Altered excitation-inhibition balance in the primary sensorimotor cortex to proprioceptive hand stimulation in cerebral palsy.

OBJECTIVE: Our objective was to clarify the primary sensorimotor (SM1) cortex excitatory and inhibitory alterations in hemiplegic (HP) and diplegic (DP) cerebral palsy (CP) by quantifying SM1 cortex beta power suppression and rebound with magnetoencephalography (MEG). METHODS: MEG was recorded from 16 HP and 12 DP adolescents, and their 32 healthy controls during proprioceptive stimulation of the index fingers evoked by a movement actuator. The related beta power changes were computed with Temporal Spectral Evolution (TSE). Peak strengths of beta suppression and rebound were determined from representative channels over the SM1 cortex. RESULTS: Beta suppression was stronger contralateral to the stimulus and rebound was weaker ipsilateral to the stimulation in DP compared to controls. Beta modulation strengths did not differ significantly between HP and the control group. CONCLUSIONS: The emphasized beta suppression in DP suggests less efficient proprioceptive processing in the SM1 contralateral to the stimulation. Their weak rebound further indicates reduced intra- and/or interhemispheric cortical inhibition, which is a potential neuronal mechanism for their bilateral motor impairments. SIGNIFICANCE: The excitation-inhibition balance of the SM1 cortex related to proprioception is impaired in diplegic CP. Therefore, the cortical and behavioral proprioceptive deficits should be better diagnosed and considered to better target individualized effective rehabilitation in CP.

Functional connectivity of sensorimotor network is enhanced in spastic diplegic cerebral palsy: A multimodal study using fMRI and MEG.

OBJECTIVE: To assess the effects to functional connectivity (FC) caused by lesions related to spastic diplegic cerebral palsy (CP) in children and adolescents using multiple imaging modalities. METHODS: We used resting state magnetoencephalography (MEG) envelope signals in alpha, beta and gamma ranges and resting state functional magnetic resonance imaging (fMRI) signals to quantify FC between selected sensorimotor regions of interest (ROIs) in 11 adolescents with spastic diplegic cerebral palsy and 24 typically developing controls. Motor performance of the hands was quantified with gross motor, fine motor and kinesthesia tests. RESULTS: In fMRI, participants with CP showed enhanced FC within posterior parietal regions; in MEG, they showed enhanced interhemispheric FC between sensorimotor regions and posterior parietal regions both in alpha and lower beta bands. There was a correlation between the kinesthesia score and fronto-parietal connectivity in the control population. CONCLUSIONS: CP is associated with enhanced FC in sensorimotor network. This difference is not correlated with hand coordination performance. The effect of the lesion is likely not fully captured by temporal correlation of ROI signals. SIGNIFICANCE: Brain lesions can show as increased temporal correlation of activity between remote brain areas. We suggest this effect is likely separate from typical physiological correlates of functional connectivity.

Altered corpus callosum structure in adolescents with cerebral palsy: connection to gait and balance.

Cerebral palsy (CP) is the most common motor disorder in childhood. Recent studies in children with CP have associated weakened sensorimotor performance with impairments in the major brain white-matter (WM) structure, corpus callosum (CC). However, the relationship between CC structure and lower extremity performance, specifically gait and balance, remains unknown. This study investigated the transcallosal WM structure and lower limb motor stability performance in adolescents aged 10-18 years with spastic hemiplegic (n = 18) or diplegic (n = 13) CP and in their age-matched controls (n = 34). The modern diffusion-weighted MRI analysis included the diffusivity properties of seven CC subparts and the transcallosal lower limb sensorimotor tract of the dominant hemisphere. Children with CP had comprehensive impairments in the cross-sectional area, fractional anisotropy, and mean diffusivity of the CC and sensorimotor tract. Additionally, the extent of WM alterations varied between hemiplegic and diplegic subgroups, which was seen especially in the fractional anisotropy values along the sensorimotor tract. The diffusion properties of transcallosal WM were further associated with static stability in all groups, and with dynamic stability in healthy controls. Our novel results clarify the mechanistic role of the corpus callosum in adolescents with and without CP offering valuable insight into the complex interplay between the brain's WM organization and motor performance. A better understanding of the brain basis of weakened stability performance could, in addition, improve the specificity of clinical diagnosis and targeted rehabilitation in CP.

