Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

Decoding kinematic information from beta-band motor rhythms of speech motor cortex: a methodological/analytic approach using concurrent speech movement tracking and magnetoencephalography.

Introduction: Articulography and functional neuroimaging are two major tools for studying the neurobiology of speech production. Until now, however, it has generally not been feasible to use both in the same experimental setup because of technical incompatibilities between the two methodologies. Methods: Here we describe results from a novel articulography system dubbed Magneto-articulography for the Assessment of Speech Kinematics (MASK), which is technically compatible with magnetoencephalography (MEG) brain scanning systems. In the present paper we describe our methodological and analytic approach for extracting brain motor activities related to key kinematic and coordination event parameters derived from time-registered MASK tracking measurements. Data were collected from 10 healthy adults with tracking coils on the tongue, lips, and jaw. Analyses targeted the gestural landmarks of reiterated utterances/ipa/ and /api/, produced at normal and faster rates. Results: The results show that (1) Speech sensorimotor cortex can be reliably located in peri-rolandic regions of the left hemisphere; (2) mu (8-12 Hz) and beta band (13-30 Hz) neuromotor oscillations are present in the speech signals and contain information structures that are independent of those present in higher-frequency bands; and (3) hypotheses concerning the information content of speech motor rhythms can be systematically evaluated with multivariate pattern analytic techniques. Discussion: These results show that MASK provides the capability, for deriving subject-specific articulatory parameters, based on well-established and robust motor control parameters, in the same experimental setup as the MEG brain recordings and in temporal and spatial co-register with the brain data. The analytic approach described here provides new capabilities for testing hypotheses concerning the types of kinematic information that are encoded and processed within specific components of the speech neuromotor system.

Parietofrontal oscillations show hand-specific interactions with top-down movement plans.

To generate a hand-specific reach plan, the brain must integrate hand-specific signals with the desired movement strategy. Although various neurophysiology/imaging studies have investigated hand-target interactions in simple reach-to-target tasks, the whole brain timing and distribution of this process remain unclear, especially for more complex, instruction-dependent motor strategies. Previously, we showed that a pro/anti pointing instruction influences magnetoencephalographic (MEG) signals in frontal cortex that then propagate recurrently through parietal cortex (Blohm G, Alikhanian H, Gaetz W, Goltz HC, DeSouza JF, Cheyne DO, Crawford JD. NeuroImage 197: 306-319, 2019). Here, we contrasted left versus right hand pointing in the same task to investigate 1) which cortical regions of interest show hand specificity and 2) which of those areas interact with the instructed motor plan. Eight bilateral areas, the parietooccipital junction (POJ), superior parietooccipital cortex (SPOC), supramarginal gyrus (SMG), medial/anterior interparietal sulcus (mIPS/aIPS), primary somatosensory/motor cortex (S1/M1), and dorsal premotor cortex (PMd), showed hand-specific changes in beta band power, with four of these (M1, S1, SMG, aIPS) showing robust activation before movement onset. M1, SMG, SPOC, and aIPS showed significant interactions between contralateral hand specificity and the instructed motor plan but not with bottom-up target signals. Separate hand/motor signals emerged relatively early and lasted through execution, whereas hand-motor interactions only occurred close to movement onset. Taken together with our previous results, these findings show that instruction-dependent motor plans emerge in frontal cortex and interact recurrently with hand-specific parietofrontal signals before movement onset to produce hand-specific motor behaviors.NEW & NOTEWORTHY The brain must generate different motor signals depending on which hand is used. The distribution and timing of hand use/instructed motor plan integration are not understood at the whole brain level. Using MEG we show that different action planning subnetworks code for hand usage and integrating hand use into a hand-specific motor plan. The timing indicates that frontal cortex first creates a general motor plan and then integrates hand specificity to produce a hand-specific motor plan.

Speech Kinematics and Coordination Measured With an MEG-Compatible Speech Tracking System.

