2012 — 2016 |
Salisbury, Dean F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mismatch Negativity and Complex Second-Order Sensory Memory in Schizophrenia @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): A major component of the pathophysiology in schizophrenia involves an imbalance between excitatory glutamate and inhibitory GABA in the cortex, and consequent problems in coherent local circuit function and at the NMDA receptor related to neuronal plasticity and learning. Coherent local circuit activity is crucial for real tie pattern analysis in sensory cortex and for rule learning involving frontal, temporal, and parietal cortices. Mismatch negativity (MMN) is a brainwave that is sensitive to Glu-GABA imbalance, and is abolished by drugs that block NMDA. MMN to simple stimulus changes (a soft tone among repetitive loud tones, or a high note among repetitive low notes) arises in primary and initial secondary auditory cortices, and is reduced in chronic schizophrenia. Yet the simple MMN is healthy at first psychotic break, though it declines during the early disease course in conjunction with primary auditory cortex gray matter loss, and is also normal in relatives. Because of this simple MMN cannot be used for family/genetic studies or for pre- or pro-dromal identification. Recently it has been discovered that MMN is elicited by more complex stimulus patterns and learned rules. These higher-order MMNs have not been studied in schizophrenia. Because of their complexity, abstraction of these rules requires involvement of sophisticated brain circuits spanning secondary cortices across frontal and temporal lobes. Complex MMN, intimately tied to NMDA-modulated memory formation, is likely to be more sensitive to and provide a more precise index of Glu-GABA imbalance in schizophrenia, even at or before first break, and in relatives. The main aim of this project is to detect the presence of complex memory MMN deficits in tasks that require second-order analysis of stimulus patterns and learned rules. As a first step, this project aims to identify complex MMN deficits in well characterized schizophrenia participants and first break patients before moving to at risk persons and relatives. Nine experiments will examine increasingly more complex second-order memory. If 5 tones played with a short delay between them are always followed by a long delay, gestalt proximity makes one form a unit of 5 tones. Violating that rule by adding or subtracting from the group of 5 elicits a complex MMN. Violations of second order rules of increasing pitch, duration, or loudness trends generate a MMN. Experience with language is used to aid perception of phonemes. (Consider how one needs to hear a foreign language for some time before perceiving the gap between words.) We predict that schizophrenics will not use learned rules for phoneme categories and will actually be more sensitive to acoustic differences in syllables than will controls. Demonstrating defects in MMN to second order memory is important for understanding the basic pathophysiology in schizophrenia, will provide novel and more sensitive indices of Glu-GABA imbalance in the disorder, and increase the utility of MMN as a tool for early identification and treatment of at risk persons before they have a full blown psychotic break, and for family studies and discovery of the basic genetic risk factors for the disease.
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0.958 |
2016 — 2021 |
Salisbury, Dean F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Auditory Attention in First Episode Psychosis @ University of Pittsburgh At Pittsburgh
Selective attention, the ability to focus on one percept among others, is one of the first executive functions affected by psychosis. Basic neuroscience work has begun to elucidate the underlying mechanisms of how selective attention, arising in prefrontal cortex, modulates sensory cortex activity via connections with posterior parietal cortex. In terms of physiology, alpha waves (~10 Hz) and gamma waves (~40 Hz) appear to play a central role in the effects of attention, by which sensory activity to to-be-attended events is increased, while sensory activity to to-be-ignored events is decreased. In human cognitive neuroscience research, studies that examine functional connectivity between different areas of the brain on the basis of specific oscillations (rather than at the scalp) are relatively few. The proposed studies will expand our knowledge of how attention increases sensory activity in the human brain, and how these processes go awry in newly emerging psychosis. In human psychopathology research, several emerging threads have changed the way psychosis is understood. First, evidence indicates progressive cognitive and cortical gray matter decline during the early disease course, even prior to the emergence of psychosis. Second, increasing evidence suggests that psychosis not only affects the highest levels of cognition, but that sensory processes are affected as well. What is not known is to what degree these sensory deficits are due to progressive pathology of cortical sensory areas or to progressive pathology of executive control centers in prefrontal cortex and posterior parietal cortex, such that modulation of sensory activity by executive centers is impaired via reduced functional connectivity. Both schizophrenia and affective psychosis are thought to be late neurodevelopmental disorders with progressive worsening. We hypothesize that higher-order operations that require long range communication and synchronization between multiple distal cortical areas and highly complex integrated processing will be affected first. Hence, we suggest selective attention-based modulation of sensory activity will be impaired quite early in disease course. Our primary goal is to examine how attention affects sensory activity in the auditory system as subjects attend or ignore one tone, two tones, or four tones, thereby increasing the attentional demand for each task. We will use combined EEG & MEG reconstructed into individual brain morphology from structural MRI which will allow for highly precise measurement of neural activity within the brain as participants perform the tasks. Subjects will be tested at first psychotic episode and 6 months later to follow any progressive pathology, and at 12 months to assign definitive diagnoses. A secondary goal is to determine if deficits in the ability to modulate sensory activity by attention, as indicated in our preliminary data, may serve as biomarkers for emerging psychosis. If so, our next step would be to examine attentional modulation of sensory signals in high-risk possibly prodromal help seekers. Thus our strategy is to validate potential pre- psychosis biomarkers right at the emergence of psychosis in known cases, which may then be used to detect the relatively few high-risk help seekers that are actually prodromal for psychosis.
