Magnetic Source Imaging and High Density ...



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 Health[i] 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 year[ii],[iii]. 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)[iv]. 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 disease[v],[vi],[vii]. 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 tumors[viii],[ix]

• Epilepsy4,[x],[xi]

• Head trauma[xii],[xiii]

• Stroke[xiv]

• Alzheimer’s dementia[xv]-[xvi][xvii]

• Psychiatric conditions, including schizophrenia, depression, and PTSD[xviii]-[xix][xx]

• Learning disorders, including dyslexia and ADHD[xxi]-[xxii][xxiii]

• Autism and pervasive development disorder[xxiv].

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) To develop a normative database with parameters for spontaneous brain activity including spectral characteristics and regional and global coherence measures.

2) To develop a normative database with source parameters for visual, auditory, olfactory, tactile, motor, and cognitive function.

3) 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.

4) 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.

5) 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 recruited from an already established local and national medical referral network to the principal investigator’s brain imaging program. Patients 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:

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, human[xxv],[xxvi] and monkey[xxvii]-[xxviii][xxix] 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 areas[xxx],[xxxi]. 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 veracity[xxxii]. 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 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 (T1-weighted, 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. 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.

References:

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[i] National Institute of Mental Health. The Numbers Count: Mental Disorders in America. NIMH Publication No. 01-4584. Bethesda, MD: National Institute of Mental Health, 1/2001. .

[ii] United States Department of Health and Human Services: Centers for Disease Control and Prevention: National Center for Chronic Disease Prevention and Health Promotion Chronic Disease Prevention. Fact sheet on epilepsy, 12/2001. .

[iii] American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association, 2001.

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[ix] Roberts TP, Ferrari P, Perry D, Rowley HA, Berger MS (2000) Presurgical mapping with magnetic source imaging: comparisons with intraoperative findings. Brain Tumor Pathol 17(2): 57-64.

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[xxxii] Fitzgerald PB, Brown TL, Daskalakis ZJ, Kulkarni J (2002) A transcranial magnetic stimulation study of inhibitory deficits in the motor cortex in patients with schizophrenia. Psychiatry Res 114(1): 11-22.

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