Michael Funke

Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders

Background. One-third of children diagnosed with autism spectrum disorders (ASDs) are reported to have had normal early development followed by an autistic regression between the ages of 2 and 3 years. This clinical profile partly parallels that seen in Landau-Kleffner syndrome (LKS), an acquired language disorder (aphasia) believed to be caused by epileptiform activity. Given the additional observation that one-third of autistic children experience one or more seizures by adolescence, epileptiform activity may play a causal role in some cases of autism. Objective. To compare and contrast patterns of epileptiform activity in children with autistic regressions versus classic LKS to determine if there is neurobiological overlap between these conditions. It was hypothesized that many children with regressive ASDs would show epileptiform activity in a multifocal pattern that includes the same brain regions implicated in LKS. Design. Magnetoencephalography (MEG), a noninvasive method for identifying zones of abnormal brain electrophysiology, was used to evaluate patterns of epileptiform activity during stage III sleep in 6 children with classic LKS and 50 children with regressive ASDs with onset between 20 and 36 months of age (16 with autism and 34 with pervasive developmental disorder–not otherwise specified). Whereas 5 of the 6 children with LKS had been previously diagnosed with complex-partial seizures, a clinical seizure disorder had been diagnosed for only 15 of the 50 ASD children. However, all the children in this study had been reported to occasionally demonstrate unusual behaviors (eg, rapid blinking, holding of the hands to the ears, unprovoked crying episodes, and/or brief staring spells) which, if exhibited by a normal child, might be interpreted as indicative of a subclinical epileptiform condition. MEG data were compared with simultaneously recorded electroencephalography (EEG) data, and with data from previous 1-hour and/or 24-hour clinical EEG, when available. Multiple-dipole, spatiotemporal modeling was used to identify sites of origin and propagation for epileptiform transients. Results. The MEG of all children with LKS showed primary or secondary epileptiform involvement of the left intra/perisylvian region, with all but 1 child showing additional involvement of the right sylvian region. In all cases of LKS, independent epileptiform activity beyond the sylvian region was absent, although propagation of activity to frontal or parietal regions was seen occasionally. MEG identified epileptiform activity in 41 of the 50 (82%) children with ASDs. In contrast, simultaneous EEG revealed epileptiform activity in only 68%. When epileptiform activity was present in the ASDs, the same intra/perisylvian regions seen to be epileptiform in LKS were active in 85% of the cases. Whereas primary activity outside of the sylvian regions was not seen for any of the children with LKS, 75% of the ASD children with epileptiform activity demonstrated additional nonsylvian zones of independent epileptiform activity. Despite the multifocal nature of the epileptiform activity in the ASDs, neurosurgical intervention aimed at control has lead to a reduction of autistic features and improvement in language skills in 12 of 18 cases. Conclusions. This study demonstrates that there is a subset of children with ASDs who demonstrate clinically relevant epileptiform activity during slow-wave sleep, and that this activity may be present even in the absence of a clinical seizure disorder. MEG showed significantly greater sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, and 24-hour clinical EEG. The multifocal epileptiform pattern identified by MEG in the ASDs typically includes the same perisylvian brain regions identified as abnormal in LKS. When epileptiform activity is present in the ASDs, therapeutic strategies (antiepileptic drugs, steroids, and even neurosurgery) aimed at its control can lead to a significant improvement in language and autistic features. autism, pervasive developmental disorder–not otherwise specified, epilepsy, magnetoencephalography, Landau-Kleffner syndrome.

Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI.

ObjectiveTo determine to what extent magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG) can provide objective evidence of brain injury in adult patients with persistent (>1 year) postconcussive symptoms following mild blunt head trauma. DesignA retrospective and blind review of imaging data with respect to the presence of specific somatic, psychiatric, and cognitive complaints. Setting/ParticipantsThirty complete data sets (with MRI, SPECT, MEG, and neuropsychological testing results) were collected between 1994 and 2000 from the MEG programs at the Albuquerque VAMC and the University of Utah. Main Outcome MeasuresMRI data were evaluated for focal and diffuse structural abnormalities, SPECT data for regions of hypoperfusion, and resting MEG data for abnormal dipolar slow wave activity (DSWA) and epileptiform transients. ResultsStructural MRI was abnormal for 4 patients. SPECT showed regions of hypoperfusion in 12 patients, while MEG showed abnormal activity in 19 patients. None of the imaging methods produced findings statistically associated with postconcussive psychiatric symptoms. A significant association was found between basal ganglia hypoperfusion and postconcussive headaches. For patients with cognitive complaints, abnormalities were more likely to be detected by MEG (86%) than either SPECT (40%) or MRI (18%) (P < .01). MEG also revealed significant (P < .01) associations between temporal lobe DSWA and memory problems, parietal DSWA and attention problems, and frontal DSWA and problems in executive function. ConclusionsFunctional brain imaging data collected in a resting state can provide objective evidence of brain injury in mild blunt head trauma patients with persistent postconcussive somatic and/or cognitive symptoms. MEG proved to be particularly informative for patients with cognitive symptoms.

