Ghrelin is related to lower brain reward activation during touch.

The gut hormone ghrelin drives food motivation and increases food intake, but it is also involved in the anticipation of and response to rewards other than food. This pre-registered study investigated how naturally varying ghrelin concentrations affect the processing of touch as a social reward in humans. Sixty-seven volunteers received slow caressing touch (so-called CT-targeted touch) as a social reward and control touch on their shins during 3T functional imaging on two test days. On one occasion, participants were fasted, and on another, they received a meal. On each occasion, plasma ghrelin was measured at three time points. All touch was rated as more pleasant after the meal, but there was no association between ghrelin concentrations and pleasantness. CT-targeted touch was rated as the most pleasant and activated somatosensory and reward networks (whole brain). A region-of-interest in the right medial orbitofrontal cortex (mOFC) showed lower activation during all touches, the higher the ghrelin concentrations were. During CT-targeted touch, a larger satiety response (ghrelin decrease after the meal) was associated with higher mOFC activation, and this mOFC activation was associated with higher experienced pleasantness. Overall, higher ghrelin concentrations appear to be related to a lower reward value for touch. Ghrelin may reduce the value of social stimuli, such as touch, to promote food search and intake in a state of low energy. This suggests that the role of ghrelin goes beyond assigning value to food reward.

Interpersonal stroking touch is targeted to C tactile afferent activation.

C tactile fibers are a specialized group of fibers innervating the non-glabrous skin that are tuned to light gentle stroking applied with velocities between 1 and 10 cm/s. Those fibers add to the sensation of interpersonal caressing and pleasant touch. It is unclear whether people spontaneously apply touch that is tuned to optimally activate those fibers. This was investigated in three studies. In study one, 45 participants (21.8 ± 2.3 years, 24 women) were asked to stroke an artificial arm. In study two, 32 participants (28.3 ± 8.7 years, 16 women) were asked to stroke their partner. In study three, 11 parents (29.4 ± 5.7 years, 6 women) were asked to stroke their babies. Stroking velocity was tracked in all conditions. Stroking velocities were significantly slower in the partner touch and baby touch condition than in the artificial arm condition and all of the participants stroking their partner or baby used velocities that can activate C tactile fibers. We conclude that human social stroking is optimized for C tactile stimulation.

Feelings of helplessness increase ERN amplitudes in healthy individuals.

Experiencing feelings of helplessness has repeatedly been reported to contribute to depressive symptoms and negative affect. In turn, depression and negative affective states are associated, among others, with impairments in performance monitoring. Thus, the question arises whether performance monitoring is also affected by feelings of helplessness. To this end, after the induction of feelings of helplessness via an unsolvable reasoning task, 37 participants (20 females) performed a modified version of a Flanker task. Based on a previously validated questionnaire, 17 participants were classified as helpless and 20 as not-helpless. Behavioral measures revealed no differences between helpless and not-helpless individuals. However, we observed enhanced Error-Related Negativity (ERN) amplitude differences between erroneous and correct responses in the helpless compared to the not-helpless group. Furthermore, correlational analysis revealed that higher scores of helplessness were associated with increased ERN difference scores. No influence of feelings of helplessness on later stages of performance monitoring was observed as indicated by Error-Positivity (Pe) amplitude. The present study is the first to demonstrate that feelings of helplessness modulate the neuronal correlates of performance monitoring. Thus, even a short-lasting subjective state manipulation can lead to ERN amplitude variation, probably via modulation of mesencephalic dopamine activity.

Variants within the GABA transaminase (ABAT) gene region are associated with somatosensory evoked EEG potentials in families at high risk for affective disorders.

