NEGATIVE SYMPTOMS AND SOCIAL COGNITION IN SCHIZOPHRENIA: NEURAL CIRCUITRY, FUNCTIONAL OUTCOMES, AND...
Transcript of NEGATIVE SYMPTOMS AND SOCIAL COGNITION IN SCHIZOPHRENIA: NEURAL CIRCUITRY, FUNCTIONAL OUTCOMES, AND...
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