American Clinical Magnetoencephalography Society Clinical Practice Guideline 2: Presurgical Functional Brain Mapping Using Magnetic Evoked Fields

The following are “minimum standards” for the routine clinical recording of magnetic evoked fields (MEFs) in all age-groups. Practicing at minimum standards should not be the goal of a magnetoencephalography (MEG) center but rather a starting level for continued improvement. Minimum standards meet only the most basic responsibilities to the patient and the referring physician. These minimum standards have been put forth to improve standardization of procedures, to facilitate interchange of recordings and reports among laboratories in the United States, and to confirm the expectations of referring physicians. Recommendations regarding Laboratory (Center) Environment and Preparation for MEG Recordings are detailed in the American Clinical Magnetoencephalography Society Clinical Practice Guideline (CPG) 1 : Recording and Analysis of Spontaneous Cerebral Activity, except for its EEG aspect that is not considered necessary (although may be helpful in trained hands) for MEFs (presurgical functional brain mapping).

Recording epileptic activity with MEG in a light-weight magnetic shield

Ten patients with focal epilepsy were studied with magnetoencephalography (MEG) to determine if a new light-weight magnetically shielded room (lMSR) provides sufficient attenuation of magnetic interference to detect and localize the magnetic correlates of epileptic activity. Interictal MEG epileptic events co-localizing with the presumed location of the epileptogenic zone were found in all patients. MEG measurements performed in the lMSR provide an adequate signal-to-noise ratio for non-invasive localization of epileptic foci.

Magnetoencephalography as a putative biomarker for Alzheimer's disease

Alzheimers Disease (AD) is the most common dementia in the elderly and is estimated to affect tens of millions of people worldwide. AD is believed to have a prodromal stage lasting ten or more years. While amyloid deposits, tau filaments, and loss of brain cells are characteristics of the disease, the loss of dendritic spines and of synapses predate such changes. Popular preclinical detection strategies mainly involve cerebrospinal fluid biomarkers, magnetic resonance imaging, metabolic PET scans, and amyloid imaging. One strategy missing from this list involves neurophysiological measures, which might be more sensitive to detect alterations in brain function. The Magnetoencephalography International Consortium of Alzheimers Disease arose out of the need to advance the use of Magnetoencephalography (MEG), as a tool in AD and pre-AD research. This paper presents a framework for using MEG in dementia research, and for short-term research priorities.

Acquired auditory-visual synesthesia: A window to early cross-modal sensory interactions

Synesthesia is experienced when sensory stimulation of one sensory modality elicits an involuntary sensation in another sensory modality. Auditory-visual synesthesia occurs when auditory stimuli elicit visual sensations. It has developmental, induced and acquired varieties. The acquired variety has been reported in association with deafferentation of the visual system as well as temporal lobe pathology with intact visual pathways. The induced variety has been reported in experimental and post-surgical blindfolding, as well as intake of hallucinogenic or psychedelics. Although in humans there is no known anatomical pathway connecting auditory areas to primary and/or early visual association areas, there is imaging and neurophysiologic evidence to the presence of early cross modal interactions between the auditory and visual sensory pathways. Synesthesia may be a window of opportunity to study these cross modal interactions. Here we review the existing literature in the acquired and induced auditory-visual synesthesias and discuss the possible neural mechanisms.

American Clinical MEG Society (ACMEGS) position statement: the value of magnetoencephalography (MEG)/magnetic source imaging (MSI) in noninvasive presurgical evaluation of patients with medically intractable localization-related epilepsy.

