between regions, the patients with schizophrenia were less likely to shift to using their frontal cortex.
The insular and frontal cortex form a sensitive ‘salience’ loop within the brain — the insular should stimulate the frontal cortex while in turn the frontal cortex should inhibit the insula — but in patients with schizophrenia this system was found to be seriously compromised.
The results suggest that detecting the lack of a positive influence from the insula to the frontal cortex using fMRI could have a high degree of predictive value in identifying patients with schizophrenia.
The results of the study offer vital information for the development of more effective treatments for the condition.
Schizophrenia is one of the most common serious mental health conditions affecting around 1 in 100 people. Its onset occurs most commonly in a patient’s late teens or early 20s which can have devastating consequences for their future.
Genetic and environmental triggers
Scientists remain unsure what causes schizophrenia but believe it could be a combination of a genetic predisposition to the condition combined with environmental factors. Drug use is known to be a key trigger – people who use cannabis, or stimulant drugs, are three to four times more likely to go on to develop recurrent psychotic symptoms.
It is also believed that underdevelopment of the brain in the womb caused by complications in the mother’s pregnancy and in early childhood linked to issues such as malnutrition could play a key part. Previous observations from this research group have also uncovered the presence of unusually smooth folding patterns of the brain over the insula region in patients, suggesting an impairment in the normal development of this structure in schizophrenia.
At present, treatment involves a combination of antipsychotic medications, psychological therapies and social interventions. Currently, only one in five patients with schizophrenia achieve complete recovery and many patients who develop the condition in the long-term struggle to find a treatment that is 100 per cent effective in managing their condition.
Antipsychotic drugs, though effective in a number of patients, have poor acceptance rates due to the side effect burden meaning that many patients stop taking them in the longer run, leading to recurrence of disabling symptoms.
Researchers in Nottingham are also looking at a technique called TMS – transcranial magnetic stimulation — which uses a powerful magnetic pulse to stimulate the brain regions that are malfunctioning.
Compassion-based therapy
Despite the fact that the insular region is buried so deeply within the brain that TMS would usually be ineffective, the results of the Nottingham study suggest that the loop between the insular and the frontal cortex could be exploited for TMS– if a pulse is delivered to the frontal lobe it could stimulate the insula and reset the ‘switch’.
Other future treatment options could include the use of a compassion-based meditation therapy called mindfulness, which may have the potential to ‘reset’ the switching function of the insula and can promote physical changes within the brain. Meditation over a long period of time has been shown to increase the folding patterns within the insula area of the brain. These ideas are in its early stages at present, but may deliver more focussed treatment approaches in the longer term.
Stray prenatal gene network suspected in schizophrenia
Researchers have reverse-engineered the outlines of a disrupted prenatal gene network in schizophrenia, by tracing spontaneous mutations to where and when they likely cause damage in the brain. Some people with the brain disorder may suffer from impaired birth of new neurons, or neurogenesis, in the front of their brain during prenatal development, suggests the study, which was funded by the National Institutes of Health.
“Processes critical for the brain’s development can be revealed by the mutations that disrupt them,” explained Mary-Claire King, Ph.D., University of Washington (UW), Seattle, a grantee of NIH’s National Institute of Mental Health (NIMH). “Mutations can lead to loss of integrity of a whole pathway, not just of a single gene. Our results implicate networked genes underlying a pathway responsible for orchestrating neurogenesis in the prefrontal cortex in schizophrenia.”
King, and collaborators at UW and seven other research centers participating in the NIMH genetics repository, report on their discovery Aug. 1, 2013 in the journal Cell.
“By linking genomic findings to functional measures, this approach gives us additional insight into how early development differs in the brain of someone who will eventually manifest the symptoms of psychosis,” said NIMH Director Thomas R. Insel, M.D.
