Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384 S3

comparing the list of genes differentially methylated in the PFC of PNS rats

with similar results obtained in monkeys exposed to maternal separation

as well as with a human cohort characterized by early life stress (ELS). Such

analyses allowed us to prioritize the list of genes that may be affected by

ELS and that may therefore play a relevant role for psychopathology and

disease susceptibility. Collectively, our data provide further support to the

notion that in-utero exposure to stress leads to permanent functional and

molecular changes in the offspring. Moreover, these results highlight the

importance of the identification of methylation signatures in a convergent

approach that could serve as predictive and diagnostic markers. This will

eventually lead to the identification of novel genes and pathways that are

affected as a consequence of ELS and that may contribute to long-term

susceptibility for mental illness.

ADOLESCENT STRESS-INDUCED EPIGENETIC CONTROL OF NEURONAL

NETWORKS

Akira Sawa1, Minae Niwa2,3, Richard Lee3

1Johns Hopkins University School of Medicine; 2Department of Chemical

Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences,

Nagoya, Japan; 3Department of Psychiatry and Behavioral Sciences, Johns

Hopkins University School of Medicine, Baltimore, MD

Environmental stressors during childhood and adolescence influence post-

natal brain maturation and human behavioral patterns in adulthood. Ac-

cordingly, excess stressors result in adult-onset neuropsychiatric disorders.

Here we present an underlying mechanism by linking adolescent stressors

to epigenetic controls in neurons via glucocorticoids. A mild isolation stress

in adolescence (for 3 weeks) affects mesocortical projection of dopaminer-

gic neurons in which DNA hypermethylation of the tyrosine hydroxylase

gene is elicited, only when combined with a relevant genetic risk for neu-

ropsychiatric disorders (DISC1). Associated with these molecular changes

several neurochemical and behavioral deficits occur in this mouse model,

all of which are blocked by a glucocorticoid receptor antagonist. The face

and predictive validities of the mice offer a model for psychotic depression,

a common and debilitating psychiatric disease. Although preliminary, we

will include two published new data as follows in our presentation: we

have narrowed down the most critical term of isolation in adolescence for

just one week. We have also extended our study on epigenetic impact of

the gene-environmental interactions (e.g., adolescent isolation and DISC1)

at the whole genome levels beyond the tyrosine hydroxylase gene.

Symposium

NEGATIVE SYMPTOMS AND SOCIAL COGNITION IN

SCHIZOPHRENIA: NEURAL CIRCUITRY, FUNCTIONAL OUTCOMES,

AND TREATMENT INNOVATION

Chairperson: Aristotle Voineskos

Discussant: Celso Arango

Sunday, 6 April 2014 2:00 PM – 4:00 PM

Overall Abstract: Individuals with schizophrenia spectrum disorders (SSDs;

