Search

Changes in personality are one of the main concerns Parkinson's disease (PD) patients raise when facing the decision to undergo neurosurgery for deep brain stimulation (DBS) of the subthalamic nucleus (STN). While clinical instruments for monitoring functional changes following DBS surgery are well-established in the daily therapeutic routine, personality issues are far less systematically encompassed. Moreover, while sex disparities in the outcomes of STN-DBS therapy have been reported, little is known about the different effects that DBS treatment may have on mood and personality traits in female and male patients. To this aim, the effect of STN-DBS on personality traits was assessed in 46 PD patients (12 women and 34 men) by means of the Freiburg Personality Inventory. The Becks Depression Inventory (BDI-I) and the Parkinson's Disease Questionnaire were used to evaluate patients' level of depression and quality of life (QoL). Patients completed the questionnaires a few days before, within the first year, and 2 years after surgery. The 12 personality traits defined by the FPI-R questionnaire did not change significantly after STN-DBS surgery (p = 0.198). Women declared higher depression scores through all study stages (p = 0.009), but also showed a stronger QoL amelioration after surgery than male patients (p = 0.022). The BDI-I scores of female patients clearly correlated with their levodopa equivalent daily dose (LEDD; r = 0.621, p = 0.008). Remarkably, in both male and female patients, higher pre-operative LEDDs were related to worse post-operative QoL scores (p = 0.034). These results mitigate the concerns about systematic personality changes due to STN-DBS treatment in PD patients and encourage an early DBS approach, before severe levodopa-induced sequelae may irreparably compromise the patients' QoL. In the future, more focus should lie on sex-related effects, since female patients seem to profit more than male patients from STN-DBS, in terms of reduced depressive symptoms associated with a reduction of the LEDD and amelioration of QoL. These aspects may help to redress the sex imbalance in PD patients treated with DBS, given that women are still strongly under-represented.

Ageing is characterized by changes in sensory and cognitive abilities. While there is evidence that decline in sensory acuity and enhanced multisensory integration predict cognitive status in healthy older adults, potential mechanistic links between these age-related alterations remain unclear. In the current study, we assessed performance of younger and older healthy adults in a visuotactile delayed match-to-sample task and related indices of multisensory integration to unisensory perceptual thresholds and cognitive assessment data. Additionally, we applied transcranial alternating current stimulation (tACS) to modulate cortical networks found to underlie visuotactile interactions and working-memory matching in our previous work. Analysing response times and signal detection measures, we found older adults to show enhanced multisensory integration and benefit more from successful working memory matching. Both measures predicted cognitive status and correlated positively with each other, suggesting that they likely reflect a common underlying tendency to integrate information. Sensory capability, however, independently predicted cognitive status. tACS with beta frequency (20 Hz) accelerated task performance and this effect was more pronounced in the older group. We conclude that sensory capability and information integration represent independent predictors of cognitive status. Finally, we discuss a potential role of the parietal cortex in mediating augmented integration in older adults.

Working memory (WM) refers to the temporary retention and manipulation of information, and its capacity is highly susceptible to training. Yet, the neural mechanisms that allow for increased performance under demanding conditions are not fully understood. We expected that post-training efficiency in WM performance modulates neural processing during high load tasks. We tested this hypothesis, using electroencephalography (EEG) (N = 39), by comparing source space spectral power of healthy adults performing low and high load auditory WM tasks. Prior to the assessment, participants either underwent a modality-specific auditory WM training, or a modality-irrelevant tactile WM training, or were not trained (active control). After a modality-specific training participants showed higher behavioral performance, compared to the control. EEG data analysis revealed general effects of WM load, across all training groups, in the theta-, alpha-, and beta-frequency bands. With increased load theta-band power increased over frontal, and decreased over parietal areas. Centro-parietal alpha-band power and central beta-band power decreased with load. Interestingly, in the high load condition a tendency towards reduced beta-band power in the right medial temporal lobe was observed in the modality-specific WM training group compared to the modality-irrelevant and active control groups. Our finding that WM processing during the high load condition changed after modality-specific WM training, showing reduced beta-band activity in voice-selective regions, possibly indicates a more efficient maintenance of task-relevant stimuli. The general load effects suggest that WM performance at high load demands involves complementary mechanisms, combining a strengthening of task-relevant and a suppression of task-irrelevant processing.