Earlier studies had linked spontaneous mutations to non-familial schizophrenia and traced them broadly to genes involved in brain development, but little was known about convergent effects on pathways. King and colleagues set out to explore causes of schizophrenia by integrating genomic data with newly available online transcriptome resources that show where in the brain and when in development genes turn on. They compared spontaneous mutations in 105 people with schizophrenia with those in 84 unaffected siblings, in families without previous histories of the illness.
Unlike most other genes, expression levels of many of the 50 mutation-containing genes that form the suspected network were highest early in fetal development, tapered off by childhood, but conspicuously increased again in early adulthood – just when schizophrenia symptoms typically first develop. This adds to evidence supporting the prevailing neurodevelopmental model of schizophrenia. The implicated genes play important roles in migration of cells in the developing brain, communication between brain cells, regulation of gene expression, and related intracellular workings.
Having an older father increased the likelihood of spontaneous mutations for both affected and unaffected siblings. Yet affected siblings were modestly more likely to have mutations predicted to damage protein function. Such damaging mutations were estimated to account for 21 percent of schizophrenia cases in the study sample. The mutations tend to be individually rare; only one gene harboring damaging mutations turned up in more than one of the cases, and several patients had damaging mutations in more than one gene.
The networks formed by genes harboring these damaging mutations were found to vary in connectivity, based on the extent to which their proteins are co-expressed and interact. The network formed by genes harboring damaging mutations in schizophrenia had significantly more nodes, or points of connection, than networks modeled from unaffected siblings. By contrast, the network of genes harboring non-damaging mutations in affected siblings had no more nodes than similar networks in unaffected siblings.
When the researchers compared such network connectivity across different brain tissues and different periods of development, they discovered a notable difference between affected and unaffected siblings: Genes harboring damaging mutations that are expressed together in the fetal prefrontal cortex of people with schizophrenia formed a network with significantly greater connectivity than networks modeled from genes harboring similar mutations in their unaffected siblings at that time in development.
The study results are consistent with several lines of evidence implicating the prefrontal cortex in schizophrenia. The prefrontal cortex organizes information from other brain regions to coordinate executive functions like thinking, planning, attention span, working memory, problem-solving, and self-regulation. The findings suggest that impairments in such functions — often beginning before the onset of symptoms in early adulthood, when the prefrontal cortex fully matures – appear to be early signs of the illness.
The study demonstrates how integrating genomic data and transcriptome analysis can help to pinpoint disease mechanisms and identify potential treatment targets. For example, the mutant genes in the patients studied suggest the possible efficacy of medications targeting glutamate and calcium channel pathways, say the researchers.
"These results are striking, as they show that the genetic architecture of schizophrenia cannot be understood without an appreciation of how genes work in temporal and spatial networks during neurodevelopment," said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch.
Impaired visual signals might contribute to schizophrenia symptoms
By observing the eye movements of schizophrenia patients while playing a simple video game, a University of British Columbia researcher has discovered a potential explanation for some of their symptoms, including difficulty with everyday tasks.
The research, published in a recent issue of the Journal of Neuroscience, shows that, compared to healthy controls, schizophrenia patients had a harder time tracking a moving dot on the computer monitor with their eyes and predicting its trajectory. But the impairment of their eye movements was not severe enough to explain the difference in their predictive performance, suggesting a breakdown in their ability to interpret what they saw.
Lead author Miriam Spering, an assistant professor of ophthalmology and visual sciences, says the patients were having trouble generating or using an “efference copy” – a signal sent from the eye movement system in the brain indicating how much, and in what direction, their eyes have moved. The efference copy helps validate visual information from the eyes.
"An impaired ability to generate or interpret efference copies means the brain cannot correct an incomplete perception," says Spering, who conducted the dot-tracking experiments as a postdoctoral fellow at New York University, and is now conducting similar studies at UBC. The brain might fill in the blanks by extrapolating from prior experience, contributing to psychotic symptoms, such as hallucinations.
My vision would be a mobile device that patients could use to practice that skill, so they could more easily do common tasks that involve motion perception, such as walking along a crowded sidewalk.