Articulography and functional neuroimaging are two major tools for studying the neurobiology of speech production. Until recently, however, it has generally not been possible to use both in the same experimental setup because of technical incompatibilities between the two methodologies. Here we describe results from a novel articulography system dubbed Magneto-articulography for the Assessment of Speech Kinematics (MASK), which we used to derive kinematic profiles of oro-facial movements during speech. MASK was used to characterize speech kinematics in two healthy adults, and the results were compared to measurements from a separate participant with a conventional Electromagnetic Articulography (EMA) system. Analyses targeted the gestural landmarks of reiterated utterances /ipa/, /api/ and /pataka/. The results demonstrate that MASK reliably characterizes key kinematic and movement coordination parameters of speech motor control. Since these parameters are intrinsically registered in time with concurrent magnetoencephalographic (MEG) measurements of neuromotor brain activity, this methodology paves the way for innovative cross-disciplinary studies of the neuromotor control of human speech production, speech development, and speech motor disorders.

Somatosensory Plasticity in Hemiplegic Cerebral Palsy Following Constraint Induced Movement Therapy.

BACKGROUND: Children with hemiplegic cerebral palsy (HCP) experience upper limb somatosensory and motor deficits. Although constraint-induced movement therapy (CIMT) improves motor function, its impact on somatosensory function remains underinvestigated. OBJECTIVE: The objective of this study was to evaluate somatosensory perception and related brain responses in children with HCP, before and after a somatosensory enhanced CIMT protocol, as measured using clinical sensory and motor assessments and magnetoencephalography. METHODS: Children with HCP attended a somatosensory enhanced CIMT camp. Clinical somatosensory (tactile registration, 2-point discrimination, stereognosis, proprioception, kinesthesia) and motor outcomes (Quality of Upper Extremity Skills [QUEST] Total/Grasp, Jebsen-Taylor Hand Function Test, grip strength, Assisting Hand Assessment), as well as latency and amplitude of magnetoencephalography somatosensory evoked fields (SEF), were assessed before and after the CIMT camp with paired sample t-tests or Wilcoxon signed-rank tests. RESULTS: Twelve children with HCP (mean age: 7.5 years, standard deviation: 2.4) participated. Significant improvements in tactile registration for the affected (hemiplegic) hand (Z = 2.39, P = 0.02) were observed in addition to statistically and clinically significant improvements in QUEST total (t = 3.24, P = 0.007), QUEST grasp (t = 3.24, P = 0.007), Assisting Hand Assessment (Z = 2.25, P = 0.03), and Jebsen-Taylor Hand Function Test (t = -2.62, P = 0.03). A significant increase in the SEF peak amplitude was also found in the affected hand 100 ms after stimulus onset (t = -2.22, P = 0.04). CONCLUSIONS: Improvements in somatosensory clinical function and neural processing in the affected primary somatosensory cortex in children with HCP were observed after a somatosensory enhanced CIMT program. Further investigation is warranted to continue to evaluate the effectiveness of a sensory enhanced CIMT program in larger samples and controlled study designs.

Complexity-Dependent Modulations of Beta Oscillations for Verbal and Nonverbal Movements.

Purpose The planning and execution of motor behaviors require coordination of neurons that are established through synchronization of neural activity. Movements are typically preceded by event-related desynchronization (ERD) in the beta range (15-30 Hz) primarily localized in the motor cortex, while movement onset is associated with event-related synchronization (ERS). It is hypothesized that ERD is important for movement preparation and execution, and ERS serves to inhibit movement and update the motor plan. The primary objective of this study was to determine to what extent movement-related oscillatory brain patterns (ERD and ERS) during verbal and nonverbal tasks may be affected differentially by variations in task complexity. Method Seventeen right-handed adult participants (nine women, eight men; M age = 25.8 years, SD = 5.13) completed a sequential button press and verbal task. The final analyses included data for 15 participants for the nonverbal task and 13 for the verbal task. Both tasks consisted of two complexity levels: simple and complex sequences. Magnetoencephalography was used to record modulations in beta band brain oscillations during task performance. Results Both the verbal and button press tasks were characterized by significant premovement ERD and postmovement ERS. However, only simple sequences showed a distinct transient synchronization during the premovement phase of the task. Differences between the two tasks were reflected in both latency and peak amplitude of ERD and ERS, as well as in lateralization of oscillations. Conclusions Both verbal and nonverbal movements showed a significant desynchronization of beta oscillations during the movement preparation and holding phase and a resynchronization upon movement termination. Importantly, the premovement phase for simple but not complex tasks was characterized by a transient partial synchronization. In addition, the data revealed significant differences between the two tasks in terms of lateralization of oscillatory modulations. Our findings suggest that, while data from the general motor control research can inform our understanding of speech motor control, significant differences exist between the two motor systems that caution against overgeneralization of underlying neural control processes.

