Raymond Y. Cho - US grants

[unreadable] DESCRIPTION (provided by applicant): The cognitive impairments in schizophrenia can be characterized as disturbances in cognitive control, defined as the ability to guide one's behavior in accordance with one's goals or intentions. Both the type of control required for successful task performance, and more recently, the signaling mechanisms that elicit control, have been intensely studied. Neuroimaging studies have shown that these components of cognitive control can be anatomically dissociated, with the anterior cingulate cortex (ACC) monitoring for conflict and the dorsolateral prefrontal cortex mediating strategic adjustments in control. Questions remain, however, regarding the precise relationship between different forms of conflict and control. Does conflict signal for control that is context-specific or does it elicit more global effects that generalize across contexts? Preliminary results show that conflict can, indeed, elicit control effects that extend beyond the context within which the conflict was engendered. In this proposal, we seek to replicate and extend these initial findings to assess to what extent control effects may generalize across contexts, using EEC and fMRI to test specific predictions concerning ACC activation, and translate these paradigms to further elucidate control disturbances in schizophrenia, where studies have shown impairments in cognitive control in association with diminished conflict-induced ACC activation. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Cognitive impairments are a prominent feature of schizophrenia and the strongest predictor of functional outcome in this disabling disorder. One of the critical deficits is in context processing, which describes the ability to represent task-relevant information to guide goal-directed behavior. fMRI studies have shown that impaired context processing is associated with decreased prefrontal cortical (PFC) activations in schizophrenia. Similarly, EEG studies have found that disturbances in synchronous PFC oscillations in the gamma range (30-80 Hz) are associated with impaired context processing in schizophrenia. These parallels in the EEG and fMRI findings raise the possibility that disturbed cortical synchrony may underlie the PFC activation disturbances in fMRI studies. Disturbances in PFC gamma synchrony are also consistent with the post-mortem findings in schizophrenia of selective disturbances in fast-spiking interneurons, which are critical for sustaining gamma range synchrony. In this proposal, we aim to provide a synthesis of the above findings, hypothesizing that disturbed PFC gamma synchrony gives rise to impaired context processing in schizophrenia. We will develop a neurobiologically realistic computational model of impaired context processing task performance in schizophrenia, accounting for both impaired performance and disturbed synchrony. To inform and complement our modeling studies, EEG and fMRI studies of context processing will attempt a synthesis of previous findings demonstrating decreased PFC gamma synchrony in EEG and decreased PFC activation in fMRI with the same group of schizophrenia subjects. Establishing a neurobiologically constrained theoretical account and synthesis of empirical findings regarding context processing impairments and their neural basis will be an important step towards the long-term objective of employing biologically realistic models to facilitate novel therapeutic candidates for cognition in schizophrenia and integrated EEG-fMRI methods to evaluate their efficacy. Cognitive disturbances in schizophrenia are one of the most debilitating aspects of the disorder. One of the critical disturbances in cognition is the ability to organize appropriate responses to stimuli and events in the environment. This study seeks to attain a deep understanding of the brain mechanisms associated with such disturbances to facilitate the development of novel therapies for treating cognition in schizophrenia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Disturbances in cortical oscillations are thought to be core to the pathophysiology of sensory and cognitive processing impairments in schizophrenia, with impairments in the gamma-band (30-100 Hz) as well as lower frequency-bands such as theta (4-8 Hz) and alpha (8-12 Hz). There is growing evidence that modulation of gamma by lower frequency bands is also critical for normal sensory and cognitive processing. Accordingly, restoring gamma activity may be necessary but not sufficient for restoring cognitive function, which requires the organizing influence by lower frequency modulations. While such cross-frequency coupling (CFC) is thought to be a core neurocomputational mechanism for regulating gamma oscillations in the service of cognition, CFC has been largely ignored in in schizophrenia research. The current project aims to address this important gap by conducting the first systematic investigation of CFC disturbances in schizophrenia employing an integrated magnetoencephalography (MEG) and computational modeling approach. Investigations of CFC most commonly examine phase-amplitude coupling, reflecting lower frequency changes in membrane excitability that systematically modulates the amplitude of higher frequency oscillations of the local network. Preliminary studies show evidence of disturbances in such phase-amplitude coupling in schizophrenia. Patients performing the auditory steady-state response (ASSR) task, a sensory cortical periodic driving paradigm, showed impaired alpha-gamma coupling compared to controls. Preliminary findings also show prefrontal cortical theta-gamma CFC in healthy controls during working memory performance with strong correlations with working memory capacity, demonstrating feasibility for investigating CFC disturbances in schizophrenia patients. Finally, preliminary computational work modeled post-mortem findings of disturbances in fast-spiking interneurons (FSI) as 'lesions' to the model FSI, reproducing disturbances in alpha-gamma CFC. Given these findings, we hypothesize that sensory and prefrontal cortical CFC will be disturbed in schizophrenia and that FSI disturbances are sufficient to provide a mechanistic account of CFC disturbances. These hypotheses will be addressed through the following Specific Aims: (1) To investigate sensory cortical CFC disturbances in early psychosis; (2) To investigate prefrontal cortical CFC disturbances in early psychosis; and (3) To investigate neurocomputational mechanisms of CFC disturbance in early psychosis. We anticipate that this study in early psychosis will reveal disturbances in CFC, a critical organizing mechanism for neural activity underlying sensory and cognitive processing. Together, the findings of this project will provide a novel empirical and theoretical framework for future studies that will aim to pharmacologically target specific components of cortical circuitry o enhance CFC and cognition in schizophrenia.

