A novel, transient inactivation technique for studying the primate social brain
Principal Investigators: David G. Amaral, Ph.D. and Christopher J. Machado, Ph.D.
Electrophysiological recordings and brain lesions have been the most common methods used to identify and dissociate the function of brain structures in animal models. However, these techniques can result in unintended damage and compensatory functional reorganization, both of which complicate the interpretation of behavioral results. There are also methods for temporarily manipulating brain function in animal models, but all options currently available require repeated injections into the brain and/or permanent cranial implants, both of which cause physical trauma and preclude long-term study of awake, behaving animals. A new pharmacogenetic technique, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), has just emerged over the past few years and offers a minimally-invasive means to control brain function during long-term studies. Viral vectors transfect neurons in specific areas with a DREADD gene. These novel receptors are triggered by intravenous or oral administration of a nontoxic molecule called clozapine-N-oxide (CNO). Activation or inactivation of neural activity occurs within 15 minutes after CNO administration and lasts for up to 9 hours. This technique has been successfully used to study complex behavioral patterns in rodents, but has never been used in nonhuman primates, the model of choice for studying the neurobiology of social behavior. The overall objective of this study is to implement DREADD-based transient inactivation in the nonhuman primate amygdala. We plan to first demonstrate the utility of this technique by measuring the effect of the inactivation in paradigms known to be sensitive to permanent amygdala lesions, including fear learning and social interactions. We will then use eye-tracking techniques to measure how amygdala dysfunction influences visual scan paths with social stimuli.
Imaging of cognitive processes in schizophrenia
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 control processes in ADHD subtypes
Principal Investigators: Catherine Fassbender, Ph.D. and 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.
Limbic system function in carriers of the Fragile X premutation
Principal Investigator: David Hessl, Ph.D.
Individuals with the Fragile X premutation are “carriers” – they can transmit an expansion of the gene to their children, who may become affected by Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a common cause of autism. Until recently, these “carriers” were believed to be clinically unaffected. However, recent evidence has emerged demonstrating that a proportion of these individuals have significant social, emotional, and cognitive problems, even autism and intellectual disability in the most affected patients. In addition, we have discovered that male and rare female carriers are at significant risk for a neurodegenerative disease in later adulthood primarily characterized by intention tremor and gait ataxia called Fragile X-Associated Tremor Ataxia Syndrome. This disease is not seen in FXS and has a different genetic mechanism. This project does not involve FXTAS patients but rather younger men and women with the premutation who demonstrate psychiatric disturbances and are at risk for later neurodegeneration. The project, using structural and functional brain imaging, neuropsychological assessment and genetic measures, examines the hypothesis that dysfunction of the limbic area of the brain, especially the hippocampus and amygdala, are involved in memory, emotional and social problems in premutation carriers. This research related to the premutation that may provide insight into other disorders involving memory, social-emotional dysfunction, and the broader autism phenotype.
Functional magnetic resonance imaging of the nonhuman primate social brain
Principal Investigator: Christopher J. Machado, Ph.D.
This project is the latest extension of a series of noninvasive functional neuroimaging experiments that began in 2008. Those initial studies used high-resolution positron emission tomography (microPET) and radio-labeled glucose analogs to noninvasively measure epoch-related brain activity related to social information processing in nonhuman primates. However, the low temporal (on the order minutes) and spatial (~2.5 mm3) resolution of microPET limits its ability to study many aspects of social cognition that occur on a second-by-second basis and in structures that are composed of multiple heterogeneous subregions, such as the amygdala and orbitofrontal cortex. Therefore, the current studies are utilizing functional magnetic resonance imaging (fMRI), with its higher temporal (on the order of seconds) and spatial (0.5 - 1 mm3) resolution, and a small group of nonhuman primates to study the neurobiology of social information processing. Specifically, we aim to study the neural network responsible for social and nonsocial recognition memory. The primary advantage of fMRI experiments with nonhuman primates is that follow-up studies can be performed with the same animals using methods that manipulate brain activity, like pharmacogenetic transient activation/inactivation techniques.
Neurometabolic mechanisms in psychiatric disorders
Principal Investigator: Richard J. Maddock, M.D.
Disturbances to the metabolic infrastructure of the brain appear to have an important role in the pathogenesis of many of the major psychiatric disorders. Ongoing advances in magnetic resonance methods are making possible increasingly precise non-invasive assessment of this neurometabolic infrastructure. Across a range of neuropsychiatric disorders (including psychotic, substance use, mood, and anxiety disorders), my lab develops and applies new methods for the non-invasive measurement of neurometabolites involved in key brain functions such as neurotransmission, energy metabolism, neuroinflammation, and protection against oxidative stress. We have a particular interest in dynamic regulation of the neurometabolic infrastructure during periods of increased neural activity evoked by cognitive, pharmacological or metabolic challenges. Current studies in this area are examining the dynamic responses to ketamine infusion, physical exercise, sensory stimulation, and cognitive challenge.
