Somatosensory and motor representations following bilateral transplants of the hands: A 6-year longitudinal case report on the first pediatric bilateral hand transplant patient.

A vascularized composite tissue allotransplantation (VCA) was performed at the Children's Hospital of Philadelphia (CHOP), on an 8-year-old patient in 2015, six years after bilateral hand and foot amputation. Hand VCA resulted in reafferentation of the medial, ulnar, and radial nerves serving hand somatosensation and motor function. We used magnetoencephalography (MEG) to assess somatosensory cortical plasticity following the post-transplantation recovery of the peripheral sensory nerves of the hands. Our 2-year postoperative MEG showed that somatosensory lip representations, initially observed at "hand areas", reverted to canonical, orthotopic lip locations with recovery of post-transplant hand function. Here, we continue the assessment of motor and somatosensory responses up to 6-years post-transplant. Magnetoencephalographic somatosensory responses were recorded eight times over a six-year period following hand transplantation, using a 275-channel MEG system. Somatosensory tactile stimuli were presented to the right lower lip (all 8 visits) as well as right and left index fingers (visits 3-8) and fifth digits (visits 4-8). In addition, left and right-hand motor responses were also recorded for left index finger and right thumb (visit 8 only).During the acute recovery phase (visits 3 and 4), somatosensory responses of the digits were observed to be significantly larger and more phasic (i.e., smoother) than controls. Subsequent measures showed that digit responses maintain this atypical response profile (evoked-response magnitudes typically exceed 1 picoTesla). Orthotopic somatosensory localization of the lip, D2, and D5 was preserved. Motor beta-band desynchrony was age-typical in localization and response magnitude; however, the motor gamma-band response was significantly larger than that observed in a reference population.These novel findings show that the restoration of somatosensory input of the hands resulted in persistent and atypically large cortical responses to digit stimulation, which remain atypically large at 6 years post-transplant; there is no known perceptual correlate, and no reports of phantom pain. Normal somatosensory organization of the lip, D2, and D5 representation remain stable following post-recovery reorganization of the lip's somatosensory response.

ACR White Paper on Magnetoencephalography and Magnetic Source Imaging: A Report from the ACR Commission on Neuroradiology.

Magnetoencephalography, the extracranial detection of tiny magnetic fields emanating from intracranial electrical activity of neurons, and its source modeling relation, magnetic source imaging, represent a powerful functional neuroimaging technique, able to detect and localize both spontaneous and evoked activity of the brain in health and disease. Recent years have seen an increased utilization of this technique for both clinical practice and research, in the United States and worldwide. This report summarizes current thinking, presents recommendations for clinical implementation, and offers an outlook for emerging new clinical indications.

Synthetic aperture magnetometry and excess kurtosis mapping of Magnetoencephalography (MEG) is predictive of epilepsy surgical outcome in a large pediatric cohort.

OBJECTIVE: Resective surgery is the most effective treatment option for patients with refractory epilepsy; however identification of patients who will benefit from epilepsy surgery remains challenging. Synthetic aperture magnetometry and excess kurtosis mapping (SAM(g2)) of magnetoencephalography (MEG) is a non-invasive tool that warrants further examination in the pediatric epilepsy population. Here, we examined the utility of MEG with SAM(g2) to determine if MEG epileptiform foci correlates with surgical outcome and to develop a predictive model incorporating MEG information to best assess likelihood of seizure improvement/freedom from resective surgery. METHODS: 564 subjects who had MEG at the Children's Hospital of Philadelphia between 2010-2015 were screened. Clinical epilepsy history and prior electrographic records were extracted and reviewed and correlated with MEG findings. MEG assessments were made by both a neurologist and neuroradiologist. Predictive models were developed to assess the utility of MEG in determining Engel class at one year and five years after resective epilepsy surgery. RESULTS: The number of MEG spike foci was highly associated with Engel class outcome at both one year and five years; however, using MEG data in isolation was not significantly predictive of 5 year surgical outcome. When combined with clinical factors; scalp EEG (single ictal onset zone), MRI (lesional or not), age and sex in a logistic regression model MEG foci was significant for Engel class outcome at both 1 year (p = 0.03) and 5 years (0.02). The percent correctly classified for Engel class at one year was 78.43% and the positive predictive value was 71.43. SIGNIFICANCE: MEG using SAM(g2) analysis in an important non-invasive tool in the identification of those patients who will benefit most from surgery. Integrating MEG data analysis into pre-surgical evaluation can help to predict epilepsy outcome after resective surgery in the pediatric population if utilized with skilled interpretation.

