Del Monte Institute for Neuroscience Pilot Awards

​This research project will examine how the human brain dynamically integrates across time-varying speech structures (e.g., phonemes, words, phrases) using intracranial electrophysiology recordings and novel methods. The project is motivated by the substantial durational variability of the structures that compose speech such as phonemes and words. The brain must therefore have a mechanism to flexibly integrate across time-varying structures to derive meaning from sound. Yet while many studies have investigated neural representations of speech, little is known about whether cortical integration windows flexibly scale with the duration of speech structures (structure-yoked integration) or instead reflect physical time (time-yoked integration). Answering this question is critical to building neurocomputational models of speech perception and understanding how neurological deficits impact the perception of speech structure. This project will systematically examine whether neural integration windows throughout the human cortex are yoked to time or structure. We will test these hypotheses using intracranial electrophysiology recordings from human neurosurgical patients, which provide a rare opportunity to record human cortical responses with high spatiotemporal precision, critical for measuring and mapping neural integration windows. We will employ a novel experimental and computational method we have recently developed that can leverage the temporal precision of these recordings to directly estimate neural integration windows without resorting to coarser proxy measures. Preliminary results suggest that neural integration windows in the auditory cortex are primarily time-yoked, even in non-primary regions where selective responses to speech first emerge. Additional data will reveal if there is a transition to structure-yoked integration in higher-order regions of the superior temporal sulcus and frontal cortex or if integration windows remain time-yoked throughout the cortex. This research project is highly significant because it examines how the human brain integrates across time-varying speech structures, which convey virtually all of the semantically relevant information in speech.

Research suggests that children with autism spectrum disorder (ASD) have deficits in their ability to process speech in noisy environments, which has the potential to significantly impact their ability to participate in social interaction across settings. However, there remains controversy and limited evidence related to appropriate diagnostic and therapeutic approaches to these auditory processing difficulties. This study aims to define mechanisms underlying auditory processing deficits in ASD and the relationship between these brain processing differences and the clinical symptoms children with ASD experience.  We will combine technologies including electrophysiology (EEG) to monitor brain waves, virtual reality to allow for the development of more naturalistic paradigms, and detailed psychological testing to fully evaluate the strengths and weaknesses of individual children. This will provide a more complete understanding of how children with autism process language in noisy environments and is a necessary first step to support the design of novel and engaging mechanistically-targeted interventions.​

Rett Syndrome is a devastating genetic condition that occurs almost exclusively in girls. This condition leads to severely impaired physical and brain function that include impaired ability to speak, walk, eat, and even breathe. As individuals with Rett Syndrome lose their ability to speak and move, it becomes difficult to measure how their brain is functioning. Consequently, objective readouts of change in brain function does not exist. As such, we do not fully understand how these individuals perceive the world, this presents a substantial barrier in measuring the strengths and weakness of Rett syndrome. Understanding the extent of brain function decline caused by Rett Syndrome is important in identifying reliable brain function readouts to serve as objective markers of change after therapy.

The goal of the proposed project is to identify reliable brain readouts of dysfunction in affected individuals. We apply, cutting-edge non-invasive, high-density electrophysiological techniques combined with passive tasks made up of simple and complex features of speech. This allows us to record objective brain information even in the absence of active engagement from participants, making this approach accessible particularly in difficult to assess populations.

Participants with Rett Syndrome will be compared to age-matched controls to assess disease advancement. We recently found that despite substantial abnormalities, patients with Rett syndrome are able to passively process changes in basic features of speech. Here we expand our previous results and will study the ability of patients with Rett Syndrome to represent regularities of more complex form, such as to decode changes in the ever-changing acoustic environment.​

Glaucoma is a neurodegenerative disease that leads to the loss of neurons that relay information from the retina to the rest of the brain. Glaucoma is the most common neurodegenerative disease and the leading cause of blindness. It is expected to afflict over 110 million by 2040. The only risk factors for developing glaucoma are advanced age and ocular hypertension (elevated intraocular pressure). Despite glaucoma's prevalence, there are no treatments for glaucoma that prevent retinal cell death. The only current treatment for glaucoma is lowering intraocular pressure. Unfortunately, this treatment does not prevent glaucoma progression in many patients, and it does not restore lost vision. Once neurons in the retina die, the options for therapy are limited to neuron replacement, a difficult process with many hurdles. As a result, a major goal for glaucoma research is to identify early changes in the disease that could be reversed to prevent neuron death. In this proposal, we bring together an interdisciplinary team with complementary expertise to examine in unprecedented detail the neuronal changes that occur before retinal cell death both in the retina and in higher order visual pathways, as both areas need to perform normally for the maintenance of vision. This work will provide important information on early changes in glaucoma in the eye and in the brain, and will allow us to develop targets for early intervention in order to prevent vision loss in glaucoma patients in the future. ​

PTSD can occur after a direct or indirect traumatic experience and is a highly prevalent and debilitating disorder. This research project adds a new virtual reality paradigm specifically design to study reward context discrimination within a single environment. In the long term, this research will shed light on deficits of specific brain areas and neural circuits during reward learning and discrimination within an environment in PTSD, which will advance the development of effective diagnostics and treatments for PTSD.​

Alzheimer's Disease (AD) is a severe neurodegenerative disorder that develops as a result of multiple factors including genetics, age, and lifestyle. As the American population continues to age and lives longer, the prevalence of AD is increasing and poses a severe burden on society. Currently, there is no effective treatment for AD. New therapeutic strategies based on the mechanistic understanding of AD pathology are critically needed to meet the challenges of AD. The primary pathologic criteria for AD diagnosis include deposition of β-amyloid plaques and accumulation of tau neurofibrillary tangles. These pathological changes accumulate and spread between different brain regions, leading to patterns of cognitive decline. Multiple factors appear to contribute to this spread, including neuron activity and inflammatory changes driven by cells called microglia. The overall objective of this proposal is to establish a new research paradigm for studying the spreading of tau pathology in brain circuits known to be involved in patients with AD, and the modulation of this pathological progression by neural activity and microglia function. To accomplish this objective, we will use a viral method to express human tau protein in one part of the mouse brain and follow its spread to another region. This will be done in normal mice, and in a mouse model with β​-amyloid, which we expect to exacerbate tau spread. We will also stimulate brain regions using a technique called chemogenetics and administer a drug to reduce microglia inflammation in order to test the effects of these manipulations on AD pathology. These studies will lead to a better understanding of Alzheimer's disease and create opportunities for future research focused on reducing pathological spread.​

Healthy human societies are built on healthy social relationships that feed our mental and physical health. Maintaining healthy relationships depends on language and the ability to acquire, differentiate and predict other peoples’ beliefs, experiences and views. Without this ability we would not be able to discriminate our partner’s views from our mother, the neighbor or the president which would have its limitations! Traditional psychometric relationship tests profile peoples’ abilities to know the minds of others using self-assessments. However, self-assessments are subjective and notoriously error prone. An exciting and complementary approach might be a direct brain-based test of peoples’ spontaneous ability to anticipate others’ behavior. This could shortcut the high-level deliberative processes that go into making complex self-appraisals. Natural language might be the ideal vehicle for such an assessment because beliefs, views and experiences are usually communicated through language and the technology to recover spontaneous brain signatures of predictive natural language processing is now well established. Here, we seek to newly establish whether state-of-the-art technology can be extended to conduct brain-based assessments of interpersonal natural language prediction. We propose to conduct this initial pilot study on romantic couples (who are very familiar to one other with important relationships) as compared to strangers and explore how new brain-assessments relate to traditional relationship psychometrics. We will scan brain activity as subjects listen to recordings of their partners talking about personal beliefs, views and experiences as well as similar recordings from strangers. We will tailor Artificial Intelligence models to emulate partner’s and strangers’ language and evaluate how strongly these models differentiate corresponding partner/stranger brain recordings. We hypothesize that stronger discrimination will relate to psychometric relationship profiles. Our future vision is to develop objective brain-assessments of selective-expectation in different social relationships (parent/child, teacher/student, patient/caregiver) and how these relate to profiling disorders including autism spectrum disorder.

Object sensing and manipulation requires the selective prioritization of neural populations encoding tactile features relevant to task goals, through mechanisms which remain largely unknown. This project will investigate the selective prioritization of tactile features in the somatosensory system by probing the existence of a novel neuronal circuit for encoding feature selective signals. Accomplishing the aims within this project will improve our understanding of feature selection mechanisms in the somatosensory system and potentially inform the design of therapeutic strategies for somatosensory disorders and prosthesis control.​

Neurological problems occur in many COVID-19 patients with common reports of headache, anxiety, cognitive or memory impairment, and sleep disturbances. Encephalopathy, delirium, seizures, and stroke have also been reported. In addition, “long COVID” affects up to 30% of previously infected adults, even though most of these patients had not been hospitalized at the time of infection. Widespread inflammation has been observed in the brains of patients with severe COVID-19 and concern has arisen of long-term neurological issues after infection. How the virus associated with COVID-19 (SARS-CoV-2) induces this complex and diverse range of short and long-term neurological disorders is largely unknown. Recent studies indicate that SARS-CoV-2 can invade the brain, triggering inflammation and activation of astrocytes, a type of non-neuronal cell responsible for supporting nerve function. Sequence analysis of SARS-COV-2 Spike protein revealed that it contains a common mammalian amino acid motif – arginine (R), glycine (G), aspartic acid (D). The RGD sequence is found in many native extracellular matrix (ECM) proteins and mediates the attachment of these proteins to cells via cell surface integrin receptors. Astrocyte activation increases integrin receptor expression which may facilitate the binding of viral protein to astrocytes. We hypothesize that the RGD sequence within Spike protein acts as an ECM mimic by binding to upregulated integrin receptors on activated astrocytes, triggering changes in astrocyte morphology and behavior. In our proposed studies, we will characterize the binding of astrocyte integrins to the RGD sequence of Spike, and then ask whether this interaction increases intracellular signaling and migration of astrocytes. Altered integrin signaling is associated with a wide variety of neurological pathologies. Thus, determining whether Spike binds to astrocyte integrins and alters integrin-mediated cell signaling may provide a critical lead towards advancing our understanding of how COVID-19 affects normal functioning of the central nervous sys5tem.

Levodopa effectively treats motor symptoms of Parkinson's disease (PD). Over time, levodopa is associated with motor fluctuations between too much movement and too little movement. Combining levodopa with deep brain stimulation (DBS) can significantly ameliorate these fluctuations. However, combining levodopa and DBS can also aggravate some cognitive and motor symptoms, such as gait problems. There are no markers to predict these potential outcomes of DBS. There are important gaps in our understanding of the interactions between levodopa and DBS, cognitive and motor symptoms. Moreover, the effects of unilateral or bilateral DBS on cognition and gait problems are unclear. Our goals are to develop markers of cognitive and gait function, understand the interactions between levodopa and DBS, and the effects on cognitive and gait function, and develop methods that could predict and improve DBS outcomes in PD. In this project, we propose to determine and differentiate the impact of levodopa and DBS on cognitive-motor control and neurophysiological markers in 12 participants with PD. Once participants are in stable levodopa and DBS states, we will use our Mobile Brain/Body Imaging system to analyze changes in cognitive, gait and neurophysiological measurements while they perform a cognitive task while walking on a treadmill at the lab. We will safely evaluate participants in multiple conditions that combine the effects of levodopa, unilateral and bilateral DBS. We expect to differentiate the impact of levodopa, unilateral and bilateral DBS on cognitive-motor control and neurophysiological markers in these participants. We will use the data collected in this study to propose neurophysiological markers that could predict the cognitive and motor outcomes of DBS in future grant applications.​

Spoken communication is central to human life. As such, a tremendous amount of research has been undertaken aimed at understanding the neurobiology of speech perception and language processing. However, the overwhelming majority of that research has involved single participants listening to speech stimuli being presented them. This is not especially reflective of everyday life. In particular, most spoken communication involves direct interaction between people who are having a conversation with each other, taking turns and trying to find a common understanding at the core of their dialogue. And while a significant amount of behavioral research has been done on understanding dialogue, very little work has been done trying to explain the neuroscience of this vital human behavior. One of the main reasons for this is that such research is difficult. In particular, it is difficult to collect and interpret clean brain responses to people while they are engaged in natural conversations. In the present project, two research groups plan to exploit the respective expertise to address this issue. One group has substantial expertise in conducting interactive experiments – including those based on dialogue – among human subjects. The second group has substantial expertise in analyzing brain responses to naturalistic speech. We propose to carrying out interactive experiments between pairs of people while we record the brainwave (EEG) activity. By analyzing the neural responses using computational modeling methods established by the lead investigator's group, we plan to shed new light on this relatively unexplored area of social neuroscience.​

Neurodevelopmental disorders result in varying degrees of social, sensory, motor and cognitive disruptions. While more and more children are diagnosed with neurodevelopmental disorders, few treatments are available to mitigate their lifelong problems. Microglia are the brain's immune cells and they have increasingly been implicated as contributing to symptoms in neurodevelopmental disorders because of their roles in supporting neurons and helping guide changes in neuronal wiring especially during development. However, these cells have yet to be studied carefully in Fragile X Syndrome, the most common inherited neurodevelopmental disorder. Our preliminary experiments suggest that removing microglia in a mouse model of this disorder, improves behavioral symptoms, suggesting that these cells play an important role in brain dysfunction. Here, we propose to build on these findings to determine how microglia are altered in a mouse model of Fragile X Syndrome. We believe that understanding the behavior of these immune cells in the context of this disorder will help us uncover biological mechanisms that can be targeted therapeutically in the future to develop new medical interventions for Fragile X Syndrome. ​

​​​Schizophrenia has been described as “the worst disease affecting mankind.” It is easy to understand this characterization when considering the outcomes for individuals with a psychotic spectrum disorder (PSD), which include low rates of recovery, substantial disability, reduced quality of life, markedly increased risk of suicide, and early mortality. Given these outcomes, increased attention has been focused on prevention for those most at-risk; namely, individuals with a psychosis-risk syndrome (PRS), or those exhibiting attenuated psychotic symptoms and associated signs that portend a psychotic disorder. Despite a proliferation of treatments aimed at reducing symptoms and preventing psychosis in those with a PRS, recent accumulating evidence suggests that these treatments do not work, leaving young people facing a potentially lifelong, debilitating illness without suitable treatment options. The proposed project aims to meet this need by evaluating whether real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) can be used to train volitional control of the default mode network (DMN)—a promising neurobiological mechanism of psychosis—in those most at-risk. Thirty individuals with a psychosis-risk syndrome (PRS) will be randomized to receive either intermittent rtfMRI-NF (INF) in which the DMN feedback is delivered periodically, continuous rtfMRI-NF (CNF) in which the DMN feedback is delivered constantly, or sham (placebo control) rtfMRI-NF (SNF) in which the feedback is random. We will also evaluate how regulation strategies are associated with control of the DMN. Our hypotheses are 1) compared to SNF, INF and CNF will lead to greater learned control of the DMN, and 2) strategies involving focused attention, concentration, and mindfulness-related practices will be associated with greater learned control. Together, the proposed study will help to identify a novel, mechanism-based intervention that may ultimately help prevent the onset of a psychotic disorder.

​Our brain relies on neurons to perform its functions while communications between neurons is important for neuron's function in the brain. Neurons use axons to contact the dendrites of another neuron. Electrical signal will degrade along the long axonal processes. Oligodendrocyte cells in the CNS has many processes which wrap around axons to form lamellar structure, called myelin sheath, and prevent this degradation. Myelination is thus essential to our brain function.  We found that deleting a gene called NIPP1 in the mouse brain led to a myelination deficit. Interestingly, we found that deleting NIPP1 in oligodendrocytes, the cells directly responsible for myelination, did not have an effect on myelination. On the other hand, deleting NIPP1 gene in neurons led to a myelination deficit. Moreover, we found that neuron's ability to communicate to other cells is decreased in the KO mice. We will elucidate the neuronal mechanisms regulated by NIPP1, for example PSD93 and sk2, in determining NIPP1's function on neuron's communication ability and CNS myelination. The proposed work will elucidate the critical role of NIPP1 gene in neuron-glia interaction and CNS myelination.

Calcitonin gene-related peptide (CGRP) is a neurotransmitter that plays a critical role in chronic, migraine, and inflammatory pain.  CGRP’s effect on pain is mediated by intracellular signaling pathways, but the regulation of these pathways is unclear.  We have recently discovered that a protein named CGRP-receptor component protein (RCP) can control the signaling at the receptor for CGRP.  We have recently developed the first mice that lack RCP, and these transgenic mice will be used in this proposal to establish an animal model for the function of RCP in migraine and inflammatory pain.   Successful completion of these aims will determine if our in vitro biochemical findings are recapitulated in vivo models, and if so will provide new non-opioid therapeutic targets.

Hallucinations, or 'hearing voices', are  a core symptom of schizophrenia.  These symptoms are relieved by antipsychotic drugs, which modulate the neurotransmitter dopamine.  Although there are hints from human brain imaging studies about the brain regions involved in hallucinations, little is known about how and where brain wiring goes awry. This pilot grant will support and extend our recent work in an animal model closer to the human (monkey) investigating  the 'caudal ventral striatum', a region reliably dysregulated in humans experiencing 'voices'.  We will  delineate connections from auditory cortex, and from specific dopamine neurons that modulate information flow in this region of the striatum.​​

Auditory hallucinations (AH) are experienced by approximately 60-80% of individuals with schizophrenia (SZ). These symptoms are often associated with distress and disability, and in many cases, do not respond adequately to standard treatments. A barrier to the development of novel therapeutics for AH is lack of clarity regarding underlying neural mechanisms. Recent models of psychosis suggest that AH may result from a pathological overweighting of expectations relative to incoming sensory signals during perception. It has further been proposed that sensory processing impairments in SZ may drive this overweighting of expectations, and thus contribute to the development of AH. Our aim is to investigate these potential AH mechanisms by leveraging recent advances in electroencephalography (EEG) methods. Specifically, EEG will be used to evaluate whether AH in early-stage SZ are associated with 1) impaired auditory processing of speech; and 2) alterations in the effects of prior knowledge regarding speech content on this auditory processing. Focusing on the early stages of SZ for this project will help minimize the influence of factors associated with longstanding psychotic illness that may confound our results, such as prolonged medication exposure. We will recruit 20 young people with early-stage SZ, specifically 10 with and 10 without AH (AH+/AH-), along with 10 matched healthy controls. EEG will be recorded as participants listen to narrative speech segments, and neural responses will be modeled to derive measures of auditory processing of speech, and the effects of prior knowledge on this processing. We hypothesize that AH in early-SZ will be associated with impaired auditory encoding of speech and a greater influence of prior knowledge on this encoding, and that within AH+, these two alterations will be related. The results from this work will be used to support the application of an NIH proposal for a larger-scale investigation of AH mechanisms.

Microglia are immune cells of the brain, where they constantly probe their environment with long thin highly motile arms called “processes". The involvement of these microglial processes is known to be important in the development of new connections between brain cells and hence in the formation of new memories. The spaces between brain cells are filled with numerous filamentous proteins forming a network. We believe that when a microglial process probes and penetrates an area it 'loosens' that protein network. This is important because changes to that protein network will affect the ability of other brain cells to reach out and make connections. Hence, we believe that microglial probing loosens the protein network between brain cells and thereby affects learning and memory. To explore this idea, we will use chemicals to make microglial processes enter a specific region of the brain, or leave it, and study the resultant effects on the protein network in between brain cells. Specifically we will measure the speed with which tracer molecules can move through that network as a measure of that network's ability to hinder motion, and do so with tracers of different sizes to understand the size of the 'pores' in the network. Tracers larger than the pore size will move very slowly, while tracers smaller than the pore size will move rapidly. This study will provide preliminary data for a larger study on the detailed effects of the movement of microglial processes on the material between brain cells, and the subsequent impact on learning and memory.​​

We propose to use stimulation of brain activity during working memory to enhance performance and to alter neural activity in the ventrolateral prefrontal cortex.  This finding can help us understand what precise role the ventrolateral prefrontal cortex plays in memory and cognition.  Moreover, this type of brain stimulation may be a way to introduce therapeutic brain stimulation for future treatment of neurological impairments.  Since the area we are targeting is involved in processing and integrating social communication information we hope that this technique could provide a sort of therapeutic enhancement to lagging social communication brain circuits in the future.​​

Patients with pre-existing neurodegenerative diseases known such as Alzheimer’s Disease, Multiple Sclerosis, and Parkinson’s Disease, are particularly vulnerable to cognative decline following episodes of systemic infection including sepsis . The mechanisms underlying this decline are unknown and studies in mouse models are not good representatives of human inflammatory disease. New stem cell technologies combined with microfludic 'tissue-on-a-chip' platforms are allowing the development of human tissues in the laboratory that are derived entirely from the cells of a patient. These technologies not only overcome the limitations of animal models, they are an important tool for a new era in patient-specific medicine. Thus our project seeks to develop a 'brain-on-a-chip' model of Alzheimer's with the goal of being able to develop approaches that can protect this most vulnerable population. The project will develop the model using cells carrying the genetic risk factor for Alzheimers and test it against a healthy model that does not carry the genetic risk factor. ​

Despite advances in the use of targeted radiotherapy, whole brain radiotherapy remains a part of current treatment and prevention plans for metastatic cancer. Moreover, even with tumor focused radiotherapy, normal brain tissue is exposed to ionizing radiation and cognitive dysfunction remains a major late complication, particularly in children and young adults. Recent evidence from multiple laboratories, including our own, indicates that radiation causes loss of connections between neurons in the brain, and that this loss may be responsible for cognitive dysfunction. The immune cells of the brain, known as microglia, play important roles in removing connections between neurons, both as part of normal development and in disease states such as Alzheimer's. Thus, we tested whether microglia might be playing a role in the loss of neuron connections after radiation. We found that blocking the ability of microglia to remove connections prevented cognitive dysfunction after brain radiation exposure in mice. These findings suggest a possible therapeutic strategy for preventing brain radiation effects in patients receiving radiation treatment. To better understand the timing and involvement of microglia as key effectors of brain radiation injury, we plan to carry out additional studies that: 1) quantify molecular markers of these brain changes as a function of time after radiation exposure; 2) use special microscopes to visualize interactions between microglia and neuronal connections; and 3) determine whether we can establish a “smoking gun", namely test whether microglia actually ingest neural connections after radiation. Together, evidence generated from the pilot proposal will help us to submit a much larger grant focused on developing novel therapies to prevent CNS radiation injury.​

Alzheimer's disease is the most common age-related dementia, accounting for the progressive cognitive impairment and compromised life quality of approximately 5.8 million people in the United States. A number of lifestyle factors can increase the risk of Alzheimer's disease including the abuse of alcohol. Alcohol use is prevalent in our society, ranging from infrequent social drinking, through moderate consumption and all the way to chronic and lifelong abuse. These different drinking patterns have been shown to differentially impact the brain and modulate cognitive processes. While it is clear that alcohol use can impact the risk of developing Alzheimer's dementia, the mechanisms by which alcohol affects the brain that impact this risk are currently unknown. This is largely due to the fact that few animal models exist that accurately reflect both human drinking and clinical features of Alzheimer's disease. In this proposal we will develop and test a common mouse model of Alzheimer's disease based on mutations that have been associated with the disease in humans, coupled with an alcohol exposure paradigm that retains many features of human alcohol use, to test a candidate mechanism that may link Alzheimer's disease and alcohol. We will focus on the brain immune cell, the microglia, which is uniquely susceptible to disruptions of the environment (such as the presence of alcohol and its metabolites in the brain) and which is known to have multifaceted and important roles in modulating Alzheimer's disease progression. We believe this new model and the results of our study will yield important insights into the process by which alcohol affects Alzheimer's disease and may lead to future therapeutic avenues for treatment of patients with a history of drinking alcohol. ​  ​

​In Alzheimer’s disease (AD) a protein called tau becomes sticky and forms clumps called “oligomers” which then join to form large accumulations in nerve cells called “neurofibrillary tangles” (NFTs). When the large NFTs were first discovered, it was thought that they were what killed the nerve cells. However, recent research has shown that the NFTs are not what make the nerve cells sick, but rather the oligomers which are smaller clumps of tau. Although it is now clear that these oligomers are toxic to nerve cells, how and why they form is not well understood.  A major problem with studying tau oligomer formation is that there has not been a good way to study how they form, and thus processes that may be able to reduce their formation or stability remain unknown. Therefore, the first goal of this proposal is set up a unique and state-of-the-art system to study tau oligomer formation. To do this we attach a “module” to tau called “Cry2olig” that is sensitive to blue light and put it in nerve cells that are grown on a dish. When you shine blue light on it causes it to interact with it another Cry2olig which pulls the tau proteins together to form the oligomers.  We are then able to monitor this process using microscopy and determining how fast the tau forms the oligomers. Once we take away the light, the tau oligomers disassemble, and we can determine how fast that happens. With this new system, we can determine the effects of other proteins on tau oligomer formation and disassembly. In the future this system, has the potential to be used to test drugs or molecules that may prevent tau oligomer formation as possible treatments for AD.​​

When the immune system attacks the cerebellum, the brain region responsible for coordinating movement, it can lead to symptoms of ataxia such as stumbling, falling, incoordination, and slurred speech.  Therapeutics aimed at suppressing the immune system in this autoimmune condition may be beneficial if treatment is started early.  However, often it is not clear if the ataxia is immune-mediated or has other causes.  Antibodies that target specific proteins in the cerebellum have been shown in some cases to be excellent biomarkers for diagnosis of immune-mediated ataxias.  More research is needed to identify new antibody biomarkers of ataxia and to characterize how the immune system specifically damages the cerebellum when these problematic antibodies are present.  Antibodies targeting a protein called Sez6L2 have recently been reported in six patients with ataxia. In this proposal, we are generating two different mouse models to understand how immune attack against Sez6L2 damages the cerebellum leading to ataxia.  One model will focus on potential damaged caused directly by the Sez6L2 antibodies.  The second model will investigate whether a full-immune attack against Sez6L2 better models the human disease.  In both models, we will analyze mouse motor functions and look at brain histology for neuron death and multiple immune markers.  These studies, coupled with the previously reported human case studies, should encourage prompt and routine screening for Sez6L2 antibodies in suspected immune-mediated presentations of ataxia. We anticipate the results from these studies will also help doctors decide which available therapies will best suppress the immune system to protect the cerebellum against attacks linked to Sez6L2. ​​

Protein phosphatase 1 (PP1), an enzyme, has been dubbed as a molecule of forgetfulness based on studies performed on a transgenic mouse model. PP1 is thought to play its important role in memory via its role in communication among neurons. However, PP1 has three different isoforms, PP1α, PP1β, and PP1γ, each encoded by a different gene. It is thought that PP1γ is the PP1 isoform playing roles in synaptic plasticity.   Whole exome sequencing, a new technology of sequencing the gene coding portion of human genome, can diagnose the genetic basis of intellectual developmental disorder (IDD) in patients whose parents are normal. One of the genes mutated in IDD patients is PP1β. It is surprising because this isoform of PP1 was only known to play a role in heart development in the past.   We are using transgenic knockout (KO) or knockin (KI) mouse models to study the roles of PP1γ, PP1β as well as PP1β's human mutation in brain functions. We have obtained conditional PP1β KO mouse line from our collaborator Dr. Nairn (Yale). We have also generated a conditional KI mouse line which carries a corresponding human mutation in PP1β gene.   We will turn on the KO or mutation at specific cell type (CA1 pyramidal neurons in hippocampus) to examine the communication between CA3 and CA1 pyramidal neurons. We will also examine synapse formation. We will also introduce the human mutation in PP1β gene starting at sperm/egg stage, exactly mimicking what happens in the human patients. The effect of mutation on synaptic functions and cognition will be examined by imaging, electrophysiology recording and behavioral assays. We anticipate that PP1β KO or human mutation will lead to deficits in synapse formation, synaptic plasticity, and spatial learning and memory. ​

Interpersonal communication is central to human life. For most people, such communication typically involves spoken language. As such, neuroscience research has dedicated enormous effort to understanding how our brains transform speech sounds – even for different speakers and accents – into syllables, words, and, ultimately meaning. But speech doesn't rely only on sound. Most communication between people involves face-to-face communication where information from a speaker's face and gestures help us to understand what they are saying. Compared with our knowledge about how brains convert sounds to speech, we know relatively little about how our brains extract visual information from a speaker's face and gestures to help with speech comprehension. Our project aims to address this issue. It aims to do so by collecting EEG brainwave signals from human subjects and examining how those brainwave signals relate to different kinds of speech, including silent videos of a talker, audio speech clips with no video, and audio and video together. Importantly, our project aims to do this for a variety of participants, including people with typical hearing, as well as deaf individuals, and deaf individuals who use a cochlear implant. By exploring the brain data across these groups, we hope to be able to cleanly distinguish brain signals that reflect the processing of visual speech information from signals that reflect the processing of audio speech. With a team made up of members with complementary expertise in brain signal analysis and language processing in deaf individuals, we hope to make important new discoveries about how the human brain extracts useful information from visual speech. In turn, this will be useful for future research aimed at improving the effectiveness of cochlear implants and for a greater understanding of language processing in deaf individuals. ​​

A healthy human society is built upon healthy interpersonal relationships. In absence of these people are prone to depression, anxiety, ill health, and even early mortality. Among the most important relationships to keep healthy are those with our romantic partners. This relies in part on the ability to put oneself in one's partner's shoes – to know their tastes, experiences and views, and how they differ from one's own. This ability is underpinned by a complex network of brain systems collectively referred to as the “theory of mind" network. Whilst advances in brain scanning technology have broadly identified the whereabouts of this network in the brain, less is known about how detailed information is represented within it, and how this contributes to romantic relationship quality. Indeed, the ability to record from the brain what one envisions their partner's perspective to be, and computationally match that to brain activity recorded from the partner contemplating the same subject would be transformative for relationship and clinical science. Progress has been obstructed because it has been unclear that contemporary technology can measure sufficient brain signal to even discern interpersonal differences in personal perspectives. In recent work we introduced computational methods showing that brain scans capture person-specific elements of experience (of things like shopping). We now seek to deploy these methods to explain brain activation elicited as couples envision items and activities like chocolate, wine, dogs and shopping from each other's perspectives. We will test whether brain activity elicited when imagining one's partner's perspectives predicts that partner's actual perspectives, and how this reflects their relationship satisfaction. Success would be an exciting step toward brain-based assessments of relationship health.​​

​Survival depends on detecting behaviorally relevant information in complex, dynamic environments. The primate brain largely gathers information from the visual environment through a combination of two interacting functions: spatial attention (enhanced sensory processing) and saccades (exploratory shifts of gaze). A shared network of brain regions, the “attention network,” directs both of these functions, prompting the following fundamental question: how does a single network control both the sensory (i.e., spatial attention) and the motor (i.e., saccades) functions of environmental sampling? Recent research indicates that these competing functions are temporally isolated in the attention network, alternating over time at a frequency in the theta range (~4–6 Hz). That is, recent research indicates that environmental sampling is characterized by two rhythmically alternating attentional states, with the first promoting sampling (i.e., sensory functions of the attention network) and the second promoting shifting (i.e., motor functions of the attention network). Neurophysiological evidence indicates that these attentional states are coordinated by theta-rhythmic neural activity in the attention network, with distinct patterns of neural activity characterizing the sampling and shifting states. Yet the neural source of transitions between these theta-rhythmic attentional states remains unknown. A synthesis of previous research strongly suggests cholinergic innervation from the nucleus basalis (NB) as a potential source. The NB is the primary source of acetylcholine (ACh) in cortex, and the neuromodulatory enhancement of ACh is critical to selective attention. In addition, neurons in the NB fire at theta frequencies and are associated with theta-rhythmic neural activity in cortex. Here, we will utilize microstimulation and neuropharmalogical manipulations in macaques, while simultaneously recording from cortical nodes of the attention network. We will test the hypothesis that transitions between theta-rhythmic attentional states in cortical nodes of the attention network are attributable to ACh-inducing neural activity in the NB.​

​​In mammals, G protein coupled receptors (GPCRs) form the largest family of cell surface receptors and are involved in the regulation of every aspect of neurophysiology. GPCRs sense the presence of neurotransmitters, hormones, changes in pH, levels of light, and many other fluctuations in the extracellular environment, and they translate it into intracellular messages leading to appropriate cellular responses. Because of their role as powerful regulators, GPCRs are the most exploited molecular target by currently available drugs. Surprisingly, what activates ~100 members of the GPCR family is still unknown, hence these receptors are named orphans. Nonetheless, human and animal studies revealed relevant physiological roles for many orphan GPCRs, especially in the brain. Orphan GPCRs represent therefore unexploited pharmacological targets for the treatment of a variety of neuropsychiatric disorders. The goal of the proposed study is to build an innovative assay to identify what activates four orphan GPCRs (GPR137b, GPR156, GPR158, and GPR179) that are enriched in the central nervous system and are involved in disorders such as depression and night blindness. This deorphanization process will be completed by screening a library of biologically active molecules whose targets are unknown. With our work, we expect to identify the endogenous ligands activating these orphan GPCRs, or, at least, to find synthetic compounds that are able to modulate their activity. The identification of orphan GPCR ligands will expand our knowledge on the biology of these receptors, and, at the same time, it will boost the development of new therapeutics targeting a variety of diseases including depression, addiction, blindness, and other major neuropsychiatric disorders.

Application of minute electrical currents to the scalp (transcranial electrical stimulation; TES) has been shown to affect brain activity and, separately, has been shown to affect behavior. Thus, TES has potential to treat mental illnesses, since it can influence brain dynamics. So far, our understanding of the effects of TES is quite basic. We know that electrical stimulation can increase the excitability of nearby neurons, for example, or that it can speed learning of some simple motor tasks. For TES to be most effective as a therapy, we need a better understanding of how to affect brain dynamics in detailed and nuanced ways. The research will combine TES with direct recording of groups of neurons in multiple brain areas in subjects performing a visual-motor task requiring cognitive control. Cognitive control is an important brain function required for flexible task performance (e.g., ``task switching''), and it is affected in illnesses such as psychosis and depression. By systematically measuring the relationship of TES on neural activity and behavior simultaneously, we will improve our understanding of the neural mechanisms of TES, and hopefully develop specific and selective methods to improve cognitive control performance.

Chronic pain is a major health crisis in the United States. It is estimated that 100 million Americans live in chronic pain with an annual cost reaching between $500-600 billion dollars.  The mechanisms of chronic pain are poorly understood hence there are no objective biomedical tests that are specific or sensitive to a specific chronic pain condition. We address this problem by developing specific brain-based tests to diagnose patients suffering from chronic-low back pain, since this condition is one of the most common chronic pain condition and the number 1 cause of disability worldwide. Besides, existing diagnostic tests, like spine imaging for low-back pain are expensive, non-specific and often lead to unnecessary procedures like spine surgery. Our group has developed highly reproducible brain-based tests to diagnose patients with chronic low-back pain. These measures are obtained using magnetic resonance imaging of the brain.   An obstacle to the translation of these tests into clinical use remains, however.  While these tests were shown to be valid at separating patients from healthy non-pain controls using a research scanner their validity was not directly compared between a research and a clinical scanner like the ones used in routine diagnostic testing in a hospital setting. Therefore, in this proposal we will test the validity of our chronic low-back pain brain based diagnostic testing and develop the method of disease detection further using a hospital scanner at the University of Rochester clinical imaging facility.  The same patients and healthy controls will be scanned both on a research scanner and on a clinical non-research scanner and the validity of the diagnostic tests compared between the two data acquisition protocols. ​

There are over 1000 articles on eye movements in schizophrenia (SZ), but it remains almost completely unknown whether people with this disorder differ in their microsaccades, which are miniature, rapid eye movements.  A major goal of this grant is to establish that such differences exist (Aim 1).  We elicit group differences in microsaccades via three tasks: steady fixation, visual acuity, and reading.  The latter two tasks were chosen since each is plausibly impaired among psychosis patients, each is highly dependent on microsaccades, and each is important for normal everyday functioning.  To ensure that discovered group differences do not owe to poor mental health, our comparison “control” group will have an anxiety, mood, or substance use disorder but no psychosis   To ensure that group differences are not owing to poor general health, psychosis patients will all be younger, within five years of their first psychotic break. In contrast to possibly all prior psychosis studies, we will use cutting-edge, high-precision eye-tracking equipment and calibration procedures. Our second goal is to consider whether abnormal microsaccades can potentially explain well-documented reading or visual acuity deficits in psychosis (Aim 2).  A possibility is that microsaccades in psychosis are intrusive; that is, they are less precise and accurate and cannot be controlled or suppressed when needed, leading to impairments in high-acuity vision and reading.  Our project, if successful, could yield a novel marker for psychosis and clarify how the oculomotor system differs in early illness stages.  This project could also offer a novel explanation for poor visual acuity and reading in psychosis, which in turn might suggest new treatments focused on the oculomotor system.  Pilot data from this pilot project will increase the chances of success for a subsequent grant application to the NIH. ​

​​​How our brain senses glucose is not well defined. Moreover, high blood glucose levels in diabetes compromise the ability of the brain to sense glucose. Consequently, when individuals with diabetes are faced with life-threatening low blood glucose levels (hypoglycemia) due to overdose of insulin or other medical complications (iatrogenic), their brains fail to sense this hypoglycemia. Without any interventions to restore their blood glucose levels, these individuals may experience seizures, loss of consciousness, coma, and even death. Mechanisms underlying this phenomenon of hypoglycemia unawareness and/or impaired ability of the brain to enhance the protective counter-regulatory glucose response in diabetes are unclear. Therefore, to explain how diabetes compromises the ability of the brain to sense glucose, we produced innovative reagents in our lab and identified a glucose-binding protein (receptor) in the brain. In our preliminary experiments, we have observed that this receptor may be important for glucose sensing, and diabetes compromises the function of the receptor. In this proposed project, we will establish the role of the glucose-binding protein in brain glucose sensing and whether this protein can be targeted to improve hypoglycemia awareness and/or the brain’s response to fight hypoglycemia in diabetes. Findings from our project will help mitigate a significant problem of life-threatening iatrogenic hypoglycemia in individuals with diabetes.​

Neuroscientific research has identified adolescence as a critical period where key neurotransmitter systems are still developing, offering an important therapeutic window for interventions in psychiatric disorders. Previous work in our lab and others points to increased adolescent plasticity in dopamine signaling. Dopamine is a critical neurotransmitter which impacts reward, motivation, and cognitive processing. The protracted development of dopamine circuits in the brain aligns with the timeline of psychiatric disease progression, offering an important disease relevant developmental process to target. Our research seeks to understand how dopamine circuit plasticity during development occurs within the brain. Our proposed research will help to determine what mechanisms impact adolescent dopamine plasticity and how changing these signals could give rise to psychiatric abnormalities. With better disease understanding research can design more targeted therapeutics for neuropsychiatric patients.