The American Clinical Magnetoencephalography Society (ACMEGS) is a professional society of physicians and other professionals with doctoral degrees “involved in clinical use of magnetoencephalography (MEG), electroencephalography (EEG), magnetic resonance imaging, or computerized axial tomography” (ACMEGS, Inc, Bylaws, 2006). The ACMEGS is primarily focused on advancing clinical applications of MEG, while representing all American MEG centers and individual professionals concerned with clinical MEG. Currently, our membership is composed of more than 50 individuals and/or collective members, including the most prominent investigators who have made cardinal contributions to the development of the clinical MEG. A significant proportion of 4,000 , peer-reviewed, MEDLINE publications on “MEG” has been authored by members of the American MEG community, including the most sophisticated clinical MEG studies designed and published internationally (Knowlton et al., 2008a,b; Sutherling et al., 2008). MEG/magnetic source imaging (MSI) is a modern and powerful technology for studying brain function directly and noninvasively by analyzing magnetic fields induced by synchronized neuronal activity that are recorded outside of the skull (Cohen, 1968, 1972; reviewed in Hamalainen et al., 1993; Okada et al., 1984, 1999; Williamson et al., 1991). Routinely, MEG can attain a temporal resolution of less than a millisecond and, under optimal circumstances, spatial resolution of several millimeters (Brenner et al., 1975; Hamalainen et al., 1993; Hari et al., 1988; Okada et al., 1984, 1999; Romani et al., 1982). During the last 40 years, MEG instruments have evolved from a single-channel portable system to the modern whole head systems with more than 300 channels that are housed in multilayered shielded rooms (reviewed in Barkley and Baumgartner, 2003; reviewed in Hamalainen et al., 1993). It is now accepted that MEG/MSI can provide clinicians with accurate and critical information regarding the location of important cerebral sources, such as epileptic foci (Baumgartner, 2000; Ebersole, 1997; Fischer et al., 2005; Iwasaki et al., 2002; Kirsch et al., 2007a; Knake et al., 2006; Knowlton, 2006, 2008; Knowlton et al., 2006; Knowlton et al., 2008a,b; Lin et al., 2003; Mamelak et al., 2002; Mohamed et al., 2007; Oishi et al., 2006; Papanicolaou et al., 2005; Pataraia et al., 2004; RamachandranNair et al., 2007; Rodin et al., 2004; Smith et al., 2000; Stefan et al., 2003; Sutherling et al., 2008; Verrotti et al., 2003), sensory-motor cortex (Alberstone et al., 2000; Brenner et al., 1975; Castillo et al., 2004; Ganslandt et al., 2004; Kirsch et al., 2007b; Korvenoja et al., 2006; Nakasato and Yoshimoto, 2000; Oishi et al., 2003; Okada et al., 1984; Pang et al., 2008), visual (Alberstone et al., 2000; Brenner et al., 1975; Ganslandt et al., 2004; Grover et al., 2006; Nakasato and Yoshimoto, 2000; Nakasato et al., 1996), auditory (Alberstone et al., 2000; Godey et al., 2001; Nakasato and Yoshimoto, 2000; Romani et al., 1982), and language cortex (Bowyer et al., 2004, 2005; Flagg et al., 2005; Ganslandt et al., 2004; Grummich et al., 2006; Hirata et al., 2004; Kamada et al., 2003; Lee et al., 2006; Merrifield et al., 2007; Papanicolaou et al., 2004, 2006; Salmelin, 2007) MEG/MSI findings may be displayed on a patient’s magnetic resonance imaging or combined with other imaging modalities to form multimodal neuronavigational maps that can be used directly in stereotactic neuronavigation systems during surgery (Duffner et al., 2003; Firsching et al., 2002; Ganslandt et al., 1999; Kamada et al., 2003, 2007; Nimsky et al., 1999; Ochi and Otsubo, 2008; Rezai et al., 1995, 1996, 1997). Nearly 3 million Americans are afflicted with epilepsy (Hauser and Hesdorffer, 1990). Approximately 30% suffer from seizures that are refractory to medications despite the 20 antiepileptic drugs that are currently available (Brodie, 2005; Kwan and Brodie, 2000). These patients are responsible for 80% of the

Magnetoencephalographic spikes not detected by conventional electroencephalography

12.5 billon annual cost of epilepsy to society (Begley et al., 2000). A significant minority of these patients with epilepsy have localization-related or focal epilepsy that may be amenable to surgical therapy (Engel, 2003, 2008). Thus, competent estimates indicate that 100,000 to 200,000 patients with uncontrolled epilepsy may be surgical candidates (Engel, 2003; Engel and Shewmon, 1993). Epilepsy surgery has been proven to be superior to medical treatment in patients with temporal lobe epilepsy in a randomized controlled trial (Engel, 2008; Engel et al., 2003; Wiebe et al., 2001), and a recent analysis revealed that “the combination of surgery with medical treatment is four times as likely as medical treatment alone to achieve freedom from seizures” (Schmidt and Stavem, In press). Furthermore, long-term follow-up studies showed that many patients who underwent resective brain surgery remain seizure free (Spencer and Huh, 2008; Tellez-Zenteno et al., 2005, 2007, 2008) and that “in carefully selected patients, epilepsy surgery can control seizures, improve quality of life, and reduce costs of medical care” (Kuzniecky and Devinsky, 2007). However, for multiple reasons, epilepsy surgery, the only potential cure for epilepsy (Engel, 2003, 2008; Spencer and Huh, 2008; Wiebe et al., 2001), is offered to only 2% to 3% of potential surgical candidates (Engel, 2003). The critical and often rate-limiting factor in epilepsy surgery is functional localization of the epileptic focus that may not be adequately supplied by traditional diagnostic investigations, including EEG, video-EEG monitoring, magnetic resonance imaging, and in some cases positron emission tomography (PET) and singlephoton emission computed tomography (SPECT) scans (Barkley From the *Center for Advanced Brain Magnetic Source Imaging (CABMSI), Departments of Neurology & Neurosurgery, The University of Pittsburgh, Pittsburgh, PA; †Magnetic Source Imaging, Department of Neurology, Clinical Neurosciences Center, The University of Utah, Salt Lake City, UT; and the Department of Neurology, The University of Chicago, Chicago, IL. ISSN: 0736-0258/09/2604-0001

The role of magnetoencephalography in “nonlesional” epilepsy

OBJECTIVE To investigate some of the reasons why magnetoencephalographic (MEG) spikes are at times not apparent in conventional electroencephalograms (EEG) when the data are co-registered, and to explore to what extent modern EEG analysis methods can improve the yield. METHODS Seventy seconds of MEG-EEG co-registration on a 122 channel Neuromag system were studied in a 10-year-old boy with Landau-Kleffner syndrome. Twenty-six EEG channels were originally recorded with a left ear reference. The EEG data were subsequently reformatted (BESA) to a variety of montages for the 10-20 and 10-10 electrode array. A 10 s data epoch was compared in detail for concordance between MEG and EEG spikes. To detect the characteristics of hidden low voltage EEG spikes, MEG spikes were averaged and compared with the concomitant averaged EEG spike. RESULTS While there was an abundance of EEG as well as MEG spikes on the left; definite right-sided spikes were not visible in the EEG. Right hemispheric MEG spikes were, however, plentiful with an average strength of 757 fT. When the individual MEG spikes from the right hemisphere were compared with the corresponding EEG events their amplitude ranged between 24 and 31 microV and were, therefore, indistinguishable from background activity. The majority of them became visible, however, with further sophisticated data analysis. CONCLUSIONS When the relative merits of MEG versus EEG recordings for the detection of epileptogenic spike are investigated the 10-20 system of electrode placement and conventional methods of EEG analysis do not provide optimal data assessment. The use of the 10-10 electrode array combined with modern methods of digital data analysis can provide better concordance with MEG data.

Der Einfluß der Randelementediskretisierung auf die Vorwärtsrechnung und das inverse Problem in Elektroencephalographie und Magnetoencephalographie - The Influence of Boundary Element Discretization on the Forward and Inverse Problem in Electroencephalography and Magnetoencephalography

The surgical management of neocortical epilepsy is challenging because many patients are without obvious structural lesions, or lesions are small and easily overlooked during routine clinical interpretation of magnetic resonance imaging (MRI) data. Even when functional imaging data suggest focal epileptiform pathology, in the absence of a concordant structural lesion, invasive monitoring is often required to confirm that an appropriate surgical target has been identified. This study sought to determine the extent to which knowledge of magnetoencephalography (MEG) data can augment the MRI‐based detection of structural brain lesions. MRI and whole‐head MEG data were obtained from 40 patients with neocortical epilepsy. As a result of MEG data, 29 cases were sent for MRI reevaluation. In seven of these cases, MEG‐guided review led to specification of now clear, but previously unidentified, lesions. There were two additional cases for which follow‐up high‐resolution imaging did not confirm structural abnormalities. In patients with neocortical epilepsy, MEG is a useful adjunct to MRI for the identification of structural lesions.