Flavio Frohlich - US grants

DESCRIPTION (provided by applicant): Cognitive symptoms in psychiatric disorders are associated with changes in the temporal structure of brain activity. For example, altered rhythmic activity in the gamma frequency band (>30 Hz) in the cortex is implicated in psychiatric symptoms such as hallucinations, reduced sensory gating, and impaired cognitive control. Despite growing recognition of the functional roles of oscillations in cortex, the dynamics that govern the occurrence of different rhythmic activity states (i.e. cortical state dynamics) remain unknown. Since states with fast rhythms likely enhance sensory processing while states with slow rhythms disconnect cortex from sensory input during rest, understanding cortical state dynamics has broad implications for the study and treatment of cognitive symptoms in schizophrenia, autism, and attention-deficit disorder such as impaired attention and perception. The long-term goal is to understand the electrophysiological signatures and behavioral correlates of cortical state dynamics and to develop individualized brain stimulation to treat mental illness by modulating cortical state dynamics. The objective of the proposed research is to understand cortical state dynamics in response to sensory input and to modulate these dynamics with feedback stimulation using non-invasive transcranial current stimulation in humans. The central hypothesis of this work is that cortical networks exhibit spontaneous and induced transitions between slow and fast oscillatory activity states that can be controlled with non-invasive brain stimulation. In order to test this hypothesis, this work utilizes an interdisciplinary approach that integrates computer simulations, in vivo ferret electrophysiology, and non-invasive transcranial current stimulation coupled with electroen- cephalography (EEG) in healthy human subjects to pursue the following three specific aims: (1) to determine the electrophysiological substrate of cortical states during rest and sensory stimulation, (2) to identify optimal waveforms for transcranial current stimulation as a function of cortical state, an (3) to develop and evaluate feedback transcranial brain stimulation to control cortical state dynamics and modulate their behavioral correlates in humans. This work is significant because feedback brain stimulation radically differs from today's prevalent brain stimulation that utilizes generic, pre-programmed stimulation waveforms. The results of this work are intended to catalyze a paradigm shift in the treatment of mental illnesses to- wards effective, individualized brain stimulation based on rational design.

DESCRIPTION (provided by applicant): Cognition requires precise coordination of electric activity between cortical networks. Impairment of such functional connectivity has been associated with cognitive symptoms in psychiatric illnesses such as schizophrenia and depression. Long-range projections (LRPs) formed by axons of individual neurons likely provide the mechanism for the emergence of macroscopic activity patterns across cortical networks. Yet, it remains unknown how LRPs that exhibit substantial propagation delays can support temporally precise coordination and synchronization of activity across networks. The long-term goal is to develop non-invasive brain stimulation paradigms that reinstate impaired communication between cortical areas. The objective here is to elucidate the causal role of LRPs in the dynamics of two connected cortical networks with a novel biology-computer hybrid system motivated by large-scale computer simulations and to identify non-invasive brain stimulation paradigms to modulate the dynamics of interconnected cortical networks. The working hypothesis is that (1) the propagation delays of the LRPs create a multistable landscape composed of both synchronized and unsynchronized activity states and (2) that simultaneous transcranial alternating current stimulation (tACS) of both networks will induce transitions to synchronized states that persist after termination of stimulation due to network multistability. The rationale for this work is that understanding how non-invasive brain stimulation modulates synchronization of interconnected networks will enable the rational design of novel brain stimulation paradigms that enhance synchronization and information flow in large-scale functional networks. The following two specific aims will be pursued to test the working hypothesis: (1) to determine the role of long-range projections (LRPs) in the emergence of macroscopic activity states in interconnected cortical networks and (2) to elucidate how simultaneous transcranial alternating current stimulation (tACS) of two networks connected by LRPs alters macroscopic activity state. Our approach is innovative since it brings together computer simulations, slice electrophysiology, optogenetics, and feedback control to build a platform for the study of LRPs in a hybrid system that exhibits biological plausibility yet enables precise experimental control over the LRPs. The significance of this works is that understanding the causal role of LRPs in shaping the dynamics of interconnected networks will enable the development of tACS paradigms that directly target impaired interaction dynamics of connected cortical networks in patients with psychiatric and neurological illnesses characterized by disconnectivity.