Schizophrenia is essentially defined by the symptoms displayed by patients, with the underlying cause still not being known. Our project aims to study how people with schizophrenia perceive their world and understand social interactions with others. We aim to do so by recording electrical brain wave activity from people with schizophrenia (and healthy control subjects) while they watch episodes of the TV show The Office. This will allow us to analyze the brain wave data in terms of how the brain responds to sounds and speech in the TV show – giving us measurements of their perception. And, given the nature of the show, it will also allow us to analyze how the brain wave data changes for scenes that are more or less socially awkward – allowing us to obtain measurements of how they understand social interactions. By comparing the results from people with schizophrenia and healthy controls, we hope to obtain basic measures of brain function that will help us understand the underlying causes of this terrible, debilitating disorder.

Operations like hip repair in the elderly are frequently associated with postoperative delirium, which can lead to increased sickness, decreased quality of life, dementia and premature death. We have developed a mouse model of this type of delirium and shown that brain inflammation and cognitive abilities can be treated with an experimental drug, URMC-099 we have developed. In this project, we will use a technique to define which proteins in immune cells present in the body and brain can be returned to normal functions by treatment with URMC-099, and in so doing, provide a strong justification for advancing it to clinical trials.

The overarching goal of this proposal is to provide a new molecular understanding of how toxic oligomers of amyloid beta peptides disrupt cellular function, a major contribution to the pathology of Alzheimer’s disease (AD). Our particular focus is on enabling protective strategies that rationally combine protective agents to achieve greater benefits than can be obtained by attacking individual targets To this end, our therapeutic strategies are focused on compounds suitable for rapid movement from the laboratory to the clinic. In addition, our studies also may help better understand the white matter damage that has long been observed in Alzheimer’s disease (AD), and may be an early component of this disease. On a molecular level our studies provide new insights into how metabolic changes, such as increased oxidation, and activation of the signaling molecule Fyn kinase, cause AD-related damage to the cells that are required for generating and repairing myelin.

“Model systems" like the tiny nematode C. elegans have played outsized roles in neuroscience by allowing the identification of genes that control the development and function of the brain in all animals, including humans. In recent work, we have discovered a previously unknown C. elegans gene that is essential for the functional maturation of its nervous system during juvenile development. Excitingly, this gene does not act to make a protein, like most genes do; instead, it functions as an RNA molecule. This class of genes, called long non-coding RNAs (lncRNAs), have attracted a great deal of attention in recent years, but very little is known about their functions in brain development and neurological disease. We have good reason to believe that mammals, including humans, have a version of the nematode gene we have identified, but lncRNA genes are notoriously difficult to study using traditional approaches. In this project, we will combine the expertise of two labs, one that focuses on C. elegans neurogenetics, and another which uses computational approaches to studying RNA. Together, these two groups will work to identify candidate mammalian versions of the gene we have discovered in C. elegans. Such a discovery could have fascinating implications for understanding the molecular mechanisms that build the human brain and could provide new opportunities for the diagnosis and treatment of neurological and psychiatric disorders.

Combining expertise from our two labs, we will study and compare music and speech processing from the earliest parts of the auditory system (Experiment 1) to the more complicated later parts (Experiment 2). The first part will focus on natural speech sounds and music sounds as well as sonic “textures” whose statistics match those of speech and music, but are distinctly not either. In the second experiment we will present piano music naturally played and with all the notes out of order so that we can determine how predictability in music effects its processing, even when the acoustics of the sounds are the same. This project will not only tell us how music is processed by the brain, but will also tackle more fundamental questions like “what makes music music?”

Drinking in adolescence profoundly affects brain function in the long-term, with increased propensity for alcohol use disorder, depression and cognitive deficits in adults who abused alcohol as adolescents. We have recently shown that intoxication changes microglia-immune cells-in a way that may impact their interactions with neurons. In this proposal, we will use a mouse model of adolescent binge drinking to examine how alcohol affects microglia. By selectively removing microglia only during the adolescent period when animals are exposed to alcohol, we will be able to test whether “alcohol-exposed" microglia cause long-term changes in brain or whether these deleterious effects are mediated by other cell types in the brain. This information will provide a spring board from which to understand the biological underpinning of the effects of alcohol use during adolescence.

At present, there are no non-invasive markers of brain changes associated either with concussions or repetitive milder head hits. We therefore propose to examine the ability of changes in the retina – the neural tissue in the eye – to signal the emergence of brain changes related to hits to the head. We will examine collegiate football players before the season, immediately after the season, and then 4 months post-season. We will determine whether there are changes in retinal structure and functioning across the 3 time points, and whether these predict changes in brain structure and thinking skills across the same period. Our long-term goal is to develop rapid, non-invasive methods for detecting significant brain trauma in the immediate aftermath of a head hit, as well as tests that can be used to screen for longer-lasting or progressive changes that would require lifestyle alterations and possibly treatment to prevent further worsening of the condition.

Within the brain, billions of nerve cells are constantly communicating with one another by hurling chemicals across the tiny gap between them. This gap, known as a synapse, is less than one ten millionth of a meter or about one thousand times smaller than the width of a human hair. Using super resolution microscopes, we have learned that within the incredibly tiny region of a synapse certain classes of receptor proteins are precisely aligned right across from where neurotransmitter chemicals get released. These receptors appear well situated for hyper efficient chemical communication. Other types of receptors site on the edge of synapse, positioned to detect greater levels of neurotransmitter or barrages of chemical signals. Using the University of Rochester’s new super resolution microscope, we will determine where a particular receptor class, the acid-sensing ion channel, sits within the synapse. Understanding the exact location of these acid-sensing receptors at synapses will give important clues about their functions within our brain.

Depression is frequent for patients with brain tumors, and often under-recognized. It is not known whether radiation to specific parts of the brain can contribute to depression. The amygdala and hippocampus are structures that have a known role in depression. In a preliminary study, we evaluated a small group of patients with brain tumors who received radiation treatment. In this group, patients who had increased radiation dose to the amygdala and hippocampus had more symptoms of depression. We are interested in expanding our cohort to confirm these findings and create a model that takes into account other factors that are related to depression in order to validate this result. We also plan to look at brain MRI to examine changes in the amygdala and hippocampus and their connections to the rest of the brain. Should these findings be confirmed, future studies will evaluate interventions such as reducing radiation dose to these structures using advanced radiation techniques and creating interventions for patients at higher risk of depression after brain radiation.

Factors such as Β-amyloid deposition and tau neurofibrillary tangles have been implicated in the pathogenesis of Alzheimer’s disease (AD). It is, however, unclear what initiates the cascade of events that leads to a vulnerability to such factors. It has recently been speculated that cerebrospinal fluid (CSF) flow may be implicated in this type of pathology. Research in the murine model has suggested that an important component of CSF flow is toxin clearance from the brain. We hope to study the relationship between CSF flow measured on PC-MRI and MCI disease metrics such as brain volume, surface thickness, and White matter (WM) connectivity metrics in patients with amnestic Mild cognitive impairment (MCI).

When a person has a stroke, part of their brain is damaged. Depending on the size and location, the brain injury can cause new weakness that leaves the person disabled. Studies on animals suggest that exercising the weak part of the body after a stroke can help recover strength, and that more exercise leads to better recovery. We think this is also true in people, but it’s difficult to study because it is hard to know how much exercise each person did. In this project, we are using new sensors (made by MC10, Inc.) that measure movement (accelerometry and gyroscopy) and muscle activity (electromyography). Using information collected by these sensors we are developing a system that automatically tracks the number of rehab exercises a person has done with their weak arm. We will use the new system to measure the amount of exercise different people do after a stroke, and use this information to answer questions about how exercising affects stroke recovery. Ultimately, we hope this information will contribute to identifying better ways to help people regain their strength and independence after a stroke.

Parkinson’s disease (PD) manifests a heterogeneous clinical syndrome and this variability in the clinical phenotype highlights the need to tailor the type and/or the dose of treatment to the specific needs of individuals living with PD. The main goal of individualized, or precision, medicine is to use patient characteristics to determine an individualized treatment strategy (ITS) to promote wellness. This research is motivated by the PPMI (Parkinson’s Progression Markers Initiative) observational study. The data set includes longitudinal measurements of patients’ characteristics and treatment history and provide an excellent opportunity to construct data-driven ITSs. Existing guidelines for symptomatic drug therapy for PD can best be described as "permissive". The relative lack of comparative evidence for different classes of drugs has created challenges in devising recommendations to follow any specific therapeutic strategy; indeed, there remains substantial heterogeneity in the choice of treatment strategies. The study aims to fill this important gap.

The goal of this study is to adjudicate between two competing hypotheses – derived from predictive coding theory – as to the mechanisms underlying atypical perceptual processing in ASD. One hypothesis characterizes autistic perception in terms of reduced top-down influences on perception. While the other proposes that bottom-up sensory-perceptual processes are enhanced. We aim to test these two hypotheses using experiments involving natural speech – allowing us to link the essential RDoC constructs of perception and language. Our approach will involve using state-of-the-art methods for indexing the neurophysiology of hierarchical speech processing, while manipulating the fidelity of sensory input and the strength of prior information. Access to interpretable measures of hierarchical processing will be critical for adjudicating between the two hypotheses.

Here, for the first time, we will use the novel Mobile Brain/Body Imaging (MoBI) system in populations with an amnestic mild cognitive impairment (aMCI), Alzheimer’s disease (AD), and in age-matched healthy older adults to evaluate event-related potentials (ERPs) while stressing available cognitive resources using dual-task walking paradigms. Using electroencephalography (EEG) it was recently shown that visual evoked potentials (VEPs) can distinguish groups of older adults with an aMCI from those with AD, and from older adults that were not cognitively impaired. Our recent work using the novel MoBI EEG-based system has demonstrated that older adults show less flexibility in the reallocation of cognitive resources during dual-task walking. In addition, the risk of falling in people with AD is 2-3 times higher than in healthy older adults. We will compare neurophysiological responses in these groups while they are sitting, standing and walking on the treadmill. The overarching hypothesis that we will test in the proposed experiments is that both ERPs and gait parameters will correlate with cognitive impairment measures. MoBI and high density EEG are non-invasive tools that may lead to earlier diagnosis of aMCI/AD as well as point toward training paradigms that could stave off conversion from health to aMCI and also from aMCI to AD.

To explore the potential link between acute stroke, intestinal injury, and delayed expansion of the stroke core during the early phase of hospitalization, this collaborative effort between basic and clinical investigators will test the hypothesis that systemic inflammatory responses to pathological brain-gut coupling adversely affects the perfusion of 'at-risk' tissue within the ischemic penumbra that contributes to delayed core expansion. Paired blood specimens will be collected from patients presenting with AIS at the time of ED presentation and following hospital admission. Analyses will include acute measurement of leukocyte activation and serum-based markers of brain injury, gut injury, and systemic inflammation. These data will be analyzed in conjunction with data on stroke lesion growth extrapolated from acute CT and delayed MRI-based imaging obtained in the course of routine neurological care.

To date it is unclear how studies of the neural bases of language relate to inter-personal communication. Our long-term research goal is to harness functional Magnetic Resonance Imaging and Electroencephalography to chart the neural exchange of meaning between peoples’ brains during spontaneous conversation. Obviously, this depends on the ability to measure meaning in the brains of both speaker and listener. Recent scientific advances including those made by the current team have made strides toward solving this problem on the listener’s side. This project seeks to newly introduce computational methods that map out how meaning is processed in the speaking brain. This presents a challenge to discover the timeline that meaning is converted to outgoing speech, as opposed to incoming speech being converted to meaning.

Recent evidence suggests that individuals with Autism spectrum disorder (ASD) have poor prediction capabilities. Given that social communication is highly dependent on prediction and that individuals with poor prediction may prefer more repetitive environments, a deficit in predictive skills could explain many of the core symptoms associated with ASD. This study explores this hypothesis using EEG during an auditory mismatch negativity (MMN) paradigm. The MMN paradigm consists of playing a tone in a set rhythm pattern in most trials, and then creating a “deviant tone” by making an adjustment in the timing of a tone (e.g., making the tone come more quickly or slowly). When an individual detects a deviant tone, they demonstrates an MMN response. The MMN response to deviant tones varying in complexity will be compared between individuals with and without ASD. Additionally, the amplitude of the MMN (i.e., intensity of response) in individuals with ASD will be correlated with their symptom severity. We hypothesize that 1) individuals with ASD do not respond as dramatically to deviant tones and respond less as complexity increases and 2) the less an individual with ASD responds, the more severe their other ASD symptoms.

The focus of this project is to understand how groups of neurons in the amygdala encode social communication information and transmit it to the prefrontal cortex for evaluation, and cognitive processing. Deficits in communication and social interaction are hallmarks of autism spectrum disorders and we propose that understanding the amygdala-prefrontal circuits will help us to understand the neural basis of these deficits. Results from these studies will help us understand the processing and integration of socio-emotional information at the cellular and network level which will help us in our understanding of disorders in which these processes are disrupted.

We are investigating the role of Fragile X Mental Retardation Protein (FMRP) in the auditory brainstem. FMRP is an RNA binding protein and its absence results in Fragile X Syndrome (FXS), the most common cause of inherited autism spectrum disorder and mental retardation. We believe that FMRP has wide spread effects on gene expression and that these genes may play a role in neuroplasticity in the auditory brainstem. We will be analyzing the effects of FMRP on gene expression in the auditory brainstem by comparing the normal mouse to the FXS mouse model. Specifically, we will utilize laser capture microdissection technology to isolate specific areas of the auditory brainstem and perform RNA-seq next-generation sequencing analysis. Of the genes whose expression is altered, we will identify those that are directly controlled by FMRP through mRNA binding, versus those that are indirectly affected by other mechanisms. We will also determine if these genes are clustered in particular cellular pathways. Finally, we will test if any of these pathways are affected by deafening or loss of hearing. Results will reveal how FMRP regulates genes important in neuroplasticity to maintain normal hearing, and reveal potential therapeutic targets for symptoms of FXS such as auditory hypersensitivity.

The expansion of the cerebral cortex among primates has supported higher-level planning through specializations in frontal, parietal, and motor areas. Elucidating how these higher-level cortical areas interface with the rest of the brain remains one of the key challenges for understanding human intelligence and how aberrations in brain structure give rise to devastating disorders such as schizophrenia and autism. A major anatomical feature of higher-level cortical areas is that they make extensive feedback projections to earlier sensory areas that are involved in perception. At the behavioral level, higher level planning and movement control can have a profound influence on external perception and self-awareness, presumably through these feedback projections. However, the role of feedback at the neural level has remained elusive, in part because we lack the tools necessary to manipulate it in behaving animals, particularly in primates where the brain organization is similar to our own. The current project will develop an intersectional viral strategy based on pilot studies in mice to label and manipulate cortical feedback projection pathways in the marmoset monkey. These studies will help build a more general approach for understanding how higher-level cortical circuits in the primate interface with the rest of the brain.

Here, for the first time, we will use the novel Mobile Brain/Body Imaging (MoBI) system in populations with an amnestic mild cognitive impairment (aMCI), Alzheimer’s disease (AD), and in age-matched healthy older adults to evaluate event-related potentials (ERPs) while stressing available cognitive resources using dual-task walking paradigms. Using electroencephalography (EEG) it was recently shown that visual evoked potentials (VEPs) can distinguish groups of older adults with an aMCI from those with AD, and from older adults that were not cognitively impaired. Our recent work using the novel MoBI EEG-based system has demonstrated that older adults show less flexibility in the reallocation of cognitive resources during dual-task walking. In addition, the risk of falling in people with AD is 2-3 times higher than in healthy older adults. We will compare neurophysiological responses in these groups while they are sitting, standing and walking on the treadmill. The overarching hypothesis that we will test in the proposed experiments is that both ERPs and gait parameters will correlate with cognitive impairment measures. MoBI and high density EEG are non-invasive tools that may lead to earlier diagnosis of aMCI/AD as well as point toward training paradigms that could stave off conversion from health to aMCI and also from aMCI to AD.

This proposal develops ideas that we have been building on for some time, namely, whether the immature amygdala can add circuits during postnatal life, and if so, how the environment shapes that process. Depending on our results, we hope to use tract tracing to examine variability in amygdala circuit formation in maternally deprived monkeys compared to control. The project is entirely post-mortem work in monkeys.

This project blends a bench-based drug discover project with a vertically integrated team-based program that will provide University of Rochester undergraduate Neuroscience students research experience in a fast-paced, cross-disciplinary laboratory environment. The students will be trained in the laboratory on the essential techniques required to perform location proteomics to identify potential new drug targets in neuronal ER-stress pathways. One goal of our project is to establish a sustainable program that will expose undergraduate students to discovery science early in their academic careers and foster in them an appreciation for the rewards of collaborative science and exploration. The project will also establish a pipeline for functional gene analysis that in the future can be used to identify functional signaling nodes in other disease-relevant paradigms.

This study is aimed at understanding whether complement dependent synapse pruning is involved in the molecular neuropathology of autism (using mouse models) and whether the Sez6 gene family regulates this process. We hypothesize that the activity of complement regulatory proteins may be key to understanding why certain subsets of synapses are more vulnerable to synaptic pruning by glial cells than others during development and in the context of heightened inflammation. Enhanced pruning could lead to disrupted connectivity and neurological functions in individuals with autism spectrum disorders.

The objective of this research is to observe how acoustic stimuli affect mass transport within the cochlear fluid. The hypothesis of the full-blown R01 proposal is that the outer hair cells’ motility contributes to cochlear fluid homeostasis. We will investigate the micro-fluid dynamics within the the organ of Corti (OoC), which has been largely overlooked because there have been few means to observe it until very recently. There are three aims with different scopes toward obtaining an integral set of preliminary data, such as the time taken for mass transport along the cochlear length in vivo (Aim 1), micro-mechanics of the OoC in vitro (Aim 2), and theoretical prediction in silico (Aim 3). Aims 1 and 2 are used to validate the theoretical study of Aim 3. Aim 3 will predict the cochlear fluid homeostasis under different natural/pathological conditions.

The loss of cochlear sensory cells, termed hair cells, is a primary cause of hearing loss in mammals. Surprisingly, spontaneous regeneration of lost cochlear hair cells occurs in birds, yet this does not occur in mammals. In regenerating animals, cochlear supporting cells, which are adjacent to hair cells, proliferate and differentiate into new hair cells, with restoration of auditory discrimination in 1-2 months. Supporting cells in the young mouse cochlea retain the capacity for regeneration, however, knowledge of how regeneration is regulated is still lacking. Efforts to manipulate these pathways in mice in order to improve cochlear responses after noise exposure are still in the early stages. We have investigated a potential role for ERBB family receptors in inner ear regeneration. We hypothesize that the activation of ERBB signaling pathways using WS3 will drive cochlear supporting cell-to-hair cell differentiation and improve auditory responses in mice after noise exposure.

Auditory processing is important for communication and it has been shown that children with Autism spectrum disorder (ASD) have deficits in auditory function at the cochlear level. Additionally, difficulty in filtering relevant auditory information in background noise can significantly impair a person’s social communication abilities. We, and others, have demonstrated that children with ASD have impaired abilities to hear in the presence of background noises, but exhibit no differences in quiet.

Mouse models are essential to advance understanding of the mechanistic basis of ASD, as well as to test potential therapies. In this proposal we will examine three different mouse models of ASD (16p11.2 duplication, Cntnap2, and Shank3) that have the greatest construct and face validity, and have also been backcrossed many generations onto C57B6 strain to eliminate potential strain effects. While these mouse models exhibit differences in their output of social vocalizations and thus show communication deficits, it is not known whether they also show auditory processing deficits.

The goal of this project is to use high-density recordings of neuronal populations to investigate how anatomical circuits in the brain give rise to canonical computations across different species.

The mammalian neocortex encodes features of the sensory world through the coordinated activity of large populations of neurons (REF%). While many of the general features of neocortex are well conserved across mammals, such as the six-layered structure (REF%) and primary excitatory and inhibitory cell classes (REF%), other features such as columnar organization (REF%) and foveal overrepresentation vary considerably between species (REF%). As a result, some features of single neuronal responses to sensory stimuli are preserved across diverse species (tuning of cells to oriented bars of light REF%), while others vary between species (saccades in non-human primates REF%).

Understanding these differences in the context of neuronal coding is made more complicated by the fact that computations often reflect the joint activity of networks of neurons (REF%); computations that can be obscured when either single neurons are analyzed in isolation or when the activity of units in averaged over multiple trials. As a result, it is unclear to what extent structural differences in neocortex reflect underlying differences in neural coding. These issues could be resolved by examining the patterns of activity across large neuronal populations using comparable stimulus and behavioral conditions.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by a unique combination of progressive ataxia, seizures and anticipation. SCA10 is associated with expansion of an ATTCT repeat in intron 9 of the ATXN10 gene. While the normal repeat size is 10-22, the disease-associated repeat size is 800-4500. Given that earlier work has shown that repeat expansion does not affect ATXN10 mRNA or protein expression, the molecular mechanism of SCA10 is unlikely attribute to a simple loss of ATXN10 gene function. Based on my unpublished data, I postulate that a novel RNA-mediated gain-of-function mechanism contributes to SCA10 pathogenesis. In this mechanism, the expanded AUUCU RNA repeats accumulate in cell nuclei and sequester nuclear RNA-binding proteins, including the well-studied pre-mRNA splicing mediator poly-pyrimidine tract binding protein 1 (PTBP1). To examine this hypothesis, I propose to (1) generate human induced pluripotent stem cell (iPSC)-derived neuronal cells using SCA10-patient cells, and (2) test the ability of antisense oligonucleotides (ASOs) to block the sequestration of AUUCU-binding proteins from ATXN10 mRNA harboring expanded repeats without affecting ATXN10 mRNA harboring a normal number of repeats.

The conceptual framework for this new collaboration rests on the principle that visual orienting behaviors can be used as accurate predictors of neural dysfunction in developmental disorders such as Autism and Dyslexia, as well as in degenerative diseases like Alzheimer’s disease and also in discrete injuries like mild traumatic brain injury. Combining understanding of neural underpinnings with analyses of structural integrity and also with neurophysiological measures of function in these patient populations will produce insight into the disorders, help identify biomarkers for early diagnosis and define subpopulations for targeted remediation. While future work will be directed at other developmental disorders and degenerative diseases, in the experiments described in detail below we seek to identify a subphenotype of Autism Spectrum Disorders (ASD) based on the structure of the cerebellum and the ability to adapt the amplitude of saccadic eye movements in response to persistent visual errors.

Given these gaps in knowledge, the overarching goal of this study is to quantitatively estimate different sources of noise that limit perceptual processing in ASD using psychophysical and computational methods to test the main hypothesis that internal additive noise is broadly elevated in individuals with ASD. Given the high prevalence of inconsistent sensory responses in ASD, it is critical to test this hypothesis in a range of perceptual domains. Our study will integrate our parallel lines of work to focus on visual and auditory domains. In addition, we will employ a novel approach that dramatically increases data collection efficiency, allowing us to use a paradigm that was previously impractical to implement with non-expert participants.

The overarching aim of this study is to determine whether or not EEG responses to natural speech can be decoded based on the semantic content of that speech. The underlying hypothesis is that EEG reflects the encoding of speech based on its semantic content. More specifically, we hypothesize that the semantic processing of speech involves relating that speech to components of experience, and that this process produces discriminable patterns of activation on the scalp that are particular to the content of the specific speech input.