Neuromagnetic signatures of the spatiotemporal transformation for manual pointing.

Movement planning involves transforming the sensory signals into a command in motor coordinates. Surprisingly, the real-time dynamics of sensorimotor transformations at the whole brain level remain unknown, in part due to the spatiotemporal limitations of fMRI and neurophysiological recordings. Here, we used magnetoencephalography (MEG) during pro-/anti-wrist pointing to determine (1) the cortical areas involved in transforming visual signals into appropriate hand motor commands, and (2) how this transformation occurs in real time, both within and across the regions involved. We computed sensory, motor, and sensorimotor indices in 16 bilateral brain regions for direction coding based on hemispherically lateralized de/synchronization in the α (7-15 Hz) and ß (15-35 Hz) bands. We found a visuomotor progression, from pure sensory codes in 'early' occipital-parietal areas, to a temporal transition from sensory to motor coding in the majority of parietal-frontal sensorimotor areas, to a pure motor code, in both the α and ß bands. Further, the timing of these transformations revealed a top-down pro/anti cue influence that propagated 'backwards' from frontal through posterior cortical areas. These data directly demonstrate a progressive, real-time transformation both within and across the entire occipital-parietal-frontal network that follows specific rules of spatial distribution and temporal order.

GABA estimation in the brains of children on the autism spectrum: measurement precision and regional cortical variation.

(1)H magnetic resonance spectroscopy ((1)H MRS) and spectral editing methods, such as MEGA-PRESS, allow researchers to investigate metabolite and neurotransmitter concentrations in-vivo. Here we address the utilization of (1)H MRS for the investigation of GABA concentrations in the ASD brain, in three locations; motor, visual and auditory areas. An initial repeatability study (5 subjects, 5 repeated measures separated by ~5days on average) indicated no significant effect of reference metabolite choice on GABA quantitation (p>0.6). Coefficients of variation for GABA+/NAA, GABA+/Cr and GABA+/Glx were all of the order of 9-11%. Based on these findings, we investigated creatine-normalized GABA+ ratios (GABA+/Cr) in a group of (N=17) children with autism spectrum disorder (ASD) and (N=17) typically developing children (TD) for Motor, Auditory and Visual regions of interest (ROIs). Linear regression analysis of gray matter (GM) volume changes (known to occur with development) revealed a significant decrease of GM volume with Age for Motor (F(1,30)=17.92; p<0.001) and Visual F(1,16)=14.41; p<0.005 but not the Auditory ROI (p=0.55). Inspection of GABA+/Cr changes with Age revealed a marginally significant change for the Motor ROI only (F(1,30)=4.11; p=0.054). Subsequent analyses were thus conducted for each ROI separately using Age and GM volume as covariates. No group differences in GABA+/Cr were observed for the Visual ROI between TD vs. ASD children. However, the Motor and Auditory ROI showed significantly reduced GABA+/Cr in ASD (Motor p<0.05; Auditory p<0.01). The mean deficiency in GABA+/Cr from the Motor ROI was approximately 11% and Auditory ROI was approximately 22%. Our novel findings support the model of regional differences in GABA+/Cr in the ASD brain, primarily in Auditory and to a lesser extent Motor but not Visual areas.

Evidence for a motor gamma-band network governing response interference.

The gamma-band response is thought to represent a key neural signature of information processing in the human brain. These brain signals have been associated with a variety of sensory modalities (vision, sensation, and audition) and also following basic motor responses, yet the functional significance of the motor gamma-band response remains unclear. We used the Multi-Source Interference Task (MSIT) to assess the sensitivity of these cortical motor gamma-band rhythms to stimuli producing response interference. We recorded MEG from adult participants (N=24) during MSIT task performance and compared motor gamma-band activity on Control and Interference trials. Reaction time on MSIT Interference trials was significantly longer (~0.2 s) for all subjects. Response interference produced a significant increase in motor gamma-band activity including ~0.5 s sustained increase in gamma-band activity from contralateral primary motor area directly preceding the response. In addition, activation of increased right Inferior Frontal Gyrus (R-IFG) was observed at gamma-band frequencies ~0.2 s prior to the button press response. Post-hoc analysis of R-IFG gamma-band activity was observed to correlate with reaction time increases to response interference. Our study is the first to record MEG during MSIT task performance. We observed novel activity of the motor gamma-band on interference trials which was sustained prior to the response and in novel locations including contralateral (BA6), and R-IFG. Our results support the idea that R-IFG is specialized structure for response control that also functions at gamma-band frequencies. Together, these data provide evidence for a motor gamma-band network for response selection and maintenance of planned behavior.

Relating MEG measured motor cortical oscillations to resting γ-aminobutyric acid (GABA) concentration.

The human motor cortex exhibits characteristic beta (15-30 Hz) and gamma oscillations (60-90 Hz), typically observed in the context of transient finger movement tasks. The functional significance of these oscillations, such as post-movement beta rebound (PMBR) and movement-related gamma synchrony (MRGS) remains unclear. Considerable animal and human non-invasive studies, however, suggest that the networks supporting these motor cortex oscillations depend critically on the inhibitory neurotransmitter γ-Aminobutyric acid (GABA). Despite such speculation, a direct relation between MEG measured motor cortex oscillatory power and frequency with resting GABA concentrations has not been demonstrated. In the present study, motor cortical responses were measured from 9 healthy adults while they performed a cued button-press task using their right index finger. In each participant, PMBR and MRGS measures were obtained from time-frequency plots obtained from primary motor (MI) sources, localized using beamformer differential source localization. For each participant, complimentary magnetic resonance spectroscopy (MRS) GABA measures aligned to the motor hand knob of the left central sulcus were also obtained. GABA concentration was estimated as the ratio of the motor cortex GABA integral to a cortical reference NAA resonance at 2 ppm. A significant linear relation was observed between MI GABA concentration and MRGS frequency (R(2)=0.46, p<0.05), with no association observed between GABA concentration and MRGS power. Conversely, a significant linear relation was observed between MI GABA concentration and PMBR power (R(2)=0.34, p<0.05), with no relation observed for GABA concentration and PMBR frequency. Finally, a significant negative linear relation between the participant's age and MI gamma frequency was observed, such that older participants had a lower gamma frequency (R(2)=0.40, p<0.05). Present findings support a role for GABA in the generation and modulation of endogenous motor cortex rhythmic beta and gamma activity.

Neuromagnetic imaging of movement-related cortical oscillations in children and adults: age predicts post-movement beta rebound.

We measured visually-cued motor responses in two developmentally separate groups of children and compared these responses to a group of adults. We hypothesized that if post-movement beta rebound (PMBR) depends on developmentally sensitive processes, PMBR will be greatest in adults and progressively decrease in children performing a basic motor task as a function of age. Twenty children (10 young children 4-6 years; 10 adolescent children 11-13 years) and 10 adults all had MEG recorded during separate recordings of right and left index finger movements. Beta band (15-30 Hz) event-related desynchronization (ERD) of bi-lateral sensorimotor areas was observed to increase significantly from both contralateral and ipsilateral MI with age. Movement-related gamma synchrony (60-90 Hz) was also observed from contralateral MI for each age group. However, PMBR was significantly reduced in the 4-6 year group and, while more prominent, remained significantly diminished in the adolescent (11-13 year) age group as compared to adults. PMBR measures were weak or absent in the youngest children tested and appear maximally from bilateral MI in adults. Thus PMBR may reflect an age-dependent inhibitory process of the primary motor cortex which comes on-line with normal development. Previous studies have shown PMBR may be observed from MI following a variety of movement-related tasks in adult participants - however, the origin and purpose of the PMBR is unclear. The current study shows that the expected PMBR from MI observed from adults is increasingly diminished in adolescent and young children respectively. A reduction in PMBR from children may reflect reduced motor cortical inhibition. Relatively less motor inhibition may facilitate neuronal plasticity and promote motor learning in children.

Magnetoencephalography for clinical pediatrics: the effect of head positioning on measurement of somatosensory-evoked fields.

OBJECTIVE: At present, whole-head MEG systems are designed to accommodate adult heads, thereby introducing a technical issue unique to pediatric MEG. It is known that magnetic field strength decreases as a function of 1/distance(2). For pediatric patients, we questioned whether re-positioning the head to minimize the distance between the expected source location and the MEG sensor array would significantly improve source measurement. METHODS: Somatosensory-evoked fields (SEFs) were recorded in 17 children (mean=4.96 years) with their head placed centrally in the MEG, and then re-positioned laterally to reduce the distance between the cortical source and sensors. Equivalent current dipole (ECD) source models were evaluated for changes in residual variance (RV), signal-to-noise ratio (SNR), moment (strength), and location. RESULTS: Re-positioning the head closer to the sensors resulted in a significant shift in the mediolateral dipole coordinate location, accompanied by a significant increase in the SNR, decrease in the dipole RV, and a reduction in size of ECD confidence volumes. CONCLUSIONS: We conclude that for clinical pediatric measurement of the SEF, repositioning of the head to minimize the distance between the expected SEF source location and the sensor array will significantly improve SEF source measurement and concomitant ECD source modeling. SIGNIFICANCE: These issues are relevant to all pediatric MEG settings involving healthy or clinical populations and underscores the need for future development of a MEG helmet specifically designed for pediatric populations.

