Tri-axial rubidium and helium optically pumped magnetometers for on-scalp magnetoencephalography recording of interictal epileptiform discharges: a case study.

Cryogenic magnetoencephalography (MEG) enhances the presurgical assessment of refractory focal epilepsy (RFE). Optically pumped magnetometers (OPMs) are cryogen-free sensors that enable on-scalp MEG recordings. Here, we investigate the application of tri-axial OPMs [87Rb (Rb-OPM) and 4He gas (He-OPM)] for the detection of interictal epileptiform discharges (IEDs). IEDs were recorded simultaneously with 4 tri-axial Rb- and 4 tri-axial He-OPMs in a child with RFE. IEDs were identified visually, isolated from magnetic background noise using independent component analysis (ICA) and were studied following their optimal magnetic field orientation thanks to virtual sensors. Most IEDs (>1,000) were detectable by both He- and Rb-OPM recordings. IEDs were isolated by ICA and the resulting magnetic field oriented mostly tangential to the scalp in Rb-OPMs and radial in He-OPMs. Likely due to differences in sensor locations, the IED amplitude was higher with Rb-OPMs. This case study shows comparable ability of Rb-OPMs and He-OPMs to detect IEDs and the substantial benefits of triaxial OPMs to detect IEDs from different sensor locations. Tri-axial OPMs allow to maximize spatial brain sampling for IEDs detection with a limited number of sensors.

Helium Optically Pumped Magnetometers Can Detect Epileptic Abnormalities as Well as SQUIDs as Shown by Intracerebral Recordings.

Magnetoencephalography based on superconducting quantum interference devices (SQUIDs) has been shown to improve the diagnosis and surgical treatment decision for presurgical evaluation of drug-resistant epilepsy. Still, its use remains limited because of several constraints such as cost, fixed helmet size, and the obligation of immobility. A new generation of sensors, optically pumped magnetometers (OPMs), could overcome these limitations. In this study, we validate the ability of helium-based OPM (4He-OPM) sensors to record epileptic brain activity thanks to simultaneous recordings with intracerebral EEG [stereotactic EEG (SEEG)]. We recorded simultaneous SQUIDs-SEEG and 4He-OPM-SEEG signals in one patient during two sessions. We show that epileptic activities on intracerebral EEG can be recorded by OPMs with a better signal-to noise ratio than classical SQUIDs. The OPM sensors open new venues for the widespread application of magnetoencephalography in the management of epilepsy and other neurologic diseases and fundamental neuroscience.

A New Generation of OPM for High Dynamic and Large Bandwidth MEG: The 4He OPMs-First Applications in Healthy Volunteers.

MagnetoEncephaloGraphy (MEG) provides a measure of electrical activity in the brain at a millisecond time scale. From these signals, one can non-invasively derive the dynamics of brain activity. Conventional MEG systems (SQUID-MEG) use very low temperatures to achieve the necessary sensitivity. This leads to severe experimental and economical limitations. A new generation of MEG sensors is emerging: the optically pumped magnetometers (OPM). In OPM, an atomic gas enclosed in a glass cell is traversed by a laser beam whose modulation depends on the local magnetic field. MAG4Health is developing OPMs using Helium gas (4He-OPM). They operate at room temperature with a large dynamic range and a large frequency bandwidth and output natively a 3D vectorial measure of the magnetic field. In this study, five 4He-OPMs were compared to a classical SQUID-MEG system in a group of 18 volunteers to evaluate their experimental performances. Considering that the 4He-OPMs operate at real room temperature and can be placed directly on the head, our assumption was that 4He-OPMs would provide a reliable recording of physiological magnetic brain activity. Indeed, the results showed that the 4He-OPMs showed very similar results to the classical SQUID-MEG system by taking advantage of a shorter distance to the brain, despite having a lower sensitivity.

Performance Analysis of Optically Pumped 4He Magnetometers vs. Conventional SQUIDs: From Adult to Infant Head Models.

