Estimating cortical thickness trajectories in children across different scanners using transfer learning from normative models.

This work illustrates the use of normative models in a longitudinal neuroimaging study of children aged 6-17 years and demonstrates how such models can be used to make meaningful comparisons in longitudinal studies, even when individuals are scanned with different scanners across successive study waves. More specifically, we first estimated a large-scale reference normative model using Hierarchical Bayesian Regression from N = 42,993 individuals across the lifespan and from dozens of sites. We then transfer these models to a longitudinal developmental cohort (N = 6285) with three measurement waves acquired on two different scanners that were unseen during estimation of the reference models. We show that the use of normative models provides individual deviation scores that are independent of scanner effects and efficiently accommodate inter-site variations. Moreover, we provide empirical evidence to guide the optimization of sample size for the transfer of prior knowledge about the distribution of regional cortical thicknesses. We show that a transfer set containing as few as 25 samples per site can lead to good performance metrics on the test set. Finally, we demonstrate the clinical utility of this approach by showing that deviation scores obtained from the transferred normative models are able to detect and chart morphological heterogeneity in individuals born preterm.

The relationship between time to diagnose and diagnostic accuracy among internal medicine residents: a randomized experiment.

BACKGROUND: Diagnostic errors have been attributed to cognitive biases (reasoning shortcuts), which are thought to result from fast reasoning. Suggested solutions include slowing down the reasoning process. However, slower reasoning is not necessarily more accurate than faster reasoning. In this study, we studied the relationship between time to diagnose and diagnostic accuracy. METHODS: We conducted a multi-center within-subjects experiment where we prospectively induced availability bias (using Mamede et al.'s methodology) in 117 internal medicine residents. Subsequently, residents diagnosed cases that resembled those bias cases but had another correct diagnosis. We determined whether residents were correct, incorrect due to bias (i.e. they provided the diagnosis induced by availability bias) or due to other causes (i.e. they provided another incorrect diagnosis) and compared time to diagnose. RESULTS: We did not successfully induce bias: no significant effect of availability bias was found. Therefore, we compared correct diagnoses to all incorrect diagnoses. Residents reached correct diagnoses faster than incorrect diagnoses (115 s vs. 129 s, p < .001). Exploratory analyses of cases where bias was induced showed a trend of time to diagnose for bias diagnoses to be more similar to correct diagnoses (115 s vs 115 s, p = .971) than to other errors (115 s vs 136 s, p = .082). CONCLUSIONS: We showed that correct diagnoses were made faster than incorrect diagnoses, even within subjects. Errors due to availability bias may be different: exploratory analyses suggest a trend that biased cases were diagnosed faster than incorrect diagnoses. The hypothesis that fast reasoning leads to diagnostic errors should be revisited, but more research into the characteristics of cognitive biases is important because they may be different from other causes of diagnostic errors.

Cerebellar Cathodal Transcranial Direct Stimulation and Performance on a Verb Generation Task: A Replication Study.

The role of the cerebellum in cognitive processing is increasingly recognized but still poorly understood. A recent study in this field applied cerebellar Transcranial Direct Current Stimulation (c-tDCS) to the right cerebellum to investigate the role of prefrontal-cerebellar loops in language aspects of cognition. Results showed that the improvement in participants' verbal response times on a verb generation task was facilitated immediately after cathodal c-tDCS, compared to anodal or sham c-tDCS. The primary aim of the present study is to replicate these findings and additionally to investigate possible longer term effects. A crossover within-subject design was used, comparing cathodal and sham c-tDCS. The experiment consisted of two visits with an interval of one week. Our results show no direct contribution of cathodal c-tDCS over the cerebellum to language task performance. However, one week later, the group receiving cathodal c-tDCS in the first visit show less improvement and increased variability in their verbal response times during the second visit, compared to the group receiving sham c-tDCS in the first visit. These findings suggest a potential negative effect of c-tDCS and warrant further investigation into long term effects of c-tDCS before undertaking clinical studies with poststroke patients with aphasia.

