Dara S. Manoach, Ph.D. - US grants

This is an application for a NIMH Mentored Patient-Oriented Research Career Development Award (K-23) entitled, fMRI and TMS of Working Memory in Schizophrenia. Working memory (WM) deficits are a persistent, disabling and treatment-resistant feature of schizophrenia that are associated with dorsolateral prefrontal cortex (DLPFC) dysfunction. However, the responsible neural circuitry and the exact contribution of the DLPFC are unknown. The candidate aims to elucidate the neural basis and nature of WM deficits in schizophrenia. This work will clarify the function of the DLPFC and other components of WM neural circiutry and contribute to the development of more focused interventions to improve WM and the behaviors that rely on it. The DLPFC is a large and functionally heterogeneous area. Event- related functional magnetic resonance imaging (fMRI) on a 3.0 Tesla system and high resolution cortical flat mapping will be used to identify DLPFC subregions associated with each temporally separated behavioral subcomponent of WM performance in normal and schizophrenia subjects. Using a stereotactic mapping system, transcranial magnetic stimulation (TMS) will be applied to these DLPFC subregions, identified in each subject with fMRI, to produce reversible functional disruption with millisecond accuracy during WM performance. This will establish whether a region is necessary for WM, and the timing of its contribution. Together, these complementary methods yield more precise information about the location, timing and contribution of regional brain activity to WM than was previously available. The two WM paradigms employed in these paired fMRI/TMS studies will test the hypothesis that schizophrenia subjects fail to automate WM performance as reflected in aberrant recruitment of frontostriatal neural circuitry, a failure to show the normal lateralization of DLPFC function in response to task demands, and an increased sensitivity of DLPFC function to WM load. The training program supplements the candidate s strengths in experimental psycholpathology and neuropsychology and capitalizes on the rich, diverse neuroscience community in the Boston area. It provides didactic instruction and expert mentorship in advanced statistics, event-related fMRI, cortical flat mapping, TMS and models of brain function relevant to schizophrenia. The integrated training and research program will allow the candidate to master complex and sophisticated tools and to establish herself as an independent investigator of the neurobiology of cognitive deficits and symptoms in schizophrenia.

DESCRIPTION (provided by applicant): This is a revised application to study the neural bases of executive function deficits in schizophrenia using complementary neuroimaging techniques. Executive function deficits are reflected in behavior that is stimulus-bound rather than guided by context, perseverative, and stereotyped. They reliably predict poor functional outcome (Green et al 2000). We recently reported intact task-switching in the context of deficient saccadic inhibition during a single paradigm in schizophrenia (Manoach et al 2002b). This behavioral dissociation demonstrates that executive function deficits in schizophrenia are selective and suggests that these functions are mediated by distinct neural circuitry. The primary aim of the proposed work is to identify this spared and impaired neural circuitry using the same saccadic paradigm adapted for neuroimaging. However, a purely anatomical approach may be too limited. Accumulating evidence, including our preliminary data, suggests that the timing of neuronal processes across regions may be key to understanding these deficits. To explore this possibility, we will integrate the findings of event-related functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). MEG alone has poor spatial resolution, but by using the detailed spatial information provided by anatomical and functional MRI as constraints, the exact timing of the contribution of each region can be discerned. We will recruit 20 first episode (FE) patients (neuroleptic naive when possible), 20 chronic medicated patients and 20 healthy subjects to participate in the paired fMRUMEG saccadic studies. Saccadic eye movements utilize a control system with a well-delineated neuroanatomy and physiology. They will be measured during scanning so that correct and error trials can be separated and compared. We will isolate processes involved in inhibition and task-switching. By integrating the findings of fMRI and MEG, we will create spatiotemporal maps of task-related brain activity changes. The schizophrenic and healthy groups will be compared with regard to the timing, location, and magnitude of task-related fMRI and MEG signal changes. This will allow us to precisely delineate differences in the spatiotemporal patterns of activation associated with inhibition and task-switching in schizophrenia. Identifying the neural processes underlying intact and deficient executive function will aid investigations of neuropathology and contribute to the development of more focused interventions and rehabilitative strategies.