Optically pumped magnetometers (OPMs) are new, room-temperature alternatives to superconducting quantum interference devices (SQUIDs) for measuring the brain's magnetic fields. The most used OPM in MagnetoEncephaloGraphy (MEG) are based on alkali atoms operating in the spin-exchange relaxation-free (SERF) regime. These sensors do not require cooling but have to be heated. Another kind of OPM, based on the parametric resonance of 4He atoms are operated at room temperature, suppressing the heat dissipation issue. They also have an advantageous bandwidth and dynamic range more suitable for MEG recordings. We quantitatively assessed the improvement (relative to a SQUID magnetometers array) in recording the magnetic field with a wearable 4He OPM-MEG system through data simulations. The OPM array and magnetoencephalography forward models were based on anatomical MRI data from an adult, a nine-year-old child, and 10 infants aged between one month and two years. Our simulations showed that a 4He OPMs array offers markedly better spatial specificity than a SQUID magnetometers array in various key performance areas (e.g., signal power, information content, and spatial resolution). Our results are also discussed regarding previous simulation results obtained for alkali OPM.

Analysis of Graphomotor Tests with Machine Learning Algorithms for an Early and Universal Pre-Diagnosis of Dysgraphia.

Five to ten percent of school-aged children display dysgraphia, a neuro-motor disorder that causes difficulties in handwriting, which becomes a handicap in the daily life of these children. Yet, the diagnosis of dysgraphia remains tedious, subjective and dependent to the language besides stepping in late in the schooling. We propose a pre-diagnosis tool for dysgraphia using drawings called graphomotor tests. These tests are recorded using graphical tablets. We evaluate several machine-learning models and compare them to build this tool. A database comprising 305 children from the region of Grenoble, including 43 children with dysgraphia, has been established and diagnosed by specialists using the BHK test, which is the gold standard for the diagnosis of dysgraphia in France. We performed tests of classification by extracting, correcting and selecting features from the raw data collected with the tablets and achieved a maximum accuracy of 73% with cross-validation for three models. These promising results highlight the relevance of graphomotor tests to diagnose dysgraphia earlier and more broadly.

Helium-4 magnetometers for room-temperature biomedical imaging: toward collective operation and photon-noise limited sensitivity.

Optically-pumped magnetometers constitute a valuable tool for imaging biological magnetic signals without cryogenic cooling. Nowadays, numerous developments are being pursued using alkali-based magnetometers, which have demonstrated excellent sensitivities in the spin-exchange relaxation free (SERF) regime that requires heating to >100 °C. In contrast, metastable helium-4 based magnetometers work at any temperature, which allows a direct contact with the scalp, yielding larger signals and a better patient comfort. However former 4He magnetometers displayed large noises of >200 fT/Hz1/2 with 300-Hz bandwidth. We describe here an improved magnetometer reaching a sensitivity better than 50 fT/Hz1/2, nearly the photon shot noise limit, with a bandwidth of 2 kHz. Like other zero-field atomic magnetometers, these magnetometers can be operated in closed-loop architecture reaching several hundredths nT of dynamic range. A small array of 4 magnetometers operating in a closed loop has been tested with a successful correction of the cross-talks.

Space-Time-Frequency Multi-Sensor Analysis for Motor Cortex Localization Using Magnetoencephalography.

Brain source imaging and time frequency mapping (TFM) are commonly used in magneto/electro encephalography (M/EEG) imaging. However, these methods suffer from important limitations. Source imaging is based on an ill-posed inverse problem leading to instability of source localization solutions, has a limited capacity to localize high frequency oscillations and loses its robustness for induced responses (ill-defined trigger). The drawback of TFM is that it involves independent analysis of signals from a number of frequency bands, and from co-localized sensors. In the present article, a regression-based multi-sensor space-time-frequency analysis (MSA) approach, which integrates co-localized sensors and/or multi-frequency information, is proposed. To estimate task-specific brain activations, MSA uses cross-validated, shifted, multiple Pearson correlation, calculated from the time-frequency transformed brain signal and the binary signal of stimuli. The results are projected from the sensor space onto the cortical surface. To assess MSA performance, the proposed method was compared to the weighted minimum norm estimate (wMNE) source imaging method, in terms of spatial selectivity and robustness against an ill-defined trigger. Magnetoencephalography (MEG) recordings were performed in fourteen subjects during two motor tasks: finger tapping and elbow flexion/extension. In particular, our results show that the MSA approach provides good localization performance when compared to wMNE and statistically significant improvement of robustness against ill-defined trigger.