BACKGROUND: Depression frequently co-occurs with somatization, and somatic complaints have been reported as a vulnerability marker for affective disorders observable before disease onset. Somatization is thought to result from an increased attention to somatic sensations, which should be reflected in long-latency somatosensory evoked electroencephalogram (EEG) potentials (SSEPs) at the physiological level. Previous studies revealed that SSEPs are altered in depressed patients and suggested late SSEP components as vulnerability markers for affective disorders. Neurotransmitters such as serotonin, γ-aminobutyric acid (GABA) and the neuropeptide substance P may play an important role for both affective disorders and somatosensory processing. Method We investigated the associations between SSEPs and polymorphisms within candidate genes of the serotonergic, GABAergic as well as the substance P system in subjects at high risk for affective disorders. The sample was composed of high-risk families participating in the Munich Vulnerability Study and genetic association analyses were calculated using qfam (family-based association tests for quantitative traits) implemented in PLINK 1.05. RESULTS: We observed significant associations (false discovery rate <0.05) withstanding correction for multiple testing between late SSEP components (response strength 170-370 ms after stimulation) and four single nucleotide polymorphisms within the GABA transaminase (ABAT) gene region coding for a protein responsible for GABA degradation. No effects were found with the classical disease trait approach, suggesting SSEP marker specificity of the observed associations. CONCLUSIONS: Our findings point to a possible role of ABAT gene-regulated GABA catabolism for an altered processing of somatosensory stimuli as a potential vulnerability marker for affective disorders.

Impaired self-perception of the hand in complex regional pain syndrome (CRPS).

To investigate neglect, extinction, and body-perception in patients suffering from complex regional pain syndrome (CRPS). So-called 'neglect-like' symptoms have been reported in CRPS, however no studies have yet analyzed this phenomenon which might substantiate the theory of the central nervous system involvement in the pathophysiology of CRPS. A total of 114 patients with CRPS of the upper limb underwent bedside neurological examination. 'Neglect-like' symptoms were determined by asking all patients what kind of feeling they had toward the affected hand (feeling of foreignness). Hemispatial neglect was tested with the line bisection task in 29 patients and sensory extinction to simultaneous stimulation in 40 patients. The ability to identify fingers after tactile stimulation was tested in 73 patients. Independently of the affected side and disease duration, 54.4% of the patients reported that their hand felt 'foreign' or 'strange'. The ability to identify fingers was impaired in 48% on the affected hand and in 6.5% on the unaffected hand ( X(2) = 33.52, df = 1, p < 0.0001). These findings were related to pain intensity, illness duration and the extent of sensory deficits. No typical abnormalities indicating neglect were found in the line bisection test. Sensory extinction was normal in all patients. A large proportion of CRPS patients have disturbances of the self-perception of the hand, indicating an alteration of higher central nervous system processing. There are no indicators that classic neglect or extinction contribute to these findings. Physical therapy of such patients should take this observation into consideration.

Differential effect of a distractor on primary saccades and perceptual localization.

A distractor presented nearby the target of a goal-directed short latency saccade leads to spatial averaging, that is, the saccade lands between the target and the distractor. This so-called global effect is a characteristic feature of the spatial processing underlying the programming of saccadic eye movements. To determine whether this effect of near distractors on saccade metrics is also reflected in perceptual localization, subjects performed a saccade task and a perceptual localization task using identical, briefly flashed visual stimuli. To make the available visual processing time for saccades and perception more similar, we followed the target with a mask. Without the mask, primary saccades with short latency landed between target and distractor. The distractor had less effect on primary saccades with longer latencies (>200 ms) and did not affect the final eye position after late secondary saccades in the dark. This indicates that the oculomotor system can correctly use information about the target location 200 ms after the target flash even if no visual stimulus is present during this period. Likewise the presence of a distractor did not affect perceptual localization. Under the masking condition a similar global effect occurred for primary saccades with short latencies, but the latency dependence of the global effect was weakened. Secondary saccades and perceptual localization still did not show a global effect. The results suggest that the primary saccade is based on a specific target acquisition process that differs from that used for spatial perception and for the programming of memory-guided corrective saccades.

Assessing noise annoyance: an improvement-oriented approach.

