Brain Imaging Patterns Moving Closer To Identifying Schizophrenia on Functional MRI

MedicalResearch.com Interview with:

Irina Rish PhD IBM T.J. Watson Research Center Yorktown Heights, NY 10598

Dr. Rish

Irina Rish PhD
IBM T.J. Watson Research Center
Yorktown Heights, NY 10598 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a chronic and severe psychiatric disorder that affects roughly about 1% of population. Although it is not as common as other mental disorders, such as depression, anxiety, and attention deficit disorder (ADD), and so on, schizophrenia  is perhaps one of  the most debilitating psychiatric disorders,  preventing people from normal  functioning in daily life. It is characterized primarily by a range of psychotic symptoms, including hallucinations (false auditory, visual or tactile perceptions detached from reality), as well as delusions, disorganized thoughts, speech and behavior, and multiple other symptoms including difficulty showing (and recognizing) emotions, poor executive functioning, inattentiveness, problems with working memory,  and so one. Overall, schizophrenia has a devastating impact not only on patients and their families, but on the economy, as it was estimated to cost the US about 2% off  gross national product in treatment costs, missed work, etc.
Thus, taking steps towards better understanding of the disease can potentially lead to more accurate early diagnosis and better treatments.

In this work, the objective was to identify “statistical biomarkers’ of schizophrenia from brain imaging data (specifically, functional MRI), i.e. brain activity patterns that would be capable of accurately discriminating between schizophrenic patients and controls, and reproducible (stable) across multiple datasets. The focus on both predictive accuracy (generalization to previously unseen subjects) as well as on stability (reproducibility) across multiple datsets differentiates our work from majority of similar studies in neuroimaging field that tend to focus only on statistically significant differences between such patterns on a fixed dataset, and may not reliably generalize to new data.

Our prior work on neuroimaging-based analysis of schizoprenia http://journals.plos.org/plosone/article/related?id=10.1371/journal.pone.0050625, as well as other research in the field, suggest that disrupted functional connectivity can be a much more informative source of discriminative patterns than local changes in brain activations, since schizophrenia is well known to be a “network disease”, rather than a localized one.

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Schizophrenia: Impaired White Matter Linked To Deficits in Cognitive Processing Speed

MedicalResearch.com Interview with:

Peter Kochunov PhD Professor Maryland Psychiatric Research Center

Dr. Kochunov

Peter Kochunov PhD
Professor
Maryland Psychiatric Research Center 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a debilitating disorder that strikes young people at the point of entering adulthood. In the past, we and others demonstrated that patients with schizophrenia are characterized by deficits in the white matter of the brain. White matter is the part of the brain that serves the backbone of cerebral networks transmitting information and interconnecting brain regions.

In this report, we link the impaired white matter of the brain in schizophrenia patients with the disorder-related deficits in the processing speed. We also showed that mental processing speed is a fundamental cognitive construct that partially supports other functions like working memory in patients, where processing speed acting as the intermediate between white matter deficits and reduced working memory. This interesting relationship between processing speed, working memory, and white matter is most obvious in white matter regions most vulnerable to schizophrenia. That was the main finding of the study.

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Genetic Risk of Schizophrenia May Contribute to Cognitive Dysfunction

MedicalResearch.com Interview with:

Olav B. Smeland MD PhD Postdoctoral researcher SFF NORMENT, KG Jepsen Centre for Psychosis Research, Division of Mental  Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine University of Oslo Oslo, Norway

Dr. Smeland

Olav B. Smeland MD PhD
Postdoctoral researcher
SFF NORMENT, KG Jepsen Centre for Psychosis Research, Division of Mental
Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine
University of Oslo Oslo, Norway

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a severe mental disorder associated with widespread cognitive impairments. The cognitive deficits are associated with disabilities in social, economic and occupational functioning and lower quality of life among individuals with schizophrenia. Despite this, current treatment strategies largely fail to ameliorate these cognitive impairments.

To develop more efficient treatment strategies in schizophrenia, a better understanding of the disease mechanisms underlying cognitive deficits is needed. For a long time we have known that schizophrenia is heritable, and in recent years many schizophrenia risk genes have been identified. Moreover, several studies have indicated that genetic risk of schizophrenia may contribute to cognitive dysfunction.