Highlights • Closer association of structural connectivity with cognition than standard MRI. • Loss of structural connectivity associated with poorer cognitive performance. • Higher functional connectivity associated with dominantly poorer task performance. • Associations are accentuated in the default mode and the visual network. • Increased functional connectivity might point towards a maladaptive response., Multiple Sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), which can lead to severe cognitive impairment over time. Magnetic resonance imaging (MRI) is currently the best available biomarker to track MS pathophysiology in vivo and examine the link to clinical disability. However, conventional MRI metrics have limited sensitivity and specificity to detect direct associations between symptoms and their underlying CNS substrates. In this study, we aimed to investigate structural and resting state functional connectomes and subnetworks associated with neuropsychological (NP) performance using a graph theoretical approach. A comprehensive NP test battery was administered in a sample of patients with relapsing remitting MS (RRMS) and mild disability [n = 33, F/M = 20/13, age = 40.9 ± 9.7, median [Expanded Disability Status Scale] (EDSS) = 2, range =0–4] and compared to healthy controls (HC) [n = 29, F/M = 19/10, age = 41.0 ± 8.5] closely matched for age, sex, and level of education. The NP battery comprised the most relevant domains of cognitive dysfunction in MS including attention, processing speed, verbal and spatial learning and memory, and executive function. While standard MRI metrics showed good correlations with TAP Alertness test, disease duration and neurological exams, structural networks showed closer associations with 9-hole peg test and cognitive performances. Decreased graph strength was associated with two out of the 5 NP tests in the spatial learning and memory domain specified by BVMT [Sum 1–3] and BVMT [Recall], and with also SDMT which is one out of the 9 NP tests in the attention/processing speed domain, while no correlation was found between these scores and functional connectivity. Nodal strength was decreased in all subnetworks based on Yeo atlas in patients compared to HC; however, no difference was observed in nodal level of functional connectivity between the groups. The difference in structural and functional nodal connectivity between the groups was also observed in the relationship between structural and functional connectivity within the groups; the relationship between nodal degree and nodal strength was reversed in patients but positive in controls. On a nodal level, structural and functional networks (mainly the default mode network) were correlated with more than one cognitive domain rather than one specific network for each domain within patients. Interestingly, poorer cognitive performance was mostly correlated with increased functional connectivity but decreased structural connectivity in patients. Increased functional connectivity in the default mode network had both positive as well as negative associations with verbal and spatial learning and memory, possibly indicating adaptive and maladaptive mechanisms. In conclusion, our results suggest that cognitive performance, even in patients with RRMS and very mild disability, may reflect a loss of structural connectivity. In contrast, widespread increases in functional connectivity may be the result of maladaptive processes.

The functional relevance of crossmodal activation (e.g. auditory activation of occipital brain regions) in congenitally blind individuals is still not fully understood. The present study tested whether the occipital cortex of blind individuals is integrated into a challenged functional network. A working memory (WM) training over four sessions was implemented. Congenitally blind and matched sighted participants were adaptively trained with an n-back task employing either voices (auditory training) or tactile stimuli (tactile training). In addition, a minimally demanding 1-back task served as an active control condition. Power and functional connectivity of EEG activity evolving during the maintenance period of an auditory 2-back task were analyzed, run prior to and after the WM training. Modality-specific (following auditory training) and modality-independent WM training effects (following both auditory and tactile training) were assessed. Improvements in auditory WM were observed in all groups, and blind and sighted individuals did not differ in training gains. Auditory and tactile training of sighted participants led, relative to the active control group, to an increase in fronto-parietal theta-band power, suggesting a training-induced strengthening of the existing modality-independent WM network. No power effects were observed in the blind. Rather, after auditory training the blind showed a decrease in theta-band connectivity between central, parietal, and occipital electrodes compared to the blind tactile training and active control groups. Furthermore, in the blind auditory training increased beta-band connectivity between fronto-parietal, central and occipital electrodes. In the congenitally blind, these findings suggest a stronger integration of occipital areas into the auditory WM network.

Aus der S2k-Leitlinie Spezifischer Kreuzschmerz wird die funktionelle Entitat „myofasziale Dysfunktion“ als weitere Ursache fur den spezifischen Kreuzschmerz vorgestellt. Myofasziale Dysfunktionen sind Ursache und Folge von Fehlbelastungen des Bewegungssystems. Durch Modifikation einstromender Afferenzen sowohl propriozeptiven als auch nozizeptiven Ursprungs kommt es zur Veranderung der Bewegungs- und Haltungssteuerung (geanderte motorische Muster). Die Diagnostik der myofaszialen Dysfunktion erfolgt durch gezielte, auch anatomisch definierte klinische Funktionstests. Diese sollen in einen manualmedizinischen bzw. funktionellen orthopadischen Untersuchungsgang integriert sein und anschliesend strukturiert bewertet werden. In der Therapie werden in erster Linie neuroreflektorische und biomechanische Mechanismen genutzt.

Although depression and anxiety disorders are common comorbid conditions in alcohol dependence, few structural brain imaging studies have compared alcohol-dependent subjects with and without such comorbidity. In the current study, brain scans of 35 alcohol-dependent with and 40 individuals without diagnosis of a comorbid ICD-10 depressive or anxiety disorder receiving detoxification inpatient treatment were evaluated. Thickness and volumes of automatically segmented neuroanatomical structures were measured in FreeSurfer. Furthermore, associations of brain structure with biological markers and clinical severity markers of alcohol dependence were assessed. Despite comparable addiction severity, the non-comorbid group had evidence of higher cytotoxic effects of alcohol use on hepatic and haematological markers, and showed significantly smaller volumes of total cerebral, and cerebellar grey matter. Similarly, they showed unexpected smaller hippocampal and nucleus accumbens volumes, and thinner frontal, temporal and occipital cortices. Smaller brain volumes correlated with increased markers of hepatic and haematological dysfunction, and with longer duration of alcohol dependence in the non-comorbid group. Evidence of higher biomarkers of alcohol use may be indicative of more severe alcohol dependence or higher vulnerability to ethanol toxicity in this group. Furthermore, psychopathology-related drug treatment, which occurred in 53% of the comorbid group over the recent years, or tissue inflammation may have a moderate effect on the grade of cerebral atrophy in alcohol-dependent patients. Longitudinal studies are needed to investigate this issue more fully.

