A cerebellar deficit in sensorimotor prediction explains movement timing variability

A popular theory is that the cerebellum functions as a timer for clocking motor events (e.g., initiation, termination). Consistent with this idea, cerebellar patients have been reported to show greater deficits during hand movements that repeatedly start and stop (i.e., discontinuous movements) compared with continuous hand movements. Yet, this finding could potentially be explained by an alternate theory in which the cerebellum acts as an internal model of limb mechanics. We tested whether a timing or internal model hypothesis best explains results from a circle-drawing task, where individuals trace a circle with the hand at a desired tempo. We first attempted to replicate prior results showing greater impairment for discontinuous versus continuous circling movements, and then asked whether we could improve patient performance by reducing demands in each domain. First, we slowed the movement down to reduce the need to predict and compensate for limb dynamics. Second, we supplied external timing information to reduce the need for an internal event timer. Results showed that we did not replicate the previous findings-cerebellar patients were impaired in both discontinuous and continuous movements. Slowing the movement improved cerebellar performance to near control values. The addition of an external visual timing signal paradoxically worsened timing deficits rather than mitigating them. One interpretation of these combined results is that the cerebellum is indeed functioning as an internal model and is needed to make appropriate predictions for movement initiation and termination.     

Limited persistence of the sensorimotor memory when transferred across prehension tasks

This study investigated the effect of hyperthermia on pre-attentive processing by recording the mismatch negativity (MMN) component of ERPs. 36 right-handed young male undergraduates were divided into two groups, a control group with 1 h of exposure at 25 °C and a heat group with 1 h of exposure at 50 °C. MMNs were recorded before and after heat exposure. It was found that, although there was no group difference before heat exposure, MMN declined significantly in the heat group compared to the control group after heat exposure for 1 h, indicating that passive heat exposure could damage pre-attentive processing. The MMN component could be a good index to assess cognitive functioning in a hot environment.     

Limited persistence of the sensorimotor memory when transferred across prehension tasks

A recent study has shown that the sensorimotor memory for the fingertip forces used to grasp and lift an object can be shared across two prehension tasks. However, the persistence (or decay) of these memory resources is not known. Reports of within-task sensorimotor memory indicate persistence of lifting forces, with evidence for reduced persistence of grip forces. Here we investigated the temporal dynamics of the transfer of memory related to vertical lifting forces across prehension tasks. Young adult participants in two separate experimental groups first held the object placed on their palm and ‘hefted’ it (moved it up and down) followed by lifting the object using a precision grip (thumb-finger) with the dominant hand after a delay of 10 s, or 20 min. The Control group lifted the object with the dominant hand using a precision grip and then did so again 20 min later. The Control group used higher load force rates (LFR) for their first lift compared to subsequent lifts, both before and after the 20-min delay. This suggests that the Control group initially overestimated the weight of the object, corrected their LFRs, and then was able to retain this corrected force scaling after the 20-min delay. The Experimental 10-second delay group accurately scaled their LFRs upon their first lift, indicating that they obtained an accurate memory for LFR scaling during hefting, and transferred it to the lift task. In contrast, the Experimental 20-minute delay group was unable to scale their LFRs upon their first lift, as indicated by high LFRs that were no different than those of the Control group. Thus, the memory related to the production of LFR remained stable over 20 min when obtained from the same task, while that obtained from a different task decayed completely within 20 min. This decay may indicate weakened sensorimotor memories related to prehension forces due to its dependence not only on the memory for object mechanical properties, but also on sensory signals generated during the prehension act, along with strong visual prior estimates of a size-weight relationship.     

