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 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.

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.

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.

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.

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.

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.

Floccular complex spike response to transparent retinal slip.

The flocculus of the rabbit is involved in the plasticity of compensatory eye movements. It is generally assumed that the climbing fiber input to floccular Purkinje cells encodes "retinal slip," which in turn would be a measure for the oculomotor performance error. To test this, we used transparent motion stimuli, creating a retinal slip signal that broke up this relation. We recorded the ensuing oculomotor behavior and complex spike activity of floccular Purkinje cells. Complex spike modulation in response to transparent stimulation was identical to that of a single optokinetic pattern, despite considerably different retinal slip. These results suggest that the climbing fiber code may be effectively related to the eye movement performance error, rather than to retinal slip.

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.

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.

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.

Expression of protein kinase C inhibitor blocks cerebellar long-term depression without affecting Purkinje cell excitability in alert mice.

A longstanding but still controversial hypothesis is that long-term depression (LTD) of parallel fiber-Purkinje cell synapses in the cerebellum embodies part of the neuronal information storage required for associative motor learning. Transgenic mice in which LTD is blocked by Purkinje cell-specific inhibition of protein kinase C (PKC) (L7-PKCI mutants) do indeed show impaired adaptation of their vestibulo-ocular reflex, whereas the dynamics of their eye movement performance are unaffected. However, because L7-PKCI mutants have a persistent multiple climbing fiber innervation at least until 35 d of age and because the baseline discharge of the Purkinje cells in the L7-PKCI mutants is unknown, factors other than a blockage of LTD induction itself may underlie their impaired motor learning. We therefore investigated the spontaneous discharge of Purkinje cells in alert adult L7-PKCI mice as well as their multiple climbing fiber innervation beyond the age of 3 months. We found that the simple spike and complex spike-firing properties (such as mean firing rate, interspike interval, and spike count variability), oscillations, and climbing fiber pause in the L7-PKCI mutants were indistinguishable from those in their wild-type littermates. In addition, we found that multiple climbing fiber innervation does not occur in cerebellar slices obtained from 3- to 6-month-old mutants. These data indicate (1) that neither PKC inhibition nor the subsequent blockage of LTD induction disturbs the spontaneous discharge of Purkinje cells in alert mice, (2) that Purkinje cell-specific inhibition of PKC detains rather than prevents the developmental conversion from multiple to mono-innervation of Purkinje cells by climbing fibers, and (3) that as a consequence the impaired motor learning as observed in older adult L7-PKCI mutants cannot be attributable either to a disturbance in the baseline simple spike and complex spike activities of their Purkinje cells or to a persistent multiple climbing fiber innervation. We conclude that cerebellar LTD is probably one of the major mechanisms underlying motor learning, but that deficits in LTD induction and motor learning as observed in the L7-PKCI mutants may only be reflected in differences of the Purkinje cell signals during and/or directly after training.

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.

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.

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.

Task-dependence of saccade-related activity in monkey superior solliculus: implications for models of the saccadic system.

Current models assign a crucial role to the deep layers of the Superior Colliculus (SC) in the dynamic feedback control of saccadic eye movements. However, if the SC is to be part of the local feedback loop for saccades, it is expected that the movement-related firing patterns of deep layer SC cell maintain a fixed relation with the instantaneous saccade trajectory, regardless of the conditions that evoked the saccade. In this paper we provide three different lines of evidence, suggesting that the movement activity of SC burst cells may change as a function of the sensory conditions evoking the saccade. First, it is shown that bimodal (visual-auditory) stimulation may markedly enhance (up to about 350%) or suppress (on average down to 70%) SC motor bursts when compared to the activity for unimodal visual stimulation. Second, the movement activity associated with auditory-evoked saccades appeared to be reduced by almost 60% relative to visually-evoked saccades of the same metrics (tested in one monkey). However, for both paradigms, these relatively large changes in movement activity went without a concomitant change in the saccade properties. Third, a short-term saccadic adaptation paradigm produced saccades with a smaller amplitude (gain about 0.7) upon presentation of the adapting visual stimulus. However, we found that the movement-related activity of SC burst cells did not change in this paradigm. These findings suggest that the SC cells do neither encode saccade kinematics, nor the precise components of the saccade vector. Rather, we propose that the motor SC issues a crude desired eye displacement signal to the brainstem that is transformed into the appropriate movement signals by downstream or parallel mechanisms.

