Day 1. Introduction to 21 century of mental health careKropotov Juri D.

About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence.From Kessler et al., 2005.

Mental disorders represent one of the biggest challenges for health care systemsIn the European Union, work-related costs due to mental health problems are more than 2.5 times greater than those associated with cardiovascular disease. The prevalence of mental disorders is expected to grow in a recent future for a variety of reasons including aging of the whole population and increasing of economic-social problems such as reduced job security, work intensification, stress enhancement. Primary Mental Disorders Among People Served in the Public Mental Health SystemIn children the largest proportion has ADHD (around 24%), in each adult population, diagnoses of bipolar disorder and schizophrenia together comprise nearly 50% of all diagnoses.

Brain imaging methods of neuroscienceDuring the last 20 years the neuroscience learnt about the brain more than the mankind had learnt for the previous several hundred years. This new knowledge was obtained due to appearance of new imaging techniques such as Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), Diffuse Tensor Imaging (DTI) Event Related Potentials (ERPs). Its now time to apply the obtained knowledge in full extent to aid psychiatrists in diagnosis and treatment of brain dysfunctions

Objective neuroimaging measures are called neuromarkersThe most common are:Size of a certain anatomical structure and its age evolution (MRI), connectivity pattern (DTI), level of metabolic activity (fMRI, PET), and temporal pattern of cortical electrical activation (ERPs)

We are at an extraordinary moment when the entire scientific foundation for mental health is shifting, with the 20th century discipline of psychiatry becoming the 21st century discipline of clinical neuroscience Thomas Insel. NIH mental health director

According to Thomas Insel there are three revolutionary changes in our understanding of mental illness. First: mental illness is a disorder of brain circuitry, rather than as a chemical imbalance. Second: mental illness is a developmental disorder for which early interventions are vital.Third: mental illness is a result of complex interaction between genetic and environmental factors. This will be illustrated below by a summary of schizophrenia research.

Schizophrenia is a disorder of brain circuitryA. Gray matter Loss in Adolescents with Schizophrenia. Based on a database of 96 images from schizophrenic patients scanned repeatedly with MRI. The parallel extraction of anatomical models from all patients in the image database required 60 CPU hours, when running in parallel on an SGI RealityMonster with 32 internal CPUs. From Thompson et al., 2001. Proc Natl Acad Sci U S A. B. Dendritic spine alterations identified in layer 3 of cortex in schizophrenia.From Glausier and Lewis, 2012 Neuroscience.

Schizophrenia is a developmental disorderThe changes in brain connectivity in schizophrenia occur long before symptoms appear.Individuals at high-risk for psychosis were followed by MRI measuring. Progressive volume loss is found in the prefrontal regions during the transition to psychosis.From Sun et al., 2009, Schizophrenia Research

Schizophrenia is a result of interaction between genetic and environmental factorsThere is a strong genetic component to schizophrenia - those who have relatives with a history of schizophrenia have an increased risk for developing a psychiatric disturbance. However, genetic course is not the whole story because if one identical twin has schizophrenia, the risk for the other twin who has the exact same genes is only 50%.Neuroscience shows that schizophrenia develops as a result of complex interplay between 1) genetic predisposition, 2) complications during pregnancy and 3) stressors during child development. The first two factors lead to subtle alterations in the brain that put a person at risk for developing schizophrenia. Environmental factors later in life can either damage the brain further and eventually lead to psychosis, or lessen the expression of genetic and neurodevelopmental defects so that a person can leave a healthy life.

Neuromarker as a risk factor for developing psychiatric disorder.A neuromarker is distributed in the population and correlates with the phenotype - behavioral pattern - of the disorder. The increase of phenotypic severity is marked by vertical arrow. A diagnostic category is determined by a disorder threshold marked by red horizontal line. The healthy subjects according to the diagnostic criteria are marked by green circles, the diseased subjects are marked by red circles.Subjects who did not reach the disorder threshold but who have lower measures of the neuromarker are at risk of the developing the disorder.

P300 wave abnormalities are reliable neuromarkers of schizophreniaA. P300 amplitude is reduced and P300 latency is prolonged in schizophrenia patients. Similar abnormalities are found in patients relatives (from Bramon et all, 2005 Biological Psychology). B. Number of papers that used ERPs for diagnosis of schizophrenia and ADHD during the last 20 years.C. Effect size of discriminating schizophrenia patients from healthy controls for numerous studies of P300. X-axis number of participants in a study (From Jeon, Polich, 2003).

Reduced P300 amplitude as predictor for transition to psychosisNumerous studied showed that P300 abnormality is also present in subjects at risk for schizophrenia. In a study by (van Tricht et al., 2010) P300 was measured in 61 subjects at ultra high risk for schizophrenia of whom 30% converted to psychosis (converters) over 3-year follow-up period. The P300 neuromarker was compared to 28 healthy controls. A. The converters showed smaller parietal P300 amplitudes, compared with control subjects and non-converters. B. Reduced P3 amplitude was the best predictor for transition to psychosis

A new methodology to overcome limitations of ERP wave approachThe diversity of results of ERP research in mental illness is explained in part of heterogeneity of the common ERP waves.Indeed, ERP waves (such as P300) are not single entities but instead are decomposed into separate components with different functional meanings.Fig. A shows P300 wave in the auditory oddball task which is decomposed by independent component analysis into 6 functionally distinct components (Fig. B)

Executive control is characterized by multiple ERP componentsA psychiatric disease is characterized by multiple dysfunctions of complex brain systems, and must be indexed by multiple ERP components obtained in various behavioral paradigm.The GO/NOGO paradigm is one the task used to study functions of cognitive control such as sensory mismatch, inhibition of ongoing activity and conflict monitoring. Fig. shows independent components in the cued GO/NOGO task (from Kropotov, Ponomarev, 2009, NeuroReport and Kropotov et al., 2011, NeuroImage)

A. Independent components in ADHD, schizophrenia and healthy control groups.B. Discrimination between ADHD, schizophrenia and healthy control groups in two-dimensional space of the two independent components. Discrimination healthy vs. patients is made in a multi-dimensional space of functional components

The new methodology has been published in several books (see below) and in numerous papers

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