The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson’s disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson’s disease (1 female; age:61.3±7.3years; disease duration:12.3±5.4years; Hoehn and Yahr stage:2.2±0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS), and Parkinson’s Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

While human speech comprehension is thought to be an active process that involves top-down predictions, it remains unclear how predictive information is used to prepare for the processing of upcoming speech information. We aimed to identify the neural signatures of the preparatory processing of upcoming speech. Participants selectively attended to one of two competing naturalistic, narrative speech streams, and a temporal response function (TRF) method was applied to derive event-related-like neural responses from electroencephalographic data. The phase responses to the attended speech at the delta band (1–4 Hz) were correlated with the comprehension performance of individual participants, with a latency of − 200–0 ms relative to the onset of speech amplitude envelope fluctuations over the fronto-central and left-lateralized parietal electrodes. The phase responses to the attended speech at the alpha band also correlated with comprehension performance but with a latency of 650–980 ms post-onset over the fronto-central electrodes. Distinct neural signatures were found for the attentional modulation, taking the form of TRF-based amplitude responses at a latency of 240–320 ms post-onset over the left-lateralized fronto-central and occipital electrodes. Our findings reveal how the brain gets prepared to process an upcoming speech in a continuous, naturalistic speech context.

Background Deep brain stimulation (DBS) within the pallidum represents an effective and well-established treatment for isolated dystonia. However, clinical outcome after surgery may be variable with limited response in 10–25% of patients. The effect of lead location on clinical improvement is still under debate. Objective To identify stimulated brain regions associated with the most beneficial clinical outcome in dystonia patients. Methods 18 patients with cervical and generalized dystonia with chronic DBS of the internal pallidum were investigated. Patients were grouped according to their clinical improvement into responders, intermediate responders and non-responders. Magnetic resonance and computed tomography images were co-registered, and the volume of tissue activated (VTA) with respect to the pallidum of individual patients was analysed. Results VTAs in responders (n = 11), intermediate responders (n = 3) and non-responders (n = 4) intersected with the posterior internal (GPi) and external (GPe) pallidum and the subpallidal area. VTA heat maps showed an almost complete overlap of VTAs of responders, intermediate and non-responders. VTA coverage of the GPi was not higher in responders. In contrast, VTAs of intermediate and non-responders covered the GPi to a significantly larger extent in the left hemisphere (p Conclusions DBS of ventral parts of the posterior GPi, GPe and the adjacent subpallidal area containing pallidothalamic output projections resulted in favourable clinical effects. Of note, non-responders were also stimulated within the same area. This suggests that factors other than mere lead location (e.g., clinical phenotype, genetic background) have determined clinical outcome in the present cohort.

Parkinson's disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinson's Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

Background Only few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in multiple sclerosis. Objective and Methods This randomized controlled trial with 34 patients in the intervention group (IG) (mean: 38.2 years (±9.6)) and 34 patients in the control group (CG) (mean: 39.6 years (±9.7)) aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting multiple sclerosis (RRMS). The primary outcome was verbal learning assessed by the verbal learning and memory test (VLMT). Patients were randomized to an IG or a waitlist CG. Patients in the IG exercised according to an individually tailored training schedule (with two to three sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores. Results A total of 77 patients with RRMS were screened and 68 participants randomized (CG n = 34; IG n = 34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean expanded disability status scale of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms. Conclusion This study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS. The trial was prospectively registered at clinicaltrials.gov (NCT02005237).

We investigated the function of oscillatory alpha-band activity in the neural coding of spatial information during tactile processing. Sighted humans concurrently encode tactile location in skin-based and, after integration with posture, external spatial reference frames, whereas congenitally blind humans preferably use skin-based coding. Accordingly, lateralization of alpha-band activity in parietal regions during attentional orienting in expectance of tactile stimulation reflected external spatial coding in sighted, but skin-based coding in blind humans. Here, we asked whether alpha-band activity plays a similar role in spatial coding for tactile processing, that is, after the stimulus has been received. Sighted and congenitally blind participants were cued to attend to one hand in order to detect rare tactile deviant stimuli at this hand while ignoring tactile deviants at the other hand and tactile standard stimuli at both hands. The reference frames encoded by oscillatory activity during tactile processing were probed by adopting either an uncrossed or crossed hand posture. In sighted participants, attended relative to unattended standard stimuli suppressed the power in the alpha-band over ipsilateral centro-parietal and occipital cortex. Hand crossing attenuated this attentional modulation predominantly over ipsilateral posterior-parietal cortex. In contrast, although contralateral alpha-activity was enhanced for attended versus unattended stimuli in blind participants, no crossing effects were evident in the oscillatory activity of this group. These findings suggest that oscillatory alpha-band activity plays a pivotal role in the neural coding of external spatial information for touch.

BackgroundOnly few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in MS.Objective and methodsThis randomized controlled trial aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting MS. The primary outcome was verbal memory (Verbal learning and memory test, VLMT). Patients were randomized to an intervention group (IG) program or a waitlist control group (CG). Patients in the IG exercised according to an individually tailored training schedule (with 2-3 sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores.Results77 RRMS patients were screened and 68 participants randomized (CG n=34; IG n=34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean EDSS of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms.ConclusionThis study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS.The trial was prospectively registered at clinicaltrials.gov (NCT02005237).