"But just as a person might, through practice, improve their ability to predict the trajectory of a moving dot, a person might be able to improve their ability to generate or use that efference copy," Spering says. "My vision would be a mobile device that patients could use to practice that skill, so they could more easily do common tasks that involve motion perception, such as walking along a crowded sidewalk."
Inner Speech Speaks Volumes About the Brain
Whether you’re reading the paper or thinking through your schedule for the day, chances are that you’re hearing yourself speak even if you’re not saying words out loud. This internal speech — the monologue you “hear” inside your head — is a ubiquitous but largely unexamined phenomenon. A new study looks at a possible brain mechanism that could explain how we hear this inner voice in the absence of actual sound.
In two experiments, researcher Mark Scott of the University of British Columbia found evidence that a brain signal called corollary discharge — asignal that helps us distinguish the sensory experiences we produce ourselves from those produced by external stimuli — plays an important role in our experiences of internal speech.
The findings from the two experiments are published in Psychological Science, a journal of the Association for Psychological Science.
Corollary discharge is a kind of predictive signal generated by the brain that helps to explain, for example, why other people can tickle us but we can’t tickle ourselves. The signal predicts our own movements and effectively cancels out the tickle sensation.
And the same mechanism plays a role in how our auditory system processes speech. When we speak, an internal copy of the sound of our voice is generated in parallel with the external sound we hear.
“We spend a lot of time speaking and that can swamp our auditory system, making it difficult for us to hear other sounds when we are speaking,” Scott explains. “By attenuating the impact our own voice has on our hearing — using the ‘corollary discharge’ prediction — our hearing can remain sensitive to other sounds.”
Scott speculated that the internal copy of our voice produced by corollary discharge can be generated even when there isn’t any external sound, meaning that the sound we hear when we talk inside our heads is actually the internal prediction of the sound of our own voice.
If corollary discharge does in fact underlie our experiences of inner speech, he hypothesized, then the sensory information coming from the outside world should be cancelled out by the internal copy produced by our brains if the two sets of information match, just like when we try to tickle ourselves.
And this is precisely what the data showed. The impact of an external sound was significantly reduced when participants said a syllable in their heads that matched the external sound. Their performance was not significantly affected, however, when the syllable they said in their head didn’t match the one they heard.
These findings provide evidence that internal speech makes use of a system that is primarily involved in processing external speech, and may help shed light on certain pathological conditions.
“This work is important because this theory of internal speech is closely related to theories of the auditory hallucinations associated with schizophrenia,” Scott concludes.
Brain discovery could help schizophrenics
The discovery of brain impairment in mice may eventually lead to better therapies for people with schizophrenia and major depression.
Studying rodents that have a gene associated with mental illness, Michigan State University neuroscientist Alexander Johnson and colleagues found a link between a specific area of the prefrontal cortex, and learning and behavioral deficits.
While much work needs to be done, the discovery is a major step toward better understanding mental illness. While antipsychotic drugs can treat hallucinations related to schizophrenia, there essentially is no treatment for other symptoms such as lack of motivation or anhedonia, the inability to experience pleasure.
“This study may well suggest that if we start targeting these brain-behavior mechanisms in people with mental illness, it may help to alleviate some of the cognitive and motivational symptoms, which to date remain largely untreated with current drug therapies,” said Johnson, MSU assistant professor of psychology.
The study is published in the Proceedings of the National Academy of Sciences.
Schizophrenia, a disabling brain disorder marked by paranoia and hearing voices that aren’t there, affects some 2.4 million Americans and runs in families, according to the National Institute of Mental Health.
The researchers conducted a series of experiments with two groups of mice – those with the gene associated with mental illness and those without the gene (or the control group).
In one experiment, related to cognition, the mice were presented with tasty food when they responded on one side of a conditioning box. After repeated feedings, the food was switched to the other side of the box. The mice with the mental illness gene had a much more difficult time learning to adapt to the new side.
In another experiment, related to motivation, the mice had to respond an increasing number of times each time they wanted food. By the end of the three-hour session, all mice with the mental illness gene stopped responding for food, while half of the control group continued on.
