Functional Imaging Projects
The following projects are either ongoing or proposed. Not all projects on the list will necessarily be completed. This page is for general interest only.
PROJECT 1: COGNITIVE ACTIVATION
STUDIES OF NORMAL CONTROLS AND SCHIZOPHRENIC PATIENTS
Principal Investigators: Daniel S. O'Leary,
Ph.D., Nancy C. Andreasen, M.D., Ph.D.
Co-Investigators: Richard Hichwa, Ph.D.,
G. Leonard Watkins, Ph.D., Laura Ponto, Ph.D.
Funding Status: RO1 Grant to Andreasen,
Brain Imaging in Major Psychoses
Project Duration: Current
RO1 funded through 1998. Renewal is pending.
Specific Aims
1. To use PET imaging with [15O]water to assess rCBF
changes associated with the timing and integrative functions of the
CCTCC in healthy volunteers.
2. Using PET, to identify differences in the function of the CCTCC
in patients suffering from schizophrenia and healthy volunteers.
Background and Rationale
The focus of the Functional Imaging Unit, as well as the other core
and research units of the MH-CRC, is on understanding the neurobiology
of mental phenomena and disease processes, with a primary emphasis
on schizophrenia spectrum disorders. The experimental strategy that
we utilize in this pursuit is to focus first upon the study of normal
individuals. Although knowledge has accumulated rapidly in recent years
through PET and fMR imaging studies a great deal remains to be learned
concerning the cognitive functions of the normal brain. For example,
we have frequently observed that the cerebellum is active during the
performance of cognitive tasks, even in situations where there is no
motor activity (Andreasen et al 1997a). Understanding the role of the
cerebellum in normal cognition, and the nature of interactions of cerebellar
subregions with regions of the forebrain, is critical for exploring
the hypothesis that schizophrenia involves cognitive dysmetria. Our
PET work to date has established that patients suffering from schizophrenia
have abnormal patterns of rCBF in regions of the frontal lobe, thalamus,
and cerebellum during the performance of many different cognitive tasks.
We hypothesize that "synchrony," or fluidly coordinating sequences
of thought and action, occurs as a consequence of very rapid on-line
processing and feedback between the cerebral cortex and the cerebellum,
mediated through the thalamus. The substrate of synchrony is the CCTCC.
In the project described below we propose to assess rCBF during tasks
that will permit a more fine-grained componential analysis of the cognitive
processes and neurophysiological mechanisms leading to these rCBF abnormalities.
An interrelated set of PET imaging studies will assess rCBF changes
associated with cognitive processes that utilize the putative timing
and/or integrative functions of the CCTCC in normal volunteers and
in patients with schizophrenia.
Hypotheses for Normal Volunteers:
1. Subregions of the cerebellum play a critical function in the timing
of motor actions.
2. The cerebellar timing function is not limited to motor
movements but is involved in any perceptual or cognitive function that
requires temporal computations (e.g., time interval perception, self-initiated
action or thought, use of preparatory cues, production of connected discourse).
3. The cerebellum interacts with motor regions of the
frontal lobes (premotor and supplementary motor area) in tasks requiring
the sequencing of motor acts.
4. The cerebellum is functionally heterogeneous with discrete subregions
involved in execution, timing, and sequencing of motor acts, and with aspects
of language, attention, and memory.
5. Discrete subregions of the cerebellum interact with
subregions of the frontal lobe (e.g., DLPFC, orbital frontal lobe) in tasks
requiring aspects of language, attention and memory.
Hypotheses for Patients:
1. Patients with schizophrenia have a primary deficit in the cerebellar
timing mechanism that will be evidenced by decreased rCBF (relative
to normal volunteers) in specific subregions of the cerebellum during
tasks requiring temporal computations.
2. Because of this deficit, patients with schizophrenia
will be impaired on any motor, perceptual or cognitive task requiring temporal
computations and will show rCBF differences from normal volunteers in discrete
subregions of the cerebellum during such tasks.
3. Patients with schizophrenia will be impaired on tasks
requiring sequencing of motor acts and will show rCBF differences from
normal volunteers in premotor and supplementary motor areas as well as
the cerebellum during tasks requiring motor sequencing.
4. Patients with schizophrenia have a general deficit in cerebellar
function which results in decreased rCBF in the cerebellum during a variety
of cognitive tasks.
5. Cerebellar dysfunction in patients with schizophrenia
results in abnormal activity in associated thalamic nuclei and subregions
of the frontal lobe during language, attention and memory tasks.
Experimental Design and Methods
A total of ten studies in three conceptually-related groupings will
be performed during the funding period. Because of constraints on space,
and because specific details of studies may change with new findings,
we describe one protocol in detail in order to illustrate our approach
to the design of cognitive experiments using PET. For the remaining
studies we provide a more general description of the design, as well
as the hypotheses to be tested. Based on our previous experience with
PET, all of the proposed experiments can be readily implemented in
the PET environment with our available equipment, and all can be readily
performed by both normal volunteers and patients. Each of the ten studies
will be done with samples of twenty normals and twenty patients. Our
experience indicates that it will be feasible to carry out this number
of PET studies (approximately 80 subjects per year) in the 5 year funding
period. A total of 200 healthy volunteers and 200 patients suffering
from schizophrenia will be studied during the five year period. Their
age range will typically be between 18 and 50, although older individuals
may be studied occasionally. The normal controls will be matched to
the patients for age and gender.
It is difficult, using standard PET methods, to demonstrate that co-activated regions participate in the same functional network, or to establish the specific functions of activated regions. The hierarchical subtraction strategy that is widely used in cognitive activation studies assumes that two tasks differ only in a cognitive component of interest. Although this strategy remains a viable and important tool, the validity of the technique rests upon theoretical assumptions about the cognitive processes that are involved in an activation and control task. However, recently-developed PET strategies allow assessment of specific cognitive subprocesses that are mediated by cortical, subcortical, and cerebellar brain regions. Fewer assumptions are required by the graded task approach, in which a parameter of psychological interest is systematically varied across scans and correlations are computed between the rCBF changes and the parameter manipulated (e.g., Grady et al 1994; Beauchamp et al 1997; Rao et al 1996). A refinement of the graded task technique involves examining the effects of graded changes in aspects of a task that affect one specific component of information processing. Examples include changing the frequency of stimulus presentation to examine components of a network that are sensitive to "data-driven, bottom-up" sensory processes (Rees et al 1997), changing the frequency or complexity of motor responses to determine the components of a network that are involved in response execution (Schlaug et al 1996), and changing the load in a working memory task to isolate the executive, "top-down" components of a network (Cohen et al 1997). Using these strategies we will explore three groups of motor/cognitive processes: timing and sequencing of motor activity and perception, memory and temporal computation, and attention/executive function and temporal computation.
Group A: Timing and Sequencing of Motor Activity
and Perception:
This group of studies will directly assess the hypotheses
that the CCTCC is involved in coordinating fluid sequences of action and
thought in normal subjects, and that this system is impaired in patients
with schizophrenia. Because deficits in timing are hypothesized to be a
critical aspect of the cognitive dysmetria which is characteristic of schizophrenia,
all of the studies in this group will contain one common condition, in
which the subject must maintain a pre-defined motor rhythm by tapping with
their index finger (Ivry & Keele 1986). This condition offers a relatively
pure assessment of the hypothesized timing functions of the cerebellum.
Having a large number of subjects in this condition (5 studies with 20
controls and 20 patients) will greatly increase the power of "seed pixel" analyses
which utilize between-subject correlations to examine the covariation in
blood flow between brain regions. Placing seed pixels in the cerebellar
regions that play the largest role in timing in normal controls will allow
the generation of correlational maps of all brain regions which participate
in the timing function. Comparison of the correlational map for controls
with the map for individuals with schizophrenia will allow identification
of abnormal patterns of activation in the patient group.
Study 1. Production
of motor rhythms and the perception of timed intervals:
This study will assess the neural mechanisms mediating externally-cued
and self-paced tapping and the perception of temporal intervals. Ivry and
Keele (1989) studied patients with lesions of different types (Parkinson,
cerebellar, cortical and peripheral neuropathy) on two measures of timing
function and found that only the cerebellar lesion group showed deficits
in both the production and perception of timing. The cerebellar patients
were more variable in the tapping task and less accurate in the perception
task. Jueptner et al (1995) used PET to study time perception in 6 normal
volunteers. They found activations in inferior cerebellum ipsilateral to
the responding hand in a control minus rest subtraction reflecting finger
movements. Comparison of timing and control conditions showed additional
activations of cerebellar vermis and hemispheres bilaterally, reflecting
a timing process. Although Ivry and Keele found that rhythm production
and time perception were both impaired in patients with cerebellar damage,
it is not known whether these two processes use the same cerebellar mechanisms.
The relationship between cerebellar timing functions and frontal-striatal
mechanisms is also currently unknown. There is some evidence that time
perception in the minutes to seconds range utilizes frontal-striatal mechanisms
(Hinton et al 1996) whereas time perception in the millisecond (ms) range
utilizes the cerebellum. However, there has been little or no study of
the interaction between cerebellar and frontal-striatal mechanisms during
tasks requiring temporal computation.
The study will utilize the following eight conditions:
1. Externally-paced tapping
(1 hertz [Hz]). This condition will require subjects to tap on a response
key, using the index finger of their dominant hand, in pace with an external
auditory stimulus at a constant rhythm of 1 tap per second. In comparison
with the self-paced conditions, this condition will provide a means to "subtract
out" motor mechanisms involved in response execution. It will also provide
a condition on which patients with schizophrenia may perform equivalently
to normal volunteers. Although some studies have found that patients with
schizophrenia have abnormal rCBF during simple motor tasks (Mattay et al
1997; Schroeder et al 1994), these studies have used an unpaced finger
to thumb response, and there have also been findings of normal activation
patterns during simple motor tasks in schizophrenic patients (Buckley et
al 1997; Weinberger and Berman 1996). 2. Self-paced tapping (1 Hz); 3.
Self-paced tapping (3 Hz); 4. Self-paced tapping (6 Hz). These three
self-paced tapping conditions will utilize the same basic procedure and
will use the graded task approach (see above) to assess the brain regions
that participate in generating motor rhythms of differing frequencies.