There is evidence that besides limbic brain structures, prefrontal and insular cortical activations and deactivations are involved in the pathophysiology of panic disorder. This study investigated activation response patterns to stimulation with individually selected panic-specific pictures in patients with panic disorder with agoraphobia (PDA) and healthy control subjects using functional magnetic resonance imaging (fMRI). Structures of interest were the prefrontal, cingulate, and insular cortex, and the amygdalo-hippocampal complex. Nineteen PDA subjects (10 females, 9 males) and 21 healthy matched controls were investigated using a Siemens 3-Tesla scanner. First, PDA subjects gave Self-Assessment Manikin (SAM) ratings on 120 pictures showing characteristic panic/agoraphobia situations, of which 20 pictures with the individually highest SAM ratings were selected. Twenty matched pictures showing aversive but not panic-specific stimuli and 80 neutral pictures from the International Affective Picture System were chosen for each subject as controls. Each picture was shown twice in each of four subsequent blocks. Anxiety and depression ratings were recorded before and after the experiment. Group comparisons revealed a significantly greater activation in PDA patients than control subjects in the insular cortices, left inferior frontal gyrus, dorsomedial prefrontal cortex, the left hippocampal formation, and left caudatum, when PA and N responses were compared. Comparisons for stimulation with unspecific aversive pictures showed activation of similar brain regions in both groups. Results indicate region-specific activations to panic-specific picture stimulation in PDA patients. They also imply dysfunctionality in the processing of interoceptive cues in PDA and the regulation of negative emotionality. Therefore, differences in the functional networks between PDA patients and control subjects should be further investigated.

Die myofasziale Dysfunktion ist eine Storung der myofaszialen Funktionseinheit, die mit Schmerzen und/oder Bewegungskontrolldysfunktionen verbunden ist [1, 43]. Steht der Schmerz im Vordergrund der Symptomatik, wird haufig die Bezeichnung „myofasziales Schmerzsyndrom“ verwendet [63]. Die Dysfunktion der Muskulatur ist durch folgende Befunde gekennzeichnet: eingeschrankte Verlangerbarkeit, Abschwachung/reflektorische Hemmung, Triggerpunkte [36, 47, 63] sowie Storung von Bewegungsausmas und -ablauf. Zeichen der faszialen Dysfunktion sind Spannungsveranderungen von Faszien und daraus resultierend eine Einschrankung ihrer Verschieblichkeit gegenuber angrenzenden spezifischen Strukturen [55].

Objective While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. Methods Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6 Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5 months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. Results Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. Conclusions This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. Significance STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

The nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic neurons in the brains of two species of carnivore, the banded mongoose (Mungos mungo) and domestic ferret (Mustela putorius furo), is presented. The banded mongoose belongs to the feliform suborder and the domestic ferret to the caniform suborder, having last shared a common ancestor approximately 53 million years ago; however, they have a very similar overall morphology and life history, presenting an interesting opportunity to examine the extent of evolutionary plasticity in these systems. The brains of the two carnivore species were coronally sectioned and immunohistochemically stained with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. The overall organization and complement of the nuclei of these systems was identical between the two species, although minor differences were noted. Moreover, this overall organization is identical to other studies undertaken in the domestic cat and dog. While for the most part the nuclei forming these systems are similar to those observed in other mammals, two species differences, which appear to be carnivore-specific, were noted. First, cholinergic neurons were observed in the lateral septal nucleus of both species, an apparently carnivore specific feature not recorded previously in other mammals. Second, the serotonergic neurons of the peripheral division of the dorsal raphe complex exhibited a significant caudad expansion, intermingling with the cholinergic and catecholaminergic nuclei of the pons, a carnivore specific feature. These carnivore specific features likely have functional consequences related to coping with stress and the expression of sleep.

Altered sensory perception has been found in patients with autism spectrum disorders (ASD) and might be related to aberrant sensory perception thresholds. We used the well-established, standardized Quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain to investigate 13 somatosensory parameters including thermal and tactile detection and pain thresholds in 13 ASD adults and 13 matched healthy controls with normal IQ values. There were no group differences between somatosensory detection and pain thresholds. Two ASD patients showed paradoxical heat sensations and another two ASD subjects presented dynamic mechanical allodynia; somatosensory features that were absent in controls. These findings suggest that central mechanisms during complex stimulus integration rather than peripheral dysfunctions probably determine somatosensory alterations in ASD.

In normal-hearing listeners, localization of auditory speech involves stimulus processing in the postero-dorsal pathway of the auditory system. In quiet environments, bilateral cochlear implant (CI) users show high speech recognition performance, but localization of auditory speech is poor, especially when discriminating stimuli from the same hemifield. Whether this difficulty relates to the inability of the auditory system to translate binaural electrical cues into neural signals, or to a functional reorganization of auditory cortical pathways following long periods of binaural deprivation is unknown. In this electroencephalography study, we examined the processing of auditory syllables in postlingually deaf adults with bilateral CIs and in normal-hearing adults. Participants were instructed to either recognize (“recognition” task) or localize (“localization” task) the syllables. The analysis focused on event-related potentials and oscillatory brain responses. N1 amplitudes in CI users were larger in the localization compared with recognition task, suggesting an enhanced stimulus processing effort in the localization task. Linear beamforming of oscillatory activity in CI users revealed stronger suppression of beta-band activity after 200 ms in the postero-dorsal auditory pathway for the localization compared with the recognition task. In normal-hearing adults, effects for longer latency event-related potentials were found, but no effects were observed for N1 amplitudes or beta-band responses. Our study suggests that difficulties in speech localization in bilateral CI users are not reflected in a functional reorganization of cortical auditory pathways. New signal processing strategies of cochlear devices preserving unambiguous binaural cues may improve auditory localization performance in bilateral CI users. Hum Brain Mapp 35:3107–3121, 2014. © 2013 Wiley Periodicals, Inc.