A concept for practice-oriented assessment of noise annoyance at the workplace is presented. Employees evaluated the noise situation at their workplace by characterizing the loudest noise event with respect to relevant noise characteristics. The results from a first use of the questionnaire for Subjective Evaluation of Noise Characteristics in Office Workplaces (SENO) show (1) a general need for an additional constructive measure of subjective noise annoyance, (2) that evaluation of the loudest noise event is representative for the overall workplace situation, and (3) that coping plays a crucial role and should be explicitly controlled. Finally, examples of how to use SENO for improving the workplace situation are given.

Spatial and temporal aspects of eye-hand coordination across different tasks.

The way in which saccadic eye movements are elicited influences their latency and accuracy. Accordingly, different tasks elicit different types of saccades. Using the tasks steps, gap, memory, scanning and antisaccade, we analyzed combined eye and hand movements to determine whether both motor systems share control strategies. Errors and latencies were measured to examine whether changes in eye motor behavior are reflected in hand motor behavior. Directional and variable errors of eye and hand changed differently according to the tasks. Moreover, errors of the two systems did not correlate for any of the tasks investigated. Contrary to errors, mean latencies of eye movements were organized in the same pattern as hand movements. A correlation of latencies indicates that both motor systems rely on common information to initiate movement. Temporal coupling was stronger for intentional tasks than for reflexive tasks.

Changes in the volume of residual pituitary adenomas in patients with adult-onset growth hormone deficiency during replacement therapy with the recombinant human growth hormone.

In the course of a prospective study concerning recombinant human growth hormone replacement therapy in adult-onset growth hormone deficiency, we determined the volumes of residual tumors in six patients with pituitary macroadenomas who had formerly been treated with surgery alone or surgery and external radiotherapy. Pituitary CT scans in direct coronal views were obtained at baseline, and at 6, 12 and 18 months. The volumes of the residual tumors were calculated from the tumor diameters assuming that the tumors had an ellipsoid shape. Tumor volumes did not change in one patient and were reduced in two patients. In three patients, clinically non-significant tumor expansion by a median of 23.6 +/- 13.2% (range, 21.1-62.0%) was noted after 12 to 18 months. This tumor expansion did not cause signs or symptoms of a mass effect and did not influence further treatment. One of the six patients discontinued treatment and no further change in tumor size, as determined by MRT, was noted over a mean follow up of 34 months. Treatment was continued for up to 38 months in five patients. In four of these five patients no further change in tumor size was detected. However, treatment with the growth hormone was stopped in one patient since a 30% expansion in tumor volume, elevating the optic chiasm, was noted on MRT. None of the patients developed deterioration of visual fields. Interestingly, tumor invasion of the cavernous sinus had been present initially in all three who displayed tumor expansion while on rhGH. This first study in which diameters of residual pituitary adenomas in patients on growth hormone replacement therapy were prospectively and carefully measured, permits no conclusion regarding a causal relationship between growth hormone and tumor expansion, owing to the small number of patients. However, the observed incidence is not much different from that in former studies without growth hormone replacement therapy. Nevertheless, a close observation of the pituitary by imaging studies at regular intervals appears to be mandatory, particularly in patients with invasive residual adenomas.

Evaluation of a putative major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q14.

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy (IGE). Significant evidence for linkage has been reported for a susceptibility locus for JME in the chromosomal region 15q14 that harbors the gene encoding the alpha7 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA7). The present study was designed to test the earlier linkage finding and to explore whether this susceptibility locus is involved in the epileptogenesis of a broader spectrum of IGE syndromes. Multipoint parametric and nonparametric linkage analyses with seven microsatellite polymorphisms encompassing the region of the CHRNA7 gene were performed using two diagnostic schemes of JME-related traits in two groups of multiplex families ascertained through probands with either JME (n = 27) or idiopathic absence epilepsy (n = 30). The present linkage study failed to replicate evidence for a major susceptibility locus for JME in the region encompassing the CHRNA7 gene. In addition, we found no hint in favor of linkage to 15q14 under the broad diagnostic scheme in any of the sets of families. If genetic variation in this region confers susceptibility to JME, then its effect size might be too small or its occurrence too rare to be detected in the investigated families.

