Andrew C. Papanicolaou - US grants

The P300 or P3, a late positive component of sensory evoked potentials, is said to reflect a variety of cognitive functions and to provide an objective index of information processing in normal and neurologically compromised individuals. An important issue in cognitive neuroscience has been the identification of the brain structures that generate it. However, extensive investigations conducted for that purpose and involving intracranial recordings and mapping of its scalp distribution have been inconclusive. Using magnetoencephalography (MEG) a method akin to traditional electrophysiology, but of greater spatial resolution we have recorded the magnetic equivalent of P3 to auditory stimuli and have localized its sources on the superior surface of the temporal lobe. We also found evidence that deeper sources (possibly thalamic) may contribute to its onset. These results lead to two general hypotheses: (a) That P3s are modality-specific and (b) that activation of modality-specific cortical regions is preceded by early thalamic activity. We propose to test these general hypotheses in a series of twelve experiments where P3s to rare and to unexpectedly missing auditory, visual and somatosensory stimuli will be obtained under two conditions. One will involve attention to stimuli resulting in a long latency P3, which is thought to reflect mostly higher order cognitive operations. The other will involve ignoring the stimuli, resulting in a shorter latency P3 associated with more basic sensory functions. The estimated sources of P3s obtained with the different stimulus modalities and conditions, projected onto individual magnetic resonance images (MRIs) will be used to answer whether P3s are modality-specific, whether they share an early thalamic origin and whether different structures generate P3s to the presence or absence of attended or incidentally registered unexpected environmental events.

The P300 or P3, a late positive component of sensory evoked potentials, is said to reflect a variety of cognitive functions and to provide an objective index of information processing in normal and neurologically compromised individuals. An important issue in cognitive neuroscience has been the identification of the brain structures that generate it. However, extensive investigations conducted for that purpose and involving intracranial recordings and mapping of its scalp distribution have been inconclusive. Using magnetoencephalography (MEG) a method akin to traditional electrophysiology, but of greater spatial resolution we have recorded the magnetic equivalent of P3 to auditory stimuli and have localized its sources on the superior surface of the temporal lobe. We also found evidence that deeper sources (possibly thalamic) may contribute to its onset. These results lead to two general hypotheses: (a) That P3s are modality-specific and (b) that activation of modality-specific cortical regions is preceded by early thalamic activity. We propose to test these general hypotheses in a series of twelve experiments where P3s to rare and to unexpectedly missing auditory, visual and somatosensory stimuli will be obtained under two conditions. One will involve attention to stimuli resulting in a long latency P3, which is thought to reflect mostly higher order cognitive operations. The other will involve ignoring the stimuli, resulting in a shorter latency P3 associated with more basic sensory functions. The estimated sources of P3s obtained with the different stimulus modalities and conditions, projected onto individual magnetic resonance images (MRIs) will be used to answer whether P3s are modality-specific, whether they share an early thalamic origin and whether different structures generate P3s to the presence or absence of attended or incidentally registered unexpected environmental events.

DESCRIPTION (Investigator's abstract): Using magnetoencephalographic recordings we have repeatedly demonstrated that the late positive component of event related potentials (P3) is most likely generated by two clusters of sources. One cluster, common to all types of P3s we have recorded, involves the thalamus and/or the hippocampus. The other cluster is found in the sensory cortex specific to each stimulus modality. There appears to be no difference in the source configuration of P3s to missing and to odd-ball stimuli. This finding, along with the fact that P3s to frequent stimuli-in addition to rare and unpredictable ones- also appear in the MEG records, suggests that P3s may be indicative of mere changes in the subject's psychological state and not necessarily of the nature of the state (i.e., the type of cognitive operations occasioned by the stimulus or the significance of the stimulus). On the other hand, the sources of magnetically recorded Contingent Negative Variation (CNV) do vary according to task demands, ranging over different parts of the frontal lobes depending on the nature of the cognitive operations in which the subjects are preparing to engage. In this project, we aim to record both P3s and CNVs in the context of the same tasks and characterize their sources in an attempt to discover what aspects of the cognitive operations required by these tasks are reflected by each. In this way, in addition to identifying the sources of P3s and CNVs, we expect to advance understanding of the specialization of the frontal lobes and their functional connections with archeocortical structures and the sensory cortex in mediating complex cognitive operations.