Magnetoencephalography With Optically Pumped 4He Magnetometers at Ambient Temperature.

In this paper, we present the first proof of concept confirming the possibility to record magnetoencephalographic (MEG) signals with optically pumped magnetometers (OPMs) based on the parametric resonance of 4He atoms. The main advantage of this kind of OPM is the possibility to provide a tri-axis vector measurement of the magnetic field at room-temperature (the 4He vapor is neither cooled nor heated). The sensor achieves a sensitivity of 210 fT/ √ Hz in the bandwidth [2-300 Hz]. MEG simulation studies with a brain phantom were cross-validated with real MEG measurements on a healthy subject. For both studies, MEG signal was recorded consecutively with OPMs and superconducting quantum interference devices (SQUIDs) used as reference sensors. For healthy subject MEG recordings, three MEG proofs of concept were carried out: auditory evoked fields, visual evoked fields, and spontaneous activity. M100 peaks have been detected on evoked responses recorded by both OPMs and SQUIDs with no significant difference in latency. Concerning spontaneous activity, an attenuation of the signal power between 8-12 Hz (alpha band) related to eyes opening has been observed with OPM similarly to SQUID. All these results confirm that the room temperature vector 4He OPMs can record MEG signals and provide reliable information on brain activity.

Evidence for a hierarchy of predictions and prediction errors in human cortex.

According to hierarchical predictive coding models, the cortex constantly generates predictions of incoming stimuli at multiple levels of processing. Responses to auditory mismatches and omissions are interpreted as reflecting the prediction error when these predictions are violated. An alternative interpretation, however, is that neurons passively adapt to repeated stimuli. We separated these alternative interpretations by designing a hierarchical auditory novelty paradigm and recording human EEG and magnetoencephalographic (MEG) responses to mismatching or omitted stimuli. In the crucial condition, participants listened to frequent series of four identical tones followed by a fifth different tone, which generates a mismatch response. Because this response itself is frequent and expected, the hierarchical predictive coding hypothesis suggests that it should be cancelled out by a higher-order prediction. Three consequences ensue. First, the mismatch response should be larger when it is unexpected than when it is expected. Second, a perfectly monotonic sequence of five identical tones should now elicit a higher-order novelty response. Third, omitting the fifth tone should reveal the brain's hierarchical predictions. The rationale here is that, when a deviant tone is expected, its omission represents a violation of two expectations: a local prediction of a tone plus a hierarchically higher expectation of its deviancy. Thus, such an omission should induce a greater prediction error than when a standard tone is expected. Simultaneous EEE- magnetoencephalographic recordings verify those predictions and thus strongly support the predictive coding hypothesis. Higher-order predictions appear to be generated in multiple areas of frontal and associative cortices.

Modeling of entorhinal cortex and simulation of epileptic activity: insights into the role of inhibition-related parameters.

This paper describes a macroscopic neurophysiologically relevant model of the entorhinal cortex (EC), a brain structure largely involved in human mesio-temporal lobe epilepsy. This model is intervalidated in the experimental framework of ictogenesis animal model (isolated guinea-pig brain perfused with bicuculline). Using sensitivity and stability analysis, an investigation of model parameters related to GABA neurotransmission (recognized to be involved in epileptic activity generation) was performed. Based on spectral and statistical features, simulated signals generated from the model for multiple GABAergic inhibition-related parameter values were classified into eight classes of activity. Simulated activities showed striking agreement (in terms of realism) with typical epileptic activities identified in field potential recordings performed in the experimental model. From this combined computational/experimental approach, hypotheses are suggested about the role of different types of GABAergic neurotransmission in the generation of epileptic activities in EC.

Relationship between intracerebral gamma oscillations and slow potentials in the human sensorimotor cortex.