Limb-specific thalamocortical tracts are impaired differently in hemiplegic and diplegic subtypes of cerebral palsy.

Thalamocortical pathways are considered crucial in the sensorimotor functioning of children with cerebral palsy (CP). However, previous research has been limited by non-specific tractography seeding and the lack of comparison between different CP subtypes. We compared limb-specific thalamocortical tracts between children with hemiplegic (HP, N = 15) or diplegic (DP, N = 10) CP and typically developed peers (N = 19). The cortical seed-points for the upper and lower extremities were selected (i) manually based on anatomical landmarks or (ii) using functional magnetic resonance imaging (fMRI) activations following proprioceptive-limb stimulation. Correlations were investigated between tract structure (mean diffusivity, MD; fractional anisotropy, FA; apparent fiber density, AFD) and sensorimotor performance (hand skill and postural stability). Compared to controls, our results revealed increased MD in both upper and lower limb thalamocortical tracts in the non-dominant hemisphere in HP and bilaterally in DP subgroup. MD was strongly lateralized in participants with hemiplegia, while AFD seemed lateralized only in controls. fMRI-based tractography results were comparable. The correlation analysis indicated an association between the white matter structure and sensorimotor performance. These findings suggest distinct impairment of functionally relevant thalamocortical pathways in HP and DP subtypes. Thus, the organization of thalamocortical white matter tracts may offer valuable guidance for targeted, life-long rehabilitation in children with CP.

Proprioceptive response strength in the primary sensorimotor cortex is invariant to the range of finger movement.

Proprioception is the sense of body position and movement that relies on afference from the proprioceptors in muscles and joints. Proprioceptive responses in the primary sensorimotor (SM1) cortex can be elicited by stimulating the proprioceptors using evoked (passive) limb movements. In magnetoencephalography (MEG), proprioceptive processing can be quantified by recording the movement evoked fields (MEFs) and movement-induced beta power modulations or by computing corticokinematic coherence (CKC) between the limb kinematics and cortical activity. We examined whether cortical proprioceptive processing quantified with MEF peak strength, relative beta suppression and rebound power and CKC strength is affected by the movement range of the finger. MEG activity was measured from 16 right-handed healthy volunteers while movements were applied to their right-index finger metacarpophalangeal joint with an actuator. Movements were either intermittent, every 3000 ± 250 ms, to estimate MEF or continuous, at 3 Hz, to estimate CKC. In both cases, 4 different ranges of motion of the stimuli were investigated: 15, 18, 22 and 26 mm for MEF and 6, 7, 9 and 13 mm for CKC. MEF amplitude, relative beta suppression and rebound as well as peak CKC strength at the movement frequency were compared between the movement ranges in the source space. Inter-individual variation was also compared between the MEF and CKC strengths. As expected, MEF and CKC responses peaked at the contralateral SM1 cortex. MEF peak, beta suppression and rebound and CKC strengths were similar across all movement ranges. Furthermore, CKC strength showed a lower degree of inter-individual variation compared with MEF strength. Our result of absent modulation by movement range in cortical responses to passive movements of the finger indicates that variability in movement range should not hinder comparability between different studies or participants. Furthermore, our data indicates that CKC is less prone to inter-individual variability than MEFs, and thus more advantageous in what pertains to statistical power.

More comprehensive proprioceptive stimulation of the hand amplifies its cortical processing.