Replication analysis of a putative susceptibility locus (EGI) for idiopathic generalized epilepsy on chromosome 8q24.

PURPOSE: The present replication study was designed to test the validity of a previously mapped susceptibility locus (EGI) for common subtypes of idiopathic generalized epilepsy (IGE) in chromosomal region 8q24. METHODS: Thirty-eight multiplex families of probands with common IGE syndromes were included in the present study. Parametric and nonparametric multipoint linkage analyses were conducted between the IGE trait (either "idiopathic" generalized seizure or generalized spike-wave EEG discharges) and three microsatellite polymorphisms (D8S256, D8S284, D8S1128) encompassing the putative EGI locus. RESULTS: Parametric and nonparametric multipoint linkage analysis provided no evidence for linkage between the IGE trait and the markers encompassing the putative EGI locus. Moreover, we noted no indication favoring linkage to this chromosomal region in two distinct subsets of families subdivided by the absence (n = 18) or presence (n = 20) of family members with juvenile myoclonic epilepsy (JME). CONCLUSIONS: We failed to replicate evidence of a major locus (EGI) for common familial IGE in chromosome region 8q24. On the contrary, our present parametric linkage results provide evidence against linkage across the region under a broad range of genetic models. If there is a susceptibility locus for IGE in this region, the effect size or the proportion of linked families is too small to detect linkage in these families. Taking into account the problems in replicating initial linkage claims in oligogenic traits, further linkage studies in additional family sets are necessary to evaluate the validity of the previous linkage finding.

Choristoma of the optic nerve: neuroimaging characteristics and association with spinal cord lipoma.

A 54-year-old patient presented with amaurosis of the right eye that resulted from a dysontogenetic tumor of the right optic nerve. The tumor involved the intraorbital, intracanalicular and intracerebral portion of the right optic nerve, without involvement of the chiasm. Although the patient had refused further diagnostic surgical exploration, we show that it is possible to establish the diagnosis of choristoma of the optic nerve by means of modern neuroimaging techniques based on computed tomography and magnetic resonance imaging. It appears from neuroimaging that choristomata of the optic nerve and spinal cord lipomas represent different manifestations of the same type of tumor. The neuroimaging characteristics of both kinds of tumors are discussed.

Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism.

Juvenile absence epilepsy (JAE) is a common subtype of idiopathic generalized epilepsy (IGE). Hereditary factors play a major role in its etiology. The important function of glutamate receptors (GluRs) in excitatory neurotransmission, synaptic plasticity, and neurodevelopment suggests their involvement in epileptogenesis. A tetranucleotide repeat polymorphism in the non-coding region of the kainate-selective GluR5 receptor gene (GRIK1) on chromosome 21q22.1 provides the tool to investigate this candidate gene. The present association and linkage study tested the hypothesis that allelic variants of GRIK1 confer genetic susceptibility to the pathogenesis of JAE. Our family-based association analysis using the haplotype-based haplotype relative risk statistic revealed an association of JAE with the nine-repeat containing allele of the GRIK1 tetranucleotide polymorphism (chi2 = 8.31, df = 1, P = 0.004). Supportive evidence for linkage to a JAE related IGE spectrum (Zmax = 1.67 at GRIK1) under an autosomal dominant mode of inheritance and significant allele sharing (P < 0.05) among the affected family members suggest that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE-related phenotypes.

Linkage analysis between idiopathic generalized epilepsies and the GABA(A) receptor alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15.

