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.

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.

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.

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.

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.

Anticipatory eye movements evoked after active following versus passive observation of a predictable motion stimulus.

We used passive and active following of a predictable smooth pursuit stimulus in order to establish if predictive eye movement responses are equivalent under both passive and active conditions. The smooth pursuit stimulus was presented in pairs that were either 'predictable' in which both presentations were matched in timing and velocity, or 'randomized' in which each presentation in the pair was varied in both timing and velocity. A visual cue signaled the type of response required from the subject; a green cue indicated the subject should follow both the target presentations (Go-Go), a pink cue indicated that the subject should passively observe the 1st target and follow the 2nd target (NoGo-Go), and finally a green cue with a black cross revealed a randomized (Rnd) trial in which the subject should follow both presentations. The results revealed better prediction in the Go-Go trials than in the NoGo-Go trials, as indicated by higher anticipatory velocity and earlier eye movement onset (latency). We conclude that velocity and timing information stored from passive observation of a moving target is diminished when compared to active following of the target. This study has significant consequences for understanding how visuomotor memory is generated, stored and subsequently released from short-term memory.

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.

Internally generated smooth eye movement: its dynamic characteristics and role in randomised and predictable pursuit.

Although originally examined in the context of prediction, it is now apparent that smooth eye movements generated by internal (extra-retinal) mechanisms play a role in both predictable and randomised pursuit responses. Internally generated responses are characterised by trajectories that begin with an increasing acceleration that develops much more slowly than responses generated through retinal feedback, but which can, nevertheless, reach high velocities. They can be evoked by regularly repeated motion stimuli or by cues that occur at a regular time before target motion onset. Although frequently observed as anticipatory movements, we now provide evidence that such movements also form the basis of the extra-retinal component of a randomised step-ramp response. In such circumstances they also build up slowly in the first second or so of the initial response. They are normally masked in the presence of visual feedback, but can be revealed by prolonged target extinction immediately after response initiation. The key to release internally generated responses in both random and predictable conditions is expectation of future target motion. The key to their functionality is rapid acquisition and storage of velocity and timing information.

Evidence for a link between the extra-retinal component of random-onset pursuit and the anticipatory pursuit of predictable object motion.

During pursuit of moving targets that temporarily disappear, residual smooth eye movements represent the internal (extra-retinal) component of pursuit. However, this response is dependent on expectation of target reappearance. By comparing responses with and without such expectation during early random-onset pursuit, we examined the temporal development of the extra-retinal component and compared it with anticipatory pursuit, another form of internally driven response. In an initial task (mid-ramp extinction), a moving, random-velocity target was initially visible for 100 or 150 ms but then extinguished for 600 ms before reappearing and continuing to move. Responses comprised an initial visually driven rapid rise in eye velocity, followed by a secondary slower increase during extinction. In a second task (short ramp), with identical initial target presentation but no expectation of target reappearance, the initial rapid rise in eye velocity was followed by decay toward zero. The expectation-dependent difference between responses to these tasks increased in velocity during extinction much more slowly than the initial, visually driven component. In a third task (initial extinction), the moving target was extinguished at motion onset but reappeared 600 ms later. Repetition of identical stimuli evoked anticipatory pursuit triggered by initial target offset. Temporal development and scaling of this anticipatory response, which was based on remembered velocity from prior stimuli, was remarkably similar to and covaried with the difference between mid-ramp extinction and short ramp tasks. Results suggest a common mechanism is responsible for anticipatory pursuit and the extra-retinal component of random-onset pursuit, a finding that is consistent with a previously developed model of pursuit.

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.

The influence of briefly presented randomized target motion on the extraretinal component of ocular pursuit.

