What if you heard voices when there was no one there? What if the reality around you slowly disintegrated?
According to collaborative research between Judith M. Ford and Daniel H. Mathalon, Adjunct Professors of Psychiatry, dysfunction of a critical brain mechanism may be responsible for the symptoms of a serious disorder called schizophrenia.
What is schizophrenia?
Schizophrenia is a chronic brain disorder that affects approximately 1% of the global population with no bias towards any ethnicity or gender. The illness has, however, been linked to genetic factors, seeing as people who have close relatives diagnosed with schizophrenia are more likely to develop the disorder.
Ongoing research suggests that both chemical and physical abnormalities in the brain may also be associated with schizophrenia. For example, evidence shows that people with schizophrenia might have either excess amounts of the neurotransmitter dopamine or an unusual sensitivity to the chemical.
People with schizophrenia suffer from a distorted perception of reality. In what is called an “acute” phase of schizophrenia, patients manifest severe symptoms of psychosis, including hallucinations and delusions. In people with schizophrenia, hallucinations may occur in any of the five senses—sight, sound, touch, taste, or smell. However, auditory hallucinations are the most common as nearly 75% of people diagnosed with schizophrenia perceive nonexistent voices.
Acute phases of schizophrenia also involve delusions, which are false beliefs with no basis in reality resulting from the inability to distinguish between real and unreal. In some instances, they may falsely believe that they are famous celebrities. Schizophrenia patients might also feel that they are being controlled by others or that special messages are being sent to them.
People with schizophrenia often have an impaired ability to think rationally and logically. Many patients have difficulty concentrating, organizing their thoughts, and figuring out what information is relevant to a situation.
Another characteristic symptom of schizophrenia is avolition, a general lack of interest, desire, and motivation. People suffering from the disorder may show blunted or flat affect, which is a decrease in the expression of emotion, as demonstrated through their facial expressions and speech.
Schizophrenia can also lead to social withdrawal, and often patients with schizophrenia sit and do nothing for long periods of time. However, this state is distinct from depression. Speaking of schizophrenia patients suffering with avolition, Professor Ford said, “They are not depressed – they just don’t feel like doing anything.”
Schizophrenia and the corollary discharge mechanism
Through their research on schizophrenia, Professors Ford and Mathalon seek to identify the physiological mechanisms behind many symptoms of the illness. “We are trying to understand how people with schizophrenia have these sensory experiences that are not real,” said Professor Ford.
In the 1970’s, Irwin Feinberg first proposed that schizophrenia may be caused by a defect in the corollary discharge mechanism. Corollary discharge is a neurophysiological mechanism ubiquitous across many animal organisms. It enables us to differentiate between sensations resulting from our own thoughts or actions and externally generated sensations.
Every time an animal moves, the motor region of the brain sends two messages: one to the muscles necessary to create the movement and the other is a corollary message sent to a sensory area of the brain. This corollary message, called corollary discharge, notifies this sensory area that the sensations in that part of the body are self-generated
Perhaps most relevant to understanding schizophrenia is the function of corollary discharge in the auditory system. When you imagine your mother’s voice telling you something, you can hear her voice in your mind but you know that she is not actually talking to you at that moment. In fact, you send a message to your auditory cortex, the part of your brain that receives sounds.
“According to our theory, this part of the brain does hear your mother’s voice when you’re thinking about it, but it also gets a message from another part of your brain saying that it’s just yourself thinking,” explained Professor Ford. Professor Ford believes that patients with schizophrenia fail to send corollary discharge to the part of the brain that would beperceiving the results of that thought. He believes that people with schizophrenia are missing the mechanism that normally allows people to turn off or suppress their brain’s response to the sensations resulting from their own thoughts.
Corollary discharge could also explain why people with schizophrenia often move awkwardly or prefer not to move much at all. As people move, their muscle feedback is partially cancelled out by a corollary discharge signal, enabling people to move fluidly with little awareness of the mechanics of the movement. However, in the absence of this corollary discharge system, movements may be awkward and a person could have little motivation to move around. This could also explain why people with schizophrenia often feel like their actions are being controlled by an outside force.
Before we perform any motor action, our brain shows a synchronization of activity that is thought to be evidence of corollary discharge. In the laboratory of Professors Ford and Mathalon, researchers have monitored phase synchronization of neural activity before and after a motor action using electroencephalography (EEG), or the monitoring of electrical activity due to neurons firing in the brain.
By recording EEGs from people with and without schizophrenia, their lab demonstrated that synchronization of neural activity before an action is reduced in people with schizophrenia, suggesting that the corollary discharge mechanism is defective.
However, questions remain about the function of corollary discharge in the disorder. Because schizophrenia patients cannot be taken off their medication, studies are unable to confirm whether corollary discharge dysfunction results from the illness itself or from anti-psychotic medication.
Biomarkers of schizophrenia
In addition to his work on the corollary discharge mechanism with Professor Ford, Professor Mathalon has been using magnetic resonance imaging (MRI) and EEG to identify biomarkers associated with the risk for developing schizophrenia.
Prodromal symptoms of an illness are exhibited in the period leading up to the full development of the disease. In the case of schizophrenia, prodromal symptoms become apparent 1-3 years before the full onset of the disorder. During this time, patients are suspicious and have disorganized thinking but have yet to develop full-blown psychosis.
Early treatment of people with schizophrenia seems to prevent the illness from becoming much more serious. Professor Mathalon hopes to use MRI and EEG measurements to identify some of the abnormalities seen in schizophrenia before the full-blown illness develops. “We want to see if these abnormalities and their timing can enhance our prediction of who is really at risk of developing psychosis,” he said. “This is a first step for targeting interventions for people who need it most.”
One possible biomarker is a reduction in the P300 event-related brain potential (ERP), a neural response associated with paying attention to an infrequent but task-relevant or otherwise salient stimulus. It is already known that the amplitude of P300 is reduced in patients with schizophrenia.
Another possible biomarker is an abnormality in mismatch negativity, an auditory response to a deviant sound presented in a stream of frequent sounds, elicited automatically in the brain. Patients are presented with a stream of standard, identical sounds, but then one of the sounds is deviant—for example, it may have a different pitch. This deviant sound elicits an automatic response in the auditory cortex of the brain, called mismatch negativity.
This automatic response is abnormal in schizophrenia and also in prodromal patients. Furthermore, the abnormality of mismatch negativity seems to predict which prodromal patients will actually convert to psychosis.
“Our hope is that these biomarkers are going to be useful in finding out which patients really need treatment,” said Professor Mathalon.
The future of schizophrenia
Both Professors Ford and Mathalon are working toward a better understanding of the physiological mechanisms behind schizophrenia. They are extending their studies of corollary discharge beyond the auditory system and into to the visual and motor-sensory systems. Professor Mathalon continues his search for possible biomarkers of risk for schizophrenia. He is currently using functional MRI to study dysfunction in attention and working memory processes.
An increased understanding of these mechanisms and their dysfunction in schizophrenia would have positive implications for people suffering from schizophrenia on many different levels. The risk of developing schizophrenia could be identified earlier and more accurately, and schizophrenia may even be prevented in patients who are at risk of developing the disorder. Furthermore, explaining the symptoms of the disease through the dysfunction of corollary discharge mechanisms would raise new possibilities for the treatment of schizophrenia.
Research on this serious brain disorder still has a long way to go, but, as Professor Mathalon said, “This is a first step.”
“Research Clinics.” Department of Psychiatry. 6 November 2008. Yale University. May 2009 <https://info.med.yale.edu/psych/clinics/schizophrenia.html>
Feinberg, I. Efference copy and corollary discharge: implications for thinking and its disorders. Schizophrenia Bulletin, 1978. 4(4): 636-40.
Ford, J. M.; Roach, B.J.; Faustman, W.O.; Mathalon, D.H. Out-of-Synch and Out-of-Sorts: Dysfunction of Motor-Sensory Communication in Schizophrenia. Biol. Psychiatry, 2008. 63: 736-43.
Mathalon, D. H. and Ford, J. M. Corollary Discharge Dysfunction in Schizophrenia: Evidence for an Elemental Deficit. Clinical EEG and Neuroscience, 2008. 39(2): 82-86.
Spearing, Melissa K. “An Overview of Schizophrenia – Information from the National Institute of Mental Health.” National Institute of Mental Health. 2002. May 2009 https://www.schizophrenia.com/pdfs/szoverview.pdf
About the Author: Katherine Zhou is a Junior in Saybrook College majoring in Molecular Biophysics and Biochemistry.
Acknowledgements: The author would like to thank Professor Judith M. Ford and Professor Daniel H. Mathalon for their time and assistance.