White matter microstructural differences underlying beta oscillations during speech in adults who stutter.

The basal ganglia-thalamocortical (BGTC) loop may underlie speech deficits in developmental stuttering. In this study, we investigated the relationship between abnormal cortical neural oscillations and structural integrity alterations in adults who stutter (AWS) using a novel magnetoencephalography (MEG) guided tractography approach. Beta oscillations were analyzed using sensorimotor speech MEG, and white matter pathways were examined using tract-based spatial statistics (TBSS) and probabilistic tractography in 11 AWS and 11 fluent speakers. TBSS analysis revealed overlap between cortical regions of increased beta suppression localized to the mouth motor area and a reduced fractional anisotropy (FA) in the AWS group. MEG-guided tractography showed reduced FA within the BGTC loop from left putamen to subject-specific MEG peak. This is the first study to provide evidence that structural abnormalities may be associated with functional deficits in stuttering and reflect a network deficit within the BGTC loop that includes areas of the left ventral premotor cortex and putamen.

Inhibitory Control in the Absence of Awareness: Interactions Between Frontal and Motor Cortex Oscillations Mediate Implicitly Learned Responses.

Cognitive control of action is associated with conscious effort and is hypothesised to be reflected by increased frontal theta activity. However, the functional role of these increases in theta power, and how they contribute to cognitive control remains unknown. We conducted an MEG study to test the hypothesis that frontal theta oscillations interact with sensorimotor signals in order to produce controlled behaviour, and that the strength of these interactions will vary with the amount of control required. We measured neuromagnetic activity in 16 healthy adults performing a response inhibition (Go/Switch) task, known from previous work to modulate cognitive control requirements using hidden patterns of Go and Switch cues. Learning was confirmed by reduced reaction times (RT) to patterned compared to random Switch cues. Concurrent measures of pupil diameter revealed changes in subjective cognitive effort with stimulus probability, even in the absence of measurable behavioural differences, revealing instances of covert variations in cognitive effort. Significant theta oscillations were found in five frontal brain regions, with theta power in the right middle frontal and right premotor cortices parametrically increasing with cognitive effort. Similar increases in oscillatory power were also observed in motor cortical gamma, suggesting an interaction. Right middle frontal and right precentral theta activity predicted changes in pupil diameter across all experimental conditions, demonstrating a close relationship between frontal theta increases and cognitive control. Although no theta-gamma cross-frequency coupling was found, long-range theta phase coherence among the five significant sources between bilateral middle frontal, right inferior frontal, and bilateral premotor areas was found, thus providing a mechanism for the relay of cognitive control between frontal and motor areas via theta signalling. Furthermore, this provides the first evidence for the sensitivity of frontal theta oscillations to implicit motor learning and its effects on cognitive load. More generally these results present a possible a mechanism for this frontal theta network to coordinate response preparation, inhibition and execution.

Gender differences in navigation performance are associated with differential theta and high-gamma activities in the hippocampus and parahippocampus.

Hippocampal rhythms are important for spatial navigation. This study examined whether gender differences in human navigation performance are associated with differences in hippocampal rhythms. We measured brain activities in males and females with whole-head magnetoencephalography (MEG), while they performed a virtual Morris water maze task. Behavioural results showed clear gender differences: males were significantly faster than females; unlike males, females did not show improved navigation performance in a familiar vs. new environment. MEG results showed that the magnitudes of right hippocampal/parahippocampal theta rhythm were similar between the two groups during navigation in a new environment; however, unlike males who exhibited a significant decrease in right hippocampal/parahippocampal theta power in the familiar environment shown before, females showed no change. This result may suggest faster environmental learning in males vs. females. After navigating in the new environment during the inter-trial (ITI) rest periods, males showed significantly higher right hippocampal/parahippocampal high-gamma power than females, suggesting greater consolidation in males. Moreover, right hippocampal/parahippocampal theta power during navigation correlated with navigation performance in both genders; high-gamma power during the ITI was correlated with navigation performance only in males. These associations may provide further support for the functional importance of theta and high-gamma rhythms in navigation. Overall, this study provides new insights into the neurophysiological mechanisms underlying gender differences in spatial navigation.