Neuromagnetic responses associated with perceptual segregation of pitch.

In recent EEG investigations [Johnson, 2003] [Hautus, 2005], we described a novel late negative ERP component associated with binaural processing of auditory pitch based solely on interaural timing differences ("dichotic pitch"), an acoustic phenomenon that is closely analogous to visual perception of stereoscopic depth based on retinal disparities. The present study extends this research with neuromagnetic recordings of auditory evoked fields (AEFs) elicited by dichotically-embedded pitches. Eight healthy adult subjects listened to control stimuli consisting of 500 ms segments of broadband acoustic noise presented identically to both ears via earphones, and dichotic pitch stimuli created by introducing a dichotic delay to a narrow frequency region of the same noise segments and resulting in a perception of a pitch lateralized to the left or right of auditory space. Auditory-evoked fields (AEFs) were recorded using a 151 channel whole-head MEG system. Comparison of control and dichotic-pitch AEFs showed reliable amplitude differences during a time window of 150-350 ms. AEFs over the left hemisphere showed larger effects for contralateral than ipsilateral pitches, while the right hemisphere showed no differences for differently lateralized sources. The results indicate a relatively late stage of neural processing of binaurally-derived cues for the perceptual segregation of concurrent sound sources and support a right-hemisphere dominance for the processing of sound-source localization.

Modulation of neuromagnetic oscillatory activity during the observation of oro-facial movements.

A number of MEG/EEG studies have shown modulation of endogenous sensorimotor (mu and beta) rhythms during the observation of hand movements. These modulations are similar to patterns that occur during execution of movement and it has been hypothesised that the neural substrates of these rhythms may play a role in action representation and understanding the actions of others. In this experiment we wished to determine whether similar responses would be obtained during the observation of oro-facial movements. Neuromagnetic recordings (151 channels, CTF Systems) were obtained from six healthy subjects while they (1) observed a video of an experimenter making oro-facial movements (2) imitated the same movements and (3) observed hand movements. Source scanning using synthetic aperture magnetometry (SAM) was used to find changes in source power between these active conditions compared to pre-stimulus control conditions where no movement occurred. SAM images were created with 5 mm resolution in the beta (15-35 Hz) and mu (8-15 Hz) bands and showed source power decreases over parietal, occipital and sensorimotor areas. Time-frequency analysis of virtual SAM sensors from sensorimotor areas showed event-related desynchronisation of mu and beta bands following the onset of movement in all three conditions. These data demonstrate comparable activations of visuomotor mechanisms during observation or imitation of mouth movements and during observation of hand movements. These results support the notion that sensorimotor mechanisms play a role in achieving a representation of the oro-facial gestures of others.

Evidence for fusion and segregation induced by 21 Hz multiple-digit stimulation in humans.

Subjects were trained to detect changes in the frequency of 21 Hz tactile stimulation applied to digits 2 + 3 + 4 (fusion group) or 2 + 4 (segregation group) of the right hand. The 21 Hz steady-state response for digit 3 was measured by 64 channel EEG on mapping trials before and after training. Discrimination improved over 3 days, confirming that subjects attended to the training stimuli. The 21 Hz response was larger on training than on mapping trials, indicating sensitivity of the response to the strength of cortical activation. Under these conditions the 21 Hz response for digit 3 decreased after training in both groups on day 1. On day 3 this effect reversed in a subset of fusion subjects while segregation continued to yield decreases. The findings suggest that somatosensory representations are dynamically modified by the sensory input experienced on a task.

Motor cortex activity and predicting side of movement: neural network and dipole analysis of pre-movement magnetic fields.

Neuromagnetic fields were recorded from human subjects during the performance of left and right voluntary finger movements. Modeling of current dipole sources indicated symmetric activation of both motor cortices beginning 600 ms prior to movement onset. This activity became lateralized to the contralateral hemisphere 200-300 ms prior to movement onset, the period during which an artificial neural network showed increased ability to predict side of movement within single trials. The results describe the mechanism of lateralization of cortical brain activity preceding voluntary movement and provide further evidence of the involvement of ipsilateral motor cortex in unilateral movements.