Multi-sensor magnetoencephalography with atomic magnetometers.

The authors have detected magnetic fields from the human brain with two independent, simultaneously operating rubidium spin-exchange-relaxation-free magnetometers. Evoked responses from auditory stimulation were recorded from multiple subjects with two multi-channel magnetometers located on opposite sides of the head. Signal processing techniques enabled by multi-channel measurements were used to improve signal quality. This is the first demonstration of multi-sensor atomic magnetometer magnetoencephalography and provides a framework for developing a non-cryogenic, whole-head magnetoencephalography array for source localization.

Impact of tDCS on performance and learning of target detection: interaction with stimulus characteristics and experimental design.

We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits)-Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (ß). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed.

Transcranial direct current stimulation's effect on novice versus experienced learning.

Transcranial direct current stimulation (TDCS) is a non-invasive form of brain stimulation applied via a weak electrical current passed between electrodes on the scalp. In recent studies, TDCS has been shown to improve learning when applied to the prefrontal cortex (e.g., Kincses et al. in Neuropsychologia 42:113-117, 2003; Clark et al. Neuroimage in 2010). The present study examined the effects of TDCS delivered at the beginning of training (novice) or after an hour of training (experienced) on participants' ability to detect cues indicative of covert threats. Participants completed two 1-h training sessions. During the first 30 min of each training session, either 0.1 mA or 2.0 mA of anodal TDCS was delivered to the participant. The anode was positioned near F8, and the cathode was placed on the upper left arm. Testing trials immediately followed training. Accuracy in classification of images containing and not-containing threat stimuli during the testing sessions indicated: (1) that mastery of threat detection significantly increased with training, (2) that anodal TDCS at 2 mA significantly enhanced learning, and (3) TDCS was significantly more effective in enhancing test performance when applied in novice learners than in experienced learners. The enhanced performance following training with TDCS persisted into the second session when TDCS was delivered early in training.

Commonalities and differences among vectorized beamformers in electromagnetic source imaging.

A number of beamformers have been introduced to localize neuronal activity using magnetoencephalography (MEG) and electroencephalography (EEG). However, currently available information about the major aspects of existing beamformers is incomplete. In the present study, detailed analyses are performed to study the commonalities and differences among vectorized versions of existing beamformers in both theory and practice. In addition, a novel beamformer based on higher-order covariance analysis is introduced. Theoretical formulas are provided on all major aspects of each beamformer; to examine their performance, computer simulations with different levels of correlation and signal-to-noise ratio are studied. Then, an empirical data set of human MEG median-nerve responses with a large number of neuronal generators is analyzed using the different beamformers. The results show substantial differences among existing MEG/EEG beamformers in their ways of describing the spatial map of neuronal activity. Differences in performance are observed among existing beamformers in terms of their spatial resolution, false-positive background activity, and robustness to highly correlated signals. Superior performance is obtained using our novel beamformer with higher-order covariance analysis in simulated data. Excellent agreement is also found between the results of our beamformer and the known neurophysiology of the median-nerve MEG response.

MEG response to median nerve stimulation correlates with recovery of sensory and motor function after stroke.

OBJECTIVE: Hemiparesis due to damage by stroke in primary motor cortex (MI) or its underlying projections presents a problem for functional neuroimaging technologies that attempt to evaluate the neurophysiological basis for restoration of motor function. Traditional assessments of MI function require patients to move their fingers, hands, or limbs, which can be either impossible or markedly compromised after stroke. We recently demonstrated in normal subjects that magnetoencephalography (MEG), a non-invasive neuromagnetic functional imaging technique, detects neuronal response elicited by electrical median nerve stimulation in MI, as well as primary somatosensory cortex (SI). In the present study, we used the MEG response from median nerve stimulation to investigate the recovery of primary motor and somatosensory in acute ischemic stroke patients. METHODS: Twelve patients with unilateral ischemic strokes that affected sensorimotor functions of their hand were studied in the acute stage (4.4+/-1.2 days, mean+/-SD) and during a 1-month follow-up (38.6+/-5.6 days, except for one patient's follow-up done 6 month after stroke). RESULTS: Among the multiple cortical sources localized after median nerve stimulation, one source localized to SI and another localized to the vicinity of MI. Changes in the source strengths of the first component post-stimulus of MI and SI correlated with the extent of recovery of sensorimotor functions as determined by neurological exams. CONCLUSIONS: This study provides a novel way of indirectly assessing MI function using MEG during the acute stroke phase, when many patients often cannot perform motor tasks due to paralysis.