Approximately 60 seconds prior to bolus arrival during each PET imaging
session, an auditory stimulus will begin to externally-cue the subject
to tap at one of the specified frequencies (i.e., 1, 3, or 6 Hz). The subject
will be instructed to continue to tap at the same pace when the stimulus
is discontinued, which will occur 10 seconds prior to bolus arrival, and
to continue tapping until told to stop. Several functional imaging studies
have assessed the effects of different rates of externally-cued finger
movements on rCBF in normal volunteers (Blickenberget al 1996; Rao et al
1996; Sadato et al 1997). These studies have typically reported linear
increases with faster tapping rates in sensori-motor cortex, and increased
rCBF with no rate dependence in cerebellum and other motor regions. To
our knowledge no study has explored the effects of different movement rates
for a self-paced task or in patients with schizophrenia.
5. Time interval perception and judgment
(500 ms). This condition will test perception of time in intervals (the "internal
clock" that is hypothesized to be mediated by the cerebellum). We will
present pairs of intervals to the subject with an interstimulus interval
of about 1 s. The standard 500 ms interval will be defined by a 50 ms tone
at the beginning and end of the interval, as will comparison intervals
of 400 or 600 ms. Subjects will respond with a right index finger press
if the second interval is perceived as shorter and with a right middle
finger press if it is perceived as longer.
6. Control for condition
5. Subjects will listen to pairs of identical 500 ms intervals and alternately
press with their index and middle fingers.
7. Time interval perception and production
(500 ms). Immediately prior to PET imaging the subjects will be presented
with multiple training stimulus intervals of 500 ms, marked by 50 ms tones
at the beginning and end of the interval. During PET imaging an initial
50 ms tone will be presented and subjects will be instructed to press a
button with their index finger when 500 ms has elapsed. There will be an
interstimulus interval of about 1 s, and 30 trials will be collected during
PET imaging. Condition 1 (cued tapping at 2 Hz) and Condition 3 (self-paced
tapping at 2 Hz) will be comparison conditions.
8. Time interval perception and production (10 s). This condition will
be similar to the previous one with the exception that subjects will receive
training on 10 s intervals. During PET imaging they will be cued with a
50 ms tone and instructed to press a button with their index finger when
10 s has elapsed. There will be 5 trials during PET imaging with an interstimulus
interval of about 1 s. This condition will be contrasted with Condition
7 to determine if the same cerebellar and frontal-striatal regions are
activated by the perception of intervals in the millisecond and second
range.
Hypotheses
1. The vermis and regions of lateral cerebellum will
be activated during time interval perception in the ms range.
2. The production of motor rhythms will activate the same
cerebellar regions as does time interval perception.
3. The frequency of motor production (i.e., tapping at
1, 2, or 3 Hz) will not change the size or amplitude of the cerebellar
activation related to timing functions (vermis and regions of lateral cerebellum),
but will increase rCBF in inferior cerebellum, premotor and motor cortex
which are involved in motor execution.
4. The perception and production of time intervals in
the multiple seconds range will cause greater activation of frontal and
striatal regions and less cerebellar activation than will the perception
and production of time intervals in the millisecond range.
5. Patients with schizophrenia will perform similarly
to the normal volunteer group and show similar rCBF during externally-cued
motor tasks, but will perform more poorly and show abnormal patterns of
activation in the cerebellum during self-paced tasks and tasks requiring
the perception of time intervals.
Study 2. Timing and sequencing motor movement:
This study will compare activation conditions that
require simple motor movements (e.g., finger tapping) with tasks requiring
progressively more complex motor sequencing. One condition will involve
the self-paced tapping task (1 Hz) described above. Another condition
will involve tapping the four fingers sequentially from index to small
finger paced by a visual display of the numbers one through four on
a video monitor. In addition to the repetitive single finger movement
required in the tapping task, this task requires motor sequencing of
a relatively simple nature. Another task will again be paced by the
digits one through four on the video monitor, but will require the
subject to perform a more complex sequence of finger movements (e.g.,
the index finger must be tapped twice, the middle finger once, the
fourth finger three times, the little finger twice, and then this pattern
is reversed). Schizophrenic patients showed abnormal activation of
these areas during this finger movement task (Guenther et al 1994).
The effects of learning will then be explored by having subjects practice
the complex sequence during the interval between PET imaging conditions,
so that rCBF can be compared during the initial performance of the
complex sequence, after an intermediate amount of practice, and during
the final PET imaging condition when the sequence has been well-learned.
To confirm a recent report that rCBF differences during task performance
are seen for many hours after practice (Shadmehr et al 1997), rCBF
during the newly learned motor sequence will be compared to rCBF during
a sequence that was taught to the subject and practiced extensively
several days prior to PET imaging.
Hypotheses
1. Activation of cerebellar regions involved in timing
functions will be progressively greater in tasks with more complex
sequencing requirements.
2. Activation of frontal motor regions (premotor cortex and SMA) will
be progressively greater in tasks with more complex sequencing requirements.
3. Patients with schizophrenia will show abnormal patterns
of rCBF in cerebellar and frontal regions during motor sequencing tasks.
4. The pattern of rCBF in CCTCC will change during the
learning of a motor sequence.
5. Patients with schizophrenia will have a more normal pattern of
rCBF in CCTCC during well-practiced than during novel motor sequences.
Study 3. Stimulus-driven vs self-initiated action:
This study will examine self-initiated versus stimulus-driven
actions. Frith's model of willed action proposes that frontal lobe mechanisms
play a critical role in the initiation and monitoring of action, and that
these mechanisms are impaired in patients with schizophrenia (Frith 1987;
Frith et al 1991a). Hyder et al (1997) recently performed an fMRI study
in which they replicated the dorsolateral prefrontal (DLPFC) activations
due to willed action found by the earlier PET studies (Frith et al 1991b,
Jahanshahi et al 1995), but found that slightly different regions of the
DLPFC were activated during a self-initiated finger movement task than
in a self-initiated verbal fluency task. Hyder et al argued that the higher
resolution of fMRI versus PET revealed that willed action is not mediated
by a unitary DLPFC neural mechanism. The study proposed here will advance
knowledge concerning self-initiated action by looking at more specific
components of self-initiated action, and by examining the role of the cerebellum
in this process. We will compare conditions in which simple finger movements
and sequences of movements are triggered by external stimuli with conditions
in which subjects respond at their own initiative. We will also compare
the initiation of manual motor acts with the initiation of verbal sequences.
We will examine the relationship of activations in DLPFC and other cortical
motor regions (sensorimotor, premotor, SMA and dorsal parietal cortices)
with cerebellar activations during tasks requiring stimulus-driven and
self-initiated responses.
Hypotheses
1. Regions of the lateral cerebellum as well as regions
of DLPFC will show differences in rCBF during externally-cued and self-initiated
responses in normal volunteers.
2. Patients with schizophrenia will show abnormal rCBF
in the cerebellum as well as in cortical motor regions during the execution
of motor movements.
3. The rCBF abnormalities in the patient group will be
greater during self-initiated than during stimulus-driven responses and
will be differentially greater in the more complex than in the simpler
movement conditions.
4. Deficits will be similar in the patient group for both
manual and verbal responses.
Study 4. Use
of preparatory information and inhibition of motor action:
This study will assess the ability of subjects to utilize stimulus
information to prepare motor responses, and will also assess subjects'
ability to inhibit a motor response once it has been initiated. We will
use five conditions described in a recent PET study by Deiber et al (1996),
in which a preparatory stimulus provides either full, partial or no information
concerning two aspects of an upcoming movement: finger to be moved (index
or little finger) and type of movement (abduction or elevation). These
conditions require 4 injections, and in a fifth condition the subject will
make one of the four possible movements of their volition. Events will
be timed to emphasize response preparation rather than execution during
the critical imaging window (Hurtig et al 1994). Dieber et al found some
brain regions that were activated during all of the preparatory conditions,
suggesting a single anatomic substrate for motor preparation independent
of information context. Other brain regions were differentially activated
during preparation for self-initiated movement and during the full and
partial information conditions, giving evidence of ties between aspects
of movement preparation and specific brain regions. Inhibition of motor
movements will be assessed using a variant of a task described by Dejong
et al (1996). A warning signal is presented followed by a stimulus that
requires a response. We will use an arrow pointing to the left or right
as a stimulus to indicate a left or right move of the joystick. In the
Dejong et al study, an auditory stop signal (1000 Hz, 50 ms tone) is presented
on 40% of the trials at differing intervals following the response arrow.
We will maintain this percentage of stop signals over the course of a 2
minute task, but will increase the density of stop signals to 80% during
the critical imaging window.
Hypotheses
1. We will replicate the brain regions found by Dieber
et al to be activated during response preparation in normal volunteers.
2. Patients with schizophrenia will have abnormal rCBF
patterns during all of the response preparation conditions indicating a
deficit in the anatomic network mediating preparation.
3. Schizophrenics will also show abnormal rCBF patterns
during the condition requiring preparation for volitional movements.
4. The cerebellum and other components of the CCTCC will
be involved in activation during movement inhibition in normal volunteers,
and abnormal activation will be seen in the patient group.
Study 5. Conscious and unconscious perception:
Although consciousness may be difficult to quantify,
patients with schizophrenia often note that abnormal conscious experiences
are one of the most salient and frightening aspects of their disorder.
The study proposed here represents an initial attempt to explore brain
mechanisms underlying differences in conscious experience in normals
and in patients with schizophrenia. In order to explore conscious phenomenon
we will exploit the fact that visual stimuli that are presented at
too fast a rate to be consciously perceived may nevertheless show evidence
of being processed at a meaningful level. We will compare conditions
in which meaningful and non-meaningful stimuli are presented at rates
fast enough to preclude conscious perception. Two classes of stimuli
will be used -- familiar and unfamiliar faces, and real and nonsense
objects. For the proposed PET study we will use a titration procedure
in a preliminary session to determine a visual presentation speed for
each individual that is too fast for conscious perception of objects
and faces. Comparison conditions will involve presentation of similar
stimuli at rates that are clearly perceptible. Although the role of
the cerebellum in perception is less well explored than is its role
in motor function, our own studies as well as those of other groups
have shown that the cerebellum is activated during the processing of
faces as well as in other tasks requiring visual perception (Andreasen
et al 1996f; Fiez et al 1996). Given the role played by the cerebellum
in timing functions, it seems likely that the cerebellum will be more
evenly activated by stimuli that are presented very fast than by stimuli
that are presented at slower rates.
Hypotheses
1. Different occipital and temporal lobe regions will
be activated by the presentation of lists of real objects and lists
of familiar faces at rates that are clearly perceptible (e.g. one stimulus
per second).
2. Presentation of familiar face and object stimuli at
rates that are too fast for conscious perception will result in similar
patterns of activation in occipital and temporal lobe regions (i.e., there
will be different patterns of activation for faces and objects but these
patterns will be similar to those seen at slower rates of presentation
of each stimulus type).
3. The cerebellum will be more activated by fast than
by slower rates of stimulus presentation.
4. Although the stimuli are not consciously perceived,
unfamiliar faces presented at a very fast rate will show a different pattern
of activation than will familiar faces presented at the same rate. Difference
will be seen as well between activation patterns evoked by real and nonsense
objects presented at rates too fast for conscious perception.
5. Individuals with schizophrenia will show abnormal patterns
of activation for stimuli presented at rates that preclude conscious perception.
Group B: Memory and Temporal Computation:
This group of studies will continue our studies of
memory and assess the hypotheses that the timing functions of the CCTCC
are involved in aspects of memory performance, and that patients with
schizophrenia will show greater impairment on memory tasks that rely
more heavily on these timing functions.
Study 6. Recognition vs recall memory:
This study will compare recognition and recall memory
for materials studied one week, one day or immediately prior to PET
imaging. This will allow us to assess changes in activation that may
be due to consolidation of the material into long-term memory (or alternatively,
to forgetting). We will use verbal materials that have been shown in
previous cognitive studies (Tulving 1983) to be highly memorable after
only one or two exposures (e.g., "an exercise for the jumpy--trampoline").
Subjects will be exposed to unique sets of 30 such phrases at one week,
one day, or approximately one minute prior to imaging. In order to
prevent rehearsal of the items presented to the subjects one week and
one day prior to imaging, the subjects will be asked to rate each item
for "meaningfulness" rather than to try and memorize it. For each list
of 30, 15 items will be tested via recognition (the stem i.e., "an
exercise for the jumpy" will be on the video screen at the top, and
the correct item and a foil on the screen below--subject moves a finger
switch toward the correct item), or recall (the stem is again at the
top of the screen, "yes" and "no" are beneath--the subject moves finger
towards "yes" (I remember the answer) or "no" (I don't remember). For
recall conditions subjects will be asked to say the item after imaging
is over to check the honesty of their manual responses. A sensorimotor
baseline condition will have a sentence stem with two words beneath
it - a foil and a word that is in the sentence stem. Subjects will
be instructed to move their finger towards the repeated word. This
baseline task has the same reading requirements and response as the
recall and recognition conditions but no memory is needed. A second
baseline condition will have a sentence stem and an answer that the
subject can retrieve from memory without having been pre-exposed (e.g.,
a pointy boat paddled by Indians). This will be a recall condition--the
subject responds manually "yes/no" during PET and is asked for the
correct word after imaging.
Hypotheses
1. Recall tasks will activate the CCTCC to a greater
extent than will recognition tasks at all three exposure intervals.
2. Materials presented at one week and one day prior to
imaging will activate the CCTCC to a greater extent than will the materials
presented immediately prior to PET imaging.
3. Patients with schizophrenia will show abnormal rCBF
in all memory conditions, but will be more normal during recognition than
during recall tasks and more normal for the immediate memory conditions
than for the longer-term conditions.
Study 7. Strategy,
effortful search, and retrieval success (ecphory):
Moscovitch (1989) has distinguished two types of memory search. One,
associative or cue-dependent, depends on a neuronal network that includes
the hippocampus. A second, strategic process requires the activation of
a circuit that includes the frontal lobes and presumably other components
of the CCTCC. The Toronto PET group (Tulving et al 1995, Kapur et al 1994a,
Nyberg et al 1995) has proposed that the right frontal lobe is differentially
activated by any task that requires retrieval (i.e., frontal activation
results from "retrieval mode"), whereas posterior brain regions are activated
during successful retrieval. The Hammersmith group has argued that the
frontal lobes are more involved in successful retrieval than in the effort
of retrieval (Rugg et al 1996). Our own studies have provided support for
the importance of frontal lobe for strategic retrieval (Paradiso et al
in press), but are also consistent with a role of the right hemisphere
in retrieval and the concept that successful retrieval activates posterior
brain regions (Andreasen et al 1995e, f). The study proposed here will
attempt to disentangle the effects of effort, strategy and retrieval success
in memory. The study will have four conditions with differing levels of
success and effort i.e., high effort with high success, high effort with
low success, low effort with high success, and low effort with low success.
A second set of conditions will compare a task that is aided by a self-generated
memory strategy (e.g., remembering word lists containing categories, such
as tools, food, or clothing, is greatly aided by clustering related items)
with a task in which strategies are less useful (e.g., remembering word
lists that have no internal structure). We will compare a condition in
which subjects are told what strategy to use with the two previously described
conditions.
Hypotheses
1. Any task requiring "retrieval mode" will activate
the right DLPFC, and successful retrieval will activate posterior brain
regions (precuneus and cerebellum).
2. Greater effort will cause a similar pattern of frontal
activation as does strategic retrieval i.e., both effortful and strategic
retrieval will bilaterally activate the orbital frontal lobe.
3. Greater retrieval success will cause greater activation
of the right DLPFC and posterior brain regions than will less retrieval
success.
4. Individuals with schizophrenia will show less orbital
frontal activation concurrent with less spontaneous use of strategies.
5. Even when given a strategy the schizophrenic group
will show less activation of orbital frontal lobe and CCTCC than will the
control group.
Study 8. Declarative versus implicit memory: This study will use PET to evaluate the interaction between cerebellar brain regions which are thought to be essential for perceptual-motor learning and memory, and hippocampal and neocortical systems that are thought to mediate declarative memory. PET imaging will be used to test specific predictions concerning the interactions between regions of the cerebellum and other brain regions during the acquisition and extinction of the classically-conditioned eyeblink response in normal volunteers and in patients with schizophrenia. The PET conditions will be as follows: 1) Fixation baseline task; 2) Non-paired, presentation of tones; 3) Classical conditioning, early acquisition phase; 4) Classical conditioning, mid-acquisition phase; 5) Classical conditioning, late acquisition phase; 6) Early extinction phase; 7) Mid-extinction phase; 8) Late extinction phase.
Hypotheses
1. Because long-term depression during learning has
been seen in animal studies (Ito 1984), rCBF should decrease in cerebellar
cortex during learning.
2. In contrast, rCBF should increase in deep cerebellar nuclei during
learning.
3. Regional CBF will increase in the hippocampus during
initial learning, but decrease to baseline levels as asymptotic learning
levels are achieved.
4. Regional CBF will also change in the anterior cingulate
and basal ganglia during conditioning, but available data do not permit
predictions of the direction of change.
Group C: Attention/Executive Function and Temporal
Computation:
This group of studies will assess the role of the CCTCC
in higher-order cognitive functions that rely upon top-down mechanisms
traditionally thought to be mediated by frontal and parietal cortex with
little or no participation of the cerebellum and thalamus.
Study 9. Spatial
working memory and spatial attention:
The performance of tasks requiring spatial working memory
has been shown to be dependent in monkeys and humans upon prefrontal neurons.
Goldman-Rakic (1994) has recently suggested that working memory deficits
may be a core neuronal deficit underlying the symptomotology and cognitive
deficits of schizophrenia. Spatially-directed attention has also been studied
in both primates and humans and abnormalities in bottom-up attentional
processing have also been proposed to explain the cognitive and phenomenological
abnormalities of schizophrenia. There have been recent suggestions that
spatial working memory and spatial attention may interact, and/or be part
of the same cognitive-neural system (Desimone et al 1995). There have also
been suggestions that deficits in spatial working memory and spatial attention
may be a core problem in schizophrenia. This study will involve a direct
comparison of spatial working memory and spatially-directed attention.
The following conditions will be counterbalanced across subjects: 1) Spatial
working memory. 2) Spatial attention. 3) Sensorimotor control task. 4)
2-back spatial task. 5) Shifting attention task. 6) S-M control task with
multiple button presses. 7) Condition #1 but with background flashing at
twice the rate as in #1. 8) Condition #2 but with background flashing at
twice the rate as in #2.
Hypotheses
1. Spatial working memory and spatial attention will activate different
anatomic circuits although some brain regions will be activated by both
tasks. Spatial working memory will activate DLPFC, superior parietal cortex
and cerebellum, whereas sustained spatial attention will activate overlapping
regions of DLPFC and superior parietal lobe and the pulvinar nucleus of
the thalamus, but not the cerebellum.
2. Changing the rate of stimulus presentation will affect
occipital and temporal lobe activations for the spatial attention but not
the working memory task.
3. The shifting attention task and the 2-back task will
activate similar regions of the cerebellum, but other components of the
CCTCC will differ between the tasks.
4. Patients with schizophrenia will show less activation
in CCTCC and additional activations not seen in controls in both the spatial
attention and spatial working memory tasks.
Study 10. Executive
function and motor execution:
The working memory paradigm is now one of the most widely
used tasks in functional imaging and has consistently been shown to activate
the DLPFC (e.g., Smith et al 1996, McCarthy et al 1996). The most widely
cited model memory (Baddeley 1986, Shallice 1988) argues that a modality-free "central
executive" utilizes modality-specific "slave"-systems to maintain information.
The executive has been proposed to be localized in prefrontal cortex. The
wealth of information available at multiple levels of analysis concerning
working memory allows the working memory paradigm to be used as a tool
for the functional parcellation of information processing tasks and their
neural substrates. The study proposed here will use a graded task approach
to independently manipulate the memory load on the executive (e.g., remember
3, 4 or 5 items in a Sternberg paradigm) and the complexity of the motor
response that is required (e.g., single finger tap response versus 2 finger
sequence versus 4 finger sequence). This approach will differentiate the
regions of frontal cortex and cerebellum that are involved in executive
memory functions from frontal and cerebellar regions that are involved
in aspects of response execution.
Hypotheses
1. Regions of DLPFC and cerebellum that are activated
during working memory will show linear increases in rCBF with increasing
memory load in normal volunteers. Increases in memory load will not
affect frontal and cerebellar regions involved in response execution.
2. Different regions of frontal lobe and cerebellum will
be activated by motor response execution and these regions will show linear
increases in rCBF with increasing response complexity in normal volunteers.
These regions will not be sensitive to differences in memory load.
3. Patients with schizophrenia will show abnormal patterns
of activation in brain regions involved in executive function and response
execution and the abnormalities will be greater at higher levels of difficulty.
MR Acquisition:
As described above. All PET images are registered
on MR images using the AIR method (Woods et al 1993; West et al 1997;
Studholme et al 1997).
Data Analysis:
Papers in the Appendices discuss many of the relevant
issues in data analysis of PET data, including sample size and choice
of statistical methods. In general, we plan to continue to use exploratory
FOI analyses in the normals as the initial step in data analysis, applying
our adaptation of the Montreal method (Worsley et al 1992; Arndt et
al 1995a). For between group comparisons we will use our locally-developed
randomization method (Arndt et al 1996c). Correlational analyses using
our seed pixel method with external vectors will be used for the experiments
involving graded stimuli (Clark et al 1984; Worsley et al 1995; Strother
et al 1995; Friston et al 1993).
PROJECT 2: MOOD INDUCTION IN
NORMAL INDIVIDUALS AND PATIENTS WITH DEPRESSION AND STROKE LESIONS
Principal Investigator: Robert
G. Robinson, M.D.
Co-Investigators: Sergio Paradiso, M.D.,
Richard Hichwa, Ph.D., G. Leonard Watkins, Ph.D., Laura Boles Ponto, Ph.D.
Funding Status: RO1 Grant to Robinson
Project Status and Duration: Funded
03/31/96-04/01/01
Specific Aims
The overall aim of this proposal is to investigate
whether specific neural structures are involved in the physiological
and psychological processes leading to emotion. Specifically, we will:
1. Investigate physiologic patterns of brain response (EEG) to emotional activation in normal individuals and in patients with single vascular lesions involving orbital frontal or basal temporal cortex or basal ganglia or dorsal medial thalamus, (the ventral-lateral limbic circuit) and compare them with patients having lesions of parietal or posterior temporal cortex or brainstem, (non-limbic structures) to determine whether the lesions interfere with either the psychological or physiological response to an emotional stimulus i.e., happiness, sadness, or fear.
2. Examine the pattern of physiologic brain response (EEG and PET) in a subset of the above subjects. The subjects would be stroke patients with thalamic (limbic) lesions or brainstem (non-limbic) lesions and matched normals.
Measures of autonomic nervous system (ANS) function (pulse, heart rate, skin conductance, finger temperature, finger pulse amplitude, and pulse transmission time to finger and ear) will also be evaluated in patients with or without limbic lesions.
Background and Significance
This project investigates the neuroanatomic and neurophysiological
substrates of emotion through PET imaging and electrophysiological
studies of normal individuals and individuals with discrete vascular
lesions involving orbital frontal or basal temporal cortex or basal
ganglia or dorsal medial thalamus, (the ventral-lateral limbic circuit).
Patients having lesions of parietal or posterior temporal cortex or
brainstem, (non-limbic structures) will also be studied to determine
whether the lesions interfere with either the psychological or physiological
response to an emotional stimulus i.e., happiness, sadness, or fear.
This investigation of the effects of localized limbic and non-limbic
lesions on rCBF during the processing of emotional stimuli will provide
extremely valuable comparison data for a study we have recently completed
of rCBF and anhedonia in schizophrenic patients. In this study, individuals
with schizophrenia and normal controls were exposed to pleasant, unpleasant,
and neutral visual and olfactory stimuli to explore one of the fundamental
negative symptoms of schizophrenia.
Hypotheses
1. Following lesions of the orbitofrontal cortex,
polar basotemporal cortex, striatum or dorsal medial thalamus (ventral-lateral
limbic circuit), patients will not experience fear or sadness (with
right lesion), or happiness (with left lesion), or show the EEG correlates
of these emotions, but they will maintain their physiological response
(ANS) unless the amygdala input to the hypothalamus is destroyed.
2. Lesions of posterior temporal cortex, parietal cortex
and brain stem (non limbic lesions) will not interfere with either the
psychological perception or the physiological response to positive or negative
emotions, except when the lesion impairs input to the limbic cortex (i.e.,
some patients will have a preserved emotional perception, but a faulty
activation such as in pathological laughing and crying).
3. Normals will activate one or more portions of their left limbic
system in response to happy emotional processing and the right limbic system
with sadness and fear. Sadness will involve a frontal flow increase and
fear a temporal flow increase.
4. That patients with lesions of the thalamus (limbic
circuit) will not experience emotion processed by the side of the lesion
and will not, therefore, increase orbitofrontal or basotemporal-amygdala
blood flow in response to the presented emotional stimuli, however, patients
with brainstem lesions (also posterior circulation lesions) will experience
emotion and activate limbic areas.
Preliminary Studies
In a preliminary study, a sequence of films was shown
with another neutral (baseline) film, followed by happy, fearful, neutral,
fearful, happy, neutral film clips. Immediately after each activation
condition, the patient reported the intensity of emotional response
using an analogue scale. Facial expression was recorded via videotape
during activation/scanning utilizing a mirror placed inside the scanning
ring. We found a significant effect of emotional activation upon regional
blood flow. Using image subtraction analysis (i.e., emotional activation
state minus the combined neutral conditions), there were significant
findings which were reproducible (there were two activations of the
same emotion in each subject). There was an area in the left prefrontal
region that was activated during the viewing of happy images that was
not activated during fearful images (50% increase), and an area of
the right superior temporal gyrus that was activated in fear/disgust
that was not activated during happy images (70% increase).
Methods
PET imaging data, EEG data and ANS data will be collected
from subjects while they are undergoing an activating procedure designed
to stimulate emotion. Emotional activation will involve three types
of emotion: happiness, sadness, and fear. Emotions will be elicited
using short (average 60 sec.) segments from motion pictures. They are
presented to the subjects as video clips without sound. They have been
selected on the basis of their ability to elicit EEG evidence of emotional
activation, and have been validated in previous studies. Psychological
perception (i.e., subjective report of the patient) will be recorded
at the end of each video presentation to determine emotional responses.
Patients who have had strokes with single lesions which are identifiable on MRI or CT scan will be selected based on the criteria in Specific Aims 1 and 2 above. Since lesions are only rarely restricted to small specific structures, we will select from over 400 patients per year to find those with relatively discrete lesions (e.g., limited primarily to one specific region such as basotemporal cortex or thalamus). The selection will involve a neuroradiologist blind to any clinical data identifying a lesion as involving a structure under study (e.g., thalamus or basal ganglia). Extension to non-study structures will be allowed if the majority of the lesion is in the desired structure (e.g., orbital frontal lesion with extension to dorsal lateral cortex or white matter) as long as two study structures (e.g., frontal and temporal cortex) are not involved. The subjects to be used in these studies will also be only non-depressed, non-anxious patients (as determined by not fulfilling symptom criteria for major or minor depressive disorder or generalized anxiety disorder) and without history of having met these diagnostic criteria in the past. They will be studied approximately 3 months post-stroke when the acute medical complications and lesion characteristics have stabilized.
There will be 120 patients with stroke studied and 20 normal control subjects with a subset of 60 patients undergoing PET imaging. Numbers of patients in each category will be as follows (total 140 recruited over 5 years).
Specific Aim #1 (EEG and ANS only): Inferior frontal cortex, 20 (10 left and 10 right), Anterior temporal cortex 20 (10 left and 10 right), Thalamus 20 (10 left and 10 right), Basal ganglia 20 (10 left and 10 right), Brainstem 20, Parietal-posterior temporal 20 (10 left and 10 right), Normal Controls 20.
Specific Aim #2 (PET Study): Of the subjects above, 60 subjects will have a PET study in addition to their EEG and other studies. Thalamus 20 (10 left and 10 right), Brainstem 20, Normal Controls 20.
PET Imaging: PET imaging will utilize the methods noted above. The sequence of conditions will be neutral (baseline), happy, fearful, neutral, fearful, happy, neutral.
Autonomic Nervous System Response: During and following emotional activation, measures of blood pressure, pulse, galvanic skin conductance and facial expression will be recorded. They will be collected in a standardized way using procedures demonstrated in previous work to produce measurements which are reliable and valid. Facial expression will be recorded on videotape.
EEG: Quantitative EEG measurements will be taken during the emotion activating procedure. EEG measurement data obtained from the subjects will be analyzed by Dr. Davidson in Wisconsin. He will be blind to other experimental data. To permit computation of reference-free montages, EEG will be recorded from 30 scalp locations. In addition, two channels of EOG will be recorded (to obtain measures of vertical and horizontal eye movements) and a trigger channel will denote the onset and offset of data acquisition periods.
Other Measures:
All patients will undergo a standardized neurological
examination using the National Institute of Health (NIH) Stroke Scale.
Patients will be examined by a psychiatrist using a semi-structured
interview, the Present State Exam (PSE) including a modification to
assess lifetime diagnosis. Quantitative evaluation of social functioning
will be done using the Social Functioning Exam and the Social Ties
Checklist. The Johns Hopkins Functioning Inventory will be used to
assess the patient's ability to perform activities of daily living.
Assessment of cognitive functions will be done using a neuropsychological
test battery designed in collaboration with Dr. Edith Kaplan at the
Boston Veterans Administration Hospital.
Data Analysis:
We recognize that this study will generate a huge
amount of data, and that data analysis will represent one of the most
formidable aspects of this study. We have, therefore, put together
a team that has a track record in this kind of data analysis. Dr. Stephan
Arndt, Director of the Biostatistical Core Unit of the MH-CRC will
serve as consultant for image data analysis. Dr. Richard Davidson at
the University of Wisconsin at Madison will provide instrumentation
for recording EEG and ANS data, as well as data processing and analysis
at his lab in Wisconsin. Dr. Davidson is highly experienced in data
reduction of EEG studies. He will work closely with Dr. Arndt to implement
EEG-PET co-registration analysis. Data analysis will examine the relationship
between subjective experience of emotion, (from the post video ratings)
behavioral (i.e., facial expression) and biological (i.e., autonomic
measures and EEG measures) concomitants. This will be done both cross-sectionally
(e.g., at the end of the film does the patient's report of sadness
and EEG frontal asymmetry correlate?) and longitudinally (e.g., is
there a frontal asymmetry prior to a change of mood rating?). The analyses
will examine subjective experience of emotion (e.g., sadness) as the
dependent variable and autonomic and electrophysiological measures
as the independent variables. Logistic (for categorical) and linear
(for continuous measures) relationships of emotional and biological
variables as predictors of one another and temporal concomitants will
be carried out. In addition, we will examine if there is an effect
of the presentation order of the activating video clips. Groups will
be formed on the basis of lesion location in areas already described.
We will control for differences between groups in lesion volume and
cortical versus subcortical effects (i.e., analysis of variance will
test for independent and interaction effects). We will examine effects
of age, sex, education, cognitive impairment and the other variables
as previously described. We anticipate that most of these variables
will be controlled across groups and that multiple factors will not
have to be controlled. This has been our experience in prior research
in this area.
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PROJECT 3: A POSITRON EMISSION TOMOGRAPHY STUDY OF LANGUAGE PRODUCTION
IN ADULT AUTISTIC INDIVIDUALS
Principal Investigator: Joseph Piven,
M.D.
Co-Investigators: Daniel S. O'Leary, Ph.D., Richard Hichwa, Ph.D.
Funding Status: This project is currently
not funded
Project Status and Duration: Ongoing.
ROI submission planned 1998.
Specific Aims
This project employs PET imaging with [15O] water
to investigate rCBF during the performance of cognitive tasks in adults
who were diagnosed in childhood as autistic (hereafter called adult
autistics). Adult autistics will be imaged with PET during the performance
of cognitive tasks which are typically performed abnormally by these
subjects, and their rCBF will be compared both to normal volunteers
and to patients with schizophrenia who have performed the same tasks.
Background and Rationale
Schizophrenia and autism share many features in common, which include
symptoms such as abnormal social interactions, and cognitive abnormalities
such as atypical language use. Both schizophrenia and autism are disorders
that are clearly linked to brain abnormalities, although the exact
nature of the brain dysfunction underlying either disorder is currently
unknown. Autism has a clear developmental course which suggests abnormalities
in brain maturational processes. Neuropathological studies have demonstrated
abnormalities in the cerebellum, and medial temporal lobe structures.
A recent MRI study performed here at the University of Iowa revealed
that adult male autistics had larger brain volumes than did a group
of age-matched control males (Piven et al 1997a). The increase was
observed both in brain tissue volume and in the ventricular system.
Study of brain function with PET and [15O]water during the performance
of specific cognitive tasks may help to determine the functional consequences
of the developmental abnormality that characterizes autism. Specifically,
the present study will allow determination of whether brain regions
activated by cognitive tasks in autistics are the same or different
than areas activated in normals and in patients with schizophrenia.
There has been relatively little study of brain function in autistic
individuals. A recent review of PET studies performed with autistic
subjects (Horwitz & Rumsey 1994) notes that no focal abnormalities
in metabolism have been found. However, PET studies performed to date
have assessed glucose metabolism in either a resting state or during
low-level cognitive tasks utilizing [18F]fluorodeoxyglucose (FDG).
Horwitz and Rumsey (1994) suggest that the use of more informative
activation tasks during PET imaging is likely to be a productive strategy
for assessing brain function in autism. PET with [15O]water permits
the use of repeated back-to-back studies with differing activation
tasks, allowing the possibility of isolating specific cognitive impairments.
Hypotheses
1. Adult autistics will demonstrate rCBF abnormalities
(i.e., differences from the pattern exhibited by the normal group)
during the performance of language production tasks.
2. The rCBF abnormalities of the adult autistic group
will have both similarities and differences to those exhibited by the schizophrenic
patient group.
3. The adult autistic group will show a unique pattern
of rCBF abnormalities on the higher-level language production tasks requiring
production of an imaginative story concerning the cognitive state of others
(i.e., rCBF correlates of deficits in imaginative narrative and "theory
of mind" tasks).
Preliminary Studies
We have performed PET imaging studies on a total of
3 adult autistic subjects. Data analysis for this study requires averaging
across at least 5 subjects, and we plan an initial, preliminary analysis
after 2 more subjects have been imaged. This is the first time we have
attempted PET imaging with adult autistics and in practical terms we
have learned that the subjects tolerate the procedure well, although
they require very concrete information about each step in the procedure.
The cognitive activation protocol that we used is one with which we
have already collected data on a sample of 13 controls and 25 patients.
The data from the schizophrenia patient group has not yet been analyzed.
Analysis of the rCBF changes in the normal volunteer group that were
associated with the activation tasks below yielded the following findings:
1) Reading single words caused increased rCBF (over a baseline task)
in visual cortices in the occipital lobe, in auditory cortices in the
left and right superior temporal gyrus, and in the left frontal motor
strip. 2) The tasks in which normal subjects produced verbal narratives
all showed increases in rCBF in the cerebellum, left superior temporal
gyrus, left thalamus and regions of the left frontal lobe. Differences
between the narrative conditions were largely within the left hemisphere,
in the insula, inferior frontal lobe and inferior temporal lobe.
Methods:
Patient Sample: Twenty-two
patients will be selected from a larger sample who have been assessed
by Dr. Piven. The patients selected will be males above the age of
18 years, who have IQs above borderline. The patients selected have
already had a usable MR scan, using the same T1 weighted sequence used
by the schizophrenic research project.
The procedures to be used for PET image acquisition are as described above. The tasks are designed to require differing types of linguistic processing, beginning with simple reading, and progressing in stepwise stages to relatively complex tasks requiring the creation of narratives. The activation tasks were designed in collaboration with Dr. Andreasen's research team. The specific conditions are: #1 Read words. #2 Read words in sentences. #3 Read words in narrative. #4 Eyes-closed rest. #5 Non-imaginative neutral narrative, i.e., "Tell what you did after you woke up yesterday morning.") #6 Imaginative neutral narrative, (i.e., "Imagine that you are shopping in a grocery store and see Mickey Mouse pushing a grocery cart. Tell a story about what you did.") #7 Imaginative empathic story, (i.e., "Imagine that you meet a stranger who is crying. Tell a story about what happened to her.") #8 Generate a story using 5 specific items.
Data Analysis:
Within the autistic group the analysis will include
both a function of interest, t-statistic mapping approach, and
a region of interest-bases approach assessing rCBF within volumes traced
on co-registered MRIs. Randomization analyses (Arndt et al 1996c) will
be used for between-group analyses.
PROJECT 4: CHRONIC MARIJUANA
USE, BRAIN AND COGNITION
Principal Investigator: Robert
I. Block, Ph.D.
Co-Investigators: Daniel S. O'Leary, Ph.D., Richard Hichwa, Ph.D.
Funding Status: RO1 grant to Block
Proposed Duration: Funded 4/97-8/99
Specific Aims
The long-term objectives of this project are to understand
effects of chronic use of marijuana on brain structure, and function
and cognition. The specific aim is to compare rCBF and cognition in
chronic marijuana users who have limited experience with use of other
drugs to non-using controls.
Background and Significance
Many studies have examined effects of chronic marijuana use on human
cognition (Pope et al 1995) but only one (Block and Ghoneim 1993) has
matched marijuana users and non-users on their intellectual abilities
prior to the onset of drug use, to control for possible premorbid differences
in cognitive abilities. Four studies examined chronic marijuana users
by air encephalography (Campbell et al 1971) or computed tomography
(Co et al 1977, Hannerz and Hindmarsh 1983, Kuehnle et al 1977). Measurements
of the lateral and third ventricles provided evidence of cerebral atrophy
in the 1st study. The other 3 studies observed no abnormalities. Several
studies by Matthews and colleagues have examined rCBF of chronic marijuana
users using the 133Xenon inhalation technique. One study observed no
differences between chronic marijuana users and controls in rCBF or
overall CBF (Mathew et al 1986a; Mathew and Wilson, 1992). A second
study found that experienced marijuana users showed the lowest overall
CBF values. Other researchers observed overall CBF decreases, in the
absence of rCBF differences, in chronic marijuana users relative to
controls (Tunving et al 1986). The discrepant results may have been
due to differences in subjects' characteristics: Ss in Mathew et al's
studies were volunteers without obvious problems associated with marijuana
use, whereas the other researchers studied patients who had recently
entered treatment for marijuana use. Subcortical changes were found
in the one PET study on this topic, which used 18F-2-fluoro-2-deoxyglucose
as a tracer to measure regional cerebral glucose utilization of chronic
marijuana users and controls (Volkow et al 1996c). At baseline, chronic
users showed decreased relative metabolism compared to controls in
the cerebellum, but nowhere else. Administration of 2 mg THC increased
cerebellar metabolism in both chronic users and controls. Chronic users
also showed increased metabolism in prefrontal cortex, orbitofrontal
cortex, and basal ganglia, whereas controls did not. The authors suggested
that increased metabolism in the latter two areas could be related
to the drive to self-administer the drug. This important study indicated
that the brain area most sensitive to chronic effects (the cerebellum)
was also the most sensitive to acute effects. Subjects in all of these
studies were evaluated during "rest," i.e., undirected mental activity.
Hypotheses:
Compared to matched non-users, chronic marijuana users
will have:
1. reduced or otherwise altered patterns of rCBF during performance
of cognitive activation tests assessing: 1) memory retrieval for well-learned
and novel materials; and 2) selective attention;
2. reduced or otherwise altered patterns of rCBF during
undirected mental activity and performance of control tests (auditory reaction
time and counting);
3. mild cerebral atrophy or other changes in brain structure,
assessed by MR imaging and analyzed with innovative image averaging techniques;
4. selective deficits in memory retrieval and impairments
of verbal expression and quantitative abilities, as we found in previous
research; and deficits in selective attention.
Progress Report:
We examined effects of chronic use by comparing marijuana
users and non-users who were matched on intellectual functioning before
the onset of marijuana use, i.e., on their Iowa Test (ITBS) scores
during the 4th grade (Block & Ghoneim 1993). Under drug-free conditions,
the 12th grade versions of the ITBSs were administered along with computerized
cognitive tests to determine if chronic marijuana users were impaired
relative to non-users and, if so, whether impairments depended on the
frequency of marijuana use. Two of the 12th grade ITBS showed impairments
in heavy marijuana users relative to non-users. On a verbal memory
test heavy users showed impairment relative to non-users in long-term
retrieval for high but not low imagery words. Heavy users scored lower
percentages of correct responses than intermediate users or light users
for more difficult concepts in a concept attainment task.
Methods
Sample: Subjects will be 30 heavy
marijuana users and 30 non-using controls recruited primarily by newspaper
advertisements. The groups will be matched on mean scores on the 4th
grade ITBS and as well as possible on education, age, height, gender,
race, recent chronic use of tobacco, and their own and their parents'
socioeconomic status. Design: Following an initial screening session
subjects will be scheduled for 2 overnight inpatient hospitalizations
in the University of Iowa Clinical Research Center, separated by a
1-week interval. A biographical interview, MR imaging, and a cognitive
(non-imaging) test session will be conducted during the 1st hospitalization.
The PET session with cognitive activation tests, preceded 24 hours
earlier by practice on these tests and relearning of a word list used
in one of the cognitive activation tests, will be conducted during
the 2nd hospitalization. To verify abstention from marijuana and other
drugs, blood and urine samples will be obtained at screening, on the
days of admissions to the Clinical Research Center, and before the
cognitive test session and PET session. Saliva samples will be obtained
at admission and every 4 hour thereafter during both hospitalizations,
and breath testing for alcohol with an Alco-Sensor III unit will be
done at the same times.
Cognitive Activation Tests. Cognitive activation tests during the image acquisition periods will be as follows: Free Recall: In 3 memory tests, Ss will be instructed to recall as many words from a list as they can, in any order. 1) subjects will be asked to recall the previously learned word list. 2) subjects will again be asked to recall list 1, but, as in our previous PET study (Andreasen et al 1995f), the word list will be presented to subjects auditorily at a rate of 1 word per sec immediately before recall begins. Recall of a novel word list will be tested. Active Baseline for Free Recall: The active baseline will consist of repeatedly counting from 1 to 3 at a rate of approximately 1 number per sec. Dichotic Listening Test: The attend-right and attend-left dichotic listening task with CVCs, and the baseline task described in O'Leary et al (1996b, c) will be used. Rest: subjects will be given no specific instructions about mental activities, being asked simply to lie quietly with eyes closed.
Data Analysis
The quantitative PET blood flow images and MR images
will be transferred to the Image Processing Laboratory of the University
of Iowa Mental Health Clinical Research Center for processing. The
MR processing will produce "average brains" of marijuana users and
controls, which can represent their differences as an effect size map
(Andreasen et al 1994k). To check for individual abnormalities that
might be missed by the automated image averaging process, the MR images
will also be interpreted clinically by a neuroradiologist (Dr. Yuh).
FOI analysis of PET images will utilize our standard image subtraction
approach. Randomization analyses (Arndt et al 1996c) will be used for
between-group comparisons of chronic users and matched controls. Manual
tracings of ROIs will be made on each subject's co-registered MR images.
ROIs consist of left and right prefrontal, posterior inferior frontal,
insula, anterior and posterior cingulate; and left and right anterior
inferior temporal, thalamus, and cerebellum. The hippocampus will be
an additional ROI for the memory tests. The blood flow for each ROI,
expressed in ml/min/100 g, will be submitted to ANOVAs including group
(marijuana users vs. controls) and condition (the pairs of conditions
used for subtractions in the corresponding FOI analyses).
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PROJECT 5: ACUTE MARIJUANA
EFFECTS ON REGIONAL CEREBRAL BLOOD FLOW
Principal Investigator: Daniel
S. O'Leary, Ph.D.
Co-Investigators: Robert I. Block, Ph.D., Richard Hichwa, Ph.D.
Funding Status: Project received a fundable
priority score and percentile (16.6%) 11/97.
Project Status and Duration: Ongoing
Specific Aims
The specific aims of the project are to study the
rCBF changes in brain systems mediating cognitive functions that are
acutely impaired by smoking marijuana in occasional users, and to determine
if long-term use of marijuana alters the acute response of these brain
systems to marijuana. To accomplish these aims we will perform an interrelated
series of 4 studies using PET with [15O]water.
Study 1. Time Course of rCBF Changes Following Smoking of Marijuana: This initial study will assess the time course of rCBF changes in the brain after smoking marijuana.
Studies 2. & 3. Acute Effects of Marijuana on Memory and Attention: Two studies will assess the effects of smoking marijuana on memory and attention in occasional users.
Study 4. Acute Effects of Marijuana on rCBF and Memory in Chronic Users: This study will assess the manner in which heavy, long-term use of marijuana alters the acute response of the brain to marijuana during performance of a memory task.
Background and Significance
Marijuana (cannabis sativa) is the most commonly used illegal drug
in the United States (Preliminary Estimates From the 1994 National
Household Survey on Drug Abuse 1995). Smoking of marijuana causes subjective
effects including euphoria, depersonalization, altered time sense,
lethargy, drowsiness, confusion, anxiety, and psychosis (Hollister
1988); as well as impairment on sensory, motor, and cognitive tasks
(Block et al 1992). The major psychoactive substance in marijuana,
delta-9-tetrahydrocannabinol (THC), is one of a class of natural and
synthetic cannabinoids that appear to selectively bind to receptors
in the hippocampus and cerebellum, as well as in outflow nuclei of
the basal ganglia (Herkenham et al 1990). The few imaging studies that
have assessed the effects of marijuana and THC on brain blood flow
and metabolism in humans have all utilized a "resting" baseline condition
in which subjects perform no explicit task and have produced conflicting
results. The studies proposed here will control the subject's mental
activities following the smoking of marijuana or placebo by engaging
them in challenging tasks. We will systematically assess the changes
caused by smoking marijuana versus placebo on rCBF and tasks requiring
attention and memory. This will permit assessment of the changes in
brain activity that are associated with impaired behavioral performance.
Hypotheses Study 1:
1. Global blood flow will increase following the smoking
of both placebo and marijuana cigarettes, but task-related rCBF decreases
in temporal lobe will be seen only following marijuana smoking.
2. Significantly increased rCBF will also be observed
in the cerebellum and frontal lobes studies (Mathew and Wilson 1993; 1995;
Volkow et al 1991, 1996c), and the cerebellar increase will be positively
correlated with subjective ratings of intoxication (Volkow et al 1991).
Hypotheses Study 2 and 3:
The general hypothesis for the two studies is that smoking marijuana
will attenuate the task-specific pattern of rCBF that is characteristic
of normal cognitive function in occasional users. That is, we hypothesize
that areas of activation will be smaller in spatial extent and lower
in magnitude following marijuana, in conjunction with poorer cognitive
performance.
Memory:
1. The rCBF activations in the placebo condition will
be similar to our previous findings. That is, we expect both novel
and familiar recall conditions to activate right frontal, left inferior
temporal, anterior cingulate, thalamus, and cerebellum.
2. Activation in the regions noted in Hypothesis #1 will
be smaller in extent and lower in magnitude in the marijuana session, in
conjunction with poorer recall scores.
3. The effects of marijuana on rCBF will be significantly
greater in the more difficult novel word list condition than in the practiced
condition.
Attention:
1. We will replicate findings from our prior PET studies
in the placebo session. That is, we expect that rCBF asymmetries will
vary with attention, with greater flow in the superior temporal gyrus
(STG) contralateral to the direction of attention.
2. Smoking marijuana will attenuate this attention-related
asymmetry.
3. Smoking marijuana will decrease attention-specific
changes in rCBF in the planum temporale and in the superior parietal lobe,
but will not change rCBF in primary auditory cortex in Heschl's gyrus.
Hypotheses Study 4:
1. The acute rCBF response to marijuana in chronic
users during the baseline task will replicate the pattern of cerebral
metabolism change recently reported by Volkow et al (1996c) in marijuana
abusers injected with THC. That is, we expect that chronic users will
show rCBF increases in orbitofrontal cortex, prefrontal cortex and
basal ganglia.
2. Task-specific patterns of rCBF change observed during
memory task performance will show the same general pattern of attenuation
as in occasional users (i.e., rCBF changes smaller in extent and lower
in magnitude following marijuana versus placebo), but the attenuation will
be significantly greater in the chronic user group.
Progress Report
We have completed PET imaging utilizing the protocol
described in Study 1 above in four subjects and have recently completed
our first group t-map analysis of the effects of smoking marijuana. To
our knowledge, we are the first to investigate the effects of smoking
marijuana on brain function using PET during the performance of a cognitive
task. We found rCBF increases in a number of brain regions (e.g., frontal
lobes, lateral cerebellum) that showed increased rCBF in previous imaging
studies (Mathew and Wilson 1993; 1995; Volkow et al 1991; 1996c), which
assessed the effects of marijuana on subjects during a resting state.
Additionally, we found dramatic rCBF reductions following marijuana
smoking in regions of the temporal lobe that we have found to be sensitive
to attentional effects during the auditorily-presented cognitive task
(O'Leary et al 1996 a, b; 1997a, submitted a). It seems possible that
the reduction of task-related rCBF in temporal lobe cortices may be
a direct neurobiological correlate of the acute cognitive impairment
that is caused by smoking marijuana.
Research Plan:
Sample: Each study
will utilize 20 subjects (10 males and 10 females). Three studies will
use subjects who report using marijuana no more than 10 times a month.
Study 4 will utilize chronic users of marijuana (subjects who report
using marijuana 7 or more times weekly on average over the past two
years). Scores on the Iowa Tests will be used to match the chronic
users of marijuana in Study 4 as a group, with the scores of the subjects
in the other studies.
Smoking in each study will take place while the subject is on the PET couch, at the time point in the study noted below. We found in our nicotine study that subjects can hold their own cigarettes even with both arterial and venous lines in place. Subjects will follow a paced smoking procedure to control the dose of THC (Block et al 1992). A custom-designed ventilation hood will be in place directly above the subject to vent the smoke. Marijuana or placebo cigarettes will be obtained from NIDA and will be stored and monitored by the pharmacy at the University of Iowa Hospitals and Clinics. The active cigarette will contain 20 mg THC, a dose which we have found to produce substantial, but not incapacitating behavioral effects (Block et al 1992); and which is representative of typical social use. Placebo cigarettes will contain inactive, cannabinoid-extracted marijuana with only trace amounts of THC.
Study 1:
Year 1. Time Course of rCBF Changes Following
Smoking of Marijuana: A double-blind marijuana/placebo design will
be used, with half of the subjects randomly assigned to a condition
in which marijuana will be smoked following injection #3 and placebo
smoked following injection #5, and half of the subjects smoking placebo
and marijuana in the opposite order. The activation conditions for
this study are: Sham, reaction time (RT) baseline; condition #1, RT
baseline; conditions #2 through #8, attention task (dichotically-presented
CVCs - attend left). Should rCBF not remain stable over the time course
to be used in following studies, we will have subjects smoke a second
marijuana cigarette in these studies.
Studies 2-4:
Each of the following studies will have essentially
the same design. Studies 2 & 3 will differ in the activating tasks
that are used with subjects who are occasional users of marijuana,
whereas Study 4 will use the same memory tasks as Study 2, but will
use subjects who are chronic users of marijuana. Each of the studies
will involve two sessions at least one week apart with four conditions
per session, and will be doubly-blinded, with order of placebo or marijuana
counterbalanced. Each session will involve an initial sham injection
followed by four conditions during which [15O]water will be used to
measure rCBF. All studies will take place in the morning and will last
approximately two hours. The sham and an initial condition will use
a baseline task that is unique to each study, followed by smoking a
standard marijuana or placebo cigarette. A second repetition of the
baseline task will then take place followed by two activation conditions.
This design permits within-subject comparisons of the effects of smoking
marijuana vs placebo both within- and across- sessions. This design
yields a number of possible comparisons of conditions that will be
of interest in each study. All eight rCBF PET images (four from each
session) will be co-registered with each individual's MR images, permitting
within-subject subtractions both between- and within-sessions. Each
session has the same baseline that is repeated prior to and following
smoking of marijuana vs placebo. Since order of sessions will be counterbalanced,
this will permit an analysis of variance design with one between subject
variable (order of sessions), and two within-subject variables (pre
vs post smoking of marijuana vs placebo.
Study 2.
Effects of Marijuana on rCBF and Memory Year 2 & 3. The activation
conditions for this study, to be repeated on two occasions, are: Sham,
counting baseline; #1, counting baseline; #2, counting baseline; #3,
practiced list; #4, novel list. Smoking will occur prior to condition
2. This study will assess the effects of marijuana vs placebo on the
retrieval of practiced and novel word lists. The verbal recall conditions
will be similar to conditions we have used previously (Andreasen et
al 1995e, f). We will, however, use an active baseline task rather
than a resting baseline for reasons discussed above, and in Andreasen
et al (1995d).
Study 3.
Effects of Marijuana on rCBF and Attention Year 3. The activation
conditions for this study, to be repeated on two occasions, are: Sham,
reaction time (RT) baseline #1, RT baseline, #2, RT baseline, #3, dichotically-presented
CVCs - attend right #4, dichotically-presented CVCs - attend left.
Conditions 2 and 3 will be counter-balanced across subjects. Smoking
will occur prior to condition 2. This study will assess the effects
of marijuana vs placebo on the ability to focus attention on relevant
information and to filter out irrelevant information. The baseline
and dichotic conditions to be used are identical to conditions we have
used in our PET work with normal volunteers and patients (O'Leary et
al 1996 a, b).
Study 4.
Acute Effects of Marijuana on rCBF in Chronic Users Years 4 & 5.
This study will compare rCBF during marijuana challenge in a group
of subjects who have used marijuana on a regular basis for a number
of years to rCBF changes in subjects who are occasional users. Chronic
use is defined as using marijuana on average 7 times or more weekly
over the past two years and with a total duration of use of at least
4 years. The design of the study will be identical to Study 2 described
above. The memory activation tasks involve verbal retrieval processes
that our previous work has shown to be impaired in chronic users of
marijuana. In addition to within-group analyses of the acute effects
of marijuana we will compare the acute effects of smoking marijuana
versus placebo on rCBF in the group of subjects who are chronic users
of marijuana to rCBF changes in subjects who are occasional users.
Data Analysis:
The PET data will be analyzed utilizing the image
analysis procedures described above and in the Image Analysis Core
Unit. For Studies 2-4, within-subject analyses will utilize a subtraction
image t-map approach to compare the same conditions during the marijuana
and placebo sessions. Randomization analysis (Arndt et al 1996c) will
be used for between-subject analyses comparing chronic users (Study
4) with occasional users of marijuana.
PROJECT 6: COGNITIVE FUNCTIONING,
BRAIN STRUCTURE AND METABOLIC ACTIVITY IN CHRONIC ALCOHOL ABUSERS
Principal Investigator: Karen
M. Cocco, Ph.D.
Co-Investigators: Peter E. Nathan, Ph.D.,
Nancy C. Andreasen, M.D., Ph.D., Daniel S. O'Leary, Ph.D.
Project Status and Duration: Currently
funded through the CIFRE mechanism
Specific Aims
1. To use PET imaging with [15O]water to assess rCBF
changes in long-term alcohol abusers during the performance of attention
and memory tasks that have been shown to be sensitive to prolonged
alcohol abuse.
2. To use PET to assess rCBF changes associated with recovery
of cognitive function following abstention from alcohol for several months.
3. To use MR imaging to assess structural brain changes
associated with long-term alcohol abuse and to assess structural changes
that may occur following abstention.
4. To assess changes in cognitive function associated
with long-term alcohol abuse and abstention using an extensive neuropsychological
test battery.
Background and Rationale
Substantial data document the impact of prolonged alcohol abuse on
cognitive functioning. Approximately 50-70% of detoxified alcoholics
experience deficits in cognitive functioning. Problem-solving abilities,
the ability to make conceptual shifts, and short-term memory and attentional
processes are most sensitive to the effects of prolonged, excessive
ethanol consumption. Data also exist that suggest strongly that chronic
consumption of alcohol is related to both structural and functional
changes in the brain. Increases in the ventricular brain ratio (VBR)
and increases in CSF in sulci and interhemispheric fissures were the
most frequently reported indices of the brain damage resulting from
prolonged, excessive drinking in early CT studies, and these findings
have been confirmed in more recent MR imaging studies (Johnson et al
1986). Twin studies have demonstrated that these changes are a consequence
of prolonged heavy drinking rather than pre-existing conditions. The
modest PET data that have been reported confirm that alcoholic drinking
affects both cortical and subcortical structures (Gilman et al 1990;
Volkow et al 1992; Wik et al 1988). The medial frontal region of the
cerebral cortex seems to be most affected (Gilman et al 1990; Melgaard
et al 1990; Samson et al 1986), although a small area in the left parietal
region also appears to be involved (Melgaard et al 1990; Volkow et
al 1992; Wik et al 1988).
These initial investigations have not to date examined interrelationships among structural changes in the brain, changes in metabolic activity, and alcohol-induced deficits in neuropsychological functioning. Those studies that have looked simultaneously at indices of brain structure and function, like the investigation by Volkow et al (1992), have only done so at a single point in time, even though ample neuropsychological data suggest that substantial recovery of cognitive deficits occurs over time with abstinence. While there is modest evidence to suggest that recovery of functioning as measured by both neuropsychological test performance and structural and functional changes in the brain is likely to occur within the first 4 months of abstinence from alcohol, it is difficult to interpret the long-term implications of these findings because these assessments were all done at a single point in time, when alcohol-related changes, including the effects of withdrawal, on both brain structure and function would be expected. The interrelationships among changes in brain structure, underlying pathophysiological processes in the brain, and neuropsychological deficits as a function of the post-abstinence interval have not yet been examined since the only studies in which all three measures of dysfunction were employed did so on only a single occasion.
Hypotheses
1. Long-term abusers of alcohol will show significant
cognitive deficits and significant differences from normal volunteers
in rCBF during the performance of attention and memory tasks when assessed
within a month from abstention.
2. Regional CBF will "normalize" in association with improved
cognitive performance when the same individuals are assessed after several
months of abstinence from alcohol.
3. MR imaging will show significantly increased ventricular and surface
CSF in long-term abusers of alcohol when imaged within a month from abstention,
but this atrophy will reverse to some extent following abstention.
4. There will be a significant relationship between the
severity of cognitive deficits associated with long-term alcohol abuse
and structural and functional brain measures.
Progress Report
This project has received a small grant from the CIFRE mechanism
in order to permit collection of pilot data from 5 subjects. The data to
be gathered in this pilot study will be used to establish the feasibility
and some of the parameters of a substantially more extensive study of relationships
among neuropsychological deficits and structural and functional changes
in the brain both following prolonged alcohol abuse and after a several-month
period of abstinence from alcohol in chronic alcohol abusers. Subsequent
investigations will examine samples of chronic alcohol abusers who differ
in age, chronicity of alcoholism, gender, family history and polysubstance.
The project has been approved by the University of Iowa Human Subjects
and Radiation Protection Committees and the first subject has been recruited
for the project.
Research Plan
Patient Sample:
Subjects will be adult male inpatient volunteers participating
in a substance abuse treatment program located in Iowa City (MECCA). All
subjects will be between the ages of 21 and 35 years of age; strongly right-handed;
without a past history of hospitalization for (DSM-IV) diagnoses of schizophrenia
or major affective disorders; without a history of medical or neurological
illness or trauma that would affect the central nervous system; without
seizure disorder, related or unrelated to substance use; without a history
of polysubstance abuse; without a family history of alcohol dependence;
and at least 3 weeks but no longer than one month, abstinence from alcohol
before the first MRI, PET, and neuropsychological measurements. Control
subjects will be 13 adult male volunteers who previously participated in
an independent investigation (Andreasen et al 1995e, f) using the same
paradigm proposed herein.
Methods
The project will utilize PET with [15O]water to measure
regional cerebral blood flow at two different points in time in 5 adult,
male individuals currently in treatment for alcohol dependence. Two
recall tasks will require the subject to remember stories, each of
which contains 25 concepts. For a "practiced recall" condition, subjects
will be trained to perfect recall of the 25 concepts and will subsequently
be asked to recall as many concepts as possible during one PET imaging
condition. For the "novel recall" condition, subjects will be exposed
to a second story 1 minute prior to PET scanning and will be instructed
to recall as much of the novel story as possible during the PET imaging
condition. These two tasks have been chosen because the literature
indicates that long-term memory remains relatively intact after a period
of abusive drinking while new material is substantially more sensitive
to the effects of alcohol abuse. Therefore, the practiced recall condition
will act as a control condition for each subject. MRI will be used
to reflect brain structure at the same two time points as the PET imaging.
PET and MRI acquisition and analyses will utilize the techniques described
above and in the Image Analyses Core Unit. Within-group analyses of
changes between the two assessments will utilize randomization analysis
(Arndt et al 1996c), as will between-group analyses comparing rCBF
at each of the two time points in the alcohol abuse group to the control
group.
Data Analysis:
The PET and MR imaging data will be analyzed using
the procedures described above and in the Image Analysis Core Unit.
Within-group analyses of PET data will utilize a subtraction image,
t-map approach. Within-group changes in MR images will be analyzed
by co-registration of each subjects images from the two occasions,
subtracting the two image sets and computing an effect-size map for
the group (Andreasen et al 1994k). Analyses comparing the chronic alcohol
abuse group to controls will utilize randomization analysis (Arndt
et al 1996c).
Principal Investigator: Michael Flaum, M.D.
Co-Investigators: Daniel
O'Leary, Ph.D., Diane Mosnik, M.S., James C. Ehrhardt, Ph.D., Vincent
Magnotta, Ph.D., Stephan Arndt, Ph.D., Ted Cizadlo, B.S., Jane S. Paulsen,
Ph.D.
Funding Status: This project
is funded by a grant from the Nellie Ball Trust Research Fund to Dr. Flaum
Project Status and Duration: This
project has recently begun - the grant is for 1 year from 10/97 - 9/98
Specific Aims
1. To quantify the effects of two types of nicotine
exposure (cigarette smoking and nicotine patch) on cognitive performance
among smokers and non-smokers with schizophrenia, and control smokers
and non-smokers.
2. To estimate the location and magnitude of the effects of varying
nicotine exposure on regional brain activity during performance of selected
cognitive tasks.
Background and Significance:
The recent report (Freedman 1997) linking a gene at
the site of the alpha7-nicotinic receptor to vulnerability for information
processing deficits among patients with schizophrenia and their families,
has increased interest concerning cigarette smoking in individuals
with schizophrenia (Lohr 1992). Several lines of converging research
are of interest. First, nicotine, at least when delivered in the form
of cigarette smoking enhances performance on specific types of cognitive
tasks among normal smokers (Wesnes 1983) (there is far less certainty
regarding its effects on non-smokers); specifically, those of focused/vigilant
attention, choice reaction time (RT) tasks, motor speed and dexterity,
and certain memory tasks, including those tapping working memory. There
is some specificity to the effects, in that other cognitive functions
such as long term memory tasks, actually appear to be worsened by nicotine
(Spilich 1992). There is overlap between the nicotine enhanced tasks
and the types of cognitive deficits that have been implicated as potential
primary abnormalities in schizophrenia (Braff 1993). Second, although
the pharmacology of nicotine is complex, effects on dopaminergic systems,
particularly in the meso-limbic structures are among the most prominent
(Grenhoff 1988; 1989). Third, a series of studies over the past few
years have shown a transient "normalizing effect" of cigarette smoking
on a variety of characteristic deficits of schizophrenia including
sensory gating (Adler 1992) and smooth pursuit eye movements (Klein
1991). Combined with the extremely high rate of smoking in this population
these data suggest that schizophrenics are more prone to use nicotine
in an effort to self-medicate an underlying attentional and information
processing deficit.
Hypotheses:
1. Performance on each of the cognitive tasks
will improve following cigarette smoking relative to both the nicotine
patch and abstinence conditions across all subject groups.
2. Regional brain activity, as assessed by fMRI, will
increase as a function of task performance as evidenced by both the number
of pixels surpassing a prespecified threshold of activation, and the average
intensity of activated pixels.
3. Regional brain activity (combining hypotheses 1 and
2) will increase as a function of nicotine exposure, with recent cigarette
smoking yielding greater activations than either abstinence or the nicotine
patch condition.
4. The effect of nicotine on cognitive performance and
regional brain activity will be greater among the smokers than non-smokers,
and among the schizophrenic smokers than control smokers. (i.e., interactions
are expected between smoking status, diagnosis and nicotine exposure on
cognitive performance)
Preliminary Studies
This project required solving a number of novel technical
problems since we wished to measure rCBF and levels of nicotine and
several other substances in plasma both before and immediately after
smoking a tobacco cigarette following a period of abstinence. The study
required the construction of a ventilation system within the PET suite,
to eliminate the tobacco smoke. The study also required development
of protocols for the rapid assessment of levels of carbon dioxide,
carbon monoxide, nicotine and metabolites; as well as software permitting
the voxel by voxel correlation of circulating levels of substances
and rCBF. The equipment, software and experience was later used in
our pilot studies of the effects the smoking marijuana cigarettes.
An initial study of the effects of smoking tobacco
cigarettes has been completed in five healthy young men, all of whom
were regular cigarette smokers (Flaum et al submitted a). The conditions
across each of these ten scans were identical with one critical exception:
Immediately prior to the third and eighth scan, the subjects smoked
a full cigarette of their usual brand. All subjects abstained from
smoking for 12 hours prior to the first scan. Subjects were engaged
in the same attentional task (a dichotic listening paradigm) during
each of the ten scans. Nicotine blood levels were obtained just prior
to each scan. When whole brain blood flow was examined, no consistent
or significant effect of smoking was demonstrated across subjects.
However, regionally specific changes in flow as a function of nicotine
levels were found. Specifically, blood flow in the occipital cortex
and right medial temporal/insular cortex was positively correlated
with plasma nicotine levels over time. Interestingly, the temporal/insular
cortical areas in which flow increased as a function of nicotine level
corresponds to aspects of cortex presumed to subserve auditory association
function. Further, this cortical area also corresponded to that demonstrated
to be "activated" by a dichotic listening task in a previous study
of normal controls in our laboratory. These preliminary data suggest
that cigarette smoking does not acutely cause a consistent increase
or decrease in whole brain or regional cerebral blood flow. However,
plasma nicotine levels do affect blood flow in a regionally specific
manner, as blood flow in both the visual and auditory association cortices
vary as a function of plasma nicotine levels. These data are consistent
with neuropsychological findings which suggest that nicotine may serve
a "cognitive enhancing" function. The reviewers of this project noted
that task performance might be expected to improve following smoking,
since subjects are likely to be addicted to nicotine and become psychologically
disrupted if they do not smoke on schedule.
Methods
In this project, we are measuring performance on selected neuropsychological
tasks (chosen from those found to be most sensitive to nicotine exposure
among normal smokers) in four subject groups: those with schizophrenia
and normal controls, each divided into regular smokers and non-smokers.
Measures are obtained during multiple sessions for all groups, varying
the duration since last nicotine exposure (via cigarette smoking and nicotine
transdermal patches among the smoking groups, and transdermal patches only
among the non-smokers). Functional magnetic resonance imaging (fMRI) is
used to identify the brain regions associated with performance on selected
cognitive tasks, and to quantify the effects of varying nicotine exposure
on regional brain activity during performance on these tasks. We are extending
our pilot work in a number of ways. First, we are obtaining data on non-smokers
(both patients and controls) as well as smokers. If we are seeking a "normalizing" phenomenon,
it is critical to have a sense of what "normal" really is; normal smokers
may be a poor proxy for this. Existing data are available regarding the
cognitive performance aspect of this, but not for the physiological correlates
(e.g., brain imaging). Second, we are including a nicotine patch condition,
in addition to a recent smoking vs. abstinence condition. This allows us
to control the dose of nicotine across subjects and within subjects over
time. Third, we are using fMRI rather than PET. Reasons for this include
the ability to repeat subjects on multiple occasions as well as to lower
the expense.
We are studying four groups of 10 subjects each: patients and controls, smokers and non-smokers (smokers defined as those regularly smoking > 1 pack/ day for at least the past six months). The patient group is selected primarily from those participating in ongoing MH-CRC research protocols which require a three week psychoactive medication "washout" period. In order to minimize confounding effects of treatment, patients are being studied while off medications for at least two weeks. All patients in the study will have a diagnosis of schizophrenia or schizoafffective disorder, by DSM criteria. Controls are selected from the community on the basis of equivalence with the patient group in terms of: age, sex, parental education and parental socioeconomic status. Sample size choice was informed by effect sizes from numerous imaging studies in our lab and others (Andreasen 1996j).
Timing of cognitive testing and fMRI sessions:
Each subject undergoes three separate sessions of neuropsychological
assessment, and three corresponding fMRI sessions, varying only the timing
and type of nicotine exposure. The cognitive testing and fMRI sessions
are conducted on the same day in the following three conditions:
1) After 24 hours of abstinence from cigarette smoking
or any other form of nicotine
2) After at least a 24 hour period of smoking "ad lib" (own
brand, self-dosing), and smoking a cigarette just prior to getting in the
scanner (or just prior to beginning testing)
3) While wearing a nicotine transdermal patch (dosed to be equivalent
to usual smoking dose) for the previous three days, while abstaining from
cigarette smoking.
Cognitive Tasks:
Tasks have been chosen that have been shown to be
sensitive to nicotine effects among normals and shown to be resistant
to a learning or practice effect. Examples include: motor tasks, e.g., "Purdue
Pegboard" (manual dexterity), finger oscillation task (simple motor
speed), and a complex motor sequencing task; vigilant attention tasks,
e.g., continuous performance task; reaction time tasks, e.g., the "Flanker" task;
and working memory tasks e.g., the "1back / 2back and the "Sternberg" tasks.
fMRI Methods:
Not all of the cognitive tasks are adaptable to the
fMRI environment (e.g., vigilant attention tasks); however we have
adapted two of the motor tasks, one reaction time (RT) task (the Flanker),
and one working memory task ("1-back / 2back") for the fMRI environment.
The fMRI sessions typically consist of 3 - 4 "runs" of image acquisition,
(a motor, memory and RT task + one repeat) each lasting four minutes.
The order of the four runs is constant across sessions within subject,
but is varied across subjects in order to partially account for order
effects. All subjects are pre-exposed in our "mock scanner" which simulates
the visual, auditory and posture/positioning of the MR scanner. Nicotine
and cotinine levels are drawn at the conclusion of each fMRI session.
Tidal-breath carbon monoxide (CO) is measured prior to each fMRI run.
Behavioral data and reaction times are collected during the fMRI sessions
(via a hand held manipulandum), as well as outside of the fMRI setting.
Heart rate and blood pressur