[unreadable] DESCRIPTION (provided by applicant): Optimizing behavior depends on the ongoing monitoring and flexible adjustment of responses. Schizophrenia is characterized by responses that are rigid, stereotyped, and perseverative rather than guided by context. We propose to study the neural bases of cognitive functions that are essential to adaptive, flexible responding and how they go awry in schizophrenia. First, we will examine the neural bases of spared and impaired aspects of 'error processing'. An intact error processing system is necessary for detecting and providing feedback regarding the occurrence of errors so that behavioral adjustments can be made. While it is critical to learn from feedback regarding past performance, behavior also has to be responsive to current contingencies. We present evidence that the balance between past and present influences is upset in schizophrenia leading to perseveration - the maladaptive persistence of responses. Our second aim is to study the mechanisms underlying perseveration by examining how the requirement to inhibit a prepotent behavior leads to abnormally persistent effects on the response system. We propose to use variations of the antisaccade (AS) paradigm in these experiments because of its well-charted neuroanatomy and neurophysiology. We will combine the spatial precision of event-related functional magnetic resonance imaging (fMRI) with the high temporal resolution of magnetoencephalography (MEG) to identify the regions involved and the timing of their contribution at various stages of AS performance. Since AS performance is the product of coordinated activity across a distributed network, we will also assess the integrity of white matter tracts using Diffusion Tensor Imaging (DTI). Together, these methods will allow us to precisely delineate the neural bases of intact and compromised cognitive function in schizophrenia. In order to adapt to the environment, it is necessary to both learn from the past and to respond to present task demands. Brain networks that are critical to evaluating performance, remediating behavior, and responding flexibly to current task demands are impaired in schizophrenia, and this likely contributes to rigid and maladaptive patterns of behavior. This research will identify the neural basis of both spared and impaired cognitive processes, guide investigations of neuropathology, and provide targets for intervention aimed at improving cognition in schizophrenia. [unreadable] [unreadable] [unreadable]

CRISP; Clinical Trials; Clinical Trials, Unspecified; Cognition; Cognitive; Cognitive deficits; Computer Retrieval of Information on Scientific Projects Database; Eszopiclone; FLR; Failure (biologic function); Funding; Goals; Grant; IQ Deficit; Institution; Investigators; Learning; Left; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neurocognitive Deficit; Process; Research; Research Personnel; Research Resources; Researchers; Resistance; Resources; Schizophrenia; Schizophrenic Disorders; Sleep; Source; United States National Institutes of Health; base; clinical investigation; dementia praecox; failure; improved; resistant; schizophrenic

