Reconstructing anatomy from electro-physiological data.

Here we show how it is possible to make estimates of brain structure based on MEG data. We do this by reconstructing functional estimates onto distorted cortical manifolds parameterised in terms of their spherical harmonics. We demonstrate that both empirical and simulated MEG data give rise to consistent and plausible anatomical estimates. Importantly, the estimation of structure from MEG data can be quantified in terms of millimetres from the true brain structure. We show, for simulated data, that the functional assumptions which are closer to the functional ground-truth give rise to anatomical estimates that are closer to the true anatomy.

Reading front to back: MEG evidence for early feedback effects during word recognition.

Magnetoencephalography studies in humans have shown word-selective activity in the left inferior frontal gyrus (IFG) approximately 130 ms after word presentation ( Pammer et al. 2004; Cornelissen et al. 2009; Wheat et al. 2010). The role of this early frontal response is currently not known. We tested the hypothesis that the IFG provides top-down constraints on word recognition using dynamic causal modeling of magnetoencephalography data collected, while subjects viewed written words and false font stimuli. Subject-specific dipoles in left and right occipital, ventral occipitotemporal and frontal cortices were identified using Variational Bayesian Equivalent Current Dipole source reconstruction. A connectivity analysis tested how words and false font stimuli differentially modulated activity between these regions within the first 300 ms after stimulus presentation. We found that left inferior frontal activity showed stronger sensitivity to words than false font and a stronger feedback connection onto the left ventral occipitotemporal cortex (vOT) in the first 200 ms. Subsequently, the effect of words relative to false font was observed on feedforward connections from left occipital to ventral occipitotemporal and frontal regions. These findings demonstrate that left inferior frontal activity modulates vOT in the early stages of word processing and provides a mechanistic account of top-down effects during word recognition.

Theta oscillations orchestrate medial temporal lobe and neocortex in remembering autobiographical memories.

Remembering autobiographical events can be associated with detailed visual imagery. The medial temporal lobe (MTL), precuneus and prefrontal cortex are held to jointly enable such vivid retrieval, but how these regions are orchestrated remains unclear. An influential prediction from animal physiology is that neural oscillations in theta frequency may be important. In this experiment, participants prospectively collected audio recordings describing personal autobiographical episodes or semantic knowledge over 2 to 7 months. These were replayed as memory retrieval cues while recording brain activity with magnetoencephalography (MEG). We identified a peak of theta power within a left MTL region of interest during both autobiographical and General Semantic retrieval. This MTL region was selectively phase-synchronized with theta oscillations in precuneus and medial prefrontal cortex, and this synchrony was higher during autobiographical as compared to General Semantic knowledge retrieval. Higher synchrony also predicted more detailed visual imagery during retrieval. Thus, theta phase-synchrony orchestrates in humans the MTL with a distributed neocortical memory network when vividly remembering autobiographical experiences.

Algorithmic procedures for Bayesian MEG/EEG source reconstruction in SPM.

The MEG/EEG inverse problem is ill-posed, giving different source reconstructions depending on the initial assumption sets. Parametric Empirical Bayes allows one to implement most popular MEG/EEG inversion schemes (Minimum Norm, LORETA, etc.) within the same generic Bayesian framework. It also provides a cost-function in terms of the variational Free energy-an approximation to the marginal likelihood or evidence of the solution. In this manuscript, we revisit the algorithm for MEG/EEG source reconstruction with a view to providing a didactic and practical guide. The aim is to promote and help standardise the development and consolidation of other schemes within the same framework. We describe the implementation in the Statistical Parametric Mapping (SPM) software package, carefully explaining each of its stages with the help of a simple simulated data example. We focus on the Multiple Sparse Priors (MSP) model, which we compare with the well-known Minimum Norm and LORETA models, using the negative variational Free energy for model comparison. The manuscript is accompanied by Matlab scripts to allow the reader to test and explore the underlying algorithm.

Measuring functional connectivity in MEG: a multivariate approach insensitive to linear source leakage.