Cerebellar tDCS does not improve performance in probabilistic classification learning.

In this study, the role of the cerebellum in a cognitive learning task using transcranial direct current stimulation (tDCS) was investigated. Using a weather prediction task, subjects had to learn the probabilistic associations between a stimulus (a combination of cards) and an outcome (sun or rain). This task is a variant of a probabilistic classification learning task, for which it has been reported that prefrontal tDCS enhances performance. Using a between-subject design, all 30 subjects learned to improve their performance with increasing accuracies and shortened response times over a series of 500 trials. Subjects also became more confident in their prediction during the experiment. However, no differences in performance and learning were observed between subjects receiving sham stimulation (n = 10) or anodal stimulation (2 mA for 20 min) over either the right cerebellum (n = 10) or the left prefrontal cortex (n = 10). This suggests that stimulating the brain with cerebellar tDCS does not readily influence probabilistic classification performances, probably due to the rather complex nature of this cognitive task.

Joint position sense error in people with neck pain: A systematic review.

BACKGROUND: Several studies in recent decades have examined the relationship between proprioceptive deficits and neck pain. However, there is no uniform conclusion on the relationship between the two. Clinically, proprioception is evaluated using the Joint Position Sense Error (JPSE), which reflects a person's ability to accurately return his head to a predefined target after a cervical movement. OBJECTIVES: We focused to differentiate between JPSE in people with neck pain compared to healthy controls. STUDY DESIGN: Systematic review according to the PRISMA guidelines. METHOD: Our data sources were Embase, Medline OvidSP, Web of Science, Cochrane Central, CINAHL and Pubmed Publisher. To be included, studies had to compare JPSE of the neck (O) in people with neck pain (P) with JPSE of the neck in healthy controls (C). RESULTS/FINDINGS: Fourteen studies were included. Four studies reported that participants with traumatic neck pain had a significantly higher JPSE than healthy controls. Of the eight studies involving people with non-traumatic neck pain, four reported significant differences between the groups. The JPSE did not vary between neck-pain groups. CONCLUSIONS: Current literature shows the JPSE to be a relevant measure when it is used correctly. All studies which calculated the JPSE over at least six trials showed a significantly increased JPSE in the neck pain group. This strongly suggests that 'number of repetitions' is a major element in correctly performing the JPSE test.

Small effects of neck torsion on healthy human voluntary eye movements.

PURPOSE: Although several lines of research suggest that the head and eye movement systems interact, previous studies have reported that applying static neck torsion does not affect smooth pursuit eye movements in healthy controls. This might be due to several methodological issues. Here we systematically investigated the effect of static neck torsion on smooth pursuit and saccadic eye movement behavior in healthy subjects. METHODS: In twenty healthy controls, we recorded eye movements with video-oculography while their trunk was in static rotation relative to the head (7 positions from 45° to the left to 45° to right). The subject looked at a moving dot on the screen. In two separate paradigms, we evoked saccadic and smooth pursuit eye movements, using both predictable and unpredictable target motions. RESULTS: Smooth pursuit gain and saccade peak velocity decreased slightly with increasing neck torsion. Smooth pursuit gains were higher for predictable target movements than for unpredictable target movements. Saccades to predictable targets had lower latencies, but reduced gains compared to saccades to unpredictable targets. No interactions between neck torsion and target predictability were observed. CONCLUSION: Applying static neck torsion has small effects on voluntary eye movements in healthy subjects. These effects are not modulated by target predictability.

Differences in muscle load between computer and non-computer work among office workers.

