Hesheng Liu - US grants

DESCRIPTION (provided by applicant): Pre-surgical evaluation benefits from information about the location of functional brain systems and dysfunctional tissue. Recently, methods based on analysis of spontaneous activity measured by functional MRI have shown promise for identifying brain systems in subjects resting and while asleep. Here we will develop and evaluate a novel method using rest-state intrinsic activity to map multiple systems within the brain including language, memory, and motor systems. Specifically, this project aims to address three critical challenges in pre-surgical mapping. First, this project will seek to develop a new language and memory lateralization technique as a candidate to replace the traditional invasive Wada test. Second, we hypothesize that essential areas of cortex can be mapped using intrinsic functional connectivity linked to specific brain systems. Finally, by assessing the disruption of functional connectivity, we will seek to localize brain lesions and epileptogenic cortex. This project proposes a new approach for pre-surgical mapping for patients with brain lesions and has the potential to significantly improve surgical planning. PUBLIC HEALTH RELEVANCE: This project aims to replace the traditional pre-surgical mapping by providing a means to determine functional laterality, eloquent cortex and epileptic foci simultaneously and with minimal task requirements.

DESCRIPTION (provided by applicant): Pre-surgical evaluation benefits from information about the location of functional brain systems and dysfunctional tissue. Recently, methods based on analysis of spontaneous activity measured by functional MRI have shown promise for identifying brain systems in subjects resting and while asleep. Here we will develop and evaluate a novel method using rest-state intrinsic activity to map multiple systems within the brain including language, memory, and motor systems. Specifically, this project aims to address three critical challenges in pre-surgical mapping. First, this project will seek to develop a new language and memory lateralization technique as a candidate to replace the traditional invasive Wada test. Second, we hypothesize that essential areas of cortex can be mapped using intrinsic functional connectivity linked to specific brain systems. Finally, by assessing the disruption of functional connectivity, we will seek to localize brain lesions and epileptogenic cortex. This project proposes a new approach for pre-surgical mapping for patients with brain lesions and has the potential to significantly improve surgical planning. PUBLIC HEALTH RELEVANCE: This project aims to replace the traditional pre-surgical mapping by providing a means to determine functional laterality, eloquent cortex and epileptic foci simultaneously and with minimal task requirements.

? DESCRIPTION (provided by applicant): Localization of brain function is important to minimize functional deficits after neurosurgical procedures. A long-standing goal has been to obtain this information pre-operatively to better predict risk and plan the surgical approach. Although many non-invasive tools are available, fMRI has seen the greatest clinical use. Unfortunately, pre-operative mapping with fMRI suffers from poor signal to noise ratio (SNR) and test-retest reliability at the single-subject level, and the resulting maps are not always consistent with the findings of invasive electrical cortical stimulation (ECS), causing many to question its clinical utility. Recently, our laboratory and others have made major advances that may help address these limitations. Many of these advances have focused on connectivity imaging based on spontaneous activity, catalyzed in part by the NIH Human Connectome Project (HCP). These technical innovations and theoretical advancements are now ripe for being translated to individual clinical patients, but require optimization and validation. The goal of this project is o translate cutting-edge connectivity-based imaging technology to the clinical arena by developing and validating a set of functional mapping tools that can provide individual-level precision and guide surgical intervention. Specifically, we will develop and validate a connectivity-based parcellation technology that can localize functional networks in individual subjects, including in patients with altered brain anatomy. Second, we will develop and validate a connectivity-based method to quantify the lateralization of important cognitive functions and overcome the influence of anatomical asymmetry. Finally, we propose a strategy to improve mapping accuracy when patients are able to perform tasks by flexibly combining the information obtained from spontaneous connectivity and task-evoked responses. This strategy will allow us to leverage the lessons learned from 20 years of exploration using task fMRI and recent revolutionary advancements in connectivity research. The successful completion of this project will greatly improve the clinical value of fMRI in surgical planning, as well as in a wide range of clinical applications. The project will offer a set of comprehensive and extensively tested functional mapping tools suitable for the study of individual subjects with greater sensitivity and reliabilit than are currently available. This increase in mapping precision will directly translate into an enhanced ability to a) predict and reduce postoperative functional deficits, as well as to b) design individualized treatment plans for many neurological and psychiatric patients.