Auditory responses in multiple sensorimotor song system nuclei are co-modulated by behavioral state

Auditory responsiveness in nucleus HVC, a high-order sensorimotor area of the avian song system, is modulated by changes in behavioral state. Modulation is not observed in the primary thalamo-recipient auditory area Field L, the indirect source of auditory input to HVC. In this study, we show that auditory responsiveness in nucleus interfacialis (NIf), the immediate auditory afferent to HVC, is modulated by behavioral state. While auditory responsiveness is generally greater in NIf during wakefulness and in HVC during sedation, simultaneous recordings reveal a co-variation of auditory response magnitude. This co-variation is observed both in awake birds, where responses are spontaneously variable, and in sedated birds during manipulations of arousal levels. Auditory responses in NIf and HVC, which are selective for the bird's own song (BOS) during sedation, become predominantly unselective during wakefulness. This loss of selectivity is accompanied by a decrease in the similarity of NIf and HVC response patterns. To explore the role of NIf in shaping HVC auditory responses, we pharmacologically manipulated NIf while recording in HVC. Injection of the GABA(A) agonist muscimol into NIf eliminated most spontaneous activity and all auditory responses in the ipsilateral HVC, while injections of the GABA(A) antagonist bicuculline increased HVC auditory responsiveness and selectivity. These findings indicate that HVC is not the initial site of behavioral state-dependent modulation in the song system. Together with the suppression of HVC auditory responses by muscimol in NIf, these results suggest that NIf plays an important role in the flow of auditory information to HVC.     

Measures of performance in nonlinear estimation tasks: prediction of estimation performance at low signal-to-noise ratio

Maximum-likelihood (ML) estimation is an established paradigm for the assessment of imaging system performance in nonlinear quantitation tasks. At high signal-to-noise ratio (SNR), ML estimates are asymptotically Gaussian-distributed, unbiased and efficient, thereby attaining the Cramer-Rao bound (CRB). Therefore, at high SNR the CRB is useful as a predictor of the variance of ML estimates and, consequently, as a basis for measures of estimation performance. At low SNR, however, the achievable parameter variances are often substantially larger than the CRB and the estimates are no longer Gaussian-distributed. These departures imply that inference about the estimates that is based on the CRB and the assumption of a normal distribution will not be valid. We have found previously that for some tasks these effects arise at noise levels considered clinically acceptable. We have derived the mathematical relationship between a new measure, chi2(pdf-ML), and the expected probability density of the ML estimates, and have justified the use of chi2(pdf-ML)-isocontours in parameter space to describe the ML estimates. We validated this approach by simulation experiments using spherical objects imaged with a Gaussian point spread function. The parameters, activity concentration and size, were estimated simultaneously by ML, and variances and covariances calculated over 1000 replications per condition from 3D image volumes and from 2D tomographic projections of the same object. At low SNR, where the CRB is no longer achievable, chi2(pdf-ML)-isocontours provide a robust prediction of the distribution of the ML estimates. At high SNR, the chi2(pdf-ML)-isocontours asymptotically approach the analogous chi2(pdf-F)-contours derived from the Fisher information matrix. The chi2(pdf-ML) model appears to be suitable for characterization of the influence of the noise level and characteristics, the task, and the object on the shape of the probability density of the ML estimates at low SNR. Furthermore, it provides unique insights into the causes of the variability of estimation performance.     

Voxel model in BNCT treatment planning: performance analysis and improvements

In recent years, many efforts have been made to study the performance of treatment planning systems in deriving an accurate dosimetry of the complex radiation fields involved in boron neutron capture therapy (BNCT). The computational model of the patient's anatomy is one of the main factors involved in this subject. This work presents a detailed analysis of the performance of the 1 cm based voxel reconstruction approach. First, a new and improved material assignment algorithm implemented in NCTPlan treatment planning system for BNCT is described. Based on previous works, the performances of the 1 cm based voxel methods used in the MacNCTPlan and NCTPlan treatment planning systems are compared by standard simulation tests. In addition, the NCTPlan voxel model is benchmarked against in-phantom physical dosimetry of the RA-6 reactor of Argentina. This investigation shows the 1 cm resolution to be accurate enough for all reported tests, even in the extreme cases such as a parallelepiped phantom irradiated through one of its sharp edges. This accuracy can be degraded at very shallow depths in which, to improve the estimates, the anatomy images need to be positioned in a suitable way. Rules for this positioning are presented. The skin is considered one of the organs at risk in all BNCT treatments and, in the particular case of cutaneous melanoma of extremities, limits the delivered dose to the patient. Therefore, the performance of the voxel technique is deeply analysed in these shallow regions. A theoretical analysis is carried out to assess the distortion caused by homogenization and material percentage rounding processes. Then, a new strategy for the treatment of surface voxels is proposed and tested using two different irradiation problems. For a parallelepiped phantom perpendicularly irradiated with a 5 keV neutron source, the large thermal neutron fluence deviation present at shallow depths (from 54% at 0 mm depth to 5% at 4 mm depth) is reduced to 2% on average. Reassigning fluence values in the case of this phantom in angular position produced the maximum deviation in the thermal fluence to decrease from 140% to 23% at the surface of the phantom. Thus, even for the largest deviations, obtained by intentionally placing the phantom in the most disadvantageous position with respect to the voxel grid, the reassignment shows very good performance. Since these results substantially improve the performance of the 1 cm based voxel model in surface boundary regions, the proposed strategy will be implemented in future versions of the NCTPlan code.     

