Document text
Principal Investigator: Brian A Coffman
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $737,239
Funding agency: National Institute of Mental Health
Schizophrenia (Sz) is a debilitating major mental illness with life-long disability that disproportionately burdens the
healthcare system and society. Despite decades of research, the underlying mechanisms of pathophysiology in
Sz are unknown. Attempts for determining brain abnormalities in Sz have gone beyond searching for one to a few
lesion locations to focusing on functional (dys)connectivity between systems-level brain circuits and the associated
neural events that underlie the failure in functional integration of information across distributed circuits. Effective
connectivity refers to the influence of activity in one area on activity in another at a later time, allowing inferences
about directionality. Our overarching hypothesis is that long-range cortical effective connectivity is a fundamental
biological system abnormality in schizophrenia, particularly between prefrontal cortex and sensory areas. This
proposal comprises a systems-level examination of structure, function, and connectivity in a distributed system
known to be impaired in Sz, the temporal lobe auditory cortices and the inferior frontal gyrus auditory-executive
cortex involved in the generation of mismatch negativity (MMN), an index of automatic auditory change detection.
We will examine effective connectivity between nodes of this distributed system, and use computational modeling
to translate neurophysiological information from EEG & MEG to synaptic conductances, indicating possible
molecular mechanisms of the systems-level deficits. Central to our approach is testing of individuals at their first
clinical contact for schizophrenia-spectrum psychosis (first episode schizophrenia-spectrum, FESz), where the
progressive primary and secondary disease effects on brain structure and function are minimized. Pathophysiology
proximal to disease onset very likely reflects processes critical to disease etiology. In FESz, we test 3 auditory
tests of increasing pattern complexity to differentially tax the auditory change detection system, measure brain
activity with combined high-temporal resolution EEG & MEG measures of neurophysiology, and construct
high-spatial resolution measures of brain structure to project sensor activity to cortical sources, compared and
contrasted between FESz and well individuals (AIM 1). Using advanced measures of spectral effective connectivity
(phase transfer entropy) on the source-resolved activity, we will determine dysconnectivity between the frontal and
temporal cortical sources in FESz on these tasks (AIM 2). Next, using computational modeling of a laminar cortical
circuit to replace single equivalent dipoles at each source, we will determine synaptic conductance deficits in
AMPA, GABA, and NMDA activity that may underlie the dysconnectivity in FESz (AIM 3). Finally, to assess
changes in brain structure, function, and connectivity after the onset of psychosis, we will test participants
longitudinally 6 months later to track progressive impairments (AIM 4). We believe studying the interactions
between bottom-up and top-down cortical processes shows great promise for understanding the basic molecular
mechanisms of predictive coding, learning, memory, attention, and other key brain functions that seem to be
compromised by Sz.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Accounting><Aminalon><Aminalone><Area><Attention><Audiogram><Audiometric Test><Audiometry><Auditory><Auditory Cortex><Auditory area><Automobile Driving><Biologic Models><Biological Models><Brain><Brain Nervous System><Causality><Clinical><Code><Coding System><Communication><Complex><Computer Models><Computerized Models><Data><Detection><Disease><Disorder><Distributed Systems><Dysfunction><EEG><Ear><Electroencephalogram><Electroencephalography><Encephalon><Entropy><Environment><Etiology><Event><Failure><Frequencies><Functional disorder><GABA><Generations><Glutamates><Head><Health Care Systems><Healthcare Systems><Hearing Tests><Impairment><Individual><Inferior Frontal Convolution><Inferior frontal gyrus><L-Glutamate><Learning><Left><Lesion><Lifelong disability><Location><Loudness><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Major Mental Illness><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Memory><Model System><Modeling><Molecular><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-Aspartate Receptors><N-Methyl-D-aspartate><N-Methylaspartate><N-Methylaspartate Receptors><NMDA><NMDA Receptor-Ionophore Complex><NMDA Receptors><NMR Imaging><NMR Tomography><Nuclear Magnetic Resonance Imaging><Onset of illness><Participant><Pathology><Pattern><Permanent disability><Phase><Physiopathology><Play><Prefrontal Cortex><Process><Psychoses><Pyramidal Cells><Research><Resolution><Role><Scanning><Schizophrenia><Schizophrenic Disorders><Sensory><Social Functioning><Societies><Source><Structure><Synapses><Synaptic><System><Taxes><Temporal Lobe><Testing><Time><Translating><Zeugmatography><auditory tests><biological systems><brain abnormalities><causal diagram><causal model><causation><computational modeling><computational models><computer based models><computerized modeling><dementia praecox><detection platform><detection system><deviancy><deviant><disease causation><disease onset><disorder onset><driving><first episode psychosis><first episode schizophrenia><frontal cortex><frontal lobe><function socially><functioning social><gamma-Aminobutyric Acid><glutamatergic><gray matter><healthcare burden><hearing assessment><indexing><neural><neural circuit><neural circuitry><neurocircuitry><neurophysiological><neurophysiology><novel><pathophysiology><resolutions><schizophrenic><sensor><social role><sound><substantia grisea><synapse><synaptic circuit><synaptic circuitry><temporal cortex><temporal measurement><temporal resolution><time measurement><tool><γ-Aminobutyric Acid>