? DESCRIPTION (provided by applicant): Cognitive deficits are a strong predictor of functional outcome in schizophrenia, yet poorly remediated by current treatments. Disturbances in dorsolateral prefrontal cortex (DLPFC) function underlie core impairments such as in cognitive control and thus represent a critical target for novel therapeutics. Initial studies indicate transcranial direct-current stimulation (tDCS) may be effective in reducing symptoms due to DLPFC dysfunction. While tDCS potentially represents an exciting, novel therapeutic advance, a number of basic questions should be addressed prior to conducting larger-scale clinical trials, including: verifying therapeutic target engagement, optimizing treatment parameters, and evaluating for meaningful clinical effects. Recent studies employing tDCS to enhance prefrontal cortical function in schizophrenia applied stimulating electrodes over the left frontal scalp regio, putatively targeting the left DLPFC. However, explicit confirmation of such target engagement is lacking. Further, EEG studies have demonstrated close links of frontal cortical gamma oscillations to cognitive control processes but modulation of this critical physiologic process has not been investigated. Accordingly, the primary R61 aim (R61-Aim 1) will employ multimodal imaging to explicitly test for the assumed DLPFC engagement (fMRI) and modulation of frontal gamma activity (EEG) by tDCS. The R61-Aim 2 will investigate the optimization of tDCS application parameters. Analogous to dose-finding investigations in drug studies, we will conduct a parametric investigation of optimal current strengths. Also, while there is extensive evidence for tolerability of single session tDCS, confirmation of feasibility of multi- session optimized protocols in schizophrenia is lacking and so will be explicitly evaluated (R61-Aim 3). The R33 phase will be predicated on initial demonstration of target engagement, namely, tDCS modulation of DLPFC BOLD and frontal gamma oscillatory activity (R61-Aim 1). With such demonstration and equipped with an optimized tDCS protocol (R61-Aim 2) that has been verified to be well-tolerated (R61-Aim 3), the R33 phase would then seek to demonstrate clinical effect, namely, the modulation of cognitive control probed by a cued stimulus-response reversal paradigm (R33-Aim 1). We will also evaluate clinical and functional outcome employing relevant assessment tools (BPRS/SANS/SAPS and SLOF/SFS/UPSA-B, respectively) (R33-Aim 2). Finally, we will investigate whether any observed improvements in cognitive control and functional outcome are mediated by DLPFC and frontal gamma oscillation engagement (R33-Aim 3). In summary, a successful outcome of this study would provide tDCS the sound mechanistic, methodologic and clinical-relevance basis for more definitive testing in large-scale clinical trials as a highly innovative therapeutic intervention for cognitive impairments in schizophrenia.

PROJECT SUMMARY Treatment of Major Depressive Disorder (MDD) is a serious clinical challenge as nearly 50% of depressed patients do not fully respond to treatment, referred to as Treatment Resistant Depression (TRD). Current antidepressants take few weeks to work and further, there are no reliable clinical biomarkers available to predict treatment response which leads to several trial-and-error attempts of different treatment strategies. The two leading challenges in MDD research are ? (i) developing better treatments and (ii) developing noninvasive clinically useful biomarkers of antidepressant treatment response. The main objective of this award is to investigate prefrontal cortical excitability as neurobiological mechanisms underlying depression and antidepressant effect of rTMS in patients with TRD by using concurrent Transcranial Magnetic Stimulation- Electroencephalography (TMS-EEG). This project uses an innovative research strategy by deploying TMS-EEG to study cortical excitability in dorsolateral prefrontal cortex in TRD patients at baseline and after intermittent theta burst stimulation (iTBS), a state-of-the-art FDA approved TRD treatment. For baseline comparison with patients, demographically matched healthy controls will have TMS-EEG. The project aims will be accomplished by: 1) Investigating the prefrontal cortical excitability in patients with depression compared with healthy control subjects; 2) Investigating the effect of iTBS on prefrontal cortical excitability; and 3) Investigating the baseline dorsolateral prefrontal cortical excitability measures and its relationship to improvements in mood in patients with TRD. The findings from this study will strengthen our understanding of mechanisms underlying anti-depressant action and thus facilitate development of non-invasive surrogate markers of antidepressant response to iTBS in TRD. This work will contribute to: 1) personalized medicine in MDD by establishing markers of treatment response, 2) understanding rTMS antidepressant effect.