This research project uses an interdisciplinary approach to large-scale educational interventions that provides for the integration of research and education around issues involving the cognitive development of beginning reading skills. Three projects are centered around a large suburban school district in Houston, TX. The participants are children who receive two types of classroom instruction (N=384) and their teachers (N=40). Within each type of classroom instruction, children are assigned to one of 4 groups (N=48) as part of a 2 (Classroom Instruction) X 4 (Group) design. The 4 groups include a no-risk group and 3 groups of children at risk for reading problems. Children in these 3 groups receive only classroom instruction or classroom instruction that matches or doesn't match the type of classroom reading instruction. All children will receive longitudinal assessments of growth in reading and reading-related skills, yearly norm-referenced achievement measures, and assessment of behaviour and the home/school environment. The intervention study (project 1) involves: a) identification of children at risk for reading problems in kindergarten; b) providing a controlled study of the efficacy of a first grade educational intervention designed to prevent reading problems in multiple high-risk schools; and c) evaluation of the use of information and computing technologies (ICT) to provide professional development of teachers on the translation of research on reading development into practice. The second project explores neural changes representing reading development using magnetoencephalography (MEG) to evaluate a) functional neural changes that occur as reading develops; and b) changes in the neural representation of reading skills as an indicator of response to intervention. The second study involves 120 children from the overall sample assigned to 3 groups (N=40 each): no risk, at-risk interventions; and at-risk classroom instruction. These children receive MEG evaluations before and after grade 1 and after grade 2. The final project addresses decodability skills and evaluates: a) how lexical and text characteristics of the basal reading programs used in archival intervention studies relate to student outcomes; b) psycholinguistic factors that moderate the impact of decodability; and c) the relationships of reading instruction in project 1 at classroom and intervention levels to the child's ability to read texts with pre-specified lexical and text characteristics. This study uses both archival data and will also collect monthly prospective data involving preconstructed textual material on the entire sample of 384 children.

Functional imaging data we have obtained with the method of whole-head Magnetoencephalography (MEG), also referred to as Magnetic Source Imaging or MSI, indicate that the spatiotemporal profiles of brain activation of individual dyslexic children differ dramatically from those of individual non-dyslexic children during the performance of tasks that entail phonological decoding. The main differences in the profiles center on the degree of activation of the posterior superior temporal and supramarginal gyri, the inferior frontal area, and, most notably, the angular gyrus. Accordingly, our first aim in this project will be to assess the reliability of these preliminary findings with adequate samples of 80 non-dyslexic and 160 dyslexic children. The second aim will be to assess whether, in addition to differences in phonological processing, differences in orthographic and visual form processing, between normal and dyslexic children, contribute to the aberrant activation profile of the latter. The third aim will be to evaluate the hypothesis that the observed reduction of activity of the left temporoparietal area including the angular gyrus, may be attributed to a more general dysfunction of that region that may underlie many of the cognitive deficits associated with dyslexia. In addition to the above aims, we will investigate that possible contribution of attention deficits to the activation profiles and their differences using additional statistical analyses. Finally, taking advantage of the fact that MEG activation profiles are (a) computed for individual subjects, and (b) are characterized by excellent temporal resolution, we will explore the possibility of uncovering subtle differences in the profiles of normal and dyslexic children through the use of fuzzy clustering techniques. Detailed characterization of the spatiotemporal features of individual profiles may become useful in future studies for assessing the effects of intervention strategies on the functional cerebral reorganization of individual dyslexic children.