Background and objective The extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression. Patients and methods We retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinson's disease (82), dystonia (18), tremor of different etiology (21), Huntington's disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy. Results Over a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs. Conclusions DBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Dysfunctions of the human mirror neuron system have been postulated to underlie some deficits in autism spectrum disorders including poor imitative performance and impaired social skills. Using three reaction time experiments addressing mirror neuron system functions under simple and complex conditions, we examined 20 adult autism spectrum disorder participants and 20 healthy controls matched for age, gender and education. Participants performed simple finger-lifting movements in response to (1) biological finger and non-biological dot movement stimuli, (2) acoustic stimuli and (3) combined visual-acoustic stimuli with different contextual (compatible/incompatible) and temporal (simultaneous/asynchronous) relation. Mixed model analyses revealed slower reaction times in autism spectrum disorder. Both groups responded faster to biological compared to non-biological stimuli (Experiment 1) implying intact processing advantage for biological stimuli in autism spectrum disorder. In Experiment 3, both groups had similar ‘interference effects’ when stimuli were presented simultaneously. However, autism spectrum disorder participants had abnormally slow responses particularly when incompatible stimuli were presented consecutively. Our results suggest imitative control deficits rather than global imitative system impairments.

Neural cell adhesion molecule (NCAM) is the predominant carrier of the unusual glycan polysialic acid (PSA). Deficits in PSA and/or NCAM expression cause impairments in hippocampal long-term potentiation and depression (LTP and LTD) and are associated with schizophrenia and aging. In this study, we show that impaired LTP in adult NCAM-deficient (NCAM−/−) mice is restored by increasing the activity of the NMDA subtype of glutamate receptor (GluN) through either reducing the extracellular Mg2+concentration or applyingd-cycloserine (DCS), a partial agonist of the GluN glycine binding site. Pharmacological inhibition of the GluN2A subtype reduced LTP to the same level inNCAM−/−and wild-type (NCAM+/+) littermate mice and abolished the rescue by DCS inNCAM−/−mice, suggesting that the effects of DCS are mainly mediated by GluN2A. The insufficient contribution of GluN to LTD inNCAM−/−mice was also compensated for by DCS. Furthermore, impaired contextual and cued fear conditioning levels were restored inNCAM−/−mice by administration of DCS before conditioning. In 12-month-oldNCAM−/−, but notNCAM+/+mice, there was a decline in LTP compared with 3-month-old mice that could be rescued by DCS. In 24-month-old mice of both genotypes, there was a reduction in LTP that could be fully restored by DCS inNCAM+/+mice but only partially restored inNCAM−/−mice. Thus, several deficiencies ofNCAM−/−mice can be ameliorated by enhancing GluN2A-mediated neurotransmission with DCS.

Alcohol addiction is associated with alterations of central nervous dopaminergic and serotonergic functions. Acute tryptophan depletion has not yet been applied in detoxified alcohol-addicted patients in order to investigate its impact on psychopathology, psychoneuroendocrinology, and substance craving behaviour. 25 alcohol-addicted males randomly either received a tryptophan-free or tryptophan-containing amino acid drink and 7 days later the respective other drink. Anxiety, depression, and craving were assessed before and 5 h after the drink. Tryptophan, 5-HIAA, dopamine, norepinephrine, epinephrine, and HVA in serum were measured before and after both treatments. Nocturnal urinary cortisol measurements and genotyping for the HTTLPR polymorphism of the SLC6A4 gene were performed. Tryptophan depletion resulted in a significant reduction of total and free serum tryptophan while the tryptophan-rich drink increased serum levels. Both treatments caused a significant increase of serum serotonin levels, however, serum 5-HIAA was decreased after depletion but increased after sham depletion. Dopamine and norepinephrine were elevated after tryptophan depletion and sham. Depletion increased depression scores (MADRS), while the full amino acid drink improved state and trait anxiety ratings (STAI) and substance craving. Urinary cortisol excretion was not affected by both treatments. Patients with the ll genotype of the serotonin transporter gene displayed lower baseline tryptophan levels compared to patients with the heterozygous genotype. Results suggest an impaired serotonergic function in alcohol-addicted males.

Background and objective To determine rates of adverse events (AEs) related to deep brain stimulation (DBS) surgery or implanted devices from a large series from a single institution. Sound comparisons with the literature require the definition of unambiguous categories, since there is no consensus on the reporting of such AEs. Patients and methods 123 consecutive patients (median age 63 yrs; female 45.5%) treated with DBS in the subthalamic nucleus (78 patients), ventrolateral thalamus (24), internal pallidum (20), and centre median-parafascicular nucleus (1) were analyzed retrospectively. Both mean and median follow-up time was 4.7 years (578 patient-years). AEs were assessed according to three unambiguous categories: (i) hemorrhages including other intracranial complications because these might lead to neurological deficits or death, (ii) infections and similar AEs necessitating the explantation of hardware components as this results in the interruption of DBS therapy, and (iii) lead revisions for various reasons since this involves an additional intracranial procedure. For a systematic review of the literature AE rates were calculated based on primary data presented in 103 publications. Heterogeneity between studies was assessed with the I2 statistic and analyzed further by a random effects meta-regression. Publication bias was analyzed with funnel plots. Results Surgery- or hardware-related AEs (23) affected 18 of 123 patients (14.6%) and resolved without permanent sequelae in all instances. In 2 patients (1.6%), small hemorrhages in the striatum were associated with transient neurological deficits. In 4 patients (3.3%; 0.7% per patient-year) impulse generators were removed due to infection. In 2 patients electrodes were revised (1.6%; 0.3% per patient-year). There was no lead migration or surgical revision because of lead misplacement. Age was not statistically significant different (p>0.05) between patients affected by AEs or not. AE rates did not decline over time and similar incidences were found among all patients (423) implanted with DBS systems at our institution until December 2016. A systematic literature review revealed that exact AE rates could not be determined from many studies, which could not be attributed to study designs. Average rates for intracranial complications were 3.8% among studies (per-study analysis) and 3.4% for pooled analysis of patients from different studies (per-patient analysis). Annual hardware removal rates were 3.6 and 2.4% for per-study and per-patient analysis, respectively, and lead revision rates were 4.1 and 2.6%, respectively. There was significant heterogeneity between studies (I2 ranged between 77% and 91% for the three categories; p< 0.0001). For hardware removal heterogeneity (I2 = 87.4%) was reduced by taking study size (p< 0.0001) and publication year (p< 0.01) into account, although a significant degree of heterogeneity remained (I2 = 80.0%; p< 0.0001). Based on comparisons with health care-related databases there appears to be publication bias with lower rates for hardware-related AEs in published patient cohorts. Conclusions The proposed categories are suited for an unequivocal assessment of AEs even in a retrospective manner and useful for benchmarking. AE rates in the present cohorts from our institution compare favorable with the literature.