Johnson said the deficiencies may suggest a problem in the prefrontal cortex area known as the orbitofrontal cortex, and that further research should target this area.
Genes Involved in Birth Defects May Also Lead to Mental Illness
Gene mutations that lead to major birth defects may also cause subtle disruptions in the brain that contribute to psychiatric disorders such as schizophrenia, autism, and bipolar disorder, according to new research by UC San Francisco scientists.
Over the past several years, researchers in the laboratory of psychiatrist Benjamin Cheyette, MD, PhD, have shown that mutations in a gene called Dact1 cause cell signaling networks to go awry during embryonic development. Researchers observed that mice with Dact1 mutations were born with a range of severe malformations, including some reminiscent of spina bifida in humans.
This new study was designed to explore whether Dact1 mutations exert more nuanced effects in the brain that may lead to mental illness. In doing so, Cheyette, John Rubenstein, MD, PhD, and colleagues in UCSF’s Nina Ireland Laboratory of Developmental Neurobiology used a genetic technique in adult mice to selectively delete the Dact1 protein only in interneurons, a group of brain cells that regulates activity in the cerebral cortex, including cognitive and sensory processes. Poor function of interneurons has been implicated in a range of psychiatric conditions.
As reported in the June 24 online issue of PLOS ONE, researchers found that the genetically altered interneurons appeared relatively normal and had managed to find their proper position in the brain’s circuitry during development. But the cells had significantly fewer synapses, the sites where communication with neighboring neurons takes place. In additional observations not included in the new paper, the team also noted that the cells’ dendrites – fine extensions that normally form bushy arbors studded with synapses – were poorly developed and sparsely branched.
“When you delete this gene function after initial, early development – just eliminating it in neurons after they’ve formed – they migrate to the right place and their numbers are correct, but their morphology is a little off,” Cheyette said. “And that’s very much in line with the kinds of pathology that people have been able to identify in psychiatric illness.
"Neurological illnesses tend to be focal, with lesions that you can identify or pathology you can see on an imaging study," Cheyette explained. "Psychiatric illnesses? Not so much. The differences are really subtle and hard to see.”
Key Gene’s Role in Development of Human Nervous System
The Dact1 protein is part of a fundamental biological system known as the Wnt (pronounced “wint”) signaling pathway. Interactions among proteins in the Wnt pathway orchestrate many processes essential to life in animals as diverse as fruit flies, mice and humans, including the proper development of the immensely complex human nervous system from a single fertilized egg cell.
One way the Wnt pathway manages this task is by maintaining the “polarity” of cells during development, said Cheyette, “a process of sequestering, increasing the concentration of one set of proteins on one side of the cell and a different set of proteins on the other side of the cell.” Polarity is particularly important as precursor cells transform into nerve cells, Cheyette said, because neurons are “the most polarized cells in the body,” with specialized input and output zones that must wind up in the proper spots if the cells are to function normally.
Cheyette said his group is now conducting behavioral experiments with the mice analyzed in the new PLOS ONE paper and with genetically related mouse lines to test whether these mice have behavioral abnormalities in sociability, sensory perception, anxiety or motivation that resemble symptoms in major psychiatric disorders.
He also hopes to collaborate with UCSF colleagues on follow-up experiments to determine whether the activity of neurons lacking Dact1 is impaired in addition to the structural flaws identified in the new study and prior published work from his lab.
Meanwhile, as-yet-unpublished findings from human genetics research conducted by Cheyette’s group suggest that individuals with autism are significantly more likely than healthy comparison subjects to carry mutations in a Wnt pathway gene called WNT1.
“Just because a gene plays an important role in the embryo doesn’t mean it isn’t also important in the brain later, and might be involved in psychiatric pathology,” said Cheyette. “When these genes are mutated, someone may look fine, develop fine and have no obvious medical problems at birth, but they may also develop autism in childhood or have a psychotic break in adulthood and develop schizophrenia.”