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.

The associations of alcohol, coffee and tobacco consumption with gait in a community-dwelling population.

BACKGROUND/OBJECTIVES: Gait is an important health indicator, relating strongly to the risk of falling, morbidity and mortality. In a community-dwelling population, we investigated associations of alcohol, coffee and tobacco consumption with gait. SUBJECTS/METHODS: Two thousand forty-six non-demented participants from the Rotterdam Study underwent gait assessment by electronic walkway. We measured gait velocity and Global Gait, which is the average of seven gait domains: Rhythm, Phases, Variability, Pace, Tandem, Turning and Base of Support. Alcohol, coffee and tobacco consumption was assessed by questionnaires. With analysis of covariance, we investigated associations of consumption of alcoholic beverages, coffee consumption and smoking with Global Gait, gait velocity and the seven individual gait domains. RESULTS: In all, 81.9% of participants drank alcohol, 92.4% drank coffee, 17.3% were current smokers and 50.9% were past smokers. Moderate alcohol consumption (1-3 glasses per day) associated with better gait, as measured by Global Gait (0.20 standard deviations (s.d.) (95% confidence interval: 0.10; 0.31)), gait velocity (2.65 cm/s (0.80; 4.50)), Rhythm and Variability. Consuming high amounts of coffee (>3 cups per day) associated with better Global Gait (0.18 s.d. (0.08; 0.28)), gait velocity (2.63 cm/s (0.80; 4.45)), Pace, Turning and Variability. Current smoking associated with worse Global Gait (-0.11 s.d. (-0.21; 0.00)), gait velocity (-3.47 cm/s (-5.33; -1.60)), Rhythm and Pace, compared with non-smokers. CONCLUSIONS: In a community-dwelling population, consuming >1 cup of coffee and 1-3 glasses of alcohol relate to better gait, whereas smoking is related to worse gait. Further studies are required to evaluate whether interventions targeting substance consumption may aid to prevent or reduce gait deterioration and thereby related health problems.

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.

Standard and individually determined thermal pain stimuli induce similar brain activations.

BACKGROUND: Several functional magnetic resonance imaging (fMRI) studies use thermal pain stimuli to determine brain activation patterns during pain. Studies use either a standard temperature condition for all participants or an individualized temperature condition based on the individually determined pain threshold of the participant. The aim of the present study was to compare both conditions in the same participants. METHODS: Eighteen healthy participants (21-29 years) underwent four fMRI runs, in each of which they received three types of thermal stimuli: neutral (32 °C), warm (37 °C) and painfully hot. In two runs, the painfully hot stimulus was set at a standard temperature of 46 °C; in the other two runs, the temperature was set at the subject's individual pain threshold (46-48 °C). fMRI (blood oxygen level dependent) was performed on a 1.5 T MR scanner (GE Signa). Pre-processing and statistical analyses were performed using Statistical Parametric Mapping (SPM8) software. RESULTS: While the stimulation temperatures were lower in the standard temperature condition, both conditions activated the same brain regions. When comparing the conditions directly to each other, we did not find significantly different grey matter activation patterns. CONCLUSIONS: The similar activation patterns between the two conditions suggest that it is not necessary to use individualized stimuli per se. The temperature of 46 °C appeared to be an adequate temperature for standardized stimulation to observe significant brain activations related to thermal pain.

Gait patterns in a community-dwelling population aged 50 years and older.

Poor gait is an important risk factor for falls and associated with higher morbidity and mortality. It is well established that older age is associated with worse gait, but it remains unclear at what age this association is first seen. Moreover, previous studies focused mainly on normal walking, but gait also encompasses turning and tandem walking. In a large study of community-dwelling middle-aged and elderly persons we investigated the association of age with gait, focusing on normal walking, turning and tandem walking. In 1500 persons aged 50 years and over, we measured gait using an electronic walkway. Participants performed normal walks, turning and a tandem walk. With principal components analysis of 30 variables we summarized gait into five known gait factors: Rhythm, Variability, Phases, Pace and Base of Support; and uncovered two novel gait factors: Tandem and Turning. The strongest associations with age were found for Variability (difference in Z-score -0.29 per 10 years increase (95% confidence interval: -0.34; -0.24)), Phases (-0.31 per 10 years (-0.36; -0.27)) and Tandem (-0.25 per 10 years (-0.30; -0.20)). Additionally, these factors already showed association with the youngest age groups, from 55 to 60 years of age and older. Our study shows that Variability, Phases and Tandem have the strongest association with age and are the earliest to demonstrate a poorer gait pattern with higher age. Future research should further investigate how these gait factors relate with gait-related diseases in their earliest stages.

Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes.

OBJECTIVE: Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels. METHODS: 15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10,000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score ≤3 and improvement of neurological impairment assessed with the Edinburgh Functional Impairment Tests (EFIT). Secondary end points included the change in activities of daily living as evaluated using the Barthel Index. RESULTS: Seven of 15 patients (47%) improved on the mRS or stabilised at mRS score ≤3. Four patients (27%) showed significant improvement of neurological impairment as indicated by an overall Edinburgh Functional Impairment Tests score of ≥1 point. Five patients improved on the Barthel Index (33%). CONCLUSION: Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.

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.

Savings and extinction of conditioned eyeblink responses in fragile X syndrome.

The fragile X syndrome (FRAXA) is the most widespread heritable form of mental retardation caused by the lack of expression of the fragile X mental retardation protein (FMRP). This lack has been related to deficits in cerebellum-mediated acquisition of conditioned eyelid responses in individuals with FRAXA. In the present behavioral study, long-term effects of deficiency of FMRP were investigated by examining the acquisition, savings and extinction of delay eyeblink conditioning in male individuals with FRAXA. In the acquisition experiment, subjects with FRAXA displayed a significantly poor performance compared with controls. In the savings experiment performed at least 6 months later, subjects with FRAXA and controls showed similar levels of savings of conditioned responses. Subsequently, extinction was faster in subjects with FRAXA than in controls. These findings confirm that absence of the FMRP affects cerebellar motor learning. The normal performance in the savings experiment and aberrant performance in the acquisition and extinction experiments of individuals with FRAXA suggest that different mechanisms underlie acquisition, savings and extinction of cerebellar motor learning.

Effects of object complexity and type on the gaze behavior of children with pervasive developmental disorder.

The looking behavior of children with pervasive developmental disorder (PDD) and age- and IQ-matched normal control children was studied using infrared oculography. Stimuli varying in complexity and topic were presented to test whether children with PDD have specific abnormalities in looking behavior to complex stimuli and/or to faces. All children showed more and longer fixations on the complex objects than on the simple objects, especially the complex nonsense figure, but group differences were not found. The results show no evidence for specific abnormalities in looking behavior to either faces or to complex stimuli in high functioning children with PDD.

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.

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.

In search of neurophysiological markers of pervasive developmental disorders: smooth pursuit eye movements?

Genetic studies of autism would benefit from the identification of (neurophysiological) markers of the disease. Reports that subjects with autism suffer from abnormalities of visual motor processing, indicate that abnormalities in smooth pursuit eye movements (SPEM) may be a marker of the disorder. Sixteen high-functioning school-aged children with pervasive developmental disorder (PDD) were compared with a matched group of eighteen normally developing controls on performance of a SPEM task and a task which tested the integrity of visually guided saccadic eye movements. Both groups of children had normal eye movements during performance of these tasks. Thus abnormalities in SPEM would appear not to be a marker of PDD. The earlier reported abnormalities in visual motion processing might need to be reinterpreted.

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.

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.