Muskuloskelettale Dysfunktionen werden als Risikofaktor fur die Entwicklung chronischer Schmerzsyndrome angesehen. Problematisch ist jedoch die ungenugende Reliabilitat und Validitat der derzeit vorhandenen klinischen Tests zur Erhebung von funktionellen Befunden im Bewegungssystem. Die Intra- und Interraterreliabilitat von klinischen Tests zur Einschatzung der Bewegungssteuerung und -stabilisation sowie der Hypermobilitat wurde in einer Multicenterstudie untersucht. 68 Patienten mit chronischen vertebragenen Schmerzsyndromen wurden in 6 Zentren von 2 Untersuchern unabhangig (Interraterreliabilitat) und von einem Untersucher 2-mal (Intraraterreliabilitat) untersucht. Die klinischen Tests fur die Hypermobilitat zeigten eine gute bis sehr gute Reliabilitat. Die Reliabilitat des Tests fur die Bewegungssteuerung und -stabilisation war variabel. 23 Tests erzielten κ-Werte >0,5 und 15 Tests eine gute bis sehr gute Reliabilitat. Alle Tests zur Hypermobilitat und 23 Tests zur Bewegungssteuerung und -stabilisation sind fur die weitere Validitatstestung geeignet. Die grose Bandbreite der Testreliabilitat lasst sich am ehesten durch die unterschiedlichen Schwierigkeiten in der Testausfuhrung erklaren. In Abhangigkeit von der Validitat werden einige Tests aufgrund dieser verschiedenen Schwierigkeitsgrade eher sekundaren oder tertiaren Versorgungsformen vorbehalten bleiben, wahrend andere in der Primarversorgung als Screeninginstrument verwendet werden konnten.

Neuroimaging studies have gained increasing importance in validating neurobiological network hypotheses for anxiety disorders. Functional imaging procedures and radioligand binding studies in healthy subjects and in patients with anxiety disorders provide growing evidence of the existence of a complex anxiety network, including limbic, brainstem, temporal, and prefrontal cortical regions. Obviously, “normal anxiety” does not equal “pathological anxiety” although many phenomena are evident in healthy subjects, however to a lower extent. Differential effects of distinct brain regions and lateralization phenomena in different anxiety disorders are mentioned. An overview of neuroimaging investigations in anxiety disorders is given after a brief summary of results from healthy volunteers. Concluding implications for future research are made by the authors. peerReviewed

Wahrend manche Dinge oder Situationen dem Gesunden vollig alltaglich erscheinen, versetzen diese den Angstpatienten in einen Ausnahmezustand. Nicht wenige von ihnen suchen Entspannung in Alkohol oder Hypnotika und bereiten damit den Weg in die Abhangigkeit. Wenn Sie Ausloser, Vorboten und Begleitsymptome von Angst- und Panikstorungen kennen, konnen Sie gerade als Hausarzt lenkend eingreifen, noch bevor sich die Storung manifestiert.

The

The effect of DPG on the affinity of hemoglobin for oxygen, expressed as P50 (the PO2 at which Hb is 50% saturated with O2), is well known. In the present investigation whole blood from newborns with hyaline membrane disease (HMD) and cardiac malformations (CM) revealed a statistically significant difference between the two groups in both P50 and DPG content (HMD: P50 24.6 mm Hg = 3.5 S.D., DPG 0.78 mol/mol/Hb±0.16; CM: P50 29.1 mm Hg±3.4, DPG 1.31 mol/mol Hb±0.30). Patients with CM were more mature with higher birth weights and had lower arterial PO2 and O2 content (10.2 vol % O2 = 4.0 vs 16.7±4.9). BE, pH, PCO2, Hb and HbF were comparable. The effect of the observed difference in P50 between babies with HMD and CM can possibly explain the greater tolerance to hypoxemia of infants with CM since blood with P50 of 29.1 mm Hg can unload 15% more O2 to the tissues than blood with P50 of 24.1 assuming the same PvO2, CaO2 and cardiac output. Such differences in P50 have almost no effect on the amount of O2 loaded in the lungs. Further observations showed that DPG concentration varied directly with pH in normoxemic patients (> 90% saturation, > 15 vol% O2). Low pH could cause a decrease in DPG by inhibition of enzymes responsible for the synthesis, but also low DPG could produce a decrease in pH by impairment of unloading of O2 to the tissues. The hypoxemic patients showed a higher DPG concentration than predicted from their Hp, again suggesting that hypoxemia causes an increase in DPG concentration.