Changes in sensorimotor rhythms (mu, beta and gamma) and movement-related cortical potentials (MRCPs) are both generated principally by the contralateral sensorimotor areas during the execution of self-paced movement. They appear to reflect movement control mechanisms, which remain partially unclear. With the aim of better understanding their sources and significance, we recorded MRCPs and sensorimotor rhythms during and after self-paced movement using intracerebral electrodes in eight epileptic subjects investigated by stereoelectroencephalography. The results showed that: (i) there is a strong spatial relationship between the late components of movement--the so-called motor potential (MP) and post-movement complex (PMc)--and gamma event-related synchronization (ERS) within the 40-60 Hz band, as the MP/PMc always occurred in contacts displaying gamma ERS (the primary sensorimotor areas), whereas mu and beta reactivities were more diffuse; and (ii) MPs and PMc are both generated by the primary motor and somatosensory areas, but with distinct sources. Hence, this could mean that kinesthesic sensory afferences project to neurons other than those firing during the pyramidal tract volley. The PMc and low gamma ERS represent two electrophysiological facets of kinesthesic feedback from the joints and muscles involved in the movement to the sensorimotor cortex. It could be suggested that gamma oscillations within the 40-60 Hz band could serve to synchronize the activities of the various neuronal populations involved in control of the ongoing movement.

Role of hypokinesia and bradykinesia in gait disturbances in Huntington's disease: a biomechanical study.

OBJECTIVE: To evaluate specific patterns of locomotion in Huntington's disease (HD) and notably the respective roles of hypokinesia (i. e. a decrease in the amplitude of movement) and bradykinesia (i. e. difficulty in executing a movement, slowness) in gait disturbance. METHODS: Kinematic, spatial (stride length, speed), temporal (cadence, speed, and stride time) and angular gait parameters (joint ankle range) were recorded in 15 early-stage HD patients by means of a video motion analysis system and then compared with 15 controls and 15 Parkinson's disease (PD) patients. Hypokinesia was studied in terms of both spatial (decrease in stride length) and angular gait parameters (decrease in joint ankle range), whereas hyperkinesia was characterized by an increase in joint ankle range. Bradykinesia (defined by a decrease in gait velocity) was also assessed in terms of temporal parameters (cadence, stride time). We studied the influence of clinical symptoms (motor dysfunction, chorea, overall disability and cognitive impairment) and the CAG repeat number on gait abnormalities. RESULTS: we observed a clear decrease in gait speed, a decrease in cadence and an increase in stride time (i. e. bradykinesia) for HD, with significant intra-individual variability. Cadence remained normal in PD. In HD, there was no evidence for a clear decrease in stride length, although the latter is a characteristic feature of hypokinetic gait (such as that observed in PD). Angle analysis revealed the coexistence of hyperkinesia and hypokinesia in HD, which thus participate in gait abnormalities. Gait speed in HD was correlated to the motor part of the UHDRS. CONCLUSION: Gait in HD is mainly characterized by a timing disorder: bradykinesia was present, with severe intra-individual variability in temporal gait parameters.

Effect of age on anticipatory postural adjustments in unilateral arm movement.

Aging is frequently accompanied by a deterioration in postural control. Accordingly, the elderly adopt postural strategies in order to maintain balance. The purpose of this study was to compare anticipatory postural adjustments in (healthy) 10 young and 10 elderly subjects using electromyography (EMG) and biomechanical parameters. While standing on a force platform, subjects performed voluntary, arm-raising movements under five conditions: self-paced at three different velocities, self-paced with load and an externally triggered, both at maximal velocity. The force platform provided information on vertical torque (T(z)) and center of pressure anteroposterior displacements (COP). EMG activity was recorded from the biceps femoris, quadriceps, tibialis anterior and soleus muscles. Voluntary movements were associated with an early COP backward shift and an anticipatory T(z). At low velocity, elderly subjects did not show any impairment in stability. At maximal velocity, T(z) was delayed in all conditions in the elderly group, whereas COP latency was reduced only in the self-paced condition without load. Despite this decrease in anticipation, the movement was performed at the same velocity as in younger subjects. The elderly adopted various muscle strategies in order to perform the same movement with less stability. In the self-paced condition, elderly subjects used a hip strategy, whereas young subjects used an ankle strategy. In the triggered condition, the strategy corresponded to increased activation of certain thigh muscles, rather than a sequence modification. Hence, local muscle strategies were used to counteract the overall delay in postural preparation revealed by biomechanical parameters.

Abnormal cortical mechanisms in voluntary muscle relaxation in de novo parkinsonian patients.

