ACR White Paper on Magnetoencephalography and Magnetic Source Imaging: A Report from the ACR Commission on Neuroradiology.

Magnetoencephalography, the extracranial detection of tiny magnetic fields emanating from intracranial electrical activity of neurons, and its source modeling relation, magnetic source imaging, represent a powerful functional neuroimaging technique, able to detect and localize both spontaneous and evoked activity of the brain in health and disease. Recent years have seen an increased utilization of this technique for both clinical practice and research, in the United States and worldwide. This report summarizes current thinking, presents recommendations for clinical implementation, and offers an outlook for emerging new clinical indications.

Neural dynamics of semantic categorization in semantic variant of primary progressive aphasia.

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex.

BACKGROUND: The unambiguous identification of the epileptogenic tubers in individuals with tuberous sclerosis complex (TSC) can be challenging. We assessed whether magnetic source imaging (MSI) and coregistration of (18)fluorodeoxyglucose PET (FDG-PET) with MRI could improve the identification of the epileptogenic regions noninvasively in children with TSC. METHODS: In addition to standard presurgical evaluation, 28 children with intractable epilepsy from TSC referred from 2000 to 2007 had MSI and FDG-PET/MRI coregistration without extraoperative intracranial EEG. RESULTS: Based on the concordance of test results, 18 patients with TSC (64%) underwent surgical resection, with the final resection zone confirmed by intraoperative electrocorticography. Twelve patients are seizure free postoperatively (67%), with an average follow-up of 4.1 years. Younger age at surgery and shorter seizure duration were associated with postoperative seizure freedom. Conversely, older age and longer seizure duration were linked with continued seizures postoperatively or prevented surgery because of nonlateralizing or bilateral independent epileptogenic zones. Complete removal of presurgery MSI dipole clusters correlated with postoperative seizure freedom. CONCLUSIONS: Magnetic source imaging and (18)fluorodeoxyglucose PET/MRI coregistration noninvasively localized the epileptogenic zones in many children with intractable epilepsy from tuberous sclerosis complex (TSC), with 67% seizure free postoperatively. Seizure freedom after surgery correlated with younger age and shorter seizure duration. These findings support the concept that early epilepsy surgery is associated with seizure freedom in children with TSC and intractable epilepsy.

Performance of prewhitening beamforming in MEG dual experimental conditions.

This paper presents an analysis on the performance of the prewhitening beamformer when applied to magnetoencephalography (MEG) experiments involving dual (task and control) conditions. We first analyze the method's robustness to two types of violations of the prerequisites for the prewhitening method that may arise in real-life two-condition experiments. In one type of violation, some sources exist only in the control condition but not in the task condition. In the other type of violation, some signal sources exist both in the control and the task conditions, and that they change intensity between the two conditions. Our analysis shows that the prewhitening method is very robust to these nonideal conditions. In this paper, we also present a theoretical analysis showing that the prewhitening method is considerably insensitive to overestimation of the signal-subspace dimensionality. Therefore, the prewhitening beamformer does not require accurate estimation of the signal subspace dimension. Results of our theoretical analyses are validated in numerical experiments and in experiments using a real MEG data set obtained during self-paced hand movements.

High gamma power is phase-locked to theta oscillations in human neocortex.

We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at higher theta amplitudes. Furthermore, different behavioral tasks evoke distinct patterns of theta/high gamma coupling across the cortex. The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.

NUTMEG: a neuromagnetic source reconstruction toolbox.

We have developed an analysis toolbox called NUTMEG (Neurodynamic Utility Toolbox for Magnetoencephalography) for reconstructing the spatiotemporal dynamics of neural activations and overlaying them onto structural MR images. The toolbox runs under MATLAB in conjunction with SPM2 and can be used with the Linux/UNIX, Mac OS X, and even Windows platforms. Currently, evoked magnetic field data from 4-D Neuroimaging, CTF, and KIT systems can be imported to the toolbox for analysis. NUTMEG uses an eigenspace vector beamforming algorithm to generate a tomographic reconstruction of spatiotemporal magnetic source activity over selected time intervals and spatial regions. The MEG coordinate frame is coregistered with an anatomical MR image using fiducial locations and, optionally, head shape information. This allows the reconstruction to be superimposed onto an MRI to provide a convenient visual correspondence to neuroanatomy. Navigating through the MR volume automatically updates the displayed time series of activation for the selected voxel. Animations can also be generated to view the evolution of neural activity over time. Since NUTMEG displays activations using SPM2's engine, certain SPM functions such as brain rendering and spatial normalization may be applied as well. Finally, as a MATLAB package, the end user can easily add customized functions. Source code is available at http://bil.ucsf.edu/ and distributed under a BSD-style license.