PROJECT SUMMARY/ABSTRACT This R21 proposal aims to provide detailed understanding of how finely parcellated subareas of the auditory cortex (AC) are functionally connected with one another and with cerebellar regions in schizophrenia (SZ) patients with auditory hallucinations (AH). AH can be disabling, and do not always respond to existing treatments. A clear understanding of AH pathophysiology is needed to guide the development of more effective treatments for AH, but such knowledge is currently lacking. Previous research suggests that the AC is abnormal in AH, suggesting a possible perceptual basis for AH. The AC, however, is one of many brain regions implicated in AH pathogenesis, and a better understanding of how AC interacts with other critical brain areas is needed. The cerebellum coordinates a host of cerebral cortical functions?including higher-level cognitive, affective, and perceptual processes?rather than just motor functions, as traditionally believed. Consistent with this framework, the myriad symptoms of psychosis have been proposed to reflect ?dysmetria,? or incoordination, of mental activity due to disruptions in cerebro-cerebellar circuits (Andreasen, et al., 1996; Schmahmann, 1998). Given evidence that the cerebellum is reciprocally connected to AC and coordinates auditory processing, there is motivation to understand how abnormal AC-cerebellar circuitry might lead to `auditory dysmetria', and AH. We propose to examine features of local AC circuitry and AC-cerebellar circuitry underlying AH by utilizing an innovative and highly reliable AC parcellation strategy based on resting state functional magnetic resonance imaging (rsfMRI). This parcellation method, which computes functional connectivity (FC) between voxels in AC and the rest of the brain, will be used to segment AC into multiple subareas. Subdividing the AC at this fine- grained a level could only be achieved before with postmortem (e.g., cytoarchitectonic) methods. Here, these individual-specific and functionally defined AC subareas will serve as the seeds for FC between AC subareas and between AC and cerebellum. Our aims are to identify features of AC inter-subarea FC (Aim 1) and features of AC-cerebellar FC (Aim 2) that track with AH severity in SZ. We also aim to validate how these markers change with intra-subject variations in AH (Aim 3), using data from an independent interventional longitudinal study. Our hypotheses are two-fold: (1) The AC is comprised of a complex local network of both primary sensory and association subareas, and FC between AC subareas is meaningfully associated with AH. (2) The cerebellum plays a key role in coordinating activity in AC subareas, and this process is `dysmetric' in AH. This project is significant because it is the first step in a continuum of research that is expected to lead to the development of more targeted and personalized treatments for AH. Repetitive transcranial magnetic stimulation (rTMS) is a promising non-pharmacological treatment for AH. We propose that stimulation of cerebellar regions that are connected to association subareas of AC may provide access to circuits that are dysmetric in AH. We expect that this proposal will identify potential cerebellar targets for rTMS that can be tested in a future clinical trial.

Mapping the intrinsic functional organization of auditory cortex in individual subjects using 7T MRI Despite countless studies, only broader processing streams of the human auditory cortex (AC) are currently known. The lack of a widely accepted model of human ACs, analogous to that described in non-human primates, has contributed to fundamental theoretical disagreements on sound processing in the human brain. Better understanding of human ACs is crucial for the development of biomarkers and interventions for disorders involving auditory processing deficits and speech and language impairments. Studies of human ACs have been complicated by unique technical barriers, such as their small anatomical scale that hinders fMRI studies at conventional resolutions. However, there are also theoretically important reasons why ACs have been harder to map than other sensory areas: Compared to early visual cortices, human ACs are activated by broader combinations of features and show larger inter-individual variability in anatomy and function. Instead of a feature-specific area only, human ACs could constitute a higher-level processing center, which is needed to support the increasingly complex auditory skills that have evolved in humans only. Achieving a more fundamental understanding of human auditory cognition requires a novel perspective, which considers how human ACs work as a whole and interact with the rest of the human brain. This calls for techniques suited for individual-level studies of dynamic functional networks, instead of group analyses of fMRI localizer data. Unfortunately, to date, such techniques have been lacking. This project combines advanced computational analyses and ultra-high resolution 7T fMRI, to achieve an entirely novel way to characterize the functional organization of human AC in individual subjects. Our proposed work is built on recent revolutionary advances in our laboratories that allow focusing on individual subjects and dynamic functional activity patterns using ultra-high resolution 7T MRI. We will use these novel techniques to study AC activity during (a) the resting state and (b) complex auditory stimulation, and (c) compare the results to the traditional gold standard, tonotopy and bandwidth sensitivity mapping. To precisely map the functional organization of AC in individual subjects, we will use sub-millimeter resolution 7T fMRI, complemented with advanced anatomical MRI analyses of cortical folding patterns, thickness, and intracortical myelin content. fMRI results will be validated using intracranial EEG data from pre-operative patients. These methods will be utilized to localize fine-grained subareas of ACs in individual subjects (Aim 1), characterize AC co-activation patterns that are distributed but stimulus-category specific (Aim 2), and finally to examine the individual variability of the functional arrangement of ACs and compare it to auditory-cognitive abilities (Aim 3).