Corticokinematic coherence (CKC) quantifies the phase coupling between limb kinematics and cortical neurophysiological signals reflecting proprioceptive feedback to the primary sensorimotor (SM1) cortex. We studied whether the CKC strength or cortical source location differs between proprioceptive stimulation (i.e., actuator-evoked movements) of right-hand digits (index, middle, ring, and little). Twenty-one volunteers participated in magnetoencephalography measurements during which three conditions were tested: 1) simultaneous stimulation of all four fingers at the same frequency, 2) stimulation of each finger separately at the same frequency, and 3) simultaneous stimulation of the fingers at finger-specific frequencies. CKC was computed between MEG responses and accelerations of the fingers recorded with three-axis accelerometers. CKC was stronger (P < 0.003) for the simultaneous (0.52 ± 0.02) than separate (0.45 ± 0.02) stimulation at the same frequency. Furthermore, CKC was weaker (P < 0.03) for the simultaneous stimulation at the finger-specific frequencies (0.38 ± 0.02) than for the separate stimulation. CKC source locations of the fingers were concentrated in the hand region of the SM1 cortex and did not follow consistent finger-specific somatotopic order. Our results indicate that proprioceptive afference from the fingers is processed in partly overlapping cortical neuronal circuits, which was demonstrated by the modulation of the finger-specific CKC strengths due to proprioceptive afference arising from simultaneous stimulation of the other fingers of the same hand as well as overlapping cortical source locations. Finally, comprehensive simultaneous proprioceptive stimulation of the hand would optimize functional cortical mapping to pinpoint the hand region, e.g., prior brain surgery.NEW & NOTEWORTHY Corticokinematic coherence (CKC) can be used to study cortical proprioceptive processing and localize proprioceptive hand representation. Our results indicate that proprioceptive stimulation delivered simultaneously at the same frequency to fingers (D2-D4) maximizes CKC strength allowing robust and fast localization of the human hand region in the sensorimotor cortex using MEG.

Identification of proprioceptive thalamocortical tracts in children: comparison of fMRI, MEG, and manual seeding of probabilistic tractography.

Studying white matter connections with tractography is a promising approach to understand the development of different brain processes, such as proprioception. An emerging method is to use functional brain imaging to select the cortical seed points for tractography, which is considered to improve the functional relevance and validity of the studied connections. However, it is unknown whether different functional seeding methods affect the spatial and microstructural properties of the given white matter connection. Here, we compared functional magnetic resonance imaging, magnetoencephalography, and manual seeding of thalamocortical proprioceptive tracts for finger and ankle joints separately. We showed that all three seeding approaches resulted in robust thalamocortical tracts, even though there were significant differences in localization of the respective proprioceptive seed areas in the sensorimotor cortex, and in the microstructural properties of the obtained tracts. Our study shows that the selected functional or manual seeding approach might cause systematic biases to the studied thalamocortical tracts. This result may indicate that the obtained tracts represent different portions and features of the somatosensory system. Our findings highlight the challenges of studying proprioception in the developing brain and illustrate the need for using multimodal imaging to obtain a comprehensive view of the studied brain process.

Stronger proprioceptive BOLD-responses in the somatosensory cortices reflect worse sensorimotor function in adolescents with and without cerebral palsy.

Cerebral palsy (CP) is a motor disorder where the motor defects are partly due to impaired proprioception. We studied cortical proprioceptive responses and sensorimotor performance in adolescents with CP and their typically-developed (TD) peers. Passive joint movements were used to stimulate proprioceptors during functional magnetic resonance imaging (fMRI) session to quantify the proprioceptive responses whose associations to behavioral sensorimotor performance were also examined. Twenty-three TD (15 females, age: mean ± standard deviation 14.2 ± 2.4 years) and 18 CP (12 females, age: mean ± standard deviation, 13.8 ± 2.3 years; 12 hemiplegic, 6 diplegic) participants were included in this study. Participants' index fingers and ankles were separately stimulated at 3 Hz and 1 Hz respectively with pneumatic movement actuators. Regions-of-interest were used to quantify BOLD-responses from the primary sensorimotor (SM1) and secondary (SII) somatosensory cortices and were compared across the groups. Associations between responses strengths and sensorimotor performance measures were also examined. Proprioceptive responses were stronger for the individuals with CP compared to their TD peers in SM1 (p < 0.001) and SII (p < 0.05) cortices contralateral to their more affected index finger. The ankle responses yielded no significant differences between the groups. The CP group had worse sensorimotor performance for hands and feet (p < 0.001). Stronger responses to finger stimulation in the dominant SM1 (p < 0.001) and both dominant and non-dominant SII (p < 0.01, p < 0.001) cortices were associated with the worse hand sensorimotor performance across all participants. Worse hand function was associated with stronger cortical activation to the proprioceptive stimulation. This association was evident both in adolescents with CP and their typically-developed controls, thus it likely reflects both clinical factors and normal variation in the sensorimotor function. The specific mechanisms need to be clarified in future studies.