Auditory sensory gating deficit and cortical thickness in schizophrenia.

Both an EEG P50 sensory gating deficit and abnormalities of the temporal lobe structure are considered characteristic of schizophrenia. The standard P50 sensory gating measure does not foster differential assessment of left- and right-hemisphere contributions, but its analogous MEG M50 component may be used to measure gating of distinct auditory source dipoles localizing to left- and right-hemisphere primary auditory cortex. The present study sought to determine how sensory gating ratio may relate to cortical thickness at the site of the auditory dipole localization. A standard auditory paired-click paradigm was used during MEG for patients (n=22) and normal controls (n=11). Sensory gating ratios were determined by measuring the strength of the 50 ms response to the second click divided by that of the first click (S2/S1). Cortical thickness was assessed by two reliable raters using 3D sMRI. Results showed that: (1) patients had a P50 and left M50 sensory gating deficit relative to controls; (2) cortex in both hemispheres was thicker in the control group; (3) in schizophrenia, poorer left-hemisphere M50 sensory gating correlated with thinner left-hemisphere auditory cortical thickness; and (4) poorer right-hemisphere M50 auditory sensory gating ratio correlated with thinner right-hemisphere auditory cortical thickness in patients. The MEG-assessed hemisphere-specific auditory sensory gating ratio may be driven by this structural abnormality in auditory cortex.

Interpreting abnormality: an EEG and MEG study of P50 and the auditory paired-stimulus paradigm.

Interpretation of neurophysiological differences between control and patient groups on the basis of scalp-recorded event-related brain potentials (ERPs), although common and promising, is often complicated in the absence of information on the distinct neural generators contributing to the ERP, particularly information regarding individual differences in the generators. For example, while sensory gating differences frequently observed in patients with schizophrenia in the P50 paired-click gating paradigm are typically interpreted as reflecting group differences in generator source strength, differences in the latency and/or orientation of P50 generators may also account for observed group differences. The present study examined how variability in source strength, amplitude, or orientation affects the P50 component of the scalp-recorded ERP. In Experiment 1, simulations examined the effect of changes in source strength, orientation, or latency in superior temporal gyrus (STG) dipoles on P50 recorded at Cz. In Experiment 2, within- and between-subject variability in left and right M50 STG dipole source strength, latency, and orientation was examined in 19 subjects. Given the frequently reported differences in left and right STG anatomy and function, substantial inter-subject and inter-hemispheric variability in these parameters were expected, with important consequences for how P50 at Cz reflects brain activity from relevant generators. In Experiment 1, simulated P50 responses were computed from hypothetical left- and right-hemisphere STG generators, with latency, amplitude, and orientation of the generators varied systematically. In Experiment 2, electroencephalographic (EEG) and magnetoencephalographic (MEG) data were collected from 19 subjects. Generators were modeled from the MEG data to assess and illustrate the generator variability evaluated parametrically in Experiment 1. In Experiment 1, realistic amounts of variability in generator latency, amplitude, and orientation produced ERPs in which P50 scoring was compromised and interpretation complicated. In Experiment 2, significant within and between subject variability was observed in the left and right hemisphere STG M50 sources. Given the variability in M50 source strength, orientation, and amplitude observed here in nonpatient subjects, future studies should examine whether group differences in P50 gating ratios typically observed for patient vs. control groups are specific to a particular hemisphere, as well as whether the group differences are due to differences in dipole source strength, latency, orientation, or a combination of these parameters. Present analyses focused on P50/M50 merely as an example of the broader need to evaluate scalp phenomena in light of underlying generators. The development and widespread use of EEG/MEG source localization methods will greatly enhance the interpretation and value of EEG/MEG data.

Predicting EEG responses using MEG sources in superior temporal gyrus reveals source asynchrony in patients with schizophrenia.