Localization of interictal spikes using SAM(g2) and dipole fit.

SAM(g2) is an automated analysis that transforms the MEG data into a functional image of spike-like activity, giving the source waveforms for those locations. Since the source waveforms estimated by SAM have higher signal-to-noise ratio (SNR) than does the raw MEG data, it is possible to automatically mark the location and timing of each spike for comparisons with dipole fit procedures. Both SAM(g2) and equivalent current dipole (ECD) fits were used to analyze MEG interictal spike recordings in 10 patients with cortical dysplasias and medial temporal lobe epilepsy. The ECD fit locations obtained by manual spike classification and latency marking were compared with those found by automated SAM(g2) procedures. When the SNR of interictal activity was high (compared to the background) with a clear single focus, there was excellent agreement between the ECD cluster location and the SAM(g2) maximum. However, when the SNR of spikes was low, manual single ECD location scatter was larger than SAM(g2) reconstructions. When multiple independent interictal spike loci were present, there was some disagreement between SAM(g2) and ECD scatter in the cases of low SNR spikes. When SAM(g2) indicated multiple coupled spike loci, the residual variance for the dipole fit was high and its scatter unacceptably large--even for multiple dipole models. This study demonstrates that SAM(g2) is equivalent to ECD fit for localizing interictal spikes when there is a single locus and good SNR. Further studies are required to validate cases in which there are multiple spike loci or poor SNR.

Somatosensory representation of the digits and clinical performance in patients with focal hand dystonia.

OBJECTIVE: The purpose of this study was to incorporate magnetoencephalography and clinical testing to describe differences in somatosensory organization and sensorimotor function of the hand in patients with focal hand dystonia, a target-specific disorder of voluntary movement that interferes with fine motor control during the performance of rapid, repetitive, skilled movements. DESIGN: This descriptive study included prospective, quasi-experimental comparisons between groups. RESULTS: Patients with focal hand dystonia demonstrated deficits in physical variables, sensory processing, and motor control when compared with age- and sex-matched controls. They also had altered patterns of firing (amplitude and latency integrated over time) and abnormal somatosensory representations on magnetoencephalography. CONCLUSIONS: These study findings suggest that there are alterations in both somatosensory representation of the digits and clinical performance in patients with focal hand dystonia. Future studies to determine if alterations in the sensorimotor feedback loop contribute to the development of focal hand dystonia are indicated. If so, intervention strategies may need to include specific types of somatosensory retraining as part of the rehabilitation program for patients with focal hand dystonia.

Reconstructing spatio-temporal activities of neural sources using an MEG vector beamformer technique.

We have developed a method suitable for reconstructing spatio-temporal activities of neural sources by using magnetoencephalogram (MEG) data. The method extends the adaptive beamformer technique originally proposed by Borgiotti and Kaplan to incorporate the vector beamformer formulation in which a set of three weight vectors are used to detect the source activity in three orthogonal directions. The weight vectors of the vector-extended version of the Borgiotti-Kaplan beamformer are then projected onto the signal subspace of the measurement covariance matrix to obtain the final form of the proposed beamformer's weight vectors. Our numerical experiments show that both spatial resolution and output signal-to-noise ratio of the proposed beamformer are significantly higher than those of the minimum-variance-based vector beamformer used in previous investigations. We also applied the proposed beamformer to two sets of auditory-evoked MEG data, and the results clearly demonstrated the method's capability of reconstructing spatio-temporal activities of neural sources.

Auditory cortical neuron response differences under isoflurane versus pentobarbital anesthesia.

Response properties of the middle layers of feline primary auditory cortex neurons to simple sounds were compared for isoflurane versus pentobarbital anesthesia in a within subject study control design. Initial microelectrode recordings were made under isoflurane anesthesia. After a several hour washout period, recordings were repeated at spatially matched locations in the same animal under pentobarbital. The median spatial separation between matched recording locations was 50 microns. Excitatory frequency tuning curves (n=71 pairs) to tone bursts and entrainment to click train sequences (n=64 pairs) ranging from 2 to 38 Hz were measured. Characteristic frequency and BW10 and BW30 were not different under either anesthetic. The spontaneous rate was slightly decreased (P<0.05) for isoflurane (median 4.2 spikes/s) compared to pentobarbital (median 5.8 spikes/s). Minimum median threshold and latency were elevated by 12 dB and 2 ms, respectively, under isoflurane. Entrainment to click sequences assumed a lowpass filter profile under both anesthetics, but was markedly impoverished under isoflurane. Responses to click sequences under isoflurane were phasic to the first click but had very poor following to subsequent elements. Compared to pentobarbital, isoflurane appears to have a profound impact on response sensitivity and temporal response properties of auditory cortical neurons.