Theta oscillations support the interface between language and memory.

Recent evidence shows that hippocampal theta oscillations, usually linked to memory and navigation, are also observed during online language processing, suggesting a shared neurophysiological mechanism between language and memory. However, it remains to be established what specific roles hippocampal theta oscillations may play in language, and whether and how theta mediates the communication between the hippocampus and the perisylvian cortical areas, generally thought to support language processing. With whole-head magnetoencephalographic (MEG) recordings, the present study investigated these questions with two experiments. Using a violation paradigm, extensively used for studying neural underpinnings of different aspects of linguistic processing, we found increased theta power (4-8 â€‹Hz) in the hippocampal formation, when participants read a semantically incorrect vs. correct sentence ending. Such a pattern of results was replicated using different sentence stimuli in another cohort of participants. Importantly, no significant hippocampal theta power increase was found when participants read a semantically correct but syntactically incorrect sentence ending vs. a correct sentence ending. These findings may suggest that hippocampal theta oscillations are specifically linked to lexical-semantic related processing, and not general information processing in sentence reading. Furthermore, we found significantly transient theta phase coupling between the hippocampus and the left superior temporal gyrus, a hub area of the cortical network for language comprehension. This transient theta phase coupling may provide an important channel that links the memory and language systems for the generation of sentence meaning. Overall, these findings help specify the role of hippocampal theta in language, and provide a novel neurophysiological mechanism at the network level that may support the interface between memory and language.

Mapping neural dynamics underlying saccade preparation and execution and their relation to reaction time and direction errors.

Our ability to control and inhibit automatic behaviors is crucial for negotiating complex environments, all of which require rapid communication between sensory, motor, and cognitive networks. Here, we measured neuromagnetic brain activity to investigate the neural timing of cortical areas needed for inhibitory control, while 14 healthy young adults performed an interleaved prosaccade (look at a peripheral visual stimulus) and antisaccade (look away from stimulus) task. Analysis of how neural activity relates to saccade reaction time (SRT) and occurrence of direction errors (look at stimulus on antisaccade trials) provides insight into inhibitory control. Neuromagnetic source activity was used to extract stimulus-aligned and saccade-aligned activity to examine temporal differences between prosaccade and antisaccade trials in brain regions associated with saccade control. For stimulus-aligned antisaccade trials, a longer SRT was associated with delayed onset of neural activity within the ipsilateral parietal eye field (PEF) and bilateral frontal eye field (FEF). Saccade-aligned activity demonstrated peak activation 10ms before saccade-onset within the contralateral PEF for prosaccade trials and within the bilateral FEF for antisaccade trials. In addition, failure to inhibit prosaccades on anti-saccade trials was associated with increased activity prior to saccade onset within the FEF contralateral to the peripheral stimulus. This work on dynamic activity adds to our knowledge that direction errors were due, at least in part, to a failure to inhibit automatic prosaccades. These findings provide novel evidence in humans regarding the temporal dynamics within oculomotor areas needed for saccade programming and the role frontal brain regions have on top-down inhibitory control.

Individual differences in motor development during early childhood: An MEG study.

In a previous study, we reported the first measurements of pre-movement and sensorimotor cortex activity in preschool age children (ages 3-5 years) using a customized pediatric magnetoencephalographic system. Movement-related activity in the sensorimotor cortex differed from that typically observed in adults, suggesting that maturation of cortical motor networks was still incomplete by late preschool age. Here we compare these earlier results to a group of school age children (ages 6-8 years) including seven children from the original study measured again two years later, and a group of adults (mean age 31.1 years) performing the same task. Differences in movement-related brain activity were observed both longitudinally within children in which repeated measurements were made, and cross-sectionally between preschool age children, school age children, and adults. Movement-related mu (8-12 Hz) and beta (15-30 Hz) oscillations demonstrated linear increases in amplitude and mean frequency with age. In contrast, movement-evoked gamma synchronization demonstrated a step-like transition from low (30-50 Hz) to high (70-90 Hz) narrow-band oscillations, and this occurred at different ages in different children. Notably, pre-movement activity ('readiness fields') observed in adults was absent in even the oldest children. These are the first direct observations of brain activity accompanying motor responses throughout early childhood, confirming that maturation of this activity is still incomplete by mid-childhood. In addition, individual children demonstrated markedly different developmental trajectories in movement-related brain activity, suggesting that individual differences need to be taken into account when studying motor development across age groups.

Disrupted reinforcement learning during post-error slowing in ADHD.

ADHD is associated with altered dopamine regulated reinforcement learning on prediction errors. Despite evidence of categorically altered error processing in ADHD, neuroimaging advances have largely investigated models of normal reinforcement learning in greater detail. Further, although reinforcement leaning critically relies on ventral striatum exerting error magnitude related thresholding influences on substantia nigra (SN) and dorsal striatum, these thresholding influences have never been identified with neuroimaging. To identify such thresholding influences, we propose that error magnitude related activities must first be separated from opposite activities in overlapping neural regions during error detection. Here we separate error detection from magnitude related adjustment (post-error slowing) during inhibition errors in the stop signal task in typically developing (TD) and ADHD adolescents using fMRI. In TD, we predicted that: 1) deactivation of dorsal striatum on error detection interrupts ongoing processing, and should be proportional to right frontoparietal response phase activity that has been observed in the SST; 2) deactivation of ventral striatum on post-error slowing exerts thresholding influences on, and should be proportional to activity in dorsal striatum. In ADHD, we predicted that ventral striatum would instead correlate with heightened amygdala responses to errors. We found deactivation of dorsal striatum on error detection correlated with response-phase activity in both groups. In TD, post-error slowing deactivation of ventral striatum correlated with activation of dorsal striatum. In ADHD, ventral striatum correlated with heightened amygdala activity. Further, heightened activities in locus coeruleus (norepinephrine), raphe nucleus (serotonin) and medial septal nuclei (acetylcholine), which all compete for control of DA, and are altered in ADHD, exhibited altered correlations with SN. All correlations in TD were replicated in healthy adults. Results in TD are consistent with dopamine regulated reinforcement learning on post-error slowing. In ADHD, results are consistent with heightened activities in the amygdala and non-dopaminergic neurotransmitter nuclei preventing reinforcement learning.

Treatment of neurotrophic keratopathy with minimally invasive corneal neurotisation: long-term clinical outcomes and evidence of corneal reinnervation.

AIM: To report clinical outcomes and evidence of corneal innervation in patients with neurotrophic keratopathy (NK) treated with minimally invasive corneal neurotisation (MICN) using a sural nerve graft and donor sensory nerves from the face. METHODS: Patients undergoing MICN at The Hospital for Sick Children, Toronto, Canada were prospectively recruited. Data on central corneal sensation (CCS, measured with Cochet-Bonnet aesthesiometer), best-corrected visual acuity (BCVA) and corneal epithelial integrity were collected. In four patients who subsequently underwent keratoplasty, immunohistochemical analysis was performed on the corneal explants. One patient underwent magnetoencephalography (MEG) after MICN to characterise the neurophysiological pathways involved. RESULTS: Between November 2012 and February 2017, 19 eyes of 16 patients underwent MICN. Mean follow-up was 24.0±16.1 months (range, 6-53). Mean CCS significantly improved from 0.8±2.5 mm to 49.7±15.5 mm at final follow-up (p<0.001). Mean BCVA remained stable, and the number of episodes of corneal epithelial defects after MICN was significantly reduced compared with the year leading up to the procedure (21% vs 89%, respectively; p<0.0001). In the four eyes that underwent keratoplasties after MICN, all transplants fully re-epithelialised and regained sensation subsequently. Immunohistochemistry of the corneal explants demonstrated evidence of corneal reinnervation. In one patient who was 8 months after MICN, novel neuroactivity was detected on MEG in the ipsilateral somatosensory cortex on mechanical stimulation of the reinnervated cornea. CONCLUSIONS: By providing an alternative source of innervation, MICN improves corneal sensation and stabilises the corneal epithelium, permitting optical keratoplasty for patients with NK-related corneal opacity.