Converging lines of evidence support the hypothesis that the sleep spindle deficit in schizophrenia (SZ), contributes to highly disabling and treatment-refractory cognitive deficits and to symptoms and, importantly, is treatable. In the first three-year cycle of this R01, we examined the effects of eszopiclone (Lunesta) on sleep spindles and sleep-dependent memory consolidation in SZ. Although it significantly increased spindles, and spindles correlated with memory, disappointingly, eszopiclone failed to improve memory. Recent findings from our labs and others provide an explanation for this failure and motivate the present proposal. Memory consolidation relies not only on the number of spindles, but also on their temporal coordination with other sleep oscillations. During sleep, hippocampal sharp wave ripples (SWRs), which correspond to memory reactivation, coordinate with spindles and cortical slow waves (CSWs) to transfer new memories from temporary storage in the hippocampus to more permanent representation in the cortex. In SZ we recently showed that both the number of spindles and their temporal coordination with CSWs predict memory consolidation. Our preliminary findings indicate that eszopiclone disrupts this spindle-CSW timing in humans and suppresses SWRs in rats. These effects of eszopiclone on sleep oscillations may account for its failure to improve memory. The goal of this grant cycle is to develop and validate a pipeline to efficiently identify the most promising drugs for improving sleep-dependent memory consolidation by determining their effects on all three oscillations (spindles-CSWs-SWRs), their temporal coordination and memory consolidation before moving to larger and more costly clinical trials. Because hippocampal SWRs are difficult to measure noninvasively, this pipeline requires complementary rodent and human studies. The rodent studies will use large-scale neuronal ensemble recordings to examine the effects of zolpidem and eszopiclone on the coordination of hippocampal SWRs, sleep spindles and CSWs and on memory. The parallel human study will obtain high-density spatial data from simultaneously-acquired EEG/magnetoencephalography (MEG) during a daytime nap from both healthy individuals and SZ patients to test the effects of zolpidem on spindles, CSWs, and their coordination and how these effects correlate with changes in sleep-dependent declarative memory consolidation. The choice of zolpidem is based on findings that it increases both spindle-CSW coupling and hippocampal SWRs and also improves sleep-dependent declarative memory, but has not been tested in SZ. In addition to identifying the most promising drugs for future clinical trials to ameliorate cognitive deficits in SZ and evaluating zolpidem as a potential candidate, this research program will elucidate how sleep oscillations act in concert to mediate memory consolidation. This knowledge will open new avenues for identifying and treating sleep- related cognitive deficits in a range of disorders characterized by abnormal sleep.

DESCRIPTION (provided by applicant): I am a licensed clinical neuropsychologist and a cognitive neuroscientist. I have devoted my career to understanding the neural basis and nature of fundamental cognitive deficits in neuropsychiatric disorders, primarily schizophrenia. I serve as a Psychologist and an Associate Professor of Psychology in the Department of Psychiatry at Massachusetts General Hospital (MGH) and Harvard Medical School. I also serve as the Director of the Laboratory for Multimodal Neuroimaging of Executive Function in the Division of Psychiatric Neuroimaging at MGH. I have been conducting NIMH sponsored patient oriented research (POR) continuously since the initiation of my K23 award in 1999. Since 2003, I have been the PI on an R01 entitled, Spatiotemporal dynamics of context processing in schizophrenia. The goal of this work is to identify the neural bases of fundamental cognitive deficits using complementary neuroimaging techniques. I am also the PI on the new parent R01 entitled, Sleep-Dependent Memory Processing in Schizophrenia, which will link a specific cognitive deficit (impaired memory consolidation) to a particular mechanism (abnormal sleep spindles) and provide an effective treatment (eszopiclone, which restored sleep spindles and memory in a placebo-controlled pilot study). More broadly, this research program has the potential to substantially expand current models of cognitive deficits in neuropsychiatric disorders and lead to effective interventions. I work in an incredibly rich environment for clinica research and have assembled a dream team of collaborators. I receive no institutional support for mentoring or research and without additional funding, I will have to curtail these activities t assume significant clinical responsibilities beginning in 2012. The K24 will protect time that would otherwise be diverted to clinical responsibilities and allow me to devote more time to providing intensive ongoing mentorship to junior investigators in POR (30%) and to further develop my expertise in the neuroscience and measurement of sleep via new training and research (20%) while continuing to devote 50% of my effort to conducting funded POR that translates advances in neuroscience into treatments for cognitive deficits.