Functional organization of squirrel monkey primary auditory cortex: responses to pure tones.

The spatial organization of response parameters in squirrel monkey primary auditory cortex (AI) accessible on the temporal gyrus was determined with the excitatory receptive field to pure tone stimuli. Dense, microelectrode mapping of the temporal gyrus in four animals revealed that characteristic frequency (CF) had a smooth, monotonic gradient that systematically changed from lower values (0.5 kHz) in the caudoventral quadrant to higher values (5--6 kHz) in the rostrodorsal quadrant. The extent of AI on the temporal gyrus was approximately 4 mm in the rostrocaudal axis and 2--3 mm in the dorsoventral axis. The entire length of isofrequency contours below 6 kHz was accessible for study. Several independent, spatially organized functional response parameters were demonstrated for the squirrel monkey AI. Latency, the asymptotic minimum arrival time for spikes with increasing sound pressure levels at CF, was topographically organized as a monotonic gradient across AI nearly orthogonal to the CF gradient. Rostral AI had longer latencies (range = 4 ms). Threshold and bandwidth co-varied with the CF. Factoring out the contribution of the CF on threshold variance, residual threshold showed a monotonic gradient across AI that had higher values (range = 10 dB) caudally. The orientation of the threshold gradient was significantly different from the CF gradient. CF-corrected bandwidth, residual Q10, was spatially organized in local patches of coherent values whose loci were specific for each monkey. These data support the existence of multiple, overlying receptive field gradients within AI and form the basis to develop a conceptual framework to understand simple and complex sound coding in mammals.

Differences in somatosensory hand organization in a healthy flutist and a flutist with focal hand dystonia: a case report.

Focal hand dystonia is a disabling, involuntary disorder of movement that can disrupt a successful musician's career. This problem is difficult to treat, to some extent because we do not fully understand its origin. Somatosensory degradation has been proposed as one etiology. The purpose of this case study was to compare the differences in the somatosensory hand representation of two female flutists, one with focal dystonia of the left hand (digits 4 and 5) and one a healthy subject (the control). Noninvasive magnetic source imaging was performed on both subjects. The somatosensory evoked potentials of controlled taps to the fingers were measured with a 37-channel biomagnetometer and reported in terms of the neuronal organization, latency, amplitude, density, location, and spread of the digits on each axis (x, y, and z). The somatosensory representation of the involved hand of the flutist with dystonia differed from that of the healthy flutist. The magnetic fields evoked from the primary somatosensory cortex had a disorganized pattern of firing, with a short latency and excessive amplitude in the involved digits of the affected hand, as well as inconsistency (decreased density). In addition, the patterns of firing were different in terms of the location of the digits on the x, y, and z axes and sequential organization of the digits. This study confirms that somatosensory evoked magnetic fields can be used to describe the representation of the hand on the somatosensory cortex in area 3b. Degradation in the hand representation of the flutist with focal hand dystonia was evident, compared with the hand representation of the healthy flutist. It is not clear whether the sensory degradation was the cause or the consequence of the dystonia. The questions are whether re-differentiation of the representation could be achieved with aggressive sensory retraining and whether improvement in structure would be correlated with improvement in function.

Estimating neural sources from each time-frequency component of magnetoencephalographic data.

We have developed a method that incorporates the time-frequency characteristics of neural sources into magnetoencephalographic (MEG) source estimation. This method, referred to as the time-frequency multiple-signal-classification algorithm, allows the locations of neural sources to be estimated from any time-frequency region of interest. In this paper, we formulate the method based on the most general form of the quadratic time-frequency representations. We then apply it to two kinds of nonstationary MEG data: gamma-band (frequency range between 30-100 Hz) auditory activity data and spontaneous MEG data. Our method successfully detected the gamma-band source slightly medial to the N1m source location. The method was able to selectively localize sources for alpha-rhythm bursts at different locations. It also detected the mu-rhythm source from the alpha-rhythm-dominant MEG data that was measured with the subject's eyes closed. The results of these applications validate the effectiveness of the time-frequency MUSIC algorithm for selectively localizing sources having different time-frequency signatures.

Influence of pulse sequence, polarity and amplitude on magnetic stimulation of human and porcine peripheral nerve.