Objective: The effects of stimulus size, duration and eccentricity on the visual gamma-band response (GBR) in human EEG were investigated and compared to visual evoked potentials (VEPs) in order to differentiate in future (and past) experiments whether changes in GBRs are due to stimulus-related (exogenous) or cognitive effects. Methods: EEG was recorded from 23 subjects while they performed a simple choice reaction time task requiring discrimination of squares and circles. In separate blocks stimulus size, duration, and eccentricity were manipulated. EEG was recorded from 64 electrodes. A wavelet transform based on Morlet wavelets was employed for the analysis of gamma-band activity. Results: Amplitude of the GBR was diminished for small and peripheral stimuli. With short stimulus durations ON and OFF responses of the GBR merged into one peak. In comparison, VEP amplitudes were less susceptible to stimulus features. In contrast to VEP latencies, however, GBR latency did not show a lateralization for eccentric stimuli. Conclusions: In addition to previous experiments which have shown a modulation of the GBR by various cognitive processes, the present results demonstrate the susceptibility of the GBR in human EEG to exogenous factors, as numerous intracortical recordings in non-human primates have shown before. The results suggest that the human GBR resides in early visual areas. Significance: The demonstration of the susceptibility of the GBR to stimulus properties implies that studies aimed at exploring the involvement of the GBR in information processing have to be designed carefully. It also constrains the localization of the human GBR. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

b Abstract An auditory novelty-oddball task, which is known to evoke a P3 event-related potential (ERP) in a target condition and a novelty-P3 ERP in response to task-irrelevant unique environmental sounds, was repeatedly applied to healthy participants (ns14) on two separate recording sessions, 7 days apart. Both target-P3 and novelty-P3 were internally consistent and test-retest reliable. Interestingly, novelty-P3 amplitude declined from the first to the second half of each recording session, whereas no systematic alteration between both sessions occurred. The target-P3 showed the opposite pattern, i.e. a reduced amplitude from the first to the second session, but no systematic change within each session. These findings suggest that novelty-P3 amplitude changes reflect habituation, whereas target-P3 session effects may indicate the adjusted amount of processing resources invested into the task. In general, the results support the interpretation of the novelty-P3 as indicating automatic, bottom-up related aspects of attention, whereas the target-P3, in the present paradigm, seems to reflect voluntary, top-down related aspects of attention. 2002 Elsevier Science B.V. All rights reserved.

Interhemispheric auditory connectivity via the corpus callosum has been demonstrated to be important for normal speech processing. According to the callosal relay model, directed information flow from the right to the left auditory cortex has been suggested, but this has not yet been proven. For this purpose, 33 healthy participants were investigated with 64-channel EEG while performing the dichotic listening task in which two different consonant-vowel syllables were presented simultaneously to the left (LE) and right ear (RE). eLORETA source estimation was used to investigate the functional (lagged phase synchronization/LPS) and effective (isolated effective coherence/ICoh) connectivity between right and left primary (PAC) and secondary auditory cortices (SAC) in the gamma-band (30-100 Hz) during right and left ear reports. The major finding was a significantly increased effective connectivity in the gamma-band from the right to the left SAC during conscious perception of LE stimuli. In addition, effective and functional connectivity was significantly enhanced during LE as compared to RE reports. These findings give novel insight into transcallosal information transfer during auditory perception by showing that LE performance requires causal interhemispheric inputs from the right to the left auditory cortices, and that this interaction is mediated by synchronized gamma-band oscillations.

Atrial fibrillation (AF) is the most common heart rhythm disorder. Transient postoperative AF can be elicited by high sympathetic nervous system activity. Catecholamines and serotonin cause arrhythmias in atrial trabeculae from patients with sinus rhythm (SR), but whether these arrhythmias occur in patients with chronic AF is unknown. We compared the incidence of arrhythmic contractions caused by norepinephrine, epinephrine, serotonin, and forskolin in atrial trabeculae from patients with SR and patients with AF. In the patients with AF, arrhythmias were markedly reduced for the agonists and abolished for forskolin, whereas maximum inotropic responses were markedly blunted only for serotonin. Serotonin and forskolin produced spontaneous diastolic Ca(2+) releases in atrial myocytes from the patients with SR that were abolished or reduced in myocytes from the patients with AF. For matching L-type Ca(2+)-current (ICa,L) responses, serotonin required and produced ∼ 100-fold less cAMP/PKA at the Ca(2+) channel domain compared with the catecholamines and forskolin. Norepinephrine-evoked ICa,L responses were decreased by inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) in myocytes from patients with SR, but not in those from patients with AF. Agonist-evoked phosphorylation by CaMKII at phospholamban (Thr-17), but not of ryanodine2 (Ser-2814), was reduced in trabeculae from patients with AF. The decreased CaMKII activity may contribute to the blunting of agonist-evoked arrhythmias in the atrial myocardium of patients with AF.

High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson’s disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.