A number of recent studies have begun to show the promise of magnetoencephalography (MEG) as a means to non-invasively measure functional connectivity within distributed networks in the human brain. However, a number of problems with the methodology still remain--the biggest of these being how to deal with the non-independence of voxels in source space, often termed signal leakage. In this paper we demonstrate a method by which non-zero lag cortico-cortical interactions between the power envelopes of neural oscillatory processes can be reliably identified within a multivariate statistical framework. The method is spatially unbiased, moderately conservative in false positive rate and removes linear signal leakage between seed and target voxels. We demonstrate this methodology in simulation and in real MEG data. The multivariate method offers a powerful means to capture the high dimensionality and rich information content of MEG signals in a single imaging statistic. Given a significant interaction between two areas, we go on to show how classical statistical tests can be used to quantify the importance of the data features driving the interaction.

A general Bayesian treatment for MEG source reconstruction incorporating lead field uncertainty.

There is uncertainty introduced when a cortical surface based model derived from an anatomical MRI is used to reconstruct neural activity with MEG data. This is a specific case of a problem with uncertainty in parameters on which M/EEG lead fields depend non-linearly. Here we present a general mathematical treatment of any such problem with a particular focus on co-registration. We use a Metropolis search followed by Bayesian Model Averaging over multiple sparse prior source inversions with different headlocation/orientation parameters. Based on MEG data alone we can locate the cortex to within 4mm at empirically realistic signal to noise ratios. We also show that this process gives improved posterior distributions on the estimated current distributions, and can be extended to make inference on the locations of local maxima by providing confidence intervals for each source.

Influence of previous target motion on anticipatory pursuit deceleration.

During visual pursuit of a moving target, expected changes in its trajectory often evoke anticipatory smooth pursuit responses. In the present study, we investigated characteristics of anticipatory smooth pursuit decelerations before a change or the end of a target trajectory. Healthy humans had to pursue with the eyes a target moving along a circular path that predictably or unpredictably reversed direction and then retraced its movement back to the starting position. We found that anticipatory eye decelerations were often evoked in temporal expectation of target reversal and of the end of the trajectory. The latency of anticipatory decelerations initiated before target reversal was variable, had poor temporal accuracy and depended on the history of previous trials. Anticipations of the end of the trajectory were more accurate, more precise and were not influenced by previous trials. In this case, subjects probably based their estimate of the end of the trajectory on the duration just experienced before target motion reversal. These results suggest that anticipatory eye decelerations are based on the characteristics of the current or preceding trials depending on the most reliable information available.

Effective electromagnetic noise cancellation with beamformers and synthetic gradiometry in shielded and partly shielded environments.

The major challenge of MEG, the inverse problem, is to estimate the very weak primary neuronal currents from the measurements of extracranial magnetic fields. The non-uniqueness of this inverse solution is compounded by the fact that MEG signals contain large environmental and physiological noise that further complicates the problem. In this paper, we evaluate the effectiveness of magnetic noise cancellation by synthetic gradiometers and the beamformer analysis method of synthetic aperture magnetometry (SAM) for source localisation in the presence of large stimulus-generated noise. We demonstrate that activation of primary somatosensory cortex can be accurately identified using SAM despite the presence of significant stimulus-related magnetic interference. This interference was generated by a contact heat evoked potential stimulator (CHEPS), recently developed for thermal pain research, but which to date has not been used in a MEG environment. We also show that in a reduced shielding environment the use of higher order synthetic gradiometry is sufficient to obtain signal-to-noise ratios (SNRs) that allow for accurate localisation of cortical sensory function.

Brain and behavior: a task-dependent eye movement study.

Recent electrophysiological and behavioral studies have found similarities in the neurology of pursuit and saccadic eye movements. In a previous study on eye movements using closely matched paradigms for pursuit and saccades, we revealed that both exhibit bimodal distributions of latency to predictable (PRD) and randomized (RND) stimuli; however, the latency to each type of stimulus was different, and there was more segregation of latencies in saccades than pursuit (Burke MR, Barnes GR. 2006. Quantitative differences in smooth pursuit and saccadic eye movements in humans. Exp Brain Res. 175(4):596-608). To investigate the brain areas involved in these tasks, and to search for correlates of behavior, we used functional magnetic resonance imaging during equivalent PRD and RND target presentations. In the contrast pursuit > saccades, which reflects velocity-dependent versus position-dependent activities, respectively, we found higher activation in the dorsolateral prefrontal cortex (DLPFC) for pursuit and in the frontopolar region for saccades. In the contrast RND > PRD, which principally reflects activation related to visually driven versus memory-driven responses, respectively, we found a higher sustained level of activation in the frontal eye fields during visually guided eye movements. The reverse contrast revealed higher activity for the memory-guided responses in the supplementary eye fields and the superior parietal lobe. In addition, we found learning-related activation during the PRD condition in visual area V5, the DLPFC, and the cerebellum.