We assessed the ability to extract velocity information from brief exposure of a moving target and sought evidence that this information could be used to modulate the extraretinal component of ocular pursuit. A step-ramp target motion was initially visible for a brief randomized period of 50, 100, 150, or 200 ms, but then extinguished for a randomized period of 400 or 600 ms before reappearing and continuing along its trajectory. Target speed (5-20 degrees /s), direction (left/right), and intertrial interval (2.7-3.7 s) were also randomized. Smooth eye movements were initiated after about 130 ms and comprised an initial visually dependent component, which reached a peak velocity that increased with target velocity and initial exposure duration, followed by a sustained secondary component that actually increased throughout extinction for 50- and 100-ms initial exposures. End-extinction eye velocity, reflecting extraretinal drive, increased with initial exposure from 50 to 100 ms but remained similar for longer exposures; it was significantly scaled to target velocity for 150- and 200-ms exposures. The results suggest that extraretinal drive is based on a sample of target velocity, mostly acquired during the first 150 ms, that is stored and forms a goal for generating appropriately scaled eye movements during absence of visual input. End-extinction eye velocity was significantly higher when target reappearance was expected than when it was not, confirming the importance of expectation in generating sustained smooth movement. However, end-extinction eye displacement remained similar irrespective of expectation, suggesting that the ability to use sampled velocity information to predict future target displacement operates independently of the control of smooth eye movement.

Population-level inferences for distributed MEG source localization under multiple constraints: application to face-evoked fields.

We address some key issues entailed by population inference about responses evoked in distributed brain systems using magnetoencephalography (MEG). In particular, we look at model selection issues at the within-subject level and feature selection issues at the between-subject level, using responses evoked by intact and scrambled faces around 170 ms (M170). We compared the face validity of subject-specific forward models and their summary statistics in terms of how estimated responses reproduced over subjects. At the within-subject level, we focused on the use of multiple constraints, or priors, for inverting distributed source models. We used restricted maximum likelihood (ReML) estimates of prior covariance components (in both sensor and source space) and show that their relative importance is conserved over subjects. At the between-subject level, we used standard anatomical normalization methods to create posterior probability maps that furnish inference about regionally specific population responses. We used these to compare different summary statistics, namely; (i) whether to test for differences between condition-specific source estimates, or whether to test the source estimate of differences between conditions, and (ii) whether to accommodate differences in source orientation by using signed or unsigned (absolute) estimates of source activity.

Quantitative differences in smooth pursuit and saccadic eye movements.

Recently it has been suggested that smooth pursuit (SP) and saccadic (SAC) eye movements share many common brain substrates in the planning and control of eye movements (Krauzlis in J Neurophysiol 91:591-603, 2004). Evidence is mounting that these two types of eye movements may also share similar mechanisms used to drive both reactive and predictive eye movement responses (Missal and Keller in J Neurophysiol 88:1880-1892, 2002, Keller and Missal in Ann NY Acad Sci 1004:29-39, 2003). The objective of this study was to quantify these similarities by establishing whether the behavioural response properties of human eye movements to predictive (PRD) and randomized (RND) conditions are quantitatively similar for both SP and SAC in directly comparable paradigms. Two previous studies have attempted to evaluate the coordination and motor preparation time of SP and saccadic eye movements (Erkelens in Vis Res 46:163-170, 2006; Joiner and Shelhamer in Exp Brain Res, Epub ahead of print, 2006). However, no previous study has quantitatively evaluated PRD and RND conditions to discretely presented SP and SAC tasks. We used simple SAC and SP paradigms in blocks of PRD and RND presentations, with eye movements monitored throughout using an IR-limbus eye-tracking system (Skalar). Twelve normal subjects (aged between 20 and 39 years) participated in the study which took place over two recording sessions, on two separate days. Data were analysed for two main comparable descriptive statistics: latency and eye velocity/displacement gain. The results presented here support the notion that SP and SAC share common brain substrates/mechanisms in the generation of responses to PRD and RND visual targets but differ in the movement preparation time.

The occluded onset pursuit paradigm: prolonging anticipatory smooth pursuit in the absence of visual feedback.