DESCRIPTION (provided by applicant): Patients with schizophrenia exhibit impaired neuronal network dynamics that can be targeted by non- invasive brain stimulation. In particular, rhythmic stimulation waveforms (transcranial alternating current stimulation, tACS) that enhance cortical synchronization may represent a targeted and therefore more effective approach to treat these network abnormalities. The long-term goal is to develop a new, noninvasive treatment for schizophrenia that is based on a mechanistic understanding of the network- level pathology. The overall objective of the R21 phase is to compare tACS and sham, with tDCS as a positive control for assay sensitivity, for treatment of auditory hallucinations in patients with schizophrenia in a double-blind, placebo-controlled pilot clinical trial. Additionally, the mechanism of action will be studied with electroencephalogram (EEG)-based biomarkers to elucidate the network- level effects of non-invasive brain stimulation. The objective of the R33 phase is to perform a double- blind, sham-controller clinical trial to assess the reduction in AHRS scores by five days of twice-daily tACS compared to sham stimulation (primary outcome) and the additional benefit of low-dose maintenance tACS (secondary outcome). The central hypothesis is that tACS is an effective treatment modality for auditory hallucinations and that the effectiveness of tACS correlates with changes in neuronal synchronization measured by EEG. The hypothesis will be objectively tested by pursuing the following specific aims: (R21: 1) evaluate tACS for the treatment of medication resistant auditory hallucinations in patients with schizophrenia, (R21: 2) elucidate the network-level mechanisms that are targeted by tACS and determine the predictive value of EEG synchronization measures for treatment outcome, and (R33: 3) perform a larger pilot clinical trial to assess tACS versus sham stimulation (primary outcome) and low-dose tACS maintenance treatment versus sham maintenance (secondary) outcome for reduction in AHRS scores. The significance of the proposed research is the chance of significant improvement in quality of life of affected patients with successfully treated medication resistant symptoms of schizophrenia, specifically auditory hallucinations.

PROJECT SUMMARY - UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH The alpha oscillation is a thalamo-cortical rhythm (8-12 Hz) that serves important functional roles in cognition and behavior. Transcranial alternating current stimulation (tACS) has been shown to alter cortical alpha oscillations and associated cognitive function in healthy human participants. However, it remains unclear how tACS engages and modulates thalamo-cortical oscillations as a function of stimulation dose (frequency, amplitude, and duration). Bridging this gap will enable the development of tACS paradigms for targeting pathological changes in alpha oscillations in psychiatric illnesses such as depression, schizophrenia, and autism. The long-term goal of our research is to combine computational modeling, in vitro and in vivo animal experiments, and human studies to develop and validate tACS paradigms for the treatment of psychiatric disorders. The objective of this application is to (1) mechanistically dissect and optimize the modulation of thalamo-cortical network dynamics by tACS as a function of stimulation parameters, and (2) validate the target engagement by tACS in healthy control participants and patients. We will test the central hypothesis that tACS modulates alpha oscillations in the thalamo-cortical system as a function of the stimulation parameters frequency, amplitude, and duration. The rationale of this work is that mechanism-based dose optimization of tACS will increase its efficacy and thus provide new scientific and therapeutic opportunities. Based on comprehensive preliminary data, the three specific aims are: (1) to understand the role of tACS frequency and amplitude in modulating thalamo-cortical alpha oscillations, (2) to map and mechanistically dissect the outlasting effects as a function of tACS duration, and (3) to validate tACS for the modulation of alpha oscillations in human participants. The work is innovative in its interdisciplinary and translational design; the proposed research overcomes the limitations of individual methods by integrating in vivo and in vitro animal studies with computational modelling to optimize tACS for targeting thalamo-cortical alpha oscillations and validates these findings in human participants. This is a critical step forward from today?s approach to tACS, which does not consider how functional interaction with subcortical structures such as the thalamus shapes target engagement. The proposed research is significant since it provides mechanistic understanding how to optimize tACS to target alpha oscillations, which play a central role in both physiological and pathological states. Ultimately, this work will enable the rational choice of stimulation dose in the next generation of tACS studies, both for studying the functional role of thalamo-cortical oscillations in behavior and for treating psychiatric disorders.

PROJECT SUMMARY - UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH & SHIN Treating cognitive deficits in patients with disorders of the central nervous system such as epilepsy has remained a challenge of great clinical urgency. Modulating the temporal structure of cortical network activity with brain stimulation enables (1) the study of the causal role of oscillatory activity patterns in cognition and (2) the development of treatments for cognitive dysfunction by enhancement of pathologically impaired cortical oscillations. Both transcranial alternating current stimulation (tACS) and repetitive transcranial magnetic stimulation (rTMS) employ periodic stimulation waveforms that interact with endogenous cortical oscillations. Yet, due to the limitations of the non-invasive electrophysiology that can be performed in conjunction with such stimulation modalities in humans, it has remained unclear if and how these modalities indeed modulate local cortical oscillations and long-range functional connectivity in a targeted way. The long-term goal of our research is to develop novel brain stimulation treatments that engage network-level pathologies as targets for the treatment of cognitive impairment in neurological and psychiatric illnesses. The objective here is to elucidate how periodic stimulation modulates cortical oscillations associated with working memory by benefitting from the unique neurophysiological access to the human brain in epilepsy patients implanted with electrode grids for electrocorticography (ECoG). The working hypothesis is that periodic stimulation can enhance endogenous rhythmic activity underlying working memory and therefore modulate cognitive performance. The rationale for this work is that this approach in human patients will provide direct demonstration of target engagement by modulating cortical oscillations with periodic stimulation and therefore enable the development of individualized brain stimulation paradigms for the treatment of working memory impairment. The following two specific aims will be pursued to test the working hypothesis: (1) to modulate working memory performance by target engagement of local cortical oscillations with periodic intracranial stimulation through local electrode pairs, and (2) to modulate working memory performance by target engagement of inter-area functional connectivity with periodic intracranial stimulation through distant electrode pairs. Our approach is innovative since it combines the emerging framework of cortical oscillations as treatment target with the unique access to human brain function with ECoG by employing low-amplitude periodic stimulation through ECOG electrode grids for oscillation modulation. The significance of this works is that understanding how endogenous network activity shapes response to stimulation and how targeting of stimulation determines modulation of working memory will enable the development of (non-invasive) stimulation paradigms that directly target oscillation dynamics for the treatment of cognitive impairment in patients with neurological and psychiatric illnesses.

PROJECT SUMMARY ? Pulvinar Neuro LLC, FROHLICH Transcranial current stimulation is a form of non-invasive brain stimulation that has recently become a key tool in human neuroscience research and has emerged as a potential treatment strategy for psychiatric disorders such as depression and schizophrenia. Yet, many questions about TCS remain unanswered and its clinical potential has not yet been delineated. We believe a key reason for this is that current TCS research devices do not have the required features for double-blind, placebo controlled studies of targeted stimulation waveforms. The objective of this proposal is to develop the XCSITE 200, a transformative TCS research device which will build upon our XCSITE platform. The XCSITE 200 will allow the study of more targeted stimulation waveforms that carry the promise of increased efficacy in terms of target engagement and behavior outcomes. In addition, XCSITE 200 devices will be managed via the cloud and thus enable cheaper and more effective administration of large, multi-site studies, which are essential in order for the technology to reach FDA clearance. In this Phase I project, we propose to implement custom-waveform and feedback stimulation in XCSITE 200 as well as perform extensive testing both at the bench and in a human pilot study (Aim 1) and to finalize and bench-test the cloud-based device and study management infrastructure (Aim 2). Quantitative milestones for both proposed aims are defined based on component and systems test benchmarks. The development of XCSITE 200 will enable the next generation of large-scale TCS studies with individualized and adaptive stimulation strategies targeting specific brain activity patterns to investigate their causal role in behavior and treat psychiatric disorders caused by altered brain network dynamics (e.g., depression and schizophrenia).

PROJECT SUMMARY ? UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH Sustained attention represents a fundamental dimension of cognitive control and refers to the process of allocating cognitive resources to appropriately respond to infrequent but task-relevant stimuli. Sustained attention differs from the more commonly studied shifting or dividing attention since it lacks the defining features of capacity limitation and competition. Deficits in sustained attention are common in psychiatric illnesses including attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia. Understanding the network substrate of sustained attention will thus significantly advance our ability to develop circuit-based therapeutics that selectively engage and restore the activity patterns that drive sustained attention. Synchronization in two higher-order networks have emerged as neural sub- strate of sustained attention and cognitive control in general. First, the frontoparietal network acts as a generator of top-down control signals. Second, the posterior thalamo-cortical network gates processing of input and exhibits task- modulation during sustained attention. Yet, it remains unclear if the synchronization through oscillations in these two networks plays a causal in sustained attention and more broadly in cognitive control. Targeted brain stimulation of individual network nodes with rhythmically patterned stimulation offers the opportunity to manipulate specific network oscillatory patterns and examine the resulting change in behavioral performance to establish a causal role of the targeted activity pattern. Such causal neuroscience of higher-order brain function will fundamentally advance our understanding of how cognition arises from large-scale electrical activity patterns in the brain. The overall objective is to identify the causal role of oscillatory functional interactions in sustained attention by rhythmic optogenetic stimula- tion. We will employ a widely used paradigm of sustained attention in animals, the five-choice serial reaction time task (5-CSRTT), in combination with rhythmic optogenetic stimulation and multisite electrophysiology in ferrets. We use the ferret (instead of more commonly used rodent species) for the study of the oscillatory substrate of cognitive function since we previously found that the ferret shares two fundamental top-down brain rhythms with humans: frontal theta oscillations that provide control of posterior parietal cortex and posterior alpha oscillations that gate visual perception. The proposed project builds on our published work of oscillatory interactions in these two networks as a function of engagement with both the 5-CSRTT and sensory input in ferrets, and our preliminary data of suc- cessful modulation of neuronal spiking, functional connectivity, and behavioral performance in the 5-CSRTT by fre- quency-specific rhythmic optogenetic stimulation. We hypothesize that oscillatory functional interaction in these two networks is dynamically regulated to drive sustained attention in this task. Completion of these three aims will pro- vide an in-depth understanding of the causal role of frontoparietal and posterior thalamo-cortical network in sustained attention. The rationale of this project is that advancing the causal investigation of synchronization in higher-order brain structures in cognitive control will open new avenues for the development of novel diagnostic and therapeutic strategies for deficits in cognitive control. The proposed work is thus of high translational significance and broad impact since sustained attention is impaired in numerous psychiatric illnesses.

PROJECT SUMMARY ? UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH Cognitive control requires the brain to dynamically allocate limited resources to manipulate internal representations as a function of behavioral demands, a process referred to as output-gating. Output-gating comprises two intertwined cognitive processes: the selection of relevant information and the suppression of irrelevant information. These two cognitive processes have been correlated with oscillatory neuronal network activity in two distinct frequency bands and network locations: theta oscillations (4-7 Hz) in prefrontal cortex (PFC) for selection and alpha oscillations (8-12 Hz) in posterior parietal cortex for suppression. However, the causal role of these oscillations and their interactions in output-gating has yet to be established. To address this gap, this proposal examines the causal role of theta and alpha oscillations in output-gating across multiple scales with individualized brain stimulation paradigms to provide a mechanistic delineation of how these oscillations support behavior, coordinate network activity, and regulate neuronal spiking activity. The objective of AIM 1 is to demonstrate the causal role of theta and alpha oscillations in selection and suppression, respectively. To accomplish this, theta and alpha frequency rhythmic transcranial magnetic stimulation is applied in healthy participants to frontal and parietal sites with simultaneous electroencephalography (EEG) during a working memory task with a retrospective cue that drives output-gating. The hypothesis of AIM 1 is that frontal theta activity coordinates the selection of relevant information, while parietal alpha activity coordinates the suppression of irrelevant information. The objective of AIM 2 is to spatially resolve the theta and alpha network dynamics that support selection and suppression, respectively. To achieve this objective, direct cortical stimulation combined with invasive EEG will be used in epilepsy patients with implanted electrodes for clinical purposes. The hypothesis of AIM 2 is that connectivity between frontal and parietal regions establishes oscillatory dynamics critical for selection and suppression. The objective of AIM 3 is to determine how oscillatory network dynamics regulate neuronal spiking activity. This is examined by applying theta and alpha frequency rhythmic optogenetic stimulation to frontal and parietal sites in the ferret with simultaneous electrophysiology recordings during an attentional task that modulates theta and alpha oscillations. The hypothesis of AIM 3 is that theta oscillations increase spiking and alpha oscillations decrease spiking activity. The proposed work is significant since it will provide a multi-scale mechanistic understanding of how theta and alpha oscillations coordinate output-gating. The proposed aims are innovative since they employ synergistic causal perturbations through targeted brain stimulation paradigms with concurrent electrophysiology, enabling the manipulation of oscillatory dynamics and the delineation of their role in coordinating neuronal spiking, network organization, and behavior. This work will provide the foundation for the future development of brain stimulation interventions that target impaired brain network oscillations for the restoration of cognitive deficits in psychiatric illnesses.