Cognitive processes involved in smooth pursuit eye movements.

Ocular pursuit movements allow moving objects to be tracked with a combination of smooth movements and saccades. The principal objective is to maintain smooth eye velocity close to object velocity, thus minimising retinal image motion and maintaining acuity. Saccadic movements serve to realign the image if it falls outside the fovea, the area of highest acuity. Pursuit movements are often portrayed as voluntary but their basis lies in processes that sense retinal motion and can induce eye movements without active participation. The factor distinguishing pursuit from such reflexive movements is the ability to select and track a single object when presented with multiple stimuli. The selective process requires attention, which appears to raise the gain for the selected object and/or suppress that associated with other stimuli, the resulting competition often reducing pursuit velocity. Although pursuit is essentially a feedback process, delays in motion processing create problems of stability and speed of response. This is countered by predictive processes, probably operating through internal efference copy (extra-retinal) mechanisms using short-term memory to store velocity and timing information from prior stimulation. In response to constant velocity motion, the initial response is visually driven, but extra-retinal mechanisms rapidly take over and sustain pursuit. The same extra-retinal mechanisms may also be responsible for generating anticipatory smooth pursuit movements when past experience creates expectancy of impending object motion. Similar, but more complex, processes appear to operate during periodic pursuit, where partial trajectory information is stored and released in anticipation of expected future motion, thus minimising phase errors associated with motion processing delays.

High-dose cisplatin and vinblastine infusion with or without radiation therapy in patients with advanced non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) patients with locally advanced or metastatic measurable disease were given a combination of cisplatin, 200 mg/m2 divided in five daily doses, and simultaneously, vinblastine, 7.5 mg/m2 as a continuous intravenous (IV) infusion over five days. Five courses of chemotherapy were planned. Afterwards or on progression, patients were randomized to receive maximally tolerated radiation to all sites of disease v observation only. Forty males and seven females were entered. Median age was 60 years (range, 37 to 74), median Karnofsky performance status was 70 (range, 30 to 90). Five patients had previous brain radiation therapy for metastatic disease, all others were previously untreated. Side effects in the 87 courses of chemotherapy administered included leukopenia (WBC less than 1,000/microL following nine courses) and thrombocytopenia (platelets less than 20,000/microL following four courses). Ten patients became septic, nine of them while leukopenic. Elevations of serum creatinine followed eight courses; in all cases the level was less than 3.0 mg/dL. Nausea and vomiting were mild to moderate. Five patients experienced mild hypoacusis and six had sensory polyneuropathy. The deaths of three patients were considered drug-related. The response rate was 28%. The median survival for the group was 22 weeks, 63.2 weeks for responders and 17.9 weeks for nonresponders. Twenty-six patients received radiation therapy, 16 randomized to this arm as planned, ten to palliate symptoms. Median survival of all irradiated patients was 24.8 weeks. Seven responders to chemotherapy were randomized to receive radiotherapy; their median survival was 25 weeks. In six responders randomized not to receive radiation, the median survival was 77.8 weeks (P greater than .3). Among nonresponding patients, the median survival of those radiated was 22.2 weeks, while that of nonradiated patients was 11 weeks. This regimen is cumbersome and toxic. It has offered no major survival benefits, or improvement in response rates, therefore, we do not recommend it for the standard treatment of NSCLC.

Attention and selection for predictive smooth pursuit eye movements.

Humans cannot typically produce smooth eye movements in the absence of a moving stimulus. However, they can produce predictive smooth eye movements if they expect a target of a known velocity to reappear. Here, we observed that participants could extract velocity information from two simultaneously presented moving targets in order to produce a subsequent predictive smooth eye movement for one of the two targets. Subjects fixated a stationary cross during the presentation of two targets, moving rightward at different velocities. In the next presentation, a single target was presented, which participants tracked with their eyes. A static cue, presented 700 ms before the moving target, indicated which of the two targets would be presented. Predictive eye movements were of an appropriate velocity, even when participants did not know in advance which of the two targets would subsequently be cued. However, the scaling of predictive eye velocity was marginally less accurate in this divided attention condition than when participants knew the identity of the cued target in advance, or a single target was presented during fixation. In a second experiment, we found that the velocity cued on the previous trial had a greater effect than the uncued velocity on the current trial. The negligible effect of the uncued velocity indicates that participants were extremely effective at selectively reproducing one of two recently viewed velocities. However, other influences, such as past history, also affected predictive smooth eye movements.