Humans can produce anticipatory smooth pursuit (ASP) for a few hundred ms prior to the appearance of a moving target. Once visual feedback is available, however, it is difficult to distinguish ASP from the visually-driven response with which it merges. Here we have developed a paradigm that extends the anticipatory period to show unequivocally how ASP can evolve over periods of up to 600 ms before being influenced by visual feedback. ASP was evoked by repeated presentation of constant velocity (ramp) stimuli preceded by auditory cues. The target was occluded during the initial part of the ramp, so that when it became visible it had already moved to an eccentric position. The occlusion period (T occ) varied from 0 to 500 ms in 100 ms increments; for each period ramps were presented in blocks of 8 with velocity held constant at 8, 16, 24 or 32 degrees/s. Eye displacement trajectories showed that subjects attempted to match the unseen target trajectory with a mixture of saccades and smooth pursuit. The smooth component was initiated progressively earlier in relation to target appearance as T occ increased, leading to progressively higher ASP gains by the time the target became visible. This prolongation of ASP throughout the occlusion period reveals the underlying internal drive that produces it, a drive that under normal circumstances quickly becomes masked by visual feedback.

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.

Scaling of smooth anticipatory eye velocity in response to sequences of discrete target movements in humans.

We investigated the ability to generate anticipatory smooth pursuit to sequences of constant velocity (ramp) stimuli of increasing complexity. Previously, it was shown that repeated presentation of sequences composed of four ramps with two speeds in two directions, evoked anticipatory smooth pursuit after only one or two presentations. Here, sequences of four or six ramps, each having a choice of four speeds and either one or two directions (uni- or bi-directional) were examined. The components of each sequence were presented as discrete ramps (duration: 400 ms; randomised velocity: 10-40 degrees/s), each starting from the centre with 1,200 ms periods of central fixation between ramps, allowing anticipatory activity to be segregated from prior eye movement. Auditory warning cues occurred 600 ms prior to each target presentation. Anticipatory smooth eye velocity was assessed by calculating eye velocity 50 ms after target onset (V 50), prior to the availability of visual feedback. Despite being required to re-fixate centre during inter-ramp gaps, subjects could still generate anticipatory smooth pursuit with V 50 comparable to single speed control sequences, but with less accuracy. In the steady state V 50 was appropriately scaled in proportion to upcoming target velocity for each ramp component and thus truly predictive. Only one to two repetitions were required to attain a steady-state for unidirectional sequences (four or six ramps), but three or four repeats were required for bi-directional sequences. Results suggest working memory can be used to acquire multiple levels of velocity information for prediction, but its use in rapid prediction is compromised when direction as well as speed must be retained.

Predicting the duration of ocular pursuit in humans.

This study examines the effects of expectation on the timing of ocular pursuit termination. Human subjects pursued repeated, constant velocity (15 or 30 degrees/s) target motion stimuli (ramps), moving left or right. Ramps were of constant duration (RD = 240, 480, 720 or 960 ms), resulting in anticipatory slowing of eye velocity prior to ramp termination and target extinction. At unexpected intervals RD was increased or decreased, but velocity remained constant. When RD increased eye velocity continued to decline, even though the target remained visible and continued to move. It took approximately 180 ms before eye velocity started to recover towards the steady state velocity level for the continued target motion. When RD decreased, eye velocity continued as if for a longer ramp duration, again taking approximately 180 ms before eye velocity started to decrease. These results suggest that timing of the response to the expected ramp duration had been pre-programmed on the basis of prior experience of ramp duration. Moreover, adjustments to timing occurred rapidly, within the second presentation of the new RD. Responses were compared to control conditions with randomised ramp duration. Eye velocity declined later in the controls for RD < or = 720 ms, as expected, but exhibited similar decline in predictable and randomised conditions for RD = 960 ms. Further controls established that eye velocity could only be reliably maintained until the end of the ramp when the target was expected to continue in motion after the end of the ramp. The results suggest that estimates of stimulus duration are made continuously in all conditions, based on expectancy of target termination.