OBJECTIVE: An integrated analysis using Electroencephalography (EEG) and magnetoencephalography (MEG) is introduced to study abnormalities in early cortical responses to auditory stimuli in schizophrenia. METHODS: Auditory responses were recorded simultaneously using EEG and MEG from 20 patients with schizophrenia and 19 control subjects. Bilateral superior temporal gyrus (STG) sources and their time courses were obtained using MEG for the 30-100 ms post-stimulus interval. The MEG STG source time courses were used to predict the EEG signal at electrode Cz. RESULTS: In control subjects, the STG sources predicted the EEG Cz recording very well (97% variance explained). In schizophrenia patients, the STG sources accounted for substantially (86%) and significantly (P<0.0002) less variance. After MEG-derived STG activity was removed from the EEG Cz signal, the residual signal was dominated by 40 Hz activity, an indication that the remaining variance in EEG is probably contributed by other brain generators, rather than by random noise. CONCLUSIONS: Integrated MEG and EEG analysis can differentiate patients and controls, and suggests a basis for a well established abnormality in the cortical auditory response in schizophrenia, implicating a disorder of functional connectivity in the relationship between STG sources and other brain generators.

Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks.

We review evidence from experiments conducted in our laboratory on retrograde amnesia in rats with damage to the hippocampal formation. In a new experiment reported here, we show that N-methyl-D-aspartate (NMDA)-induced hippocampal damage produced retrograde amnesia for both hidden platform and two-choice visible platform discriminations in the Morris water task. For both problems there was a significant trend for longer training-surgery intervals to be associated with worse retention performance. Little support is offered by our work for the concept that there is a process involving hippocampal-dependent consolidation of memories in extrahippocampal permanent storage sites. Long-term memory consolidation may take place within the hippocampus. The hippocampus may be involved permanently in storage and/or retrieval of a variety of relational and nonrelational memories if it was intact at the time of learning, even involving information which is definitely not affected in anterograde amnesia after hippocampal damage.

Sources on the anterior and posterior banks of the central sulcus identified from magnetic somatosensory evoked responses using multistart spatio-temporal localization.

A Multi-Start Spatio-Temporal (MSST) multidipole localization algorithm was used to study sources on the anterior and posterior banks of the central sulcus localized from early somatosensory magnetoencephalography (MEG) responses. Electrical stimulation was applied to the right and left median nerves of 8 normal subjects. Two sources, one on the anterior and one on the posterior bank of the central sulcus, were localized from 16 data sets (8 subjects, 2 hemispheres). Compared with the more traditional practice of single-dipole fits to peak latencies, MSST provided more reliable source locations. The temporal dynamics of the anterior and posterior central sulcus sources, obtained using MSST, showed considerable temporal overlap. In some cases, the two sources appeared synchronous. On the other hand, in the traditional single-dipole peak-latency fit approach, there is no time course other than a focal dipole moment activated only at the selected peak latency. The same group of subjects also performed a motor task involving index-finger lifting; the anterior central sulcus source obtained from electrical median nerve stimulation localized to the same or similar region in the primary motor area identified from the finger-lift task. The physiological significance of the anterior central sulcus source is discussed. The findings suggest that one can test the integrity of cortical tissue in the region of primary motor cortex using electrical somatosensory stimulation.

Magnetoencephalographic characterization of sleep spindles in humans.

Sleep spindles in EEG recordings of adults are most prominent over the central and frontal midline regions. Early magnetoencephalographic recordings agreed with conventional EEG findings. However, more recent small-array magnetoencephalography and quantitative EEG studies suggest that the source areas for spindles are more widespread. We used a whole-head 122-channel biomagnetometer to characterize the sources of sleep spindles in four normal volunteers. Parallel interactive and automated multiple dipole spatiotemporal source modeling was conducted on the data sets of 10 spindles from each subject. Principal component analysis was used to estimate the number of sources in interactive source modeling, and singular value decomposition was used in automated dipole modeling. Spectral analysis of the epochs containing sleep spindles was performed. Principal component analysis and singular value decomposition suggested that all sleep spindles were made up of activity from multiple sources. Similarly, interactive and automated multiple dipole source modeling showed that three or more sources were present in 75% of spindle bursts. The sources for sleep spindles localized to all four cerebral lobes. Parietal and frontal lobes were the areas most frequently involved. Interactive source modeling resulted in more frequent temporal lobe than occipital dipole localizations; automated source modeling showed more frequent occipital than temporal sources. Spindle source localizations varied across subjects and across different spindles within subjects. Our results indicate that individual sleep spindles are generated by multiple cortical sources that are widespread within and across individuals.

Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations.

