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.

Principal Investigator:  Prabhakara Choudary, Ph.D.

Multiple lines of recent evidence implicate glial cells in the etiology of major depression. For example, lowered astrocyte counts have been documented in the frontal cortex, in regions important for cognition, mood and motivation. Neuroimaging studies and postmortem histological and morphometric studies of depressed individuals who died young by suicide suggest a possible role for astroglia. Yet, hypotheses concerning depression etiology dogmatically approach major depression as a disorder of neurons and ignore glia. To resolve this paradox, we profiled gene expression pattern in postmortem frontal cortex of depressed individuals using high density oligonucleotide microarrays. To our dismay, we found significant downregulation of glutamatergic genes, e.g., glial high-affinity glutamate transporters (SLC1A2 and SLC1A3) and glutamine synthetase (GS), concomitant with upregulation of the genes encoding glutamate (NMDA) and GABA receptor subunits. These results provide further compelling evidence for the role of astroglia in major depression, since astrocytes are the site of biosynthesis of SLC1A2, SLC1A3 and GS. They also raise several tantalizing questions, e.g., (1) what changes in these genes (DNA) cause their transcript levels to drop?; (2) do translational changes corroborate the transcriptional changes observed?; and (3) will these genes potentially be useful as biomarkers of major depression? We are addressing these questions using a variety of tools and techniques, including: Laser Capture Microdissection (LCM); miRNA; and immunochemical and biological assays of functional activities. We anticipate the results will lead to the development of early detection screens with increased sensitivity and specificity. Similarly, the abnormal molecules/ circuits identified here could serve as targets for novel drugs, e.g., NMDA receptor antagonists or agents that can selectively restore the balance between inhibitory and excitatory synaptic transmission, and curtail excessive excitatory activity, ushering in an era of mechanism-targeted rather than symptom-based therapeutics. These studies are a part of an interdisciplinary multi-investigator study, carried out in close collaboration with fellow members of the Conte Center and Pritzker Consortium (of five US universities); Dr. Edward Jones leads the UC Davis component. In parallel, in collaboration with Dr. Cameron Carter, we are initiating attempts to ask similar phenomics questions about schizophrenia, using whole genome scanning to identify SNPs.

Principal Investigator:  Blythe Corbett, Ph.D.

Converging evidence from neuropathological, neuropsychological, lesion and neuroimaging studies support an important role for the amygdala in the neuropathology of autism. A central hypothesis of this series of studies is that dysregulation of the amygdala may contribute to various impairments in autism including increased response to potentially threatening stimuli, deficits in implicit and explicit emotion perception and limited social cognition. Functional magnetic resonance imaging (fMRI) permits the in vivo study of underlying brain regions involved in the execution of a cognitive, affective, motor or perceptual task. The goal of this project is to use established fMRI probes of amygdalar function to study the processing of various social and emotional stimuli in children with autism and neurotypical children 8 to 12 years of age.

Principal Investigator:  Robert Hendren, D.O.

Children with bipolar disorder, schizophrenia or autism ppectrum disorder are being studied using structural MRI and MR spectroscopy and selected neuropsychological tests to subtype their symptoms into meaningful symptom domains. Current domains include affective instability and cognitive disorganization. This line of inquiry follows an NIMH RO1 and two Foundation grants to Dr. Hendren.

Principal Investigator:   Ruth Salo, Ph.D.
E-mail:  resalo@ucdavis.edu

In the past decade the use of the stimulant methamphetamine has increased in schizophrenia patients as well as the general population. In persons without a psychiatric diagnosis methamphetamine is known to be neurotoxic to dopaminergic rich frontostriatal brain regions, including the anterior cingulate cortex and the  prefrontal cortex with accompanying deficits in attention and executive control.   Little is known however about the additive effects of methamphetamine abuse on brain function and cognitive control in schizophrenia patients.  Our research program is examining the effects of methamphetamine abuse on brain function and attention in schizophrenia patients using Functional Magnetic Resonance Imaging [fMRI], magnetic resonance spectroscopy [MRS]  and experimental measures of cognitive control. The use of MRS in conjunction with fMRI will determine whether or not neuronal pathology as measured with MRS is linked to functional brain activation as measured by fMRI during tests of cognitive control. These data will provide insight into the neural substrates underlying attentional control and may contribute to clinical interventions in those schizophrenia patients who abuse stimulants.

Principal Investigator:  Ruth Salo, Ph.D.
E-mail:  resalo@ucdavis.edu

There is increasing evidence that methamphetamine is neurotoxic to dopaminergic frontostriatal brain regions with corresponding deficits in selective attention and cognitive control. Our research program is investigating the relationship between alterations in brain function and attentional control in methamphetamine abusers. We are employing magnetic resonance spectroscopy [MRS] and diffusion tensor imaging [DTI] in conjunction with sensitive computerized measures of attention to examine these links. Our findings thus far indicate a dysregulation of attentional control associated with long-term methamphetamine abuse. Such breakdowns in attentional control may contribute to behaviors associated with maladaptive decision-making often associated with drug-seeking behavior. Careful characterization of cognitive functioning is relevant to the treatment of substance abuse as many treatment programs rely on cognitive behavioral therapy as part of their intervention approach.

Principal Investigator:  Julie Schweitzer, Ph.D.