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0.958 |
2017 — 2021 |
Salisbury, Dean F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Auditory Cortex Connectivity in Emerging Psychosis @ University of Pittsburgh At Pittsburgh
Summary Auditory verbal hallucinations (AVH) are a pervasive debilitating symptom of psychosis. Understanding the pathology and pathophysiology underlying AVH would provide scientific knowledge about brain abnormalities in psychosis, and reveal a target neurobiological system for novel interventions such as brain stimulation. Yet, it is not known where in the brain disorders of structure or function lead to AVH, what role gray matter (local information processing) and white matter (information flow between distributed gray matter areas) abnormalities play, whether distinct patterns of pathophysiology underlie different types of AVH, when neurobiological abnormalities emerge in the prepsychotic prodromal phase, and how pathology and pathophysiology progress in the early disease course after psychosis and AVH emerge. This project aims to understand the neurobiology of AVH by examining structure and function in a left-hemisphere dominant language circuit thought to be involved in the genesis of AVH cross-diagnostically during initial stages of psychosis comprising the clinical high risk stage, the first psychotic episode stage, and longitudinally into the early psychosis stage. Individuals will express a range of severity of auditory perceptual aberrations, beginning with no symptoms, progressing through attenuated psychotic auditory misperceptions and then AVH of increasing intensity and duration, culminating in severe constant AVH. Our overarching hypothesis is that AVH are caused by a final common pathway of overactivity in left Wernicke's area that leads to overstimulation of upstream auditory sensory cortices and downstream semantic language stores. We will examine neurophysiology (simultaneous EEG and MEG) and hemodynamic measures of brain activity (MRI-based arterial spin labeling) to assess resting level activation and network functional connectivity in a distributed frontal (Broca's area), temporal (Wernicke's area and primary auditory cortex), and limbic system (putamen) language-related circuit, gray matter volumes in these areas (structural MRI) and the integrity of the white matter tracts connecting them (MRI-based Diffusion Spectrum Imaging), and EEG & MEG during a verbal fluency task. Our pilot data indicate that worse AVH are associated with increased verbal fluency at all disease stages. Further AVH of voices commenting appear to arise due to hypo-connected Broca's and Wernicke's areas, whereas AVH of other (typically negative) voices are associated with hyper-connectivity with the limbic putamen. We hypothesize that abnormalities in this language system will be detected in the prodromal and at risk stage that will correlate with auditory perceptual aberrations, in the first episode stage that correlate with AVH intensity, and that the pathology and pathophysiology will worsen during the first year post-psychotic break, particularly in the white matter integrity and the network functional connectivity dynamics. Regarding therapeutic targets, if Wernicke's overactivity is shown to be the final common pathway for AVH, then a rationale for inhibitory brain stimulation is provided, and if different components of the language circuit are implicated in the phenomenology of AVH, then strategies to differentially target cortical and subcortical structures are warranted.
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0.958 |
2017 — 2018 |
Doiron, Brent D. (co-PI) [⬀] Salisbury, Dean F Teichert, Tobias |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Understanding the Synaptic, Cellular and Circuit Events of Meg & Eeg Using a Vertically Translational Cross-Species Approach @ University of Pittsburgh At Pittsburgh
7. PROJECT SUMMARY Background. Electro- and magneto-encephalographic (EEG/MEG) responses to a stimulus are systematically attenuated? by up to 80%? if the same stimulus was presented less than 8-12 seconds ago. This dynamic modulation of response amplitude to identical stimuli is one of the most striking and fundamental properties of the EEG/MEG signal. The proposed work will test the hypotheses (1) that the attenuation of EEG/MEG amplitude to repeated identical stimuli is caused by short-term synaptic depression at cortical synapses and (2) that the manifestation of synaptic depression at the micro- and meso-scopic level critically depends on local circuit and network architecture leading to a complex but systematic relationship between macroscopic modulation of EEG/MEG responses and several micro- and mesoscopic measures of neural function.
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0.958 |