Using a within-subjects design, rats were trained on two place-memory problems and five object-discrimination problems at different intervals prior to receiving either ibotenate lesions of the hippocampal formation or sham surgery. Places # 1 and 2 were fixed-platform water-maze tasks that were run in different rooms and they were learned during the 14th and 2nd week before surgery, respectively. Object-discrimination problems # 1-5 were learned during the 13th, 10th, 7th, 4th, and 1st week before surgery, respectively. Rats with hippocampal lesions displayed impaired retention of both Place problems with no evidence of a temporal gradient to the impairment. In contrast to their retrograde place-memory deficits, the hippocampal rats displayed normal retention of the five object-discriminations that were learned before surgery. Hippocampal lesions had similar consequences for anterograde learning, as the lesioned rats were impaired in acquisition of a new water-maze problem that was run in a third room (Place #3), whereas they showed normal acquisition of two new object-discriminations. The findings indicate that the hippocampal formation is not required for long-term consolidation of information underlying accurate performance of object-discriminations, and that its critical role in memory for places persists for at least 14 weeks, and probably for as long as those memories exist.

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 significa

The relationship between traumatic brain injury-induced changes in brain temperature and behavioral and anatomical outcome.

Alteration of brain temperature, experimentally induced or spontaneous, has been shown to affect the symptoms resulting from a variety of cerebral insults. This study examined the effect of traumatic brain injury (TBI) on brain and body temperature in rats and the relationship between TBI-induced temperature changes, neuropathology, and behavioral recovery. Anesthesia, surgery and TBI all caused changes in brain and body temperatures. The level of brain (but not body) temperature at the time of TBI was positively correlated with the severity of hippocampal and thalamic pathology. In contrast, the measured levels of both brain and body temperatures after TBI were not related to behavioral or neuroanatomical outcome. Interestingly, the increase in brain (but not body) temperature from the time of TBI to 5 to 10 minutes after termination of anesthesia was negatively correlated with behavioral and anatomical outcome. Simply stated, the more rapidly brain temperature returned toward normal, the better the rats' behavioral and anatomical outcome. This rate of return toward normal brain temperature is not interpreted as causally related to outcome but rather as an index of the severity of brain injury.

Noradrenergic pharmacotherapy, intracerebral infusion and adrenal transplantation promote functional recovery after cortical damage.

The research described in this review briefly summarizes evidence that short term pharmacological enhancement of noradrenergic (NA) synaptic activity, combined with symptom relevant experience (SRE), promotes functional recovery of some symptoms of cortical damage in rat, cat and human beings even when treatment is initiated from days to weeks after injury. A summary is provided of the numerous drugs tested in rodent cortical injury models which have been proven useful for predicting beneficial or harmful effects on behavioral outcome in human stroke. The pattern of drug effects indicates a central role for NA in functional recovery. Additionally, studies of the effects of direct intraventricular infusion of monoamine neurotransmitters are reviewed and further support the hypothesized role of NA in recovery from some symptoms of cortical injury. The site of NA/SRE interaction to promote recovery from hemiplegia apparently involves the cerebellar hemisphere contralateral to the cortical injury. Microinfusions of NA into the contra- but not ipsilateral cerebellar hemisphere dramatically enhance recovery. Furthermore, like its systemic action, microinfusion of the alpha 1-NA receptor antagonist, phenoxybenzamine, reinstates hemiplegia. A "permanent" symptom of motor cortex injury in the cat is the complete loss of tactile placing contralateral to the injury which does not spontaneously recover for as long as seven years after ablation. This postural reflex is temporarily restored for 8-12 hours following amphetamine administration. However, this permanently lost reflex can be enduringly restored by transplanting catecholamine secreting adrenal tissue into the wound cavity. The experiment is reviewed in detail and involves chromaffin cell autografts into the frontal cortex ablation wound cavity producing a restoration of tactile placing for the 7-10 month duration of the study. This enduring restoration of tactile placing is considered a result of the release of catecholamines into the CNS from the grafted chromaffin cells found, by histochemical methods, surviving 7-10 months after transplant. Lastly, we attribute these delayed treatment effects to an attenuation of a diaschisis, or remote functional depression, in morphologically intact areas anatomically connected to the area of injury. The widespread reduction of glycolytic and oxidative metabolism, produced by focal cortical injury, is normalized by the same treatment which alleviates symptoms and is worsened by drugs which exacerbate deficits. These data support the hypothesis that providing SRE during a period of enhanced NA synaptic activity produces an enduring functional recovery after cortical injury by attenuating remote functional depression. This treatment for enhancing recovery is especially attractive since it is effective even when begun weeks after cortical damage.