Introduction of more non-computer tasks has been suggested to increase exposure variation and thus reduce musculoskeletal complaints (MSC) in computer-intensive office work. This study investigated whether muscle activity did, indeed, differ between computer and non-computer activities. Whole-day logs of input device use in 30 office workers were used to identify computer and non-computer work, using a range of classification thresholds (non-computer thresholds (NCTs)). Exposure during these activities was assessed by bilateral electromyography recordings from the upper trapezius and lower arm. Contrasts in muscle activity between computer and non-computer work were distinct but small, even at the individualised, optimal NCT. Using an average group-based NCT resulted in less contrast, even in smaller subgroups defined by job function or MSC. Thus, computer activity logs should be used cautiously as proxies of biomechanical exposure. Conventional non-computer tasks may have a limited potential to increase variation in muscle activity during computer-intensive office work.

Cerebellar contributions to the processing of saccadic errors.

Saccades are fast eye movements that direct the point of regard to a target in the visual field. Repeated post-saccadic visual errors can induce modifications of the amplitude of these saccades, a process known as saccadic adaptation. Two experiments using the same paradigm were performed to study the involvement of the cerebrum and the cerebellum in the processing of saccadic errors using functional magnetic resonance imaging and in-scanner eye movement recordings. In the first active condition, saccadic adaptation was prevented using a condition in which the saccadic target was shifted to a variable position during the saccade towards it. This condition induced random saccadic errors as opposed to the second active condition in which the saccadic target was not shifted. In the baseline condition, subjects looked at a stationary dot. Both active conditions compared with baseline evoked activation in the expected saccade-related regions using a stringent statistical threshold [the frontal and parietal eye fields, primary visual area, MT/V5, and the precuneus (V6) in the cerebrum; vermis VI-VII; and lobule VI in the cerebellum, known as the oculomotor vermis). In the direct comparison between the two active conditions, significantly more cerebellar activation (vermis VIII, lobules VIII-X, left lobule VIIb) was observed with random saccadic errors (using a more relaxed statistical threshold). These results suggest a possible role for areas outside the oculomotor vermis of the cerebellum in the processing of saccadic errors. Future studies of these areas with, e.g., electrophysiological recordings, may reveal the nature of the error signals that drive the amplitude modification of saccadic eye movements.

Tragedy of conducting a clinical trial; generic alert system needed.

Stopping a clinical trial without reaching the final objective is not the ideal outcome any researcher wants; sometimes ceasing is inevitable. Due to marginal inclusion of patients we were forced to cease our randomized clinical trial on the effectiveness of proprioceptive training on the development of chronic whiplash complaints a year after the start. Although incidence figures demonstrate that recruitment of the planned number of whiplash patients would be easily feasible, we were unable to enroll the amount of subjects. Several motives can be proposed that would have prevented this obliged halting from happening. Other studies also report impracticability of the planned number of whiplash injury patients.

The effects of pause software on the temporal characteristics of computer use.

The study investigated the natural work-pause pattern of computer users and the possible effects of imposing pause regimes on this pattern. Hereto, the precise timing of computer events was recorded across a large number of days. It was found that the distribution of the pause durations was extremely skewed and that pauses with twice the duration are twice less likely to occur. The effects of imposing pause regimes were studied by performing a simulation of commercially available pause software. It was found that depending on the duration of the introduced pause, the software added 25-57% of the pauses taken naturally. Analysis of the timing of the introduced pauses revealed that a large number of spontaneous pauses were taken close to the inserted pause. Considering the disappointing results of studies investigating the effects of introducing (active) pauses during computer work, this study has cast doubt on the usefulness of introducing short duration pauses.

Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome.

Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25-30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions.

Eye movements as a marker for cerebellar damage in paraneoplastic neurological syndromes.

Cerebellar disturbances can induce a variety of motor deficits, ranging from severe ataxia to mild deficits of fine motor control. Although motor disturbances appear as an important clinical feature in many neurological disorders, mild disturbances are often difficult to assess properly. Eye movement recordings using video-oculography in a group of patients with a paraneoplastic neurological disorder revealed subtle saccadic and smooth pursuit deficits when compared to controls. We conclude that an easy quantification of eye movement control may assist in the diagnosis and follow-up of mild motor disturbances in patients with neurological disorders, especially when such signs are not overt during clinical neurological examination.