Uterine leiomyomata of 34 premenopausal women undergoing leiomyomectomy or hysterectomy, and in four cases the corresponding myometrium, were collected at laparotomy or laparoscopy to investigate the ability of these benign smooth muscle cell tumors to express different connexins. Immunohistochemical and Northern blot analyses were performed for the characterization of the expression of connexins Cx43, Cx45, Cx26 and Cx32. Immunofluorescence revealed the presence of Cx43 in most leiomyomata. Only seven leiomyomata lacked Cx43 expression. Cx45 was expressed in 13, a weak Cx26 immunostaining was found in seven cases, whereas Cx32 could not be detected. No correlations between the 17 beta-estradiol or progesterone serum levels and the expression patterns of the connexins Cx43, Cx45 and Cx26 could be observed. Gonadotropin-releasing hormone (GnRH)-agonist or progestin treatment did not influence the connexin expression pattern. Northern blot analyses confirmed these results; however, transcripts of Cx26 were not detectable. Connexin transcripts between myomata and the corresponding myometrium showed no obvious differences. Our data show that uterine leiomyomata are capable of expressing different connexins comparable to the corresponding myometrium, but do not respond to different hormonal conditions. The ability to express the appropriate connexins could explain why these tumors, though developing independently of hormonal levels, are still differentiated benign smooth muscle tumors.

Objective: To examine the influence of subthalamic nucleus (STN) deep brain stimulation (DBS) on driving in patients with Parkinson disease (PD). Methods: Using a driving simulator setup proven to reflect on-road driving, 2 main analyses were performed: 1) comparison of driving performance among 23 patients with deep brain surgery (DBS patients), 21 patients without surgery (no-DBS patients), and 21 controls; and 2) analysis of the effect of stimulation vs levodopa on driving performance. To this end, 3 tests were run in the medicated DBS patient cohort, with 3 different conditions: “stimulation on” (STIM) (equated to daily treatment), “stimulation off” (OFF), and “stimulation off/levodopa” (LD) (dosage aimed at maintaining motor status). Differences in driving times and errors among conditions were analyzed. Results: Age and cognitive deficits influenced driving performance negatively. The no-DBS patient group performed worse in driving time and driving errors than controls. DBS patients drove slower than controls and no-DBS patients. Driving safety was comparable to controls but higher than in no-DBS patients. Within the DBS patient group, driving was more accurate with STIM than with LD, although motor effects did not differ. Driving with STIM, but not with LD, was superior to driving in the OFF condition. Conclusion: DBS of the STN seems to have a beneficial effect on driving ability in patients with PD, potentially because of nonmotor driving-relevant aspects. Our data suggest that driving permission for DBS-treated patients with PD should not be handled more restrictively than permissions for patients with PD in general. Classification of evidence: This study provides Class IV evidence that STN-DBS in patients with PD is associated with a reduction in driving errors and improvements in driving accuracy in driving simulations.

Endometriosis is one of the most frequent diseases in gynecology. It is histologically defined as a non-malignant pathology in which endometrial-like tissue is found outside the uterus. The pathogenesis and mechanisms involved in the development of endometriosis-associated pain symptoms are still under investigation. A local peritoneal inflammation seems to play an important role in the origin of these symptoms. Selectins belong to a group of cell adhesion molecules that mediate the localization of circulating leukocytes on the endothelium at the sites of inflammation. The aim of this study was to investigate the expression of E- and P-selectins in endometriotic tissues and the corresponding endometria. Thirty endometriotic samples, 13 corresponding endometria and six endometria of patients without endometriosis were analyzed using an immunohistochemical technique. Just two endometriotic tissues expressed E-selectin, while five samples were positive for P-selectin. The selectin expression of the corresponding endometria was also very weak. No correlations between the revised American Fertility Society (rAFS) score or the hormonal situation of the patients at the time of biopsy and the selectin expression could be found. In conclusion, the selectin expression in endometriotic glands does not play an important role in the initiation of inflammatory processes caused by endometriosis. This inflammation must be considered as a secondary reaction after the implantation of the endometriotic glands, so that endometriotic tissues are not able to induce, by the expression of selectins, a direct inflammation.

To investigate whether abnormally accumulated betaAPP may be responsible for denervation of muscle fibers that are present in hereditary inclusion-body myopathy (h-IBM) and sporadic inclusion-body myositis (s-IBM), we cultured five h-IBM and eight normal muscle biopsies. In eight other experiments, a 3 kb human 751-betaAPP-cDNA was transferred, using adenovirus vector, into cultured normal myotubes immediately after myoblast fusion. In all experiments, cultured muscle fibers were co-cultured with fetal rat spinal cord. Controls had no detectable betaAPP epitopes, whereas betaAPP epitopes were greatly increased in cultured h-IBM muscle and in cultured normal muscle after betaAPP-gene transfer. Innervated normal cultured muscle fibers were continuously contracting and fully cross-striated, and they had acetylcholine receptors (AChRs) and acetylcholinesterase (AChE) accumulated only at the neuromuscular junctions (NMJs). By contrast, both groups of betaAPP-overexpressing cultured muscle fibers were not contracting and not cross-striated; and did not have NJMs containing AChRs and AChE. Our results suggest that over-expression of betaAPP in cultured muscle fibers inhibits their innervation, and that the accumulation of betaAPP in muscle fibers of both h- and s-IBM patients may be responsible for their not becoming or remaining properly innervated or reinnervated, i.e. a 'myogenous-dysinnervation' mechanism.

American Academy of Neurology Dedicated to advancing the art and science of neurology, and thereby promoting the best possible care for patients with neurological disorders A Celebration of the First 50 years of the American Academy of Neurology Neurology 1962;12:778-794 In the investigation of neuromuscular disease, histologic examination of skeletal muscle biopsies is generally accepted as an important part both of routine diagnostