2020 — 2021 |
Ford, Judith M |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Secondary Data Analysis of Existing Data to Explore the Rdoc Construct of Agency Across the Psychosis Spectrum Using Fmri and Eeg @ Northern California Institute/Res/Edu
Cardinal symptoms of psychotic illnesses, such as delusions and hallucinations, are associated with high morbidity and mortality, motivating efforts to understand their pathophysiology. These symptoms may be underpinned by misperceptions and misinterpretations of sensations that result from a basic inability to recognize that you are the agent of the self-generated experiences you are having. If mechanisms underlying agency are dysfunctional, sensations that should have been predicted, but were not, might take on inappropriate salience and lead to the construction of delusional cognitive schema to explain aberrant experience. Abnormal functioning of this agentive system may characterize psychosis and psychosis vulnerability. Very move we make is accompanied by a copy of the motor plan that generates an expectation of its sensory consequences, which is then compared to the actual sensation. Through this comparison process errors are detected and corrected. This is likely done by rapid cerebellar side loops, out of awareness. Vocalization is used to study this comparison process across the animal kingdom. In all cases, auditory responsiveness is suppressed during vocalizing compared to when the sound is coming from other sources. In humans, this is seen as suppression of the N1 component of the EEG-based event-related potential, emanating from auditory cortex. Consistent with suggestions of deficits in this mechanism in schizophrenia, we have shown that suppression of N1 during vocalizing is reduced in psychosis and psychosis vulnerability. When N1 is decomposed into its basic elements, specifically theta band power and inter-trial coherence (ITC), suppression of theta ITC is more sensitive to psychosis and delusions. We propose to use suppression of N1 and theta ITC during vocalization as assays of agency. In a large multi-site study, we used resting state magnetic resonance imaging (fMRI) data to calculate functional connectivity and found that psychosis is associated with hypo-connectivity between thalamus and cerebellum, especially in patients with delusions. We propose to extend this work using cerebellar seeds derived from agentive tasks (vocalizing and pressing a button to hear a tone), and relate cerebellar dysconnectivity to psychotic symptoms associated with dysfunctions of agency and EEG assays of agency. We propose to align existing resting state fMRI and EEG-based vocalization data from two sites, from males and females (12-62 years old), across diagnoses and the wellness spectrum: clinical high-risk youth, schizophrenia, schizoaffective, psychotic bipolar patients and their 1st degree relatives, and healthy controls.
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0.903 |
2021 |
Ford, Judith M Weiss, Ethan |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Can Neural Network Instability in Schizophrenia Be Improved With a Very Low Carbohydrate Ketogenic Diet? @ Northern California Institute/Res/Edu
Wide ranging cognitive deficits are major drivers of functional decline and poor outcomes in people with schizophrenia (SZ). Antipsychotic medications do not target pathophysiological mechanisms thought to underlie these deficits. In the search for interventions targeting underlying cognitive impairment in schizophrenia, we look comprehensively beyond just the brain and to the potential role of dysfunctional systemic metabolism. Disrupted insulin and glucose metabolism are seen in medication-naïve first-episode SZ, suggesting that SZ itself, and not just the medications used to treat it, is associated with risk of Type 2 diabetes, cardiovascular morbidity and mortality, and more generally, accelerated aging. Even young people with SZ have increased risk of metabolic disease and cognitive deficits. Sadly, their life span is shortened by 15?20 years. Although the human brain is 2% of the body?s volume, it consumes over 20% of its energy, and accordingly, the brain is particularly vulnerable to the dysregulation of glucose metabolism seen in SZ. While glucose is considered to be the brain?s default fuel, ketones provide 27% more free energy and are a major source of energy for the brain. Ketones prevent or improve various age-associated diseases, and a ketogenic diet (70% fat, 20% protein, 10% carbohydrates) has been posited as an anti-aging and dementia antidote. The premise of the work is based on recent evidence that ketogenic diets improve dynamic neural network instability, related to cognitive deficits, aging, and Type 2 diabetes. The rigor of the work rests on findings of (1) poor glucose homeostasis in SZ, (2) neural network instability in SZ, and (3) direct effects of ketosis on network instability. Unknown is whether ketogenic diets can improve network instability in people with SZ. We propose a mechanistic, prospective, clinical pilot study of a 4-week ketogenic diet on neural network instability in overweight/obese SZ, at risk for insulin resistance. Seventy SZ (40-65 years old) will be randomized to a ketogenic diet (n=35) or diet-as-usual (n=35). Resting state 7Tesla fMRI scans will be acquired before and after the 4-week diets. Cognitive data at baseline will be used to determine if its relationship with network instability, seen in neurotypicals, is also seen in SZ. We will compare network stability following the two diets and consider the role of metabolic and inflammatory mechanisms in improvement of neural network instability. This work brings together cardiovascular metabolism and psychiatry to address two problems experienced by people with schizophrenia: (1) neural network instability associated with cognitive deficits, and (2) insulin resistance associated with morbidity and mortality. A controlled ketogenic diet has never been tried in people with SZ, who suffer from both cognitive deficits and insulin resistance. At the end of this 2-year project, we will know if deficient glucose metabolism, at least partially mediated by primary or secondary insulin-resistance, contributes to network instability in schizophrenia, a pathophysiological mechanism underlying accelerated aging and cognitive impairment in the disorder.
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0.903 |
2021 |
Ford, Judith M Mathalon, Daniel H |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Secondary Data Analysis of Auditory Steady-State Response to Explore the Rdoc Cognitive System Constructs Across the Psychosis Spectrum @ Northern California Institute/Res/Edu
Hallucinations and cognitive impairments associated with psychosis may be underpinned by N-methyl D- aspartate (NMDA) receptor hypofunction. Within the Research Domain Criteria (RDoC) developed by the National Institute of Mental Health, features of psychosis illness, which can also be transiently produced in healthy normal subjects given NMDA receptor antagonists, fall under the Cognitive System domain. Within this domain, auditory perception and processing speed are most relevant to the proposed work. Research focused on the abnormal functioning of this cognitive system in both psychosis and psychosis vulnerability subject groups may increase understanding of these symptoms. Electroencephalography (EEG) has great potential to elucidate the potential link between NMDA receptor hypofunction and symptoms of illness. Gamma (30-80Hz) oscillations are known to be generated by fast- spiking interneuron and pyramidal neuron microcircuits, and NMDA receptors play an important role in fast- spiking interneuron activity. Using spectral decomposition to analyze EEG, frequency-specific oscillations, including the gamma band, can be isolated and extracted on a millisecond basis. The auditory steady-state response (ASSR) is often used to study impaired EEG gamma oscillations in schizophrenia. These tasks use short-duration trains of repetitive auditory stimulation at a fixed frequency (e.g., every 25ms or 40-Hz) to evoke an ASSR at that same frequency. In particular, the 40-Hz ASSR is typically reduced in evoked response power and exhibits more oscillation phase variability, or reduced phase synchrony, across trials in schizophrenia. These deficits have also been observed in first-degree relatives and individuals at clinical-high risk (CHR) for psychosis. More recently, two additional measures derived from ASSR have demonstrated sensitivity to psychosis pathophysiology. These measures are (1) spontaneous gamma band power in the pre- stimulus baseline period, which is abnormally elevated in schizophrenia, and (2) the 40-Hz ASSR oscillation phase angle, which is significantly delayed in schizophrenia. In a series of previously conducted studies across 9 laboratories, we collected 40-Hz ASSRs from chronically ill (i.e. > 5 years duration) psychosis patients, early illness (i.e. <= 5 years duration) psychosis patients, CHR subjects, and a wide age range of healthy comparison controls. We propose to align these existing EEG data from over one thousand males and females (12-61 years old), across diagnoses and the wellness spectrum. This project will extend prior work by using ASSR phase delay and spontaneous (baseline) gamma power to compare stages of psychosis illness. Any association between these gamma measures and hallucination symptom ratings, neuropsychological speed of processing tests, age, or sex will be determined. Longitudinal effects on 40-Hz ASSR will be assessed in CHR.
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0.903 |