Corticokinematic coherence is stronger to regular than irregular proprioceptive stimulation of the hand.

Proprioceptive afference can be investigated using corticokinematic coherence (CKC), which indicates coupling between limb kinematics and cortical activity. CKC has been quantified using proprioceptive stimulation (movement actuators) with fixed interstimulus interval (ISI). However, it is unclear how regularity of the stimulus sequence (jitter) affects CKC strength. Eighteen healthy volunteers (16 right-handed, 27.8 ± 5.0 yr, 7 females) participated in magnetoencephalography (MEG) session in which their right index finger was continuously moved at ∼3 Hz with Constant 333 ms ISI or with 20% Jitter (ISI 333 ± 66 ms) using a pneumatic-movement actuator. Three minutes of data per condition were collected. Finger kinematics were recorded with a three-axis accelerometer. CKC strength was defined as the peak coherence value in the Rolandic MEG gradiometer pair contralateral to the movement at 3 Hz. Both conditions resulted in significant coherence peaking in the gradiometers over the primary sensorimotor cortex. Constant stimulation yielded stronger CKC at 3 Hz (0.78 ± 0.11 vs. 0.66 ± 0.13, P < 0.001) and its first harmonic (0.60 ± 0.19 vs. 0.27 ± 0.11, P < 0.001) than irregular stimulation. Similarly, the respective sustained-movement evoked field was also stronger for constant stimulation. The results emphasize the importance of temporal stability of the proprioceptive stimulation sequence when quantifying CKC strength. The weaker CKC during irregular stimulation can be explained with temporal and thus spectral scattering of the paired peripheral and cortical events beyond the mean stimulation frequency. This impairs the signal-to-noise ratio of respective MEG signal and thus CKC strength. When accurately estimating and following changes in CKC strength, we suggest using precise movement actuators with constant stimulation sequence.NEW & NOTEWORTHY Cortical proprioceptive processing can be investigated using corticokinematic coherence (CKC). The findings show that CKC method is sensitive to temporal stability in the stimulation sequence. Although both regular and irregular sequences resulted in robust coherence, the regular stimulation sequence with pneumatic movement actuator is recommended to maximize coherence strength and reproducibility to allow better comparability between groups or populations.

Attention directed to proprioceptive stimulation alters its cortical processing in the primary sensorimotor cortex.

Movement-evoked fields to passive movements and corticokinematic coherence between limb kinematics and magnetoencephalographic signals can both be used to quantify the degree of cortical processing of proprioceptive afference. We examined in 20 young healthy volunteers whether processing of proprioceptive afference in the primary sensorimotor cortex is modulated by attention directed to the proprioceptive stimulation of the right index finger using a pneumatic-movement actuator to evoke continuous 3-Hz movement for 12 min. The participant attended either to a visual (detected change of fixation cross colour) or movement (detected missing movements) events. The attentional task alternated every 3-min. Coherence was computed between index-finger acceleration and magnetoencephalographic signals, and sustained-movement-evoked fields were averaged with respect to the movement onsets every 333 ms. Attention to the proprioceptive stimulation supressed the sensorimotor beta power (by ~12%), enhanced movement-evoked field amplitude (by ~16%) and reduced corticokinematic coherence strength (by ~9%) with respect to the visual task. Coherence peaked at the primary sensorimotor cortex contralateral to the proprioceptive stimulation. Our results indicated that early processing of proprioceptive afference in the primary sensorimotor cortex is modulated by inter-modal directed attention in healthy individuals. Therefore, possible attentional effects on corticokinematic coherence and movement-evoked fields should be considered when using them to study cortical proprioception in conditions introducing attentional variation.