1. Mammalian phrenic nerve, in a trough filled with saline, was excited by magnetic coil (MC)-induced stimuli at defined stimulation sites, including the negative-going first spatial derivative of the induced electric field along a straight nerve, at a bend in the nerve, and at a cut nerve ending. At all such sites, the largest amplitude response for a given stimulator output setting was elicited by an induced damped polyphasic pulse consisting of an initial quarter-cycle hyperpolarization followed by a half-cycle depolarization compared with a predominantly 'monophasic' quarter-cycle depolarization. 2. Simulation studies demonstrated that the increased efficacy of the induced quarter-cycle hyperpolarizing-half-cycle depolarizing polyphasic pulse was mainly attributed to the greater duration of the outward membrane current phase, resulting in a greater outward charge transfer afforded by the half-cycle (i.e. quarter-cycles 2 and 3). The advantage of a fast rising initial quarter-cycle depolarization was more than offset by the slower rising, but longer duration depolarizing half-cycle. 3. Simulation further revealed that the quarter-cycle hyperpolarization-half-cycle depolarization showed only a 2.6 % lowering of peak outward current and a 3.5 % lowering of outward charge transfer at threshold, compared with a half-cycle depolarization alone. Presumably, this slight increase in efficacy reflects modest reversal of Na+ inactivation by the very brief initial hyperpolarization. 4. In vitro, at low bath temperature, the nerve response to an initial quarter-cycle depolarization declined in amplitude as the second hyperpolarizing phase progressively increased in amplitude and duration. This 'pull-down' phenomenon nearly disappeared as the bath temperature approached 37 C. Possibly, at the reduced temperature, delay in generation of the action potential permitted the hyperpolarization phase to reduce excitation. 5. Pull-down was not observed in the thenar muscle responses to median nerve stimulation in a normal human at normal temperature. However, pull-down emerged when the median nerve was cooled by placing ice over the forearm. 6. In a nerve at subnormal temperature straddled with non-conducting inhomogeneities, polyphasic pulses of either polarity elicited the largest responses. This was also seen when stimulating distal median nerve at normal temperature. These results imply excitation by hyperpolarizing-depolarizing pulse sequences at two separate sites. Similarly, polyphasic pulses elicited the largest responses from nerve roots and motor cortex. 7. The pull-down phenomenon has a possible clinical application in detecting pathologically slowed activation of Na+ channels. The current direction of the polyphasic waveform may become a significant factor with the increasing use of repetitive magnetic stimulators which, for technical reasons, induce a cosine-shaped half-cycle, preceded and followed by quarter-cycles of opposite polarity.

Speech modifications algorithms used for training language learning-impaired children.

In this paper, the details of processing algorithms used in a training program with language learning-impaired children (LLI's) are described. The training program utilized computer games, speech/language training exercises, books-on-tape and educational CD-ROM's. Speech tracks in these materials were processed using these algorithms. During a four week training period, recognition of both processed and normal speech in these children continually increased to near age-appropriate levels. We conclude that this form of processed speech is subject to profound perceptual learning effects and exhibits widespread generalization to normal speech. This form of learning and generalization contributes to the rehabilitation of temporal processing deficits and language comprehension in this subject population.

Practice-related improvements in somatosensory interval discrimination are temporally specific but generalize across skin location, hemisphere, and modality.

This paper concerns the characterization of performance and perceptual learning of somatosensory interval discrimination. The purposes of this study were to define (1) the performance characteristics for interval discrimination in the somatosensory system by naive adult humans, (2) the normal capacities for improvement in somatosensory interval discrimination, and (3) the extent of generalization of interval discrimination learning. In a two-alternative forced choice procedure, subjects were presented with two pairs of vibratory pulses. One pair was separated in time by a fixed base interval; a second pair was separated by a target interval that was always longer than the base interval. Subjects indicated which pair was separated by the target interval. The length of the target interval was varied adaptively to determine discrimination thresholds. After initial determination of naive abilities, subjects were trained for 900 trials per day at base intervals of either 75 or 125 msec for 10-15 d. Significant improvements in thresholds resulted from training. Learning at the trained base interval generalized completely across untrained skin locations on the trained hand and to the corresponding untrained skin location in the contralateral hand. The learning partially generalized to untrained base intervals similar to the trained one, but not to more distant base intervals. Learning with somatosensory stimuli generalized to auditory stimuli presented at comparable base intervals. These results demonstrate temporal specificity in somatosensory interval discrimination learning that generalizes across skin location, hemisphere, and modality.

