DIRECTOR: Jane S. Paulsen, Ph.D.
CO-DIRECTORS: Daniel S. O'Leary, Ph.D., Robert G. Robinson,
M.D., Nancy C. Andreasen, M.D., Ph.D.
Overall Aims
1. To define the fundamental cognitive deficits in patients
with schizophrenia, using principles adapted from cognitive and experimental
neuropsychology.
2. To examine the neural circuit hypothesis of schizophrenia
by investigating cognition in other conditions with known neural mechanisms
that can serve as "model syndromes" such as Huntington's disease or patients
with circumscribed lesions.
3. To study the relationships between disordered cognition and psychopathology
using patients with mood disorders and/or with psychotic disorders.
4. To develop and apply new cognitive tasks to patients
with schizophrenia, emphasizing tests found to be sensitive to brain areas
considered abnormal (according to imaging and/or animal studies) in schizophrenia.
Background and Rationale
The Cognitive Neuroscience Unit conducts a group of studies that use
techniques from experimental cognitive psychology and neuropsychology
to examine potential underlying neural substrates of cognitive and
emotional impairments in schizophrenia. To address this broad goal,
we borrow techniques from several methods. First, we examine cognitive
performance within and across several subject samples with known neural
mechanisms that share clinical characteristics with schizophrenia.
For instance, cognition and emotional functions are assessed in patients
with Huntington's disease in an effort to better characterize impairments
associated with adult-onset basal ganglia dysfunction. Similarly, cognitive
and emotional dysregulation are evaluated in patients with circumscribed
lesions of the cerebellum, prefrontal cortex, and basal ganglia. Second,
we explore the association between cognitive performances and psychiatric
symptoms in patient samples with known pathophysiology. For instance,
we compare the cognitive performances of Alzheimer's patients with
and without psychosis. This comparison may help determine which cognitive
characteristics are distinct to the presence of psychosis in a sample
of patients with well-described, but diffuse, brain damage. We also
compare the cognitive performances of mood-disordered patients with
discrete focal lesions to examine the relationship between cognition
and affect in this patient group with known focal brain damage. Finally,
we investigate emotional perception, expression and insight in all
patient groups to better understand the complex associations between
cognition, psychiatric symptoms and awareness. Although these projects
are varied in their objective relevance to cognition and schizophrenia
they are wed by virtue of pursuing a central theme: exploring behavioral
phenomena associated with specific brain function and dysfunction.
Although a significant amount of neuropsychological research has been conducted in schizophrenia, the neurobiological, neurodevelopmental and/or neurodegenerative underpinnings of the cognitive impairments are not fully understood. During the initial funding period of the MH-CRC, data were collected to characterize the neuropsychological patterns of individuals with psychosis. Findings suggested that premorbid impairment as assessed using educational indices predates disease onset (Andreasen, 1982c), thus supporting a neurodevelopmental view of this disease. Consistent with other labs, findings also demonstrated that neuropsychological performance is associated with negative symptoms and not associated with florid psychotic symptoms (hallucinations and delusions) (O'Leary et al submitted b). In addition, the longitudinal course of cognitive impairment in this sample of schizophrenia patients suggests stability of cognitive impairments over time (Nopoulos et al 1994; Gold et al submitted a). Although the CRC allowed us to begin to characterize these patient groups in terms of cognitive functions, many questions remained about the nature and prognostic significance of neuropsychological deficits associated with schizophrenia. Thus, in the previous grant renewal, a new division of the CRC entitled, The Cognitive Neuroscience Unit was initiated to assess in greater detail the relationships between disordered cognition, disordered affect, and brain dysfunction in patients with psychopathology.