Gating Patterns to Proprioceptive Stimulation in Various Cortical Areas: An MEG Study in Children and Adults using Spatial ICA.

Proprioceptive paired-stimulus paradigm was used for 30 children (10-17 years) and 21 adult (25-45 years) volunteers in magnetoencephalography (MEG). Their right index finger was moved twice with 500-ms interval every 4 ± 25 s (repeated 100 times) using a pneumatic-movement actuator. Spatial-independent component analysis (ICA) was applied to identify stimulus-related components from MEG cortical responses. Clustering was used to identify spatiotemporally consistent components across subjects. We found a consistent primary response in the primary somatosensory (SI) cortex with similar gating ratios of 0.72 and 0.69 for the children and adults, respectively. Secondary responses with similar transient gating behavior were centered bilaterally in proximity of the lateral sulcus. Delayed and prolonged responses with strong gating were found in the frontal and parietal cortices possibly corresponding to larger processing network of somatosensory afference. No significant correlation between age and gating ratio was found. We confirmed that cortical gating to proprioceptive stimuli is comparable to other somatosensory and auditory domains, and between children and adults. Gating occurred broadly beyond SI cortex. Spatial ICA revealed several consistent response patterns in various cortical regions which would have been challenging to detect with more commonly applied equivalent current dipole or distributed source estimates.

Optimization of Proprioceptive Stimulation Frequency and Movement Range for fMRI.

For vision, audition and tactile sense, the optimal stimulus frequency for fMRI is somewhat known. For proprioception, i.e., the "movement sense", however, the optimal frequency is unknown. We studied the effect of passive-finger-movement frequency on proprioceptive fMRI responses using a novel pneumatic-movement actuator. Eleven healthy right-handed volunteers participated in the study. The movement actuator passively moved the participant's right index finger at frequencies of 0.3, 1, 3, 6, 9, or 12 Hz in a blocked design. A functional localizer was used to define regions-of-interest in SI and SII cortices. In addition, effect of movement range on the fMRI responses was tested in a separate session with 1, 3, 5, and 7 mm movement ranges at a fixed 2 Hz frequency. In primary somatosensory (SI) cortex, the responses were stronger at 3 Hz than at 0.3 Hz (p < 0.001) or 1 Hz (p < 0.05), and at ≥6 Hz than 0.3 Hz (p < 0.001 for frequencies ≥ 6 Hz). In secondary somatosensory (SII) cortex, all movements, except at 0.3 Hz, elicited significant responses of similar strength. In addition, 6, 9, and 12-Hz movements elicited a significant offset response in both SI and SII cortices (p < 0.001-0.05). SI cortex required a total stimulation duration of 4 min to elicit significant activations at the group-level whereas for SII cortex 1 min 20 s was sufficient. Increase in the movement range led to stronger responses in SI cortex, but not in SII cortex. Movements above 3 Hz elicited the strongest SI cortex responses, and increase in the movement range enhanced the response strength. We thus recommend that movements at 3-6 Hz with a movement range of 5 mm or higher to be used in future studies of proprioception. Our results are in-line with previous fMRI and PET studies using tactile or median nerve stimulation at different stimulation frequencies.

Substituent effects on 13C chemical shifts of alkyl-substituted 4-oxo-1,3-dioxolanes and 5-oxo-1,3-oxathiolanes.

The 13C NMR chemical shifts for 4-oxo-1,3-dioxolane (1) and its all methyl-substituted derivatives (2-10) as well as for 5-oxo-1,3-oxathiolane (11) and its nine alkyl-substituted derivatives (12-20) are reported. The magnitude and variety of the substituent effects are in accordance with the envelope conformations in which the oxygen or sulfur atom locates at the tip of the envelope as postulated on the basis of earlier data.