DESCRIPTION: (Verbatim from the Applicant's Abstract) The purpose of this project is to evaluate the contributions of Magnetoencephalography (MEG) to the surgical management of epilepsy. Specifically, we propose the following: First, to estimate the relative accuracy of MEG, as compared to that of surface and invasive electrophysiology, in identifying epileptogenic zones to be resected in patients with focal epilepsy. Second, to explore the possibility that identification of epileptogenic zones based on MEG data combined with data from other standard non-invasive diagnostic procedures and data from the Wada procedure may, in some cases, be sufficiently accurate to obviate the need for invasive electrophysiology. In addition, we propose to examine whether judgements of differential hemispheric involvement in language and memory derived from MEG data concur with those routinely derived from Wada procedure. Finally, incidental to addressing the above main questions, we will also address the question as to whether MEG influences the planning of invasive electrophysiological procedures and we will explore alternative ways of improving its diagnostic accuracy by considering alternative, not yet standardized modes of MEG data collection and analysis.

This grant supports the acquisition of a multi-channel biomagnetometer system for Magnetic Source Imaging (MSI). This system will be used for non-invasive recording of magnetic signals emitted naturally by the human brain during performance of sensory-motor, cognitive and linguistic tasks, and for constructing functional images of brain activation. These images reflect the spatio-temporal patterns of brain activity mediating the psychological and behavioral functions required by the experimental tasks. During the past three years, we have used MSI to establish (i) the reliability and validity of functional maps of the brain mechanisms underlying cognitive functions, including motor, somatosensory, and receptive language (Breier et al., 1999a,b; Breier et al., 2000, in press; Papanicolaou et al., 1999; Simos, 1998a,b; 1999a,b; 2000a). These maps have proven so accurate that MSI is routinely used in our institution for outlining the borders of language-specific cortex in neurosurgical candidates in order to avoid damage to normally functioning neural mechanisms during resection of brain lesions lying close to these areas of the brain, thus reducing post-operative morbidity. (ii) We have accumulated sufficient data for constructing reliable maps of brain mechanisms associated with reading and phonological decoding in adults (Breier et al., 1998, 1999c, Simos et al., 1998a, 2000a, in press) and in school-age children (Simos et al., 2000b,c, in press) as well as kindergarten children learning to read. (iii) We have identified brain activation maps specific to children with identified reading difficulties and children at-risk for developing reading difficulties. We are following these children as they learn to read through different instructional methods to determine how these maps change with improved reading proficiency (Simos et al., 2000b,c,d).

These discoveries led us to consider a host of experimental questions ranging from the layout of the mechanisms of oral and written language in the brains of bilingual and polyglot children and adults to questions regarding the formation of such mechanisms in the course of brain maturation and development, and to questions relating to specific spatio-temporal activation patterns underlying component cognitive and linguistic functions. We have begun addressing these questions with the support of several NSF and NIH grants (NSF grant #9979968; NIH grants RO1 NS37941 and RO1 HD38346) using a 148-channel biomagnetometer acquired for clinical studies belonging to Hermann Hospital. Not surprisingly, the use of that system for the conduct of basic research involving normal volunteers and children has become problematic. The system we will purchase will be located on the U of Texas- Houston campus, outside Hermann Hospital, and will be exclusively used for basic research involving children and adults.

Our group has advanced MSI technology, especially in areas involving higher cortical functions. We have developed specific applications to education, literally bringing neuroscience into public schools. In order to continue to advance the technology and expand educational and training applications, a MSI laboratory dedicated to research is needed, leading to this grant under the Major Research Instrumentation Program.