In the previous submission, several specific projects were described, many of which are renewed and expanded in the current proposal and some of which have been completed or discontinued. The original Project 1 sought to examine several component processes in schizophrenia and is maintained and expanded in the current proposal. The primary purpose of Project 1 is to further define cognition in schizophrenia. Project 1 will examine several specific cognitive measures of Andreasen's (1997d) "cognitive dysmetria" hypothesis, or unitary model of schizophrenia, using both clinical and experimental measures of cognition. In addition, Project 1 will address the longitudinal stability of cognitive deficits, considering neurodevelopmental as well as neurodegenerative aspects of schizophrenia. The original Project 2 incorporated the work of Dr. Robinson on mood disorders associated with brain injury. Dr. Robinson's studies have since received NIH funding which are renewed and expanded in the current Projects 2 and 3. The emphases of Projects 2 and 3 are to examine the association between disordered affect and disordered cognition in patients with acquired brain injuries. Project 2 investigates cognition in patients with mood disorders following cerebral vascular accident, and offers the opportunity to compare cognitive performances across patient groups with discrete basal ganglia or cerebellar lesions. Given that both the basal ganglia and the cerebellum have been implicated in schizophrenia, this project will allow us to better understand cognitive and affective correlates of direct damage to these brain structures. Project 3 examines cognition in patients with early-stage Huntington's disease and in presymptomatic gene-carriers. Dr. Paulsen's funded projects in Huntington's and Alzheimer's disease have been integrated into this renewal as Projects 4 and 5. Project 4 examines cognitive correlates of psychosis in patients with Alzheimer's disease. In this study, the use of cognitive tasks is used to better understand heterogeneity in Alzheimer's disease and how cognitive correlates of clinical differences (in this case, psychosis) can be associated with varying outcome (faster progression and earlier institutionalization) and etiology (Lewy bodies). Project 5 probes cognitive correlates of post-concussive depression, and will provide yet another method of examining mood and cognition correlates in a brain damaged sample. In addition, the Cognitive Neuroscience Research Unit will encourage and allow further development of cutting-edge cognitive experimental tasks to test the types of fundamental deficits in schizophrenia. Task development will involve adaptation of tests currently found useful in other imaging and animal studies. The goal is to develop cognitive tasks for use in our patient samples to address specific hypotheses about dysfunctional circuitry in schizophrenia.
In several recent papers we have proposed that a fundamental deficit in schizophrenia is "cognitive dysmetria" (see Andreasen et al in press a; 1996i; 1996k, for a more complete description of this construct). Cognitive dysmetria is a disruption of the fluid, coordinated sequences of thought and action that are the hallmark of normal cognition. Although the basis of the "poor coordination" has not yet been identified, possibilities include timing and/or sequencing defects that would affect performances in several more specific cognitive skills, such as language and memory. In a sense, therefore, the function that is disturbed might be considered to be a "metasystem" or a "metaprocess." Our model of the cognitive deficit in schizophrenia posits that there exists basic cognitive abnormalities secondary to disruption of neural circuitry. Thus, investigation of fundamental cognitive processes may help explain the multiple symptoms of schizophrenia by identifying a basic mechanism. This approach is consistent with the shift made by others in the field to develop and explore models based upon neurocircuitry. Examples include the exploration of information processing and attention (Braff 1993), willed action (Frith et al 1991b; Frith 1992), and working memory (Goldman-Rakic 1994). This approach will also highlight the importance of examining cortical/subcortical circuitry in schizophrenia and examining the role of the thalamus and cerebellum in more detail. The anatomic substrate of such fundamental cognitive deficits may involve circuitry linking the cortex with the cerebellum, joined through nuclei in the pons and thalamus, and modulated by the basal ganglia (Holmes 1939; Ito 1984; Middleton and Strick 1994). The projects chosen for study under the Cognitive Neuroscience Research Unit will explore various aspects of this model.
In general, our working model of cognitive deficits in schizophrenia posits that such deficits are biologically based, developmental, and trait-related characteristics of the illness. They probably exist in a milder form even during development, and limit adaptive functioning in psychosocial and educational contexts even prior to disease onset. More severe, premorbid cognitive limitations may be associated with earlier disease onset. In any event, disease onset typically is associated with some exacerbation of cognitive impairment, after which cognitive impairment remains relatively stable in the majority of patients with schizophrenia (i.e., it is relatively unaffected by changes in clinical symptoms). Neuroleptic and anticholinergic drugs can affect cognitive functioning, but these effects typically are mild (when the medications are given in therapeutic doses), and involve a relatively narrow range of cognitive functions. Tardive dyskinesia also is associated with exacerbations of specific cognitive functions, especially if it is persisting (as opposed to transient) and/or is limbtruncal (as opposed to orofacial) in topography (Paulsen et al 1994). Cognitive impairment relates to abnormalities in brain structure and/or function that are widely distributed that may particularly involve circuitry of the prefrontal thalamic cerebellar system and modulated through the basal ganglia. The severity of the cognitive impairment contributes significantly to functioning throughout life, and can limit the functional outcome independent of symptom status.