Brain structure and connectivity in young children with autism
Principal Investigator: Christine Wu Nordahl, Ph.D.
The goal of this project is to use structural and functional neuroimaging techniques to investigate abnormalities in brain structure and connectivity in preschool-aged children with autism. Although previous structural imaging studies have provided some insight into the neuropathology of autism, the vast majority of studies have focused on older adolescents and adults with autism. Since autism emerges in the first years of life, during critical periods of brain development, it is critical to study children as close in time as possible to the clinical diagnosis and prior to intensive behavioral and medical interventions. Children are enrolled through the UC Davis MIND Institute’s Autism Phenome Project. Neuroimaging data is acquired at three annual time points, beginning at 3 years of age. All longitudinal imaging is carried out during natural nocturnal sleep, without the use of sedation or anesthesia. We will evaluate brain maturation trajectories in association with behavioral development over this critical period. Understanding the neural underpinnings of ASD is a critical step towards developing effective interventions and optimizing treatment outcomes.
Neural phenotypes of females with autism spectrum disorder
Principal Investigator: Christine Wu Nordahl, Ph.D.
Autism spectrum disorder (ASD) affects 1 in 88 children in the United States, but the disorder is much less common in girls than in boys. The prevalence of ASD in girls is 5 times lower than in boys, with a rate of 1 in 54 for boys and 1 in 252 for girls. Although this difference in prevalence rates is among the most highly replicated findings in studies of ASD, sex differences in ASD remain poorly understood. Because ASD is so much more common in males, females with ASD remain understudied. The goal of this study is to evaluate a large, sex-balanced cohort of preschool-aged children with ASD in order to elucidate the neural phenotypes of females with ASD and to identify sex-differences in the neuropathology of ASD. Children will be enrolled at the time of diagnosis (2-3 years of age) and followed longitudinally for two years. Imaging will be carried out at study enrollment and then at two additional annual time points and behavioral testing will be conducted twice, in conjunction with the first and third MRI time points. Imaging will include structural, diffusion-weighted and resting state functional connectivity in order to accomplish the following aims: 1) to evaluate sex differences in the neural systems that underlie core deficits in ASD 2) to investigate sex differences in brain growth trajectories in these neural systems and 3) to identify associations between distinct neural phenotypic subgroups and etiologic factors or behavioral outcomes.
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
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.
Neuroimaging and cognitive correlates of co-morbid schizophrenia and methamphetamine abuse
Principal Investigator: Ruth Salo, Ph.D.
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.
Neural and cognitive sequelae of methamphetamine abuse
Principal Investigator: Ruth Salo, Ph.D.
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.
Developmental changes in neural processes underlying impulsivity and ADHD
Principal Investigator: Julie Schweitzer, Ph.D.
Problems with self-control are of major public health relevance as they are associated with physical and mental health, substance abuse and academic success impacting both individuals and society. The development of self-control is a critical step toward successful independence in young adulthood. Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder associated with elevated problems with self-control. We hypothesize that poor self-control in ADHD leads to their impaired academic achievement and poor high school graduation rates. An improved understanding of the developmental trajectory of self-control will lead to more focused and successful intervention programs.
Despite the public health importance of self-control, no studies have directly tested how the underlying mechanisms that determine self-control develop. It is hypothesized that a balance between cognitive control and reward response processes determine degree of self-control functioning. This project will characterize for the first time how cognitive control and reward-related neural functioning during adolescence and early adulthood independently contribute to self-control in both healthy development and ADHD. We will assess how changes in brain development occur in a two system model of self-control, which includes cognitive control (dorsolateral prefrontal cortex) and reward processing (ventral striatum) systems, and how the systems relate to broader impairments associated with ADHD. An additional goal is to assess if brain activity associated with self-control can serve as a biomarker for predicting academic performance. At the conclusion of these studies we will be able to identify age-related specific targets and recommendations for improving self-control.
This study is a team effort by ADHD and functional imaging cognitive control researchers Julie Schweitzer and Catherine Fassbender at the UC Davis MIND Institute; Amanda Guyer at UC Davis with expertise in reward and emotional systems in neurodevelopment; Jamal Abedi at UC Davis with proficiency in measuring academic outcomes; and from Stanford University Samuel McClure, developer of the two-system model of self-control in neuro-economics, and Wouter van den Bos with experience in the development of social and reward based decision-making. Stephen Hinshaw at UC Berkeley brings to the contribution experience in ADHD, diagnostic issues, longitudinal research methods, measurement of academic issues in ADHD and general outcome research methods associated with the disorder. The geographic proximity of these collaborators from northern California will help to facilitate this collaboration.
A compensatory functional neuroanatomy of ADHD
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.
Cognitive analysis and brain imaging
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
Cognitive control in autism spectrum disorders
Principal 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.
Non-social rewards and autism
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.