Visual search deficits in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic condition characterized by several physical and mental traits, such as a poor visuo-spatial processing and a relative strength in language. In this study we investigated how WBS subjects search and scan their visual environment. We presented 10 search displays on a computer screen to WBS subjects as well as control subjects, with the instruction to find a target out of several stimulus elements. We analyzed the eye movement patterns for fixation characteristics and systematicy of search. Fixations generally lasted longer in WBS subjects than in control subjects. WBS subjects made more fixations at a stimulus element they had already looked at and more fixations that were not aimed at a stimulus element at all, decreasing the efficiency of search. These outcomes lead to the conclusion that visual search of individuals with Williams-Beuren syndrome is less effective than in control subjects. This finding may be related to their motor deficits, an impaired processing of global visual information and/or deficits in working memory and could reflect impairments within the dorsal stream.

Increased prevalences of left-handedness and left-eye sighting dominance in individuals with Williams-Beuren syndrome.

Handedness and eye sighting dominance were assessed in a sample of 50 individuals (25 male, 25 female; aged 5-38 years) with Williams-Beuren syndrome (WBS). The prevalences of left-handedness and left-eyedness were compared to the normative prevalences in the general population. We found significantly higher prevalences of left-handedness and left-eyedness in the WBS sample. The higher prevalences were more salient in younger than in older individuals and in male than in female individuals. We suggest that the increased prevalence of left-handedness in WBS is a consequence of a slower maturation rate, which allows deviation from a predetermined laterality pattern.

Visual depth processing in Williams-Beuren syndrome.

Patients with Williams-Beuren Syndrome (WBS, also known as Williams Syndrome) show many problems in motor activities requiring visuo-motor integration, such as walking stairs. We tested to what extent these problems might be related to a deficit in the perception of visual depth or to problems in using this information in guiding movements. Monocular and binocular visual depth perception was tested in 33 patients with WBS. Furthermore, hand movements to a target were recorded in conditions with and without visual feedback of the position of the hand. The WBS group was compared to a group of control subjects. The WBS patients were able to perceive monocular depth cues that require global processing, but about 49% failed to show stereopsis. On average, patients with WBS moved their hand too far when no visual feedback on hand position was given. This was not so when they could see their hand. Patients with WBS are able to derive depth from complex spatial relationships between objects. However, they seem to be impaired in using depth information for guiding their movements when deprived of visual feedback. We conclude that the problems that WBS patients have with tasks such as descending stairs are not due to an inability to judge distance.

Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control.

While firing rate is well established as a relevant parameter for encoding information exchanged between neurons, the significance of other parameters is more conjectural. Here, we show that regularity of neuronal spike activities affects sensorimotor processing in tottering mutants, which suffer from a mutation in P/Q-type voltage-gated calcium channels. While the modulation amplitude of the simple spike firing rate of their floccular Purkinje cells during optokinetic stimulation is indistinguishable from that of wild-types, the regularity of their firing is markedly disrupted. The gain and phase values of tottering's compensatory eye movements are indistinguishable from those of flocculectomized wild-types or from totterings with the flocculus treated with P/Q-type calcium channel blockers. Moreover, normal eye movements can be evoked in tottering when the flocculus is electrically stimulated with regular spike trains mimicking the firing pattern of normal simple spikes. This study demonstrates the importance of regularity of firing in Purkinje cells for neuronal information processing.

The cervico-ocular reflex is increased in whiplash injury patients.