Pupillary responses and reaction times index different cognitive processes in a combined Go/Switch incidental learning task.

In previous studies we have provided evidence that performance in speeded response tasks with infrequent target stimuli reflects both automatic and controlled cognitive processes, based on differences in reaction time (RT) and task-related brain responses (Cheyne et al. 2012, Isabella et al. 2015). Here we test the hypothesis that such shifts in cognitive control may be influenced by changes in cognitive load related to stimulus predictability, and that these changes can be indexed by task-evoked pupillary responses (TEPR). We manipulated stimulus predictability using fixed stimulus sequences that were unknown to the participants in a Go/Switch task (requiring a switch response on 25% of trials) while monitoring TEPR as a measure of cognitive load in 12 healthy adults. Results showed significant improvement in performance (reduced RT, increased efficiency) for repeated sequences compared to occasional deviant sequences (10% probability) indicating that incidental learning of the predictable sequences facilitated performance. All behavioral measures varied between Switch and Go trials (RT, efficiency), however mean TEPR amplitude (mTEPR) and latency to maximum pupil dilation were particularly sensitive to Go/Switch. Results were consistent with the hypothesis that mTEPR indexes cognitive load, whereas TEPR latency indexes time to response selection, independent from response execution. The present study provides evidence that incidental pattern learning during response inhibition tasks may modulate several cognitive processes including cognitive load, effort, response selection and execution, which can in turn have differential effects on measures of performance. In particular, we demonstrate that reaction time may not be indicative of underlying cognitive load.

BrainWave: A Matlab Toolbox for Beamformer Source Analysis of MEG Data.

BrainWave is an easy-to-use Matlab toolbox for the analysis of magnetoencephalography data. It provides a graphical user interface for performing minimum-variance beamforming analysis with rapid and interactive visualization of evoked and induced brain activity. This article provides an overview of the main features of BrainWave with a step-by-step demonstration of how to proceed from raw experimental data to group source images and time series analyses. This includes data selection and pre-processing, magnetic resonance image co-registration and normalization procedures, and the generation of volumetric (whole-brain) or cortical surface based source images, and corresponding source time series as virtual sensor waveforms and their time-frequency representations. We illustrate these steps using example data from a recently published study on response inhibition (Isabella et al., 2015) using the sustained attention to response task paradigm in 12 healthy adult participants. In this task participants were required to press a button with their right index finger to a rapidly presented series of numerical digits and withhold their response to an infrequently presented target digit. This paradigm elicited movement-locked brain responses, as well as task-related modulation of brain rhythmic activity in different frequency bands (e.g., theta, beta, and gamma), and is used to illustrate two different types of source reconstruction implemented in the BrainWave toolbox: (1) event-related beamforming of averaged brain responses and (2) beamformer analysis of modulation of rhythmic brain activity using the synthetic aperture magnetometry algorithm. We also demonstrate the ability to generate group contrast images between different response types, using the example of frontal theta activation patterns during error responses (failure to withhold on target trials). BrainWave is free academic software available for download at http://cheynelab.utoronto.ca/brainwave along with supporting software and documentation. The development of the BrainWave toolbox was supported by grants from the Canadian Institutes of Health Research, the National Research and Engineering Research Council of Canada, and the Ontario Brain Institute.

Non-invasive Investigation of Human Hippocampal Rhythms Using Magnetoencephalography: A Review.

Hippocampal rhythms are believed to support crucial cognitive processes including memory, navigation, and language. Due to the location of the hippocampus deep in the brain, studying hippocampal rhythms using non-invasive magnetoencephalography (MEG) recordings has generally been assumed to be methodologically challenging. However, with the advent of whole-head MEG systems in the 1990s and development of advanced source localization techniques, simulation and empirical studies have provided evidence that human hippocampal signals can be sensed by MEG and reliably reconstructed by source localization algorithms. This paper systematically reviews simulation studies and empirical evidence of the current capacities and limitations of MEG "deep source imaging" of the human hippocampus. Overall, these studies confirm that MEG provides a unique avenue to investigate human hippocampal rhythms in cognition, and can bridge the gap between animal studies and human hippocampal research, as well as elucidate the functional role and the behavioral correlates of human hippocampal oscillations.

High-gamma activity in the human hippocampus and parahippocampus during inter-trial rest periods of a virtual navigation task.

In rodents, hippocampal cell assemblies formed during learning of a navigation task are observed to re-emerge during resting (offline) periods, accompanied by high-frequency oscillations (HFOs). This phenomenon is believed to reflect mechanisms for strengthening newly-formed memory traces. Using magnetoencephalography recordings and a beamforming source location algorithm (synthetic aperture magnetometry), we investigated high-gamma (80-140 Hz) oscillations in the hippocampal region in 18 human participants during inter-trial rest periods in a virtual navigation task. We found right hippocampal gamma oscillations mirrored the pattern of theta power in the same region during navigation, varying as a function of environmental novelty. Gamma power during inter-trial rest periods was positively correlated with theta power during navigation in the first task set when the environment was new and predicted greater performance improvement in the subsequent task set two where the environment became familiar. These findings provide evidence for human hippocampal reactivation accompanied by high-gamma activities immediately after learning and establish a link between hippocampal high-gamma activities and subsequent memory performance.

A preliminary study on the neural oscillatory characteristics of motor preparation prior to dysfluent and fluent utterances in adults who stutter.

PURPOSE: Recent literature on speech production in adults who stutter (AWS) has begun to investigate the neural mechanisms characterizing speech-motor preparation prior to speech onset. Compelling evidence has suggested that stuttering is associated with atypical processing within cortical and sub-cortical motor networks, particularly in the beta frequency range, that is effective before speech production even begins. Due to low stuttering frequency in experimental settings, however, the literature has so far predominantly reported on fluent speech production in AWS. Consequently, we have limited understanding of the way in which fluent speech processing in AWS is disturbed leading to a dysfluency. This preliminary study aims to characterize neural motor preparation prior to stuttered utterances in AWS. METHODS: Eight AWS participated in the study. A total of 336 stuttered utterances were compared to the participants' own fluent utterance productions. Beta oscillatory activity was analyzed with magnetoencephalography (MEG) and localized using minimum-variance beamforming. RESULTS: Preparation for speech production induced beta suppression in the bilateral premotor and motor cortex prior to speech onset. Although the data revealed some interesting trends, no significant differences between fluent and stuttered utterances were present. This may be due to a relatively low and variable number of stuttered trials analyzed in individual subjects. CONCLUSION: While the lack of significant differences may have resulted from the relatively low numbers of stuttered utterances across subjects, the observed trends demonstrated that the proposed methodology and experimental paradigm is a promising approach for future studies aiming to characterize differences between stuttered and fluent speech.

The functional role of human right hippocampal/parahippocampal theta rhythm in environmental encoding during virtual spatial navigation.

Low frequency theta band oscillations (4-8 Hz) are thought to provide a timing mechanism for hippocampal place cell firing and to mediate the formation of spatial memory. In rodents, hippocampal theta has been shown to play an important role in encoding a new environment during spatial navigation, but a similar functional role of hippocampal theta in humans has not been firmly established. To investigate this question, we recorded healthy participants' brain responses with a 160-channel whole-head MEG system as they performed two training sets of a virtual Morris water maze task. Environment layouts (except for platform locations) of the two sets were kept constant to measure theta activity during spatial learning in new and familiar environments. In line with previous findings, left hippocampal/parahippocampal theta showed more activation navigating to a hidden platform relative to random swimming. Consistent with our hypothesis, right hippocampal/parahippocampal theta was stronger during the first training set compared to the second one. Notably, theta in this region during the first training set correlated with spatial navigation performance across individuals in both training sets. These results strongly argue for the functional importance of right hippocampal theta in initial encoding of configural properties of an environment during spatial navigation. Our findings provide important evidence that right hippocampal/parahippocampal theta activity is associated with environmental encoding in the human brain. Hum Brain Mapp 38:1347-1361, 2017. © 2016 Wiley Periodicals, Inc.