A primate model for studying focal dystonia and repetitive strain injury: effects on the primary somatosensory cortex.

BACKGROUND AND PURPOSE: Job-related repetitive strain injuries (RSIs) are increasing, and current treatment strategies often fail to return injured people to work. This study documented the neural consequences of using two different movement strategies for active, repetitive hand closing and opening. METHODS: Two owl monkeys were trained for 20 weeks to repetitively close a handpiece against an 80-g force (3-400 trials per day, training at 80%-90% accuracy). One monkey used a highly articulated hand-squeezing strategy, and the other monkey used a proximal arm-pulling strategy. Changes in motor performance were analyzed, and the electrophysiological maps of the hand representation on the trained primary sensory cortex (area 3b) were compared with those of untrained control animals and the untrained sides of the trained monkeys. RESULTS: The monkey using the articulated hand-squeezing strategy showed motor deterioration and dedifferentiation of the normally sharply segregated areas of the hand representation in area 3b. Mild degradation of the hand representation was measured in the monkey using the proximal arm-pulling strategy, but there was no motor dysfunction. CONCLUSION AND DISCUSSION: Attended, highly articulated, repetitive finger squeezing degrades the hand representation and interferes with motor control. A proximal, more variable repetitive strategy minimized the sensory degradation and preserved motor control. Restoring the hand representation may be a critical part of treatment for patients with chronic RSI and focal hand dystonia.

Mapping location of excitation during magnetic stimulation: effects of coil position.

We determined the location of excitation for different positions of a round and butterfly coil during in vitro magnetic stimulation of cut peripheral nerves. We analyzed the conditions under which excitation occurs, either at the termination or at the peak of the field gradients (first spatial derivative of the electric field). These results were then compared to predictions about the location of excitation sites from a theoretical model of magnetic stimulation of finite neuronal structures. Excitation along a straight nerve occurred at terminations when 1) a coil was positioned close to the end of a nerve (at least one diameter length from the end), 2) a nerve ended in a finite terminating impedance much greater than the axial resistance of the nerve, 3) the induced electric field was of sufficient magnitude, pointing in a direction away from the axis of a nerve. Excitation occurred at the negative peak of the field gradients along a nerve when 1) a coil was positioned far away from the ends of a nerve, 2) there were no geometric or volume conductor inhomogeneities around a nerve, and 3) it was of sufficient magnitude. Threshold strengths for excitation at terminations were significantly lower than that for field gradient excitation and comparable to that due to geometric and volume conductor inhomogeneities.

A generalized cable equation for magnetic stimulation of axons.

During magnetic stimulation, electric fields are induced both on the inside (intracellular region) and the outside (extracellular region) of nerve fibers. The induced electric fields in each region can be expressed as the sum of a primary and a secondary component. The primary component arises due to an applied time varying magnetic field and is the time derivative of a vector potential. The secondary component of the induced field arises due to charge separation in the volume conductor surrounding the nerve fiber and is the gradient of a scalar potential. The question, "What components of intracellular fields and extracellular induced electric fields contribute to excitation?" has, so far, not been clearly addressed. In this paper, we address this question while deriving a generalized cable equation for magnetic stimulation and explicitly identify the different components of applied fields that contribute to excitation. In the course of this derivation, we review several assumptions of the core-conductor cable model in the context of magnetic stimulation. It is shown that out of the possible four components, only the first spatial derivative of the intracellular primary component and the extracellular secondary component of the fields contribute to excitation of a nerve fiber. An earlier form of the cable equation for magnetic stimulation has been shown to result in solutions identical to three-dimensional (3-D) volume-conductor model for the specific configuration of an isolated axon in a located in an infinite homogenous conducting medium. In this paper, we extend and generalize this result by demonstrating that our generalized cable equation results in solutions identical to 3-D volume conductor models even for complex geometries of volume conductors surrounding axons such as a nerve bundle of different conductivity surrounding axons. This equivalence in the solutions is valid for several representations of a nerve bundle such as anisotropic monodomain and bidomain models.

Language comprehension in language-learning impaired children improved with acoustically modified speech.

A speech processing algorithm was developed to create more salient versions of the rapidly changing elements in the acoustic waveform of speech that have been shown to be deficiently processed by language-learning impaired (LLI) children. LLI children received extensive daily training, over a 4-week period, with listening exercises in which all speech was translated into this synthetic form. They also received daily training with computer "games" designed to adaptively drive improvements in temporal processing thresholds. Significant improvements in speech discrimination and language comprehension abilities were demonstrated in two independent groups of LLI children.