INTRODUCTION: We tested the hypothesis that genetic variants within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15q11-q13 confer genetic susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). MATERIAL AND METHODS: Ninety-four families were selected from IGE patients with either juvenile myoclonic epilepsy (JME), juvenile (JAE) or childhood absence epilepsy (CAE). Cosegregation was tested between dinucleotide polymorphisms associated with the human GABA(A) alpha5, beta3 and gamma3 subunit gene cluster and three different IGE trait models. RESULTS: Evidence against linkage to the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster was found in the entire family set and subsets selected from either CAE or JAE. In 61 families of JME patients, a maximum lod score (Zmax=1.40 at Theta(max)=0.00) was obtained for a broad IGE spectrum ("idiopathic" generalized seizure or generalized spike and wave discharges in the electroencephalogram) assuming genetic heterogeneity (alpha=0.37; P=0.06) and an autosomal recessive mode of inheritance. CONCLUSION: The possible hint of linkage in families of JME patients emphasizes the need for further studies to determine whether a recessively inherited gene variant within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster contributes to the pathogenesis of "idiopathic" generalized seizures and associated EEG abnormalities in a proportion of families.

Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor alpha 1 and gamma 2 subunit gene cluster on chromosome 5.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of ionotropic gamma-aminobutyric acid type A receptors (GABRs) in inhibitory neurotransmission in the mammalian central nervous system suggests that they may be involved in epileptogenesis and genetic predisposition to IGEs. Dinucleotide repeat polymorphisms associated with the human GABAA receptor alpha 1 (GABRA1) and gamma 2 subunit (GABRG2) gene cluster on chromosome 5q32-q35 offer the opportunity to test whether these candidate genes confer susceptibility to IGEs. Our linkage analyses in 63 families ascertained through IGE patients with either juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy do not support the hypothesis that variants within the GABRA1 and GABRG2 gene cluster contribute a frequent major gene effect to the expression of the common familial IGEs.

Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence.

Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of glutamate receptors (GluRs) in excitatory neurotransmission implicates their involvement in epileptogenesis and genetic susceptibility to IGEs. A trinucleotide repeat polymorphism detected in the 3' untranslated region of the kainate-selective GluR6 receptor gene (GRIK2) on chromosome 6 makes it possible to perform linkage and association studies with this high-ranking candidate gene. The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs. Linkage and association analyses were conducted in 63 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, or childhood absence epilepsy. Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21. This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus "EJM1" on the short arm of chromosome 6.

The phenotypic spectrum related to the human epilepsy susceptibility gene "EJM1".

Linkage studies of families ascertained through patients with juvenile myoclonic epilepsy (JME) suggest that an HLA-linked susceptibility gene on chromosome 6, designated "EJM1," predisposes to a group of idiopathic generalized epilepsies (IGEs) comprising JME, juvenile absence epilepsy (JAE), childhood absence epilepsies (CAE), and epilepsies with generalized tonic-clonic seizures (GTCS). To explore the EJM1-related phenotypic spectrum, we conducted linkage studies with HLA-DQ alpha restriction fragment length polymorphisms in 44 families ascertained through patients with CAE or JAE. Our results for the entire group of families provide evidence against a major susceptibility locus for idiopathic absence epilepsies and broader spectra of IGEs in the HLA region. Lod scores less than -2 were obtained for a region from 10 cM up to 23 cM on either side of the HLA-DQ alpha locus, depending on the assumed trait model. Suggestive evidence for linkage was found only for a subgroup of families with JME patients assuming an autosomal dominant mode of inheritance with 70% penetrance. A maximum lod score was obtained when family members with JME, JAE, CAE, and idiopathic GTCS were included into the affection status. Our results demonstrate that (1) the genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs is heterogeneous, (2) the gene effect of EJM1 depends on the familial genetic background, and (3) EJM1 confers genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs in the presence of family members with JME.

Impaired arithmetic facts but intact conceptual knowledge--a single-case study of dyscalculia.

We present the case of a young, highly educated patient who showed severe problems in basic arithmetic after a bone marrow transplant followed by extensive irradiation and chemotherapy. Despite his inability to resolve arithmetical fact problems (as 2 + 3), he showed intact processing of algebraic expressions and excellent understanding of complex arithmetic text problems. He perfectly knew arithmetic principles and applied them in various tasks. The performance of the patient suggests that conceptual knowledge (in addition to arithmetical fact knowledge and arithmetic procedures) is a functionally independent component of the calculation system.