DESCRIPTION (provided by applicant): The primary goals of the proposed study are to (a) develop an interdisciplinary network addressing the integration of two different methodologies for functional neuroimaging, magnetic source imaging (MSI) and functional magnetic resonance imaging (fMRI) in order to (b) evaluate a model of the cerebral mechanisms that support skilled reading. These methods differ in their sensitivity to the spatial and temporal components involved when the brain is activated while performing a cognitive task. By combining the strengths of the University of Texas-Houston MSI laboratory and the resources for fMRI at the Haskins Laboratories/Yale University, both of which have published extensively on the neural mechanisms underlying reading, we will integrate these two functional neuroimaging modalities and develop a more comprehensive model of the cerebral mechanisms underlying skilled reading. This model stipulates that printed word recognition is related to the development of a highly organized cortical system that integrates orthographic, phonological and lexical-semantic features of words. This system involves two posterior circuits in the left hemisphere (LH): a dorsal (temporo-parietal) and a ventral (occipito-temporal) circuit, along with a third circuit (inferior frontal gyms). Each circuit has a different role in reading, varying not only spatially, but also temporally. A series of experiments are proposed involving 30 healthy adults who would receive both MSI and fMRI imaging modalities while performing different reading tasks in order to (a) determine precisely which brain areas are functional components of the neural circuits supporting reading; (b) determine how the three putative neural circuits differ from one another in terms of the types of information processing performed by each. We will systematically modulate demands on different component processes in word recognition to reveal differences in the kinds of information each circuit processes; and (c) determine how the three circuits interact with each other in real time to support by integrating three types of data: spatial extent of regional activation, relative timing of the engagement of different brain areas, and functional connectivity. We also propose cross training in the two technologies and the development of an interdisciplinary network composed of investigators at both institutions. Together these efforts will expand the interpretability of imaging data by direct comparison and integration of the techniques and lead to a more elaborated theory of the cerebral mechanisms underlying reading.

ABSTRACT NOT PROVIDED

The process of recovery of basic sensory, motor, and higher cognitive and linguistic functions, following stroke, is not well understood. Also poorly understood are the neurophysiological mechanisms that mediate the effectiveness of therapies, like the Constraint-Induced Therapy (CIT), which are reputed to enhance the recovery process. It has been suggested, however, that, fundamentally, recovery is a result of functional reorganization of the brain. Before the advent of functional neuroimaging, evidence supporting this notion consisted entirely of indirect inferences from clinical or behavioral data. Recently, however, we and others, using Magnetoencephalography (MEG) and other functional neuroimaging methods, have begun accumulating direct evidence of brain plasticity and functional reorganization. In this Program Project we plan to investigate systematically the extent and type of reorganization, using MEG-derived brain activation profiles, during spontaneous recovery from stroke, of the following behavioral and cognitive functions: First, expressive and receptive language; second, motor; and third, somatosensory and spatial attention functions. We also plan to study the effects of CIT used to enhance the recovery process of language and sensorimotor functions, on these activation profiles. We expect that the extent and type of reorganization observed will vary as a function of lesion parameters, assessed through structural MRI, and neuropsychological testing. Finally, we will attempt to specify the repercussions of reorganization of the mechanisms of the compromised functions for the mechanisms of functions unaffected by the stroke using, once again, MEG mapping.

The objective of this proposal is to utilize magnetic source imaging (MSI) to evaluate the organization of brain functions in children with spina bifida (SB). Children with SB sustain a congenital insult to the brain that begins in the first trimester and results in hydrocephalus that is usually treated at birth. It is well-established that many children with SB have unusual profiles of cognitive ability, with strengths in word reading, math facts, and object-based visual perception in the face of difficulties with reading comprehension, math procedures, and many aspects of action-based visual perception, attention, and motor function. What is unclear is how the SB brain mediates these functions and the extent to which variations within the SB group reflect differences in cerebral reorganization. In this proposal, we propose systematic explorations of functional organization of key motor, somatosensory, language, and cognitive skills that characterize the modal profile associated with SB in a sample of 136 children with SB, 20 with aqueductal stenosis (AS), and 60 controls. Four specific aims are proposed, each representing a separate experiment. Aim 1 (Motor, somatosensory, and language mapping) attempts to identify the brain activation profiles indicative of the neuronal mechanisms that mediate basic somatosensory and motor functions of the upper extremities as well as receptive language function among 136 SB children and 60 controls. Aim 2 (Reading and arithmetic) addresses the representation of reading and math skills in 60 children with SB who vary in these skills. Aim 3 (Visual attention) addresses the role of the parietal lobe in mediating visual attention skills using a line bisection task in 40 children with SB divided according to whether they show or do not show a leftward bias on a horizontal line bisection task in Project 3, and 20 controls. Aim 4 (Rhythm discrimination) uses a rhythm perception task to assess cerebellar function in 20 children with SB characterized by early hydrocephalus and a congenital cerebellar malformation, 20 with AS characterized by early hydrocephalus, but no cerebellar malformation, and 20 controls. The results should help establish how the congenitally malformed brain reorganizes function as well as help establish the basis for the neurological mechanisms by which these functions are mediated in children with SB.