The effect of experimental pain on motor training performance and sensorimotor integration

Experimental pain is known to affect neuroplasticity of the motor cortex as well as motor performance, but less is known about neuroplasticity of somatosensory processing in the presence of pain. Early somatosensory evoked potentials (SEPs) provide a mechanism for investigating alterations in sensory processing and sensorimotor integration (SMI). The overall aim of this study was to investigate the interactive effects of acute pain, motor training, and sensorimotor processing. Two groups of twelve participants (N = 24) were randomly assigned to either an intervention (capsaicin cream) or placebo (inert lotion) group. SEP amplitudes were collected by stimulation of the median nerve at baseline, post-application and post-motor training. Participants performed a motor sequence task while reaction time and accuracy data were recorded. The amplitude of the P22-N24 complex was significantly increased following motor training for both groups F(2,23) = 3.533, p < 0.05, while Friedman’s test for the P22-N30 complex showed a significant increase in the intervention group [χ ² (df = 2, p = 0.016) = 8.2], with no significant change in the placebo group. Following motor training, reaction time was significantly decreased for both groups F(1,23) = 59.575, p < 0.01 and overall accuracy differed by group [χ ² (df = 3, p < 0.001) = 19.86], with post hoc testing indicating that the intervention group improved in accuracy following motor training [χ ² (df = 1, p = 0.001) = 11.77] while the placebo group had worse accuracy [χ ² (df = 1, p = 0.006) = 7.67]. The improved performance in the presence of capsaicin provides support for the enhancement of knowledge acquisition with the presence of nontarget stimuli. In addition, the increase in SEP peak amplitudes suggests that early SEP changes are markers of SMI changes accompanying motor training and acute pain.     

Development of indeterminate reasoning in early childhood

This study examined the development of the thinking strategy that leads to the conclusion that not every simple problem has a simple solution (indetermination). The development of this strategy was examined by studying the developmental process of indeterminate conditional reasoning, using the following three conditionals: category-based, causal, and deontic. The experiment was conducted with a total of 100 children between late four and early six years of age. First, the children were administered the indeterminate conditional reasoning task and the comprehension task, which examined whether or not they understood the statement that not every simple problem has a simple solution. The results revealed that although young children understood the concept of indetermination, they were not always able to draw an indeterminate conclusion. On being encouraged to change their viewpoint, the children found it easier to arrive at the correct conclusion. The development of the thinking strategy and ways to encourage it were discussed based on the results.     