Recording eye movements with video-oculography and scleral search coils: a direct comparison of two methods.

A video-based 2D eye-tracking system (EyeLink version 2.04, SR Research Ltd/SMI) was compared with the scleral search coil technique for its performance on recording the properties of fixations and saccadic eye movements. Fixation positions and saccadic properties (amplitude, duration, and peak velocity) were calculated independently from the data of the two systems that recorded eye positions simultaneously. Fixation positions were well correlated between the video and the coil output with an average discrepancy of <1 degree over a tested range of 40 by 40 degree of visual angle. With respect to the saccade analysis, the values measured by the video system were fitted as a linear function of the values measured by the coil system. Highly correlated linear fits with slopes near one were obtained for all the saccadic parameters. Main sequence relationships (amplitudes-duration and amplitude-peak velocity) were also similar for both systems. A disadvantage of the video method is its low sample rate of 250 Hz. The relatively noisier estimate of all parameters of small saccades could be attributed to this low sampling frequency.

Monkey superior colliculus activity during short-term saccadic adaptation.

This article concerns the neural mechanisms that underlie short-term saccadic adaptation in the rhesus monkey. By means of a consistent intrasaccadic target displacement, the relation between visual input and motor output was gradually changed in three monkeys, such that they made hypometric saccades. During this process, the activity of saccade-related burst neurons in the intermediate and deep layers of the Superior Colliculus (SC) was recorded in two of the monkeys. Our findings show that, like in humans, only saccades evoked within a restricted field around the adaptation target were adapted. However, unlike in humans, the kinematic properties of adapted saccades also changed systematically during the adaptation process. Typically, adapted saccades were slower and had a longer duration than would be expected on the basis of the main sequence for nonadapted visually guided movements. During adaptation, saccade-related activity of units in the SC remained appropriate for the saccade that was required to foveate the initial target, rather than for the saccade that was actually made. This means that adaptation caused a dissociation between SC activity and the ensuing saccade. Thus, the activity of the colliculus was better described in "required eye displacement coordinates" than in "actual eye displacement coordinates." Our data provide further evidence for the hypothesis that short-term saccadic adaptation acts at a level downstream from the SC, presumably at a stage that determines the kinematics of saccadic eye movements.

Visual-auditory interactions modulate saccade-related activity in monkey superior colliculus.

This paper reports on single-unit activity of saccade-related burst neurons (SRBNs) in the intermediate and deep layers of the monkey superior colliculus (SC), evoked by bimodal sensory stimulation. Monkeys were trained to generate saccadic eye movements towards visual stimuli, in either a unimodal visual saccade task, or in a bimodal visual-auditory task. In the latter task, the monkeys were required to make an accurate saccade towards a visual target, while ignoring an auditory stimulus. The presentation of an auditory stimulus in temporal and spatial proximity of the visual target influenced neither the accuracy nor the kinematic properties of the evoked saccades. However, it had a significant effect on the activity of 90% (45/50) of the SRBNs. The motor-related burst increased significantly in some neurons, but was suppressed in others. In visual-movement cells, comparable bimodal interactions were observed in both the visually evoked burst and the movement-related burst. The large differences observed in the movement-related activity of SRBNs for identical saccades under different sensory conditions do not support the hypothesis that such cells encode dynamic motor error. The only behavioral parameter that was affected by the presentation of the auditory stimulus was saccade latency. Auditory stimulation caused saccade latency changes in the majority of the experiments. Meanwhile, the timing of peak collicular motor activity and saccade onset remained tightly coupled for all stimulus configurations. In addition, saccade latency varied as function of the distance between the stimuli in 36% of the recordings. Interestingly, the occurrence of a spatial latency effect covaried significantly with a similar spatial influence on the SRBNs firing rate. These cells were always most active in the bimodal task when both stimuli were in spatial register, but activity decreased with increasing stimulus separation.