The objective of this proposal is to address the question of how changes in cortical activity that follow ischemic insult are related to functional improvement of somatosensory and attentional processes. In order to meet this objective, we will specify the parameters of cerebral reorganization underlying recovery of somatosensory and attentional functions in patients with unilateral ischemic stroke using magnetoencephalography (MEG). We will then determine the correspondence between MEG parameters of reorganization and relevant behavioral measures of recovery of function. In addition, we will outline the relation between stroke lesion variables (volume and location) and MEG-based indices of reorganization, as well as between lesion variables and behavioral measures of functional recovery. An understanding of cortical mechanisms of recovery and reorganization will help determine prognosis and optimal treatment for individuals recovering from somatosensory and attentional deficits following cortical infarction. The study design includes a baseline behavioral and neuropsychological assessment followed by MEG and MRI imaging at 2-3 months and 10-12 months post-stroke. We will obtain spatiotemporal MEG maps of brain activity associated with stimulation of the fingertips of both hands in patients with current or prior hemianesthesia at these two time intervals. A subset of these patients will have undergone constraint-induced therapy (CIT) and will be compared with control participants who have been treated with standard care therapy. We will also obtain spatiotemporal maps of cortical activity associated with selective attention to visual stimuli in patients recovering or recovered from unilateral neglect (with or without hemianesthesia) over the same time interval. Changes in MEG parameters (anatomical location, magnitude, and time course of the event-related magnetic response) will establish the nature and extent of reorganization in relation to behavioral and cognitive recovery. The relations between these parameters and detailed volumetric analyses of structural MRIs obtained at the same time periods will reveal associations between stroke type and cortical reorganization related to recovery.

The objective of this proposal is to address the question of how changes in cortical activity that follow ischemic insult are related to functional improvement of somatosensory and attentional processes. In order to meet this objective, we will specify the parameters of cerebral reorganization underlying recovery of somatosensory and attentional functions in patients with unilateral ischemic stroke using magnetoencephalography (MEG). We will then determine the correspondence between MEG parameters of reorganization and relevant behavioral measures of recovery of function. In addition, we will outline the relation between stroke lesion variables (volume and location) and MEG-based indices of reorganization, as well as between lesion variables and behavioral measures of functional recovery. An understanding of cortical mechanisms of recovery and reorganization will help determine prognosis and optimal treatment for individuals recovering from somatosensory and attentional deficits following cortical infarction. The study design includes a baseline behavioral and neuropsychological assessment followed by MEG and MRI imaging at 2-3 months and 10-12 months post-stroke. We will obtain spatiotemporal MEG maps of brain activity associated with stimulation of the fingertips of both hands in patients with current or prior hemianesthesia at these two time intervals. A subset of these patients will have undergone constraint-induced therapy (CIT) and will be compared with control participants who have been treated with standard care therapy. We will also obtain spatiotemporal maps of cortical activity associated with selective attention to visual stimuli in patients recovering or recovered from unilateral neglect (with or without hemianesthesia) over the same time interval. Changes in MEG parameters (anatomical location, magnitude, and time course of the event-related magnetic response) will establish the nature and extent of reorganization in relation to behavioral and cognitive recovery. The relations between these parameters and detailed volumetric analyses of structural MRIs obtained at the same time periods will reveal associations between stroke type and cortical reorganization related to recovery.