Synergistic improvements in cell and axonal migration across sciatic nerve lesion gaps using bioresorbable filaments and heregulin-beta1

The success of entubulation for peripheral nerve regeneration is still limited, especially with long lesion gaps. In this study, we examined if regeneration could be enhanced by constructing implants to both align axonal growth and promote Schwann cell proliferation and migration. Silicone implants were used to bridge a 1.4-cm gap in the rat sciatic nerve. Adult female Sprague-Dawley rats were divided into four groups of tubes containing either 1) Matrigel; 2) Matrigel and heregulin; 3) Matrigel and poly(L-lactic acid) (PLLA) microfilaments; or 4) Matrigel, PLLA microfilaments, and heregulin. Ten weeks postimplantation, the number of axons and Schwann cells were measured at the distal end of implants. Implants with microfilaments displayed better tissue cable formation, increased Schwann cell migration, and regeneration of anti-calcitonin gene-related peptide-positive axons, but not RMDO95-positive axons compared with nonfilament-containing groups. Heregulin treatment caused an increase in Schwann cell number, but it demonstrated no significant improvement in either tissue cable formation or axon number. Extensive regeneration was observed through implants containing Matrigel, microfilaments, and heregulin, which induced significant improvements in the number and longitudinal organization of both Schwann cells and axons. These results indicate that physical guidance of microfilaments and the Schwann cell growth factor, heregulin, act synergistically to improve nerve regeneration across long lesion gaps.     

Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data

While genetic studies of epilepsies can be performed in thousands of individuals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 individuals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of individuals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated individually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.Subject terms: Genetics research, Prognostic markers, Genetic testing, Diagnostic markers     

Two-year stability of the late positive potential across middle childhood and adolescence

The late positive potential (LPP) may be a useful measure of individual differences in emotional processing across development, but little is known about the stability of the LPP across time. We assessed the LPP and behavioral measures of emotional interference following pleasant, unpleasant, and neutral images in 8- to 13-year-old youth. Approximately two years later, the same participants completed the task again (N = 34). Results indicated that the LPP is moderately-to-highly reliable across development. Stability was lower and more inconsistent for behavioral measures. In addition, consistent with previous cross-sectional analyses, a decrease in occipital activity was observed at the second assessment. Results indicate that the LPP appears to be a stable measure of emotional processing, even across a fairly large period of development.     

Variability in Wechsler Adult Intelligence Scale-IV subtest performance across age

Normal Wechsler Adult Intelligence Scale (WAIS)-IV performance relative to average normative scores alone can be an oversimplification as this fails to recognize disparate subtest heterogeneity that occurs with increasing age. The purpose of the present study is to characterize the patterns of raw score change and associated variability on WAIS-IV subtests across age groupings. Raw WAIS-IV subtest means and standard deviations for each age group were tabulated from the WAIS-IV normative manual along with the coefficient of variation (CV), a measure of score dispersion calculated by dividing the standard deviation by the mean and multiplying by 100. The CV further informs the magnitude of variability represented by each standard deviation. Raw mean scores predictably decreased across age groups. Increased variability was noted in Perceptual Reasoning and Processing Speed Index subtests, as Block Design, Matrix Reasoning, Picture Completion, Symbol Search, and Coding had CV percentage increases ranging from 56% to 98%. In contrast, Working Memory and Verbal Comprehension subtests were more homogeneous with Digit Span, Comprehension, Information, and Similarities percentage of the mean increases ranging from 32% to 43%. Little change in the CV was noted on Cancellation, Arithmetic, Letter/Number Sequencing, Figure Weights, Visual Puzzles, and Vocabulary subtests (<14%). A thorough understanding of age-related subtest variability will help to identify test limitations as well as further our understanding of cognitive domains which remain relatively steady versus those which steadily decline.     

Development of immunoglobulin A in infancy and childhood

Serum and salivary concentrations of immunoglobulin A1 (IgA1) and IgA2 were studied in 105 Icelandic children aged 0-12 years. Serum concentrations of both IgA1 and IgA2 increased slightly (P < 0.001) during childhood. The salivary IgA1/IgA2 ratio tended to decrease during the same period; this trend is less apparent when omitting the youngest children. The salivary IgA1 and IgA2 output could be high, even in children with low levels of serum IgA. Only polymeric IgA was found in whole saliva. Interestingly, in serum, most IgA1 and IgA2 were polymeric during infancy. The proportion of polymeric IgA decreased, when the concentration of IgA increased. The polymeric form of IgA might provide the infant with better protection against invading microorganisms by activation of the innate immune mechanisms.