Attention deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder, affecting daily functioning in approximately 3 to 7 percent of school-aged children in the United States. Estimates for the prevalence of adult ADHD suggest that 4.4 percent of the population in the United States may have the disorder.  The broad objectives of the ADHD program are to further the understanding of the basic mechanisms underlying the disorder and use those findings to develop interventions to prevent and treat the disorder. One current project in our lab examines work memory impairments in ADHD, which can affect academic, social, and occupational functioning. The overall hypothesis of this proposal is that individuals with ADHD engage an altered neural system when performing working memory tasks. We are investigating working memory in children with ADHD to: 1) define the neural correlates of working memory deficits in ADHD children using subtraction techniques in conjunction with a visual serial addition task; 2) identify the relationship between BOLD signal changes generated during a working memory task and behavior (response time, error type; ADHD ratings); and 3) compare ADHD children with the combined subtype to the inattentive subtype to identify the working memory neural strategies associated with each. A better understanding of strategies used in ADHD has potential educational implications for how children with ADHD learn and targets for treatment.

Principal Investigator:  Catherine Fassbender, Ph.D.
Co-Investigator:  Julie Schweitzer, Ph.D.

Individuals with ADHD have been defined as making "spur-of-the-moment", risky decisions without planning or thought of future consequences of their actions. Successful planning requires evaluating performance and modifying behavior dependent upon current success defined by both internal goals as well as environmental cues. This flexible interplay between stimulus- and internally-driven processes may be problematic for individuals with ADHD.

ADHD is characterized according to subtypes, the two most common being the combined (i.e. symptoms of inattention, hyperactivity & impulsivity) and primarily inattentive subtypes (i.e., inattentive symptoms). Previous studies of performance monitoring in ADHD suggest that although these individuals are aware that they have made an error, they do not display the normal pattern of post-error slowing that is usually indicative of behavior correction. Our pilot data suggest differences between ADHD subtypes in their ability to use environmental cues to influence behavior; although the performance of typically developing children and combined type children both improved when they were given a warning cue to prepare a response, inattentive type children did not.

The goal of this proposal is to examine the dynamics of attention control and response modification given cues and feedback in ADHD in comparison to typically developing adolescents; to examine the interplay between internally (e.g., PFC) and stimulus-driven (e.g., cingulate) processes to elucidate the brain recruitment pattern involved in each subtype; to examine the temporal dynamics between regions implementing control. Performance between typically developing, ADHD-combined and inattentive type adolescents performing a cued arrow flanker paradigm are compared in this study. Occasional response-conflicting, incongruent stimuli are presented to engender conflict. Cues are introduced for some incongruent stimuli in order to examine response-preparation processes.  Findings from this project can inform us about how future diagnostic and intervention techniques can be designed to optimally benefit different ADHD subtypes depending upon the ability to utilize endogenous resources and environmental cues.

Principal Investigator:  Tony J. Simon, Ph.D.

The focus of research in our lab is the neurocognitive basis of developmental disability in children with genetic disorders. We have carried out most of our investigations with children who have chromosome 22q11.2 deletion syndrome (hereafter DS22q11.2) and more recently have begun to study children with Fragile X, Turner and Williams syndromes. Despite many differences, individuals in these populations typically exhibit seemingly common impairments in the visuospatial and numerical cognitive domains. In these genetic disorders there is also reduced volume in many areas of the brain, including the parietal cortex, an area linked to visuospatial and numerical cognition. We hypothesize that some key aspects of visuospatial function are disturbed by this abnormal development and that a characterization of the changes to these basic processes will generate explanations of, and possibly indicate treatments for, a range of cognitive impairments in children with these disorders. We use a range of converging methods to test hypotheses about the neurocognitive bases of the aforementioned impairments and also of other behavioral manifestations in the realm of psychopathology. These include:

• characterizing the cognitive processing impairments by employing a set of experimental tests
• specifying the volumetric changes in whole brain in terms of the tissue involved (i.e. gray matter, white matter, cerebrospinal fluid)
• determining, through the use of Diffusion Tensor Imaging, any anomalies in neural connectivity that might contribute to cognitive dysfunction
• directly measuring, through the use of functional magnetic resonance imaging (fMRI), neural activity in children as they carry out a range of cognitive processing tasks

Prinicipal Investigator:  Marjorie Solomon, Ph.D.

Cognitive control refers to the ability to flexibly allocate mental resources to guide thoughts and actions in light of internal goals. Given the behavioral inflexibility exhibited by individuals with autism spectrum disorders (ASDs), it would appear they experience cognitive control deficits. My principal research program investigates cognitive control in high functioning individuals with autism spectrum disorders, and the relationship between cognitive control and behavioral symptoms. A career development award from the National Institute of Mental Health (1 K08 MH074967-01; Mentors: Drs. Cameron Carter, Sally Ozonoff, David Amaral, and Mark Lewis) will enable me to study cognitive neuroscience methods including fMRI to better investigate the neural mechanisms underlying control deficits, including functioning of the prefrontal cortex, the anterior cingulate cortex, and the basal ganglia and their relationship to restricted and repetitive behavior symptoms and formal thought disorder.

Principal Investigator:  Marjorie Solomon, Ph.D.

Autism involves dysregulated motivation in interpersonal relationships, goal-directed behavior, and learning. Theories about social aspects of motivation impairments, including those found in joint attention and face processing, recently have been articulated, however, there has been little study of non-social forms of motivation that also can create profound problems in adaptive functioning. The behavioral intervention literature also suggests that learning is dysregulated in autism spectrum disorders (ASDs) since acquisition of new skills may require multiple discrete learning trials with very explicit reinforcement schedules. Paradoxically, while some rewards are not motivating enough, some are too attractive to children with ASDs. For example, engagement in repetitive behavior may be self-reinforcing and circumscribed interests can be so seductive that adaptive functioning is disrupted when the person with ASD becomes absorbed in them. I am the principal investigator on a grant funded by Autism Speaks to examine non-social aspects of reward processing in ASDs using behavioral and functional neuroimaging measures.