0-11 years old; 21+ years old; AD/HD; ADHD; Address; Adult; Affect; Attention deficit hyperactivity disorder; Attention-Deficit Disorder, Predominantly Hyperactive-Impulsive Type; Auditory; Bilateral; Brain; Brain imaging; Characteristics; Child; Child Youth; Children (0-21); Children with Disabilities; Classification; Comorbidity; Compensation; Comprehension; Condition; Data; Disabled Children; Disease; Disorder; Dyslexia; Early Intervention; Early Intervention (Education); Encephalon; Encephalons; Evaluation; Family; Financial compensation; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Grant; Handicapped Children; Human, Adult; Human, Child; Hyperactivity Disorder NOS; Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Hyperkinetic Syndrome; Image; Imaging Procedures; Imaging Techniques; Individual; Instruction; Intervention; Intervention Strategies; Invasive; Investigation; Lateral; Learning Disabilities; Learning disability; Left; Link; MRI, Functional; Magnetic Resonance Imaging, Functional; Magnetism; Magnetoencephalography; Maps; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Methods; Middle Temporal Gyrus; Modeling; NICHD; National Institute of Child Health and Human Development; Nature; Nervous; Nervous System, Brain; Numbers; Physiologic Imaging; Prefrontal Cortex; Procedures; Process; Purpose; Range; Reader; Reading; Reading Disabilities; Reading Disorder; Reading disability; Recruitment Activity; Relative; Relative (related person); Research; Risk; Scanning; Science of neurophysiology; Sensory Process; Series; Short-Term Memory; Source; Specific qualifier value; Specified; Staging; Stimulus; Structure of middle temporal gyrus; Structure of supramarginal gyrus; Students; Supramarginal Gyrus; Systematics; TXT; Technics, Imaging; Temporal Lobe; Testing; Texas; Text; Variant; Variation; Word Blindness; adult human (21+); attention deficit hyperactive disorder; base; brain visualization; children; computerized; disability; disease/disorder; fMRI; frontal cortex; frontal lobe; hemodynamics; imaging; interventional strategy; magnetic; neural; neurophysiology; phonological; phonology; recruit; relating to nervous system; remediation; response; spatiotemporal; stimulus processing; temporal cortex; temporal lobe/cortex; working memory; youngster

Project 4: Brain Activation Profiles of Reading Disabilities in Children: A Magnetic Source Imaging Study. Project 4 (MSI) proposes the use of magnetoencephalography, also known as magnetic source imaging (MSI), to evaluate the neural correlates of reading and reading intervention in children at risk for or with identified disabilities involving reading. This objective will be completed in relation to specific features of the brain activation profiles associated with different subtypes of poor readers based on the Reading Components model in Project 1 (Classification) and with adequate and inadequate response to different interventions in Projects 2 (Early Intervention) and 3 (Remediation). In a series of functional imaging studies using MSI, we have shown that (a) there exists a profile of brain activation recognizable at the single subject level, specific to a number of reading tasks;(b) children with dyslexia (defined as a word level reading disorder) produce a distinctly different activation profile when engaged in these same tasks, also recognizable at the single subject level;(c) that the profile is specific to dyslexia and not to the usual comorbidities (e.g. attention deficit hyperactivity disorder) and associated disorders (e.g., math difficulties); and (d) that the profile changes as a result of successful reading interventions. To build upon this research, we propose three specific aims in an evaluation of 356 children obtained and characterized in Projects 1-3: (1) Identify differences in the aberrant profiles specific to different components of reading and to subtypes of reading disabled children. Specifically, we will examine how activation profiles associated with various reading tasks that make different demands on individual component processes may vary for different reading disability subtypes;(2) Establish task-specific features of brain activation profiles associated with response to Tier II instructional remediation, and discern small profile differences contingent on the precise nature and decoding demands of several reading tasks;and (3) Examine task-specific changes of brain activation profiles associated with adequate response to intensive Tier III instruction in children who initially failed to benefit from Tier II intervention in order to assess the degree of normalization vs. compensation in the aberrant profiles of younger and older students after further, more intense intervention. To accomplish these three aims we will make use of recently developed and validated objective and computerized methods for constructing functional brain images on the basis of non-invasive MSI recordings that facilitate disengagement of minute profile differences on averaged and individual subject data. We will also use a range of tasks assessing different components of reading. Altogether, we propose a systematic investigation of different brain profiles that vary with classifications of reading disabilities and in relation to intervention that is closely linked with the other projects in this Center application.