BACKGROUND The senses of touch and proprioception evoke a range of perceptions and rely on the ability to detect and transduce mechanical force. The molecular and neural mechanisms underlying these sensory functions remain poorly defined. The stretch-gated ion channel PIEZO2 has been shown to be essential for aspects of mechanosensation in model organisms. METHODS We performed whole-exome sequencing analysis in two patients who had unique neuromuscular and skeletal symptoms, including progressive scoliosis, that did not conform to standard diagnostic classification. In vitro and messenger RNA assays, functional brain imaging, and psychophysical and kinematic tests were used to establish the effect of the genetic variants on protein function and somatosensation. RESULTS Each patient carried compound-inactivating variants in PIEZO2, and each had a selective loss of discriminative touch perception but nevertheless responded to specific types of gentle mechanical stimulation on hairy skin. The patients had profoundly decreased proprioception leading to ataxia and dysmetria that were markedly worse in the absence of visual cues. However, they had the ability to perform a range of tasks, such as walking, talking, and writing, that are considered to rely heavily on proprioception. CONCLUSIONS Our results show that PIEZO2 is a determinant of mechanosensation in humans. (Funded by the National Institutes of Health Intramural Research Program.)

Accumulating evidence suggests cortical circuits may contribute to control of human locomotion. Here, noninvasive electroencephalography (EEG) recorded from able-bodied volunteers during a novel treadmill walking paradigm was used to assess neural correlates of walking. A systematic processing method, including a recently developed subspace reconstruction algorithm, reduced movement-related EEG artifact prior to independent component analysis and dipole source localization. We quantified cortical activity while participants tracked slow and fast target speeds across two treadmill conditions: an active mode that adjusted belt speed based on user movements and a passive mode reflecting a typical treadmill. Our results reveal frequency specific, multi-focal task related changes in cortical oscillations elicited by active walking. Low γ band power, localized to the prefrontal and posterior parietal cortices, was significantly increased during double support and early swing phases, critical points in the gait cycle since the active controller adjusted speed based on pelvis position and swing foot velocity. These phasic γ band synchronizations provide evidence that prefrontal and posterior parietal networks, previously implicated in visuo-spatial and somotosensory integration, are engaged to enhance lower limb control during gait. Sustained μ and β band desynchronization within sensorimotor cortex, a neural correlate for movement, was observed during walking thereby validating our methods for isolating cortical activity. Our results also demonstrate the utility of EEG recorded during locomotion for probing the multi-regional cortical networks which underpin its execution. For example, the cortical network engagement elicited by the active treadmill suggests that it may enhance neuroplasticity for more effective motor training.

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A new method is described that allows the parallel purification of the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase multienzyme complexes from ox heart without the need for prior isolation of mitochondria. All the assayable activity of the 2-oxo acid dehydrogenase complexes in the disrupted tissue is made soluble by the inclusion of non-ionic detergents such as Triton X-100 or Tween-80 in the buffer used for the initial extraction of the enzyme complexes. The yields of the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes are many times greater than those obtained by means of previous methods. In terms of specific catalytic activity, banding pattern on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, sedimentation properties and possession of the regulatory phosphokinase bound to the pyruvate dehydrogenase complex, the 2-oxo acid dehydrogenase complexes prepared by the new method closely resemble those described by previous workers. The greatly improved yield of 2-oxo acid dehydrogenase complexes occasioned by the use of Triton X-100 or Tween-80 as solubilizing agent supports the possibility that the bulk of the pyruvate dehydrogenase complex is associated in some way with the mitochondrial inner membrane and is not free in the mitochondrial matrix space.

BackgroundBalance problems are common in cerebral palsy (CP) but etiology is often uncertain. The classic Romberg test compares ability to maintain standing with eyes open versus closed. Marked instability without vision is a positive test and generally indicates proprioceptive loss. From previous work showing diminished hip joint proprioception in CP, we hypothesized that static and dynamic balance without vision (positive Romberg) would be compromised in CP.MethodsForce plate sway and gait velocity data were collected using 3D motion capture on 52 participants, 19 with diplegic CP, 13 with hemiplegic CP, and 20 without disability. Center of mass (COM) and center or pressure (COP) velocity, excursion, and differences between COM and COP in AP and ML directions were computed from static standing trials with eyes open and closed. Mean gait velocity with and without dribble glasses was compared. Hip joint proprioception was quantified as the root mean square of magnitude of limb positioning errors during a hip rotation task with and without view of the limb. Mixed model repeated measures analysis of variance (ANOVA) was performed with condition as within-subject (EO, EC) and group as between-subject factors (hemiplegia, diplegia, controls). Sway characteristics and gait speed were correlated with proprioception values.ResultsGroups with CP had greater sway in standing with eyes open indicating that they had poorer balance than controls, with the deficit relatively greater in the ML compared to AP direction. Contrary to our hypothesis, the decrement with eyes closed did not differ from controls (negative Romberg); however, proprioception error was related to sway parameters particularly for the non-dominant leg. Gait speed was related to proprioception values such that those with worse proprioception tended to walk more slowly.ConclusionsPostural instability is present even in those with mild CP and is yet another manifestation of their motor control disorder, the specific etiology of which may vary across individuals in this heterogeneous diagnostic category.