Interdisciplinary, collaborative, analysis of neuroimmune-based schizophrenia

Principal Investigator:  Kimberley McAllister, Ph.D.
Co-Investigators (Psychiatry):  David Amaral Ph.D., Melissa D. Bauman, Ph.D., Cameron Carter, M.D.

In the past decade there has been a paradigm shift in our understanding of the interactions between the immune and nervous systems, leading researchers to explore neural-immune based mechanisms for complex brain disorders, such as schizophrenia, that have thus far eluded explanation.  While the brain was previously thought to be an immunologically “privileged” body region because it was NOT influenced by the immune system, there is now very credible evidence that immune factors influence everything from synaptogenesis to the onset of psychiatric disorders. A number of UC Davis faculty have been independently drawn to this rapidly growing field of neuroimmunology in the hope of identifying causes and ultimately developing novel treatments for disorders such as autism and schizophrenia. This three year RISE grant brings together these individuals, resulting in a team with diverse and complementary expertise in neuroscience), immunology, biomedical imaging, radiochemistry, and clinical research to evaluate neuro-immune hypotheses of schizophrenia.

Prenatal risk factors for schizophrenia: An evaluation of brain neuropathology in an animal model of maternal immune activation

Principal Investigator:  Melissa D. Bauman, Ph.D.

Schizophrenia is a devastating brain disorder that affects approximately 1% of the population worldwide. While the cause of schizophrenia remains unknown, prenatal exposure to certain environmental factors may increase the risk of developing schizophrenia later in life. We know, for example, that children who are born to mothers that experience infection during pregnancy have an increased risk of developing schizophrenia. Although the association between maternal infection and an increased risk of schizophrenia is compelling, there are many unanswered questions.  How does maternal infection alter fetal brain development? Are certain gestational time points more vulnerable than others?  What steps can be taken to decrease deleterious effects if a woman becomes ill during pregnancy?  Animal models are playing an essential role in answering these questions.  This study will determine what aspects of brain development are altered following prenatal immune challenge, compare the neuropathology of the animal models to neurpathological features of human schizophrenia, and identify future preventative and/or therapeutic strategies for schizophrenia.

Imaging of cognitive processes in schizophrenia

Principal Investigator:  Cameron Carter, M.D., Director, UC Davis Imaging Research Center 

The work in our laboratory focuses on neural mechanisms of attention and memory, and on the pathophysiological processes underlying clinical disorders that involve these cognitive systems. Our research integrates behavioral, computational, and functional neuroimaging (fMRI, PET, ERP). We are particularly interested in the relative contribution of the prefrontal cortex and anterior cingulate to executive processes and the interaction of this circuitry with related brain regions involved in motivation, learning and memory.

A second avenue of research focuses on the pathophysiology of disturbances in cognition in mental disorders such as schizophrenia and OCD, with the goal of developing more effective therapies which can improve patients’ chances of rehabilitation. We are also involved in the development of new treatments for cognitive disability in schizophrenia and other brain disorders. A key element of the philosophy of the lab is that good clinical research can only proceed if it is being constantly informed by ongoing theoretical and methodological progress in basic cognitive neuroscience, and that the experiments of nature provided by clinical brain disorders may provide us with powerful additional insights into the neural basis of normal cognition.

Cognitive neuroscience markers of outcome in youth at risk for serious mental illness

Principal Investigator:  Tara Niendam, Ph.D.

I utilize functional MRI methodologies to investigate the biological underpinnings of prefrontally mediated cognitive control and its impact on functioning across the spectrum of risk and established illness. My research seeks to understand the interplay between cognition and daily functioning within serious mental illness, and how such relationships are impacted by the course of development. I am interested in understanding 1) how early cognitive markers can predict later functional outcome and 2) how changes in cognition occurring over development can also serve as markers of risk for deterioration – or signs of resilience for improvement – in clinical and functional domains . By elucidating such markers of risk and resilience, I hope to help the field identify possible avenues for treatment.

Brain mechanisms of impaired episodic memory in schizophrenia

Principal Investigator:  J. Daniel Ragland, Ph.D.

Schizophrenia is characterized by severe memory deficits that compromise daily psycho-social function and limit long-term outcome. However, not all aspects of memory are affected, and patients are capable of showing unimpaired encoding and retrieval under certain task conditions. This research program utilizes behavioral, fMRI, eye tracking, and EEG methods to test a novel theory about a neurocognitive mechanism that can explain memory strengths and weaknesses in the disorder and, thereby, inform cognitive training procedures and identify target mechanisms for development of new pro-cognitive agents.

Neural mechanisms of memory dysfunction in schizophrenia

Principal Investigator:  J. Daniel Ragland, Ph.D.
Co-Principal Investigator:  Charan Ranganath, Ph.D.

This is a multi-modal neuroimaging study of learning and memory in people with schizophrenia. Dr. Ragland’s previous behavioral and fMRI research has shown that people with schizophrenia have a characteristic pattern of memory strengths and weaknesses rather than a generalized memory deficit. Patients can successfully recruit ventral portions of their prefrontal cortex to learn information based on specific item features, and then successfully recognize that information based upon a sense of familiarity. In contrast, they have great difficulty learning relationships between these items with each other and with the encoding context to support successful retrieval based upon recollection of the event. Moreover, these impairments are accompanied by specific hippocampal and dorsolateral prefrontal cortex (DLPFC) dysfunction.  Dr. Ragland’s new research funding will allow him to combine these previous fMRI methods with measures of electrophysiology (EEG) and brain chemistry (MRS measures of GABA concentrations) to test the central hypothesis that individuals with schizophrenia have disrupted GABAergic inhibition in the dorsolateral prefrontal cortex that impairs local circuit function and results in a reduction of neural oscillations in the theta band (4-8Hz).  This oscillatory deficit, in turn, contributes to DLPFC and hippocampal dysfunction and this specific pattern of relational memory deficits. It is hoped that providing this link to brain chemistry and neural oscillations will open new treatment options (medications and brain stimulation techniques) to restore performance of this impaired memory system and improve the daily functioning of people with schizophrenia.