The role of expectancy and volition in smooth pursuit eye movements.

The most important factor allowing the generation of pursuit eye movements prior to target onset is confidence in the likelihood of imminent target appearance. We show how these anticipatory pursuit responses are essentially ballistic motor primitives and how the signal that drives them in normally defined by stored information concerning target speed, duration and direction. But we also show how static cues may be used to grade the level of these motor primitives 'on-line'. We further demonstrate that, when concatenated, these graded motor primitives can be rapidly combined to form predictive smooth movement trajectories in response to complex multi-ramp sequences.

Co-registration of magnetoencephalography with magnetic resonance imaging using bite-bar-based fiducials and surface-matching.

OBJECTIVE: To introduce a new technique for co-registration of Magnetoencephalography (MEG) with magnetic resonance imaging (MRI). We compare the accuracy of a new bite-bar with fixed fiducials to a previous technique whereby fiducial coils were attached proximal to landmarks on the skull. METHODS: A bite-bar with fixed fiducial coils is used to determine the position of the head in the MEG co-ordinate system. Co-registration is performed by a surface-matching technique. The advantage of fixing the coils is that the co-ordinate system is not based upon arbitrary and operator dependent fiducial points that are attached to landmarks (e.g. nasion and the preauricular points), but rather on those that are permanently fixed in relation to the skull. RESULTS: As a consequence of minimizing coil movement during digitization, errors in localization of the coils are significantly reduced, as shown by a randomization test. Displacement of the bite-bar caused by removal and repositioning between MEG recordings is minimal ( approximately 0.5 mm), and dipole localization accuracy of a somatosensory mapping paradigm shows a repeatability of approximately 5 mm. The overall accuracy of the new procedure is greatly improved compared to the previous technique. CONCLUSIONS: The test-retest reliability and accuracy of target localization with the new design is superior to techniques that incorporate anatomical-based fiducial points or coils placed on the circumference of the head.

Object motion perception during ego-motion: patients with a complete loss of vestibular function vs. normals.

Object motion perception was assessed in avestibular patients and normal controls. Two experiments were conducted, in which subjects were required to assess the motion of a visual stimulus with respect to earth. In the first experiment, we measured the velocity at which a briefly presented (200 ms) grating was perceived as earth fixed, while the subject maintained fixation on a visual target fixed relative to the body, during whole-body yaw rotation (VOR suppression). In this experimental setup, the influence of the semicircular canal signals on object motion perception was evaluated. The avestibular patients judged the grating to be stationary with respect to earth, when it was moving at the same velocity as their body, whereas for normal controls, the grating was perceived as stationary when it moved at a velocity slower than their body motion, but greater than zero. The difference between the two subject groups was significant, and showed the strong contribution of the vestibular system to object motion perception. Similarly, a measurement of the velocity at which a grating was perceived as stationary was obtained during smooth pursuit eye movements. In this experiment the contribution of the efference copy of the oculomotor signal and proprioceptive signals to object motion perception were assessed. As with the first experiment, the normal controls displayed a more veridical sense of object motion perception than the patients, although the difference was only just significant. We suggest that the difference could be an adaptive change in the patients perception of motion, which allows them to reduce the effects of oscillopsia.

Predictive smooth pursuit eye movements during identification of moving acuity targets.