This study aimed at elucidating how the cortical mechanism underlying the preparation and the postmovement phase of voluntary hand muscle relaxation is affected in Parkinson's disease. Event-related mu and beta (de)synchronization (ERD/S) related to voluntary muscle contraction and relaxation were recorded in 16 untreated, akineto-rigid, predominantly hemiparkinsonian patients. The results were compared with data from 10 age-matched, healthy subjects. In the muscle relaxation task, the subject held the wrist in an extended position and then let the hand drop by voluntarily relaxing wrist extensor contraction, i.e., without any overt, associated muscle contraction. In the muscle contraction task, subjects performed a self-initiated brief wrist extension. A same pattern of ERD/S was observed in control subjects and parkinsonian patients performing the motor tasks with their less affected limb. In contrast, related to voluntary relaxation performed with the more affected limb, a delayed mu and beta ERD and a disappearance of beta ERS were revealed. These results demonstrate that the pattern of cortical oscillatory activity in a relaxation task is abnormal in parkinsonian patients. The authors suggest that this may be due to anomalous activity in inhibitory motor cortical systems and impaired sensorimotor integration of afferent inputs from muscle and joint receptors.

Basic mechanisms of central rhythms reactivity to preparation and execution of a voluntary movement: a stereoelectroencephalographic study.

OBJECTIVE: To localize the sources of mu, beta and gamma rhythms and to explore the functional significance of their reactivity. METHODS: We used the method of quantification of event-related desynchronization (ERD) and synchronization (ERS) to analyze the reactivity of intracerebral rhythms recorded in stereoelectroencephalography within the sensorimotor areas during the preparation and the execution of a simple self-paced hand movement. We recorded 3 epileptic subjects who were explored before a surgical treatment. RESULTS: An ERD of mu and beta rhythms has been recorded before the movement onset in the precentral gyrus, spreading then to the postcentral gyrus and to the frontal medial cortex. The frontal lateral cortex was inconstantly involved during the movement. The movement offset was followed by an important and focused beta ERS which was found within the pre- and post-central gyrus and the frontal medial cortex. Within the beta band, we observed several narrower bands with different reactivities and locations. Focused gamma reactivity was also found in the precentral and postcentral gyri. CONCLUSIONS: The reactivities of mu and beta rhythms are different but their locations overlap. Mu ERD is a diffuse phenomenon that reflects the activation of all the sensorimotor areas during a simple movement. Beta band is likely to be composed of different rhythms with different functional significance. The primary motor area seems to contain two distinct areas with different reactivity to the movement preparation and execution.

Relationship between oscillations in the basal ganglia and synchronization of cortical activity.

The functions of oscillations within the basal ganglia are poorly understood. We discuss in the present paper, the possible physiological or pathological roles of oscillatory activities within the basal ganglia, and their relationship to cortical oscillations. Three aspects are presented: 1. What do we know from animal studies? 2. What do we know from neurophysiological studies in parkinsonian patients? 3. What is the effect of L-dopa treatment and electrical stimulation within basal ganglia circuits on cortical oscillations? Animal studies suggest that neuronal oscillations are spontaneously generated within the basal ganglia system, especially from the GPE and the subthalamic nucleus (STN), but are mainly synchronized by cortical activity via the striatal inputs. Dopamine depletion results in a global increase of oscillations within the whole basal ganglia system, particularly in the GP-NST network. Oscillations within the basal ganglia may, in part, be related to tremor since they are enhanced, especially in the globus pallidus internus (GPI) and the STN, in human and animal dopaminergic depletion. However, they also play a role in the physiology of movement as revealed by coherence analysis between cortex, muscles and GPI/STN in parkinsonian patients undergoing deep brain stimulation. It is known that the basal ganglia may influence cortico-muscular oscillations such as the Piper rhythm and other rhythms in the beta band. In off-drug parkinsonian patients, low frequency oscillations (4-10 Hz) are favoured, presumably resulting in bradykinesia and low force. When medically (Ldopa) or surgically (deep brain stimulation) treated, these low frequency oscillations are replaced by high frequency (70 Hz) oscillations that are important for motor programs to be correctly executed. Studies of cortical reactivity related to planning of voluntary movement in parkinsonian patients provide evidence that it is possible to influence cortical reactivity through the basal ganglia system.