i.e., schizophrenia, schizoaffective disorder, schizophreniform disorder) ex-

hibit a continuum of impairment in social functioning. This symposium will

explore the neural correlates of lower-level and higher-level social cognitive

processing impairment among people with SSDs. Effort will also be made

to show how schizophrenia patients with prominent negative symptoms

demonstrate impairments in similar brain systems that may be responsible

for social cognitive performance. Finally, a novel intervention that can

improve social function by targeting motivation and emotion recognition

using an innovative neuroplasticity-based cognitive training approach will

be described. First, Dr. Michael Green will present results from 3 fMRI

studies and one EEG study that attempted to explore higher- and lower-

level systems in schizophrenia. The higher-level mentalizing system was

studied with selective belief attribution or emotion attribution tasks. The

lower-level mirroring system was studied with a mirror neuron task in the

scanner, and an EEG mu suppression task. The integration of these systems

was also examined with an empathic accuracy task. Results suggest the

mirroring system is largely intact in schizophrenia. However, individuals

with schizophrenia show impairment in other aspects of social cogni-

tion, including mentalizing. Dr. Aristotle Voineskos will then present data

demonstrating heterogeneous findings in patients with schizophrenia in cir-

cuits that may underlie these two systems. He will show that schizophrenia

patients with prominent negative symptoms, or deficit schizophrenia have

impairment in right fronto-parietal circuit structure, which predicts impair-

ment in social function. Such impairment was not found in other subjects

with a major psychotic disorder, or healthy controls. Dr. Voineskos will also

present preliminary results using a continuum-based approach that may

illuminate apparent discrepancies regarding impairment of the mirroring

system in schizophrenia. Dr. Anil Malhotra will then present data using

resting state fMRI which shows that schizophrenia patients with the deficit

subtype demonstrate alterations in the cortical midline network, which

is considered important for mentalization, introducing the possibility that

these more impaired patients may also have impairment in the higher-level

mentalizing network. Dr. Robert Buchanan will then put the previous talks

into context by utilizing the new Research Domain Criteria framework to

integrate findings from patients with prominent enduring negative symp-

toms, with newer research on social cognitive impairment, both critical

determinants of social function. Dr. Buchanan will describe the impact of

social cognitive impairment on long-term functioning in SSDs and present

data implicating right fronto-parietal white matter microstructural abnor-

malities in people with prominent negative symptoms, who are socially

impaired. Finally, Dr. Sophia Vinogradov will present data on cognitive

training approaches relevant to schizophrenia patients with negative symp-

toms, social cognitive impairment or both. The treatment approach that

she will present uses a bottom-up approach to include behaviorally salient

and ecologically meaningful social and emotional stimuli with the goal of

restoring function in the neural correlates of reward anticipation and emo-

tion recognition in people with schizophrenia. She will present preliminary

data indicating that re-engaging the dopaminergic reward system through

training facilitates the use of positive incentives to motivate behavior in

social and nonsocial domains.

NETWORK TOPOLOGY IN DEFICIT SCHIZOPHRENIA, NONDEFICIT

SCHIZOPHRENIA, AND BIPOLAR DISORDER: FROM CIRCUITS TO

FUNCTIONAL OUTCOME

Aristotle Voineskos1, Anne Wheeler2, Jason Lerch3, Mallar Chakravarty2,

Anthony Jun2, Philip R. Szeszko4, Anil K. Malhotra4, Julia Linke5,

Michele Wessa5

1Centre for Addiction and Mental Health, University of Toronto; 2Centre for

Addiction and Mental Health; 3Hospital for Sick Children; 4Zucker Hillside

Hospital; 5University of Mainz

Purpose: Recent data suggests substantial shared etiology for the major

psychoses (schizophrenia and bipolar disorder). However, a subset of pa-

tients with schizophrenia (with the “deficit” form of illness) may represent

one end of a continuum of neurobiological and social impairment among

patients with major psychoses. We sought to compare patients character-

ized by strong negative symptom burden and poor social function, who

have been classified as “deficit syndrome”, to nondeficit patients with

minimal negative symptom burden and bipolar disorder patients, using a

brain network connectivity approach, and relate abnormal brain circuitry

to impairment in social function.

Methods: Following high resolution structural magnetic resonance imag-

ing, and diffusion tensor imaging, brain-wide inter-regional correlations in

cortical thickness were examined in schizophrenia subjects ranked in the

top (n=18 deficit subjects) and bottom (n=18 nondeficit subjects) quartile

of deficit scores. Then, n=32 deficit, n=32 nondeficit subjects, and n=32

healthy controls were combined from the Hillside and Toronto samples. In

addition, n=32 bipolar subjects were compared to n=32 controls using the

same network topology methods to investigate cortical thickness networks

across the major psychoses. A subset of schizophrenia patients (n=22)

completed the quality of life scale (QLS). Correlations with altered brain

network structure in relation to social and functional outcome measures

were examined.

Results: Deficit schizophrenia subjects demonstrated a larger number of

strong positive correlations among cortical regions compared to individuals

with nondeficit schizophrenia, bipolar disorder, or healthy controls subjects

resulting in a network with increased density of connections. The network