In this study, we aimed to identify schizophrenia risk genes that also influence cognitive function. In a large international collaboration of researchers, we combined genome-wide association studies on schizophrenia and the cognitive traits of verbal-numerical reasoning, reaction time and general cognitive function. In total, we analyzed genetic data from more than 250.000 participants. We were able to identify 21 genetic variants shared between schizophrenia and cognitive traits. For 18 of these genetic variants, schizophrenia risk was associated with poorer cognitive performance.

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Long-acting Injectable Medications Reduce Relapse and Rehospitalizations in Schizophrenia

MedicalResearch.com Interview with:

Jari Tiihonen, MD, PhD Professor, Department of Clinical Neuroscience Karolinska Institutet Stockholm, Sweden

Prof. Tiihonen

Jari Tiihonen, MD, PhD
Professor, Department of Clinical Neuroscience
Karolinska Institutet
Stockholm, Sweden 

MedicalResearch.com: What are the limitations of existing analyses of the comparative effectiveness of antipsychotics?

Response: It has remained unclear if there are clinically meaningful differences between antipsychotic treatments in relapse prevention of schizophrenia, due to the impossibility of including large unselected patient populations in randomized controlled trials, and due to residual confounding from selection biases in observational studies.

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Gene Dosage at 22q11.2 Helps Determine Schizophrenia vs Autism Brain Differences

MedicalResearch.com Interview with:

Carrie Bearden, Ph.D. Professor, Departments of Psychiatry and Biobehavioral Sciences and Psychology Semel Institute for Neuroscience and Human Behavior University of California, Los Angeles

Dr. Bearden

Carrie Bearden, Ph.D.
Professor, Departments of Psychiatry and Biobehavioral Sciences and Psychology
Semel Institute for Neuroscience and Human Behavior
University of California, Los Angeles

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: A 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population.

Thus, we became interested in trying to understand whether there were differences in brain development that might predispose to one condition vs. the other.

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Probiotics May Influence Schizophrenia Symptoms Through Yeast in Microbiome

MedicalResearch.com Interview with:
Emily G. Severance PhD
Stanley Division of Developmental Neurovirology
Department of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, MD 21287

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previously, we found that people with schizophrenia and bipolar disorder had an increased susceptibility to Candida albicans yeast infections, which was sex specific and associated with memory deficits. Also in an earlier placebo-controlled probiotic study, we found that although probiotics improved the overall bowel function of people with schizophrenia, there was no effect by this treatment on psychiatric symptoms.  Given that C. albicans infections can upset the dynamics of the human microbiome, we decided to re-evaluate the potential benefit of probiotics in the context of a patient’s C. albicans yeast status.  Not only was bowel function again enhanced following intake of probiotics, but yeast antibody levels were decreased by this treatment.

Furthermore, psychiatric symptoms were actually improved over time for men receiving probiotics who did not have elevated C. albicans antibodies. Men who were positive for C. albicans exposure, however, consistently presented with worse psychiatric symptoms irrespective of probiotic or placebo treatment.

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No Increased Health Consequences After Chinese Famine Except Schizophrenia

MedicalResearch.com Interview with:

L. H. Lumey, MD, PhD Professor of Epidemiology Mailman School of Public Health Columbia University

Dr. Lumey

L. H. Lumey, MD, PhD
Professor of Epidemiology
Mailman School of Public Health
Columbia University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Chinese Great Leap Forward Famine in 1959-1961 is the largest famine in human history. Earlier studies have reported that overweight, type 2 diabetes, hyperglycemia, the metabolic syndrome and schizophrenia were more common among adults who were exposed to the famine. Our re-analysis of all previous studies shows no increases in diabetes, high blood pressure and other chronic conditions among famine births except for schizophrenia.

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Our ‘Motor Signature’ Is a Window Into Mental Health

MedicalResearch.com Interview with:

Dr. Piotr Słowiński</strong> Department of Mathematics College of Engineering Mathematics and Physical Sciences, Research Fellow University of Exeter

Dr. Piotr Słowiński

Dr. Piotr Słowiński
Department of Mathematics
College of Engineering
Mathematics and Physical Sciences,
Research Fellow
University of Exeter

MedicalResearch.com: What are the main findings?

Response: In an earlier study, we have found that every person has an individual style of moving (its own individual motor signature) and that people who have similar motor signatures are better in coordinating with each other (http://rsif.royalsocietypublishing.org/content/13/116/20151093). In the current study, we show that both these characteristics, own motor signature, and quality of interaction with others, have potential to give and insight into person’s mental health condition.

Assessment of motor symptoms is already a part of a clinical interview during a neurological evaluation by an expert psychiatrist. Our method, if confirmed in clinical trials, would speed up such examination and would allow for better allocation of the valuable time of medical professionals (for example, for more advanced tests in cases of diagnostic uncertainty). Additionally, it could allow for monitoring and personalization of treatment.

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Elevated Fasting Glucose and Insulin Resistance Seen Early in Schizophrenia

MedicalResearch.com Interview with:

Dr Toby Pillinger MA(Oxon) BM BCh MRCP Institute of Psychiatry, Psychology and Neuroscience King's College London

Dr. Toby Pillinger

Dr Toby Pillinger MA(Oxon) BM BCh MRCP
Institute of Psychiatry, Psychology and Neuroscience
King’s College London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our meta-analysis has provided strong evidence that compared with healthy controls, individuals with early schizophrenia are at increased risk of developing type 2 diabetes mellitus, even when the effects of antipsychotic drugs, diet and exercise are taken out of the equation.

Schizophrenia is associated with a dramatically reduced life expectancy, with individuals dying up to 30 years earlier than the general population. Approximately 60% of this excess mortality is due to physical health disorders such as heart attack or stroke, for which diabetes is a major risk factor.

People with long-term schizophrenia are 3 times more likely than the general population to have diabetes, something that has previously been blamed on poor diet and exercise habits, as well as the use of antipsychotic medication. However, the link between schizophrenia and diabetes was first made back in the 19th century, long before the use of antipsychotics, and in an era where diets were less likely to cause diabetes. This could suggest that there is a causative link between schizophrenia and diabetes.

Our meta-analysis examined whether diabetes risk is already raised in people at the onset of schizophrenia, before antipsychotics have been prescribed and before a prolonged period of illness that may be associated with poor diet and sedentary behaviour. We pooled data from 16 studies comprising 731 patients and 614 individuals from the general population. We collated blood data examining fasting blood glucose levels, blood glucose levels following the oral glucose tolerance test, fasting insulin levels and degree of insulin resistance.

We demonstrated that compared with healthy controls, individuals with early schizophrenia had raised fasting glucose, raised levels of glucose following the oral glucose tolerance test, raised fasting insulin and elevated insulin resistance. Furthermore, these results remained statistically significant even when we restricted our analyses to studies where individuals with schizophrenia were matched to healthy controls with regards their diet, the amount of exercise they engaged in and their ethnic background.

This suggests that our results were not wholly driven by differences in lifestyle factors or ethnicity between the two groups, and may therefore point towards a direct role for schizophrenia in increasing risk of diabetes.

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Schizophrenia: SynCav1 As Potential Target To Restore Neuron Function

MedicalResearch.com Interview with:

Brian P. Head, MS, PhD Associate Professor, UCSD Research Scientist, VASDHS Department of Anesthesiology VA San Diego Healthcare System San Diego, CA 92161-9125

Dr. Brian Head

Brian P. Head, MS, PhD
Associate Professor, UCSD
Research Scientist, VASDHS
Department of Anesthesiology
VA San Diego Healthcare System
San Diego, CA 92161-9125

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: DISC1 is a schizophrenia associated gene originally identified in a Scottish family. DISC1 protein is highly expressed in the developing brain and in the dentate gyrus of the adult hippocampus, and is involved in neuritogenesis and neuronal signaling. DISC1 is located in multiple intracellular locations including axons and synapses, and loss of DISC1 function causes deficits in neural development, neuronal proliferation, axonal growth, and cytoskeleton modulation, which are consistent with abnormal neural development in schizophrenia.

SynCav1 means synapsin-driven caveolin construct. Synapsin promoter is neuronal specific which allows us to increase caveolin expression-specifically in neurons. We have previously shown that SynCav1 increases neuronal signaling and dendritic growth and arborization in vitro (Head BP JBC 2011), and when delivered in vivo augments functional neuroplasticity and improves learning and memory in adult and aged mice (Mandyam CD Biol Psych 2015).

Since loss of DISC1 function equates to schizophrenic-like symptoms, then decreased DISC1 expression in Cav-1 KO mice agrees with this premise. Thus, loss of Cav-1 increases their likelihood of developing schizophrenia-like symptoms. Because re-espression of Cav-1 restored DISC1 expression as well as expression of key synaptic proteins, this proof-of-concept findings not only builds upon our previously results demonstrating that Cav-1 is critical for neuronal signaling and functional synaptic plasticity but also strongly links Cav-1 with maintaining normal DISC1 expression levels and potentially attenuating schizophrenia-like symptoms.

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