? DESCRIPTION (provided by applicant): A burgeoning literature suggests that sleep spindles mediate sleep-dependent memory consolidation and cognitive function more generally. At the same time, several recent studies show that sleep spindles are dramatically reduced in SZ. Cognitive deficits are a core feature of schizophrenia (SZ) that underlie significant functional disability and effective treatments are lacking. Previous work from our laboratories links the sleep spindle deficit with an impairment of sleep-dependent memory consolidation, IQ and executive function in SZ, and suggests that it is treatable. But it is unclear whether this sleep spindle deficit is present early in SZ, and whether it reflects a core disturbance central to its pathophysiology and familial risk of illness. In this study, we will examine sleep spindles, their relationship to memory consolidation and cognition more generally, and their neural underpinnings in early-course patients both with SZ (E-SZ; n=30), and with other psychoses (E-NSZ; n=30), in young relatives of SZ patients at familial high risk for SZ (FHR; n=60) and in healthy comparison (HC) subjects matched for age, sex and parental socioeconomic status. We hypothesize (i) that E-SZ and FHR, but not E-NSZ, will show reduced spindles compared with HC; (ii) that spindle number and density will correlate with sleep-dependent memory consolidation, IQ and overall cognitive function in all groups, and that deficient sleep spindles will correlate with positive and prodromal symptoms in E-SZ and FHR; and (iii) that during the sleep that follows motor task learning, HC and E-NSZ, but not E-SZ or FHR participants, will show increased spindle density and coherence, specifically in the motor network. We also predict that reduced spindle density will correlate with a reduction in thalamocortical functional and structural connectivity. Our hypotheses, if confirmed, will help establish the sleep spindle deficit as (i) an endophenotype of SZ, which can serve as a biomarker of familial risk (for studying the etiopathology of SZ), and (ii) a target for novel treatments of cognitive impairment.

This research proposal addresses a key challenge to drug development: the paucity of biomarkers that reveal whether interventions affect implicated brain circuitry at early stages, in animals and humans, before embarking on lengthy and expensive clinical trials. Studies of humans and rodents have established sleep spindles, defining EEG oscillations of stage 2 non-rapid eye movement (NREM) sleep, as a mechanism of memory consolidation. A growing body of work implicates sleep spindle abnormalities in neurodevelopmental and neurodegenerative disorders characterized by memory impairment. In schizophrenia, sleep spindle deficits predict impaired sleep- dependent memory consolidation. Findings that increasing spindles via drugs or auditory or transcranial brain stimulation during sleep improves memory in healthy people, provides the impetus to target spindles to improve memory in disorders. But targeting spindles does not inevitably improve memory. Complementary rodent and human studies provide an explanation: sleep-dependent memory consolidation relies not on spindles alone, but on their precise temporal coordination with the other two cardinal NREM sleep oscillations: cortical slow oscillations (SOs) and hippocampal sharp-wave ripples. These findings make it clear that while spindles are promising targets for improving memory, (i) effective therapies need to increase spindles AND preserve or enhance their coupling with SOs and ripples, and (ii) to evaluate efficacy, we need new assays to identify spindles that couple with SOs and ripples to mediate memory versus those that do not. We propose to: (i) identify the most powerful translational measures of sleep spindles as assays of sleep-dependent memory consolidation (UG3), and (ii) to noninvasively manipulate them to compare their responses in healthy humans and rodents (UH3). Using invasive recordings in epilepsy patients and local field potentials (LFPs) in rats, we will first demonstrate that spindles that couple with both SOs and ripples (TriCS: triple-coupled spindles) are associated with memory consolidation, thereby validating TriCS as a translational biomarker of memory. We will then use machine learning to develop a classifier that identifies TriCS based solely on their scalp EEG features. We will validate the EEG spindle classifier by applying it to a dataset from healthy humans to demonstrate that TriCS, but not non-coupled spindles, correlate with memory consolidation. In both species, we will determine which spindle assay TriCS, SO-coupled spindles (SOCS) or total spindles predicts memory best. Finally, we will noninvasively manipulate the spindle assays in humans and rats. Genetic studies are implicating specific pathophysiologic mechanisms of spindle deficits in schizophrenia and autism and identifying novel targets and treatments. The rodent and human spindle assays that we will develop will facilitate the translation of these advances to the clinic by allowing the efficient evaluation of potential interventions early in the treatment development pipeline and the identification of the most promising candidates for clinical trials.