Whiplash-associated disorders (WAD) are a major problem in the Western world, which put a formidable financial burden on modern society and which evoke an emerging debate on the true nature of their origin. To date there is no generally accepted test that allows us to diagnose WAD objectively. Because whiplash injury causes dysfunction of proprioception in the neck, we investigated the characteristics of the cervico-ocular reflex (COR) of presumptive WAD patients. These patients and age-matched healthy controls were rotated at different stimulus peak velocities in the dark while their head was fixed in space. The gain values of the COR were significantly increased in the patient population at a wide range of stimulus peak velocities with maximum difference at the lower frequencies (p = 0.037, ANOVA). Hence, although larger numbers of patients should be measured, the COR gain appears to be a parameter that may permit an objective diagnosis of WAD.

Short-term adaptation of the cervico-ocular reflex.

The cervico-ocular reflex (COR) works in conjunction with the vestibulo-ocular reflex (VOR) and the optokinetic reflex (OKR) in order to prevent visual slip over the retina during head movement. The COR induces eye movements in response to proprioceptive signals from the neck. We investigated whether the COR gain can be adapted by inducing a mismatch between vision and neck proprioception, in analogy to VOR adaptation. Thirteen healthy subjects were rotated in the dark in a trunk-to-head manner (the head fixed in space while the body passively rotated sinusoidally with a peak velocity of 1.25 degrees /s). Eye movements were recorded with infrared video-oculography under various adaptive conditions. Analysis showed a small but significant reduction in COR gain in the suppression conditions. This means that the cervico-ocular reflex can be modified after only 10 min of concurrent visual and cervical stimulation.

Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long-term depression.

Cerebellar long-term depression (LTD) at parallel fibre-Purkinje cell (P-cell) synapses is thought to embody neuronal information storage for motor learning. Transgenic L7-protein kinase C inhibitor (PKCI) mice in which cerebellar LTD is selectively blocked do indeed exhibit impaired adaptation in the vestibulo-ocular reflex (VOR) while their default oculomotor performance is unaffected. Although supportive, these data do not definitively establish a causal link between memory storage required for motor learning and cerebellar LTD. As the L7-PKCI transgene is probably activated from the early stages of P-cell development, an alternative could be that P-cells develop abnormal signals in L7-PKCI mutants, disturbing mechanisms of motor learning that rely on proper P-cell outputs. To test this alternative hypothesis, we studied simple spike (SS) and complex spike (CS) activity of vertical axis P-cells in the flocculus of L7-PKCI mice and their wild-type littermates during sinusoidal optokinetic stimulation. Both SS and CS discharge dynamics appeared to be very similar in wild-type and transgenic P-cells at all stimulus frequencies (0.05-0.8 Hz). The CS activity of all vertical axis cells increased with contralateral stimulus rotation and lagged ipsiversive eye velocity by 165-180 degrees. The SS modulation was roughly reciprocal to the CS modulation and lagged ipsiversive eye velocity by approximately 15 degrees. The baseline SS and CS discharge characteristics were indistinguishable between the two genotypes. We conclude that the impaired VOR learning in L7-PKCI mutants does not reflect fundamental aberrations of the cerebellar circuitry. The data thus strengthen the evidence that cerebellar LTD is implicated in rapid VOR learning but not in the development of normal default response patterns.

Saccade dysmetria in Williams-Beuren syndrome.

Numerous studies have described the poor visuo-spatial processing capacities of subjects with Williams-Beuren syndrome (WBS), a genetically based developmental disorder. Since visual perception and eye movements are closely related we hypothesized that the poor visuo-spatial processing capacities of subjects with WBS might be related to a poor saccadic control. Thereto, we recorded horizontal and vertical saccadic eye movements to targets using infrared video-oculography in 27 subjects with WBS and eight healthy controls. In the WBS group saccadic gains were highly variable, both between and within individual subjects, and they often needed more than one correction saccade to reach the target. Ten (out of a subgroup of 22) WBS subjects showed a large number of hypometric and/or hypermetric saccades, and, also a left-right asymmetry in saccadic gains was observed in WBS. We conclude that the observed impairments in saccadic control are likely to affect the proper processing of visuo-spatial information.