Repetitive, brief target ramp movements every few seconds lead to anticipatory acceleration before each ramp onset and anticipatory deceleration before ramp offset. We assessed whether identifying novel changes in the pursuit target would alter this pattern of anticipatory pursuit. Without target identification (TI), anticipatory acceleration increased when intervals between ramps were regular, rather than random. It increased further when, between ramps, the target was invisible rather than stationary and visible. Anticipatory deceleration increased when the target was expected to stop rather than disappear at ramp offset. For TI trials, the pursuit target changed briefly into a Landolt C acuity target that had to be identified. Compared to no TI, anticipatory acceleration decreased when a stationary C always appeared just before ramp onset. It increased when a moving C appeared just after ramp onset, but only when the target was invisible between ramps. Anticipatory deceleration was reduced when a moving C appeared just before ramp offset, but did not increase when a stationary C appeared just after ramp offset. The changes were significant, but of small magnitude, suggesting that predictive pursuit, especially with a visible target between ramps, cannot be greatly influenced by attempts to selectively improve acuity at a particular phase of the stimulus.

Assessment of the humane aspects of electric lancing of whales by measurement of current densities in the brain and heart of dead animals.

The potential physiological effects of the electric lance are assessed, as used in Japanese whaling operations. Current densities are measured in the brains and hearts of six whales to which a controlled current of 5 A is applied by two electrodes inserted at various sites in the carcasses. The whales vary in size from 1.8 m (22 kg) to 16 m (40 t). The minimum current density in the brain necessary to cause depolarisation of neurones is estimated to be 10 mA cm-2 and to cause ventricular fibrillation is estimated to be 0.5 mA cm-2. No current densities exceeding 4.8 mA cm-2 are recorded in the brain. Very few recordings of current density from the heart are above 0.5 mA cm-2, and they occur only when electrodes are in optimal positions. When electrodes are placed as in whaling operations, no whale over 3 m in length would receive current densities in the heart or brain sufficient to cause permanent dysfunction. It is concluded that electric lancing is ineffective as a secondary method of killing whales and that the current densities recorded could cause pain and suffering to an already distressed animal.

Rostral displacement of the palatopharyngeal arch: a case report.

A horse with rostral displacement of the palatopharyngeal arch was found to have a bilaterally symmetrical deformity of the laryngeal area. Both left and right cricopharyngeal muscles were absent. The shape of the thyroid cartilage was grossly abnormal and vestiges of the cricothyroid muscles were attached only to the cricoid cartilage. It was suggested that such an anomaly could have resulted from aberrant development of the fourth branchial arch.

Cervical and vestibular afferent control of oculomotor response in man.

Oculomotor response in the absence of vision has been compared in a group of 12 normal humans in two experimental conditions testing (a) the vestibulocular reflex by whole-body oscillation on a turntable, and (b) the cervico-ocular reflex by oscillation of the body with the head held stationary. The stimulus was a sinusoidal oscillation (peak angular velocity +/- 50 degrees/sec) at frequencies between 0.2 and 1.3 Hz. The slow-phase eye movements of the vestibulo-ocular response were compensatory for head movement and showed a mean gain of 0.54--0.90, increasing with frequency. The cervicoocular response was found to be very variable. The slow-phase eye movements were of low velocity (mean gain 0.05) and did not generally compensate for body movement. During neck torsion, some subjects exhibited large overall eye deviations composed of both slow and fast phase eye movements.

Visual-vestibular interaction during head-free pursuit of pseudorandom target motion in man.

Recordings of head and eye movement were made during pursuit of mixed-frequency, pseudorandom target motion to study the mechanism of vestibulo-ocular reflex (VOR) suppression during head-free pursuit. When high velocity stimuli were used, slow-phase gaze velocity gains decreased significantly with increases in both absolute target velocity and the velocity ratio between the frequency components. These changes occurred independently of changes in the head displacement gain, which remained relatively constant at the lower frequency and were directly attributable to impaired suppression of the VOR. Similar effects were seen when visual feedback was degraded by tachistoscopic illumination of the target. The results indicate that visual feedback, rather than an efference copy of the head velocity signal, is essential for suppression of slow-phase vestibular eye movement during head-free pursuit. When head-free and head-fixed pursuit were compared, striking similarities were seen for both slow phase gaze velocity gain and phase, indicating that gaze control during smooth pursuit is largely independent of the degree of associated head movement. This suggests that the VOR is not switched off during head-free pursuit. An estimate of the underlying VOR gain was obtained by recording the vestibular response produced by active head movements in darkness. The rather higher estimates of VOR gain obtained using an imaginary earth-fixed target paradigm were found to predict head-free gains more closely than the gains obtained during imaginary pursuit of a moving target, suggesting that such measures may be more representative of the underlying VOR gain.