Progress Report
The development of the Cognitive Neuroscience Research
Unit has progressed well over the past four years, resulting in numerous
publications, presentations, posters, and abstracts. In addition, several
of the projects initiated through the Cognitive Neuroscience Research Unit
have resulted in independent grant funding through the National Institutes
of Health or private foundations (i.e., 5 RO1s, 1 R29, and 2 private foundation
grants). Most important, however, studies conducted within the Cognitive
Neuroscience Unit have made substantive findings that have contributed
to the neuroscience and neuropsychology literature and advanced our knowledge
about normal cognition and emotion and dysfunctions in major psychiatric
syndromes. Based on multiple publications (Flashman et al 1996, in press;
Flaum et al 1994; Paradiso et al 1997a; Torres et al 1997; Nopoulos et
al 1994, in press; Andreasen et al 1993b; O'Leary et al submitted a, b;
Digiulio et al 1994; Starkstein et al 1994, 1997; Bokura & Robinson
1997; Paulsen et al 1995, 1996) some of the findings include:
Impaired cognitive performance in schizophrenia is
associated with neurological soft signs.
Cognitive functions in schizophrenia are stable or improve
over a two-year as well as a five-year period.
Premorbid indicators of cognitive impairment, such as
educational achievement, suggest that impaired cognitive performance antedates
the onset of clinical symptoms.
Symptom dimensions display differential relationships to cognitive
performance, as assessed at intake. Negative symptoms are associated with
global impairment, while psychotic symptoms are not associated with cognitive
impairment. The association between disorganization and cognitive primarily
affects tests of attention.
Patients with the poorest premorbid functioning were also
found to have the poorest premorbid social skills, delayed motor development,
and shorter adult stature, indicating a generalized problem in development.
Using our patients with focal lesions we have shown that
comprehension of emotional prosody is associated with double-simultaneous
stimulation and specific right-hemisphere, basal ganglia, and diencephalic
measures of brain structure.
We have also examined the cognitive and neuroanatomic
correlates of disinhibition after brain lesions and have shown that caudate
lesions can impact even subtle measures of mental status long after the
initial brain lesion.
Comparisons of cognitive profiles among patients with
schizophrenia and dementia have revealed that learning is one of the most
consistent deficits in patients with schizophrenia and that in the majority
of patients, learning and memory patterns are similar to patients with
degeneration of the basal ganglia, rather than prototypical amnesia.
Establishment of multiple inter-related data bases: To enable efficient comparison of cognitive performances across studies, samples and grants, our data needs to be accessible by all investigators. To accomplish this, we have established several methods of assuring standardization in test administration, scoring, data entry, variable labels, and data management systems. The MH-CRC and the department of psychiatry at the UIHC has a cognitive research meeting once each week to address test administration and scoring. Representatives from each laboratory participate and share responsibility for the meeting topics. New research assistants, postdoctoral fellows, interns, and residents interested in cognitive research are required to establish inter-rater reliability in administration and scoring with the members of this group. In addition, staff and faculty meet on a regular basis to discuss collaborative research efforts. All data is maintained in concert with the CRC Biostatistics Core to assure efficient merging of data sets and cross-study analyses. The data sets available through the Cognitive Neuroscience Research Unit are briefly described below:
a. We have 305 first episode or early onset schizophrenia
patients in our longitudinal data base. Over 140 of these have up to
five years of follow-up data and a growing number have 9-year follow
up data.
b. We have assessed approximately 600 subjects in our
cross-sectional MH-CRC data base since its inception 10 years ago. Nearly
all have been administered the cognitive assessment. This is a cross-sectional
evaluation of patients with schizophrenia who are at various stages of
illness.
c. We have a large group of normal controls who have been
carefully screened and have also received the cognitive battery of tests.
There are nearly 400 normals in this data base.
d. Dr. Robinson's lesion data base currently has 12 subjects and his
traumatic brain injury data base has 50.
e. Dr. Paulsen's dementia data base currently has longitudinal
evaluations on over 100 patients with Huntington's disease from UCSD, 50
patients with Huntington's disease from the University of Iowa, and 25
patients with Alzheimer's disease. In addition, Dr. Paulsen is part of
the Huntington Study Group (cognitive data base of over 1100 patients with
HD) and the Venezuela Huntington's Research Project (cognitive data base
of over 1200 patients with HD) with which our data may be compared.
Preliminary analysis of comprehensive
data bases:
a. To enable more efficient comparisons across cognitive tasks and
across subject samples, we recently computed standard (z) scores based
upon age for every variable in these cognitive data bases. We are in the
process of using these standard scores for data analyses and publications.
Thus far, we have analyzed the cognitive data for 84 first-episode patients,
200 chronic schizophrenia patients, and 203 normal controls, controlling
for demographic variables of age and education. Results suggest that both
groups of schizophrenia patients perform about one standard deviation worse
than the normal comparison group and there exist no major differences between
the first episode and chronic performances. Areas of particular deficits
include attention, learning, speed of processing, and executive functions.
b. We have also conducted preliminary analyses on the
association between cognitive performance and age of onset for 450 individuals
with diagnoses in the schizophrenia spectrum. Preliminary correlations
of age of illness onset with cognitive performances revealed positive relationships
between age of onset and 11 of 25 tests administered. In general, our preliminary
findings suggest that semantic memory, attention, speed of information
processing and learning are worse in patients with an earlier age of onset.
These findings are consistent with the literature suggesting that prognosis
in schizophrenia may be related to age of onset as well as to clinical
presentation.
In addition to our data collection, publication and funding progress, the Cognitive Neuroscience Unit has acquired additional personnel and resources. Dr. Jane Paulsen recently joined the University of Iowa and has assumed leadership of the Cognitive Neuroscience Unit. Previously she was at the University of California at San Diego where she was the Co-Principal Investigator (with Robert K. Heaton) of the Neuropsychology Core of the Mental Health Research Center for the Study of Psychosis in Late Life (PI: Dilip Jeste, M.D.). Consequently, she has the experience of developing a productive neuropsychology core within a CRC (26 publications and 16 grants over the last 5-year funding period). Upon her arrival, Dr. Paulsen recruited Dr. Jane Springer, a clinical neuropsychologist from the Medical College of Wisconsin with research training in fMRI. Drs. Springer and Paulsen will work closely with Dr. O'Leary (Director of the Functional Imaging Unit) to develop new cognitive tasks sensitive to schizophrenia. Dr. Lonnie Sears was recruited to obtain specialized training in cognitive neuroscience and neuroimaging while on faculty leave from the University of Louisville. Dr. Sears has a comprehensive background in basic neurobiology and has over a dozen publications in classical conditioning in animals and humans. Dr. Sears will oversee the classical conditioning paradigm proposed in this research unit. Dr. Sergio Paradiso was recruited by Dr. Robinson to continue his study of emotion in patients with brain dysfunction. Dr. Paradiso has 16 publications and over 29 presentations. He is very active in our cognitive science working group in the design and implementation of cognitive activation tasks as well as the comparison of cognitive performances in patients with mood disorder. Dr. Paradiso will oversee the analyses examining the relationships between psychiatric symptoms and cognition. Dr. Somaia Mohamed was recruited from the Department of Psychiatry at Yale University School of Medicine. Her clinical and research activities at Yale focused on neurocognition and schizophrenia. For example, her dissertation study investigated the neurocognitive correlates of poor insight in schizophrenia. Dr. Mohamed will work closely with the Cognitive Neuroscience Research Unit in further developing her research in the interface of cognitive ability and awareness as it relates to outcome in schizophrenia. In addition to the recruitment of personnel, the Cognitive Neuroscience Unit has been successful in being awarded additional space in which to conduct studies of cognition and emotion. Our previous space commitment was one 80 square foot office. Our new space commitment involves over 1300 square feet which will be divided into testing spaces, experimental computerized assessment labs, and a mock PET scanning room to allow pilot testing of cognitive activation studies.
As the previous reviewers had noted, the first funding
period of the Cognitive Neuroscience Unit reflected a significant expertise
and conceptual grasp of prominent issues in understanding the cognitive
underpinnings of psychopathology, yet the proposed projects were varied
in their connectivity to the major foci of the MH-CRC. The renewal
of our unit capitalizes on the strategies that have proven effective
in the past to better understand the relationship between disordered
cognition, disordered affect and brain dysfunction. The current Cognitive
Neuroscience Unit conducts a group of studies that use techniques from
experimental cognitive psychology and neuropsychology to link specific
cognitive and emotional deficits to their underlying neural substrates.
Strategies include the study of normal individuals, the study of patients
with "model" syndromes relevant to schizophrenia that are secondary
to known brain mechanisms (e.g., Huntington's disease), the use of
the lesion method, and the study of patients suffering from the major
psychoses. This approach to the study of cognition and psychopathology
offers a comprehensive and unique vantage point from which to test
specific hypotheses while capitalizing on distinct expertise and resources
at UIHC. The proposed projects for the Cognitive Neuroscience Research
Unit utilize the strengths of several investigators in our department
and capitalize on the available resources through funded research studies.
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