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Example Protocol Summary for MSI & HD-EEG in Clinical & Cognitive Neuroscience
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TEMPLATE TEXT FOR PROTOCOL SUMMARY
Magnetic Source Imaging (MSI) and High Density Electroencephalography (HD-EEG) in
Clinical and Cognitive Neuroscience
Background and Introduction:
A recent report by the National Institutes of Mental Health1 estimates that, in a given year, at
least 44 million people in the United States suffer from a diagnosable mental disorder such as
Alzheimer’s disease, autism, schizophrenia, bipolar disorder, post-traumatic stress disorder or
attention deficit hyperactivity disorder. Neurological conditions such as epilepsy, head trauma
and stroke affect at least 6 million more people in a given year2,3. Costs to society are
incalculable, and despite best efforts in primary care prevention, the number of individuals
afflicted with these conditions continues to grow. Neurobiological conditions are of a highly
specialized and serious nature and they demand the development and application of new
diagnostic and treatment methods.
The University of Utah XXXX Department, XXXX Institute and the University of Utah
Magnetic Source Imaging lab (UUMSI) conduct research in functional brain imaging at the
Center for Advanced Medical Technologies (729 Arapeen Drive). This particular study aims to
further the development of clinical applications of brain imaging strategies, including magnetic
source imaging (MSI) and high density electroencephalography (HD-EEG). MSI combines
functional information derived from magnetoencephalography (MEG) with structural
information derived from magnetic resonance imaging (MRI). Just as current within a wire
generates a surrounding magnetic field, electrical currents flowing within brain cells generate a
surrounding neuromagnetic field. Even though the brain’s magnetic signature is almost one
billion times smaller than the magnetic field generated by an ordinary light bulb, the technology
is in hand for its measurement and characterization. HD-EEG is essentially the same as routine
EEG except that more electrode contacts are used, and more sophisticated data analysis strategies
are applied than is clinically routine. Recent research indicates that the combination of MEG,
HD-EEG and MRI data can provide for precise localization of brain structure responsible for
aberrant electrophysiological signals (e.g., epileptic spikes)4. Also, using stimulus activation
paradigms, MSI and HD-EEG can be used to define and track the spatiotemporal dynamics of
information processing in health and disease5,6,7. In the end, clinicians can be provided with a
blueprint of each patient’s brain that shows the intimate relationship between brain structure and
function.
Published studies show that the application of MSI and/or HD-EEG techniques can lead to
improved management and understanding of many conditions, including the following:
 Brain tumors8,9
 Epilepsy4,10,11
 Head trauma12,13
 Stroke14
 Alzheimer’s dementia15-17
 Psychiatric conditions, including schizophrenia, depression, and PTSD18-20
 Learning disorders, including dyslexia and ADHD21-23
 Autism and pervasive development disorder24.
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Example Protocol Summary for MSI & HD-EEG in Clinical & Cognitive Neuroscience
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Despite the increasing amount learned from these and other studies, there is an acute need for: 1,
the development of advanced testing protocols for assessing higher order cognitive functions; 2,
the development of a normative database with parameters for expected activation patterns in both
resting and activated states; and 3, the development of discriminant strategies for the differential
diagnosis and treatment profiles for patients with neurobiological and psychiatric dysfunction.
Objectives:
The major objective of this study is to develop and refine clinically useful protocols for assessing
spontaneous and evoked electromagnetic activity profiles in normal subjects and patients with
neurological, psychological, behavioral, and/or learning disorders. Whereas established
protocols exist for assessment of basic visual, auditory, and somatosensory functions,
standardized protocols for assessment of higher order cognitive functions including language,
attention, and memory, are presently lacking. As part of the study, both a standardized normal
and a patient database will be generated; these will provide for the development of discriminant
functions with high diagnostic sensitivity and specificity. The specific aims of this project are:
(1)
(2)
(3)
(4)
(5)
To develop a normative database with parameters for spontaneous brain activity
including spectral characteristics and regional and global coherence measures.
To develop a normative database with source parameters for visual, auditory,
olfactory, tactile, motor, and cognitive function.
To develop a set of patient databases with parameters for spontaneous brain activity
including spectral characteristics and regional and global coherence measures.
Examples of included disorders are epilepsy, stroke, head trauma, autism, ADHD,
dyslexia, schizophrenia, bipolar disorder and dementia.
To develop a set of patient databases with source parameters for visual, auditory,
olfactory, tactile, motor, and cognitive function. Examples of included disorders are
epilepsy, stroke, head trauma, autism, ADHD, dyslexia, schizophrenia, bipolar
disorder, and dementia.
To develop discriminant functions for the diagnosis and sub-classification of patients
with neurological, psychiatric, behavioral and/or learning disorders.
Subject selection criteria:
Subjects are drawn from two pools. Normal volunteers are recruited from the University student
population, hospital staff and the local community. In order to generate a viable normative
database, it is necessary to recruit subjects from throughout the life span. The normative
database will ultimately require a minimum of 25 subjects in each age/sex category. The age
categories are: 3-5, 5-10, 10-15, 15-20, 20-40, 40-60, 60-70, and 70+.
Patients with neurobiological or psychiatric dysfunction are self referred and/or referred through
clinicians familiar with the medical treatment of the individual.
Individuals with metal clips, plates, or pacemakers will be excluded. Pregnant women will be
excluded from the MRI portion of the examination.
Study design:
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Example Protocol Summary for MSI & HD-EEG in Clinical & Cognitive Neuroscience
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The study is designed as a broad-based survey for evaluation of paradigms, normal controls, and
patients. It is not intended to test specific hypotheses about the origins of any particular
condition. Rather, the objective is to develop a large comprehensive database that can lead to
generation of specific hypotheses, like: Epileptiform activity in children diagnosed with autism
correlates with language dysfunctions but not with behavioral disturbances (just an example).
The development of new behavioral paradigms proceeds in three steps. The first step involves
piloting the protocol with normal control subjects. Protocol design is typically based upon data
drawn from available behavioral or electrophysiological data with human subjects. For example,
several clinical conditions including schizophrenia and dementia are known to be associated with
disruption of frontal lobe functions. At present, there are no good MSI or HD-EEG protocols for
assessing the integrity of the frontal lobes. However, human25,26 and monkey27-29 studies suggest
that a simple go/no-go task may be effective. In this task, subjects press a button in response to a
go stimulus, but inhibit response to a no-go stimulus. Visual (e.g., green for go, red for no-go)
and auditory stimuli have both been used to elicit responses from the frontal lobe. Studies have
shown that schizophrenic subjects performed worse than controls on the no-go task and that the
two groups showed differences in the timing and localization of event-related potentials in
frontal cortical areas30,31. Difficulties inhibiting the response on no-go trials in schizophrenic
subjects presumably arise from the failure of frontal lobe mechanisms to inhibit motor
mechanisms with sufficient speed and veracity32. This go/no-go task can be evaluated easily
using MSI and HD-EEG; also, the data can be assessed for a specific frontal lobe contribution to
stimulus-evoked responses. The first phase of testing thereby involves implementation of the
paradigm and elucidation of signal components explicitly reflecting frontal lobe activity. The
second step in paradigm development involves testing of a large group of neurologically control
subjects to define the details of the normal pattern of responsivity with respect to signal
amplitude, latency, and source configuration. The final step involves testing of patients with
neurobiologic or psychiatric dysfunction and the use of discriminant functions to determine the
diagnostic sensitivity and specificity of the protocol.
Because it is presently uncertain as to which potential protocols will be most viable, it is difficult
to provide specifics at this stage. Suffice it to say that all protocols involve presentation of
visual, auditory, olfactory, vomeronasal, or tactile stimuli, with generation of a motor response,
as based upon a cognitive manipulation of the stimuli.
Procedures:
This study is divided into several phases of testing that may be performed on a single day, or
across multiple days, depending upon time constraints and equipment availability. All
procedures are noninvasive and without known risk.
The first phase of testing is a diagnostic, neurocognitive, and behavioral evaluation. In some
cases, this may involve no more than filling out a simple, 30-minute questionnaire concerning
aspects of medical history related to brain function (example questions: “Have you ever had a
head trauma that rendered you unconscious?” “Have you ever been diagnosed with autism or
other psychiatric conditions?”). For subjects with known neurobiological dysfunction, additional
diagnostic and behavioral testing may be performed. For example, those who have experienced
reading/language/speech difficulties will be asked to complete one or more published, validated
assessments such as the Test of Language Development (TOLD) or the Comprehensive Test of
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Phonological Processing (CTOPP). Standardized tests and behavioral checklists designed to
characterize cognitive, behavioral, neurological and psychological status will be administered by
trained personnel, under the supervision of (PI name). The objective of this testing is to identify
and characterize any neurobiological or psychiatric problems that may be present.
The second phase of testing involves recording of the brain’s electrical and/or magnetic activity.
In most cases both MEG and HD-EEG will be performed; but in some, only one or the other
method may be used.
For HD-EEG, the subject is fitted with a specially designed electrode cap with 19-64 contacts.
The scalp under each electrode is mildly rubbed with paste, and the electrode is then filled with
additional paste. Additional electrodes may be placed on the ears, and above and below the eyes.
Also, electrodes may be placed on the chest to monitor heartbeat. Approximately four wire coils
will be pasted on the scalp; these are used to provide a spatial reference of the head. Abrasion of
the area under the electrodes may cause some mild, temporary discomfort. Also, removal of
electrodes and coils may cause some mild discomfort if paste pulls on the hair. The paste is
easily washed off the scalp with shampoo. HD-EEG is a passive procedure that poses no known
health risks. EEG is considered part of the routine clinical evaluation of a patient suspected to
have neurobiological dysfunction and it is frequently used in the evaluation of “normal subjects”
engaged in cognitive neuroscience experiments. The procedure will be carried out by a trained
staff, supervised by (PI name).
During HD-EEG and MEG evaluations, the subject may be asked to simply sit quietly with eyes
open or closed, or he/she may be asked to perform a variety of cognitive tasks. For example, the
subject may be presented with a set of pictures to remember and then be asked to recall these.
Subjects may be presented with visual, auditory, olfactory, vomeronasal, or tactile stimuli, and
may be asked to make motor responses with hands, feet, or mouth. For example, the subject may
be asked to watch a computer monitor and press a button whenever a green stimulus appears, but
to do nothing when a red stimulus appears.
Following electrophysiological evaluation, the subject may be asked to participate in an MRI
examination. In this protocol, MRI will be used to acquire anatomical images of the brain.
During the procedure, the subject lies in a long cylinder (the magnet). The MR machine uses
small radio-frequency signals to assess the behavior of water molecules. It produces a picture of
the brain that is used in conjunction with the MEG and HD-EEG to identify exactly what brain
structures are responsible for producing specific brain waves. There are no known health risks
associated with the MRI procedure. The evaluation is performed using a 1.5T magnet. Standard
clinical protocols at the University of Utah involve a 3D-volumetric sagittal acquisition (T1weighted, 1.0 mm contiguous slices), coronal FLAIR images (5mm, skip 2), and T2-weighted
axial images (5mm, skip 2). These data are evaluated by a neuroradiologist for evidence of
structural pathology. Sedation will not be used in this study.
Statistical methods, data analysis & interpretation:
Spontaneous data are evaluated for epileptiform activity and slowing by visual inspection.
Multiple-dipole, spatiotemporal modeling is performed to localize relevant brain regions. Data
are also evaluated in the frequency domain, and coherence measures are calculated. Database
values for normal subjects and patient groups are compared using a multivariate strategy.
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Analyses include the use of neural networks and discriminant functions for identification of
specific pathophysiological conditions. This computer-based strategy provides for a completely
objective evaluation of the data.
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2
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Prevention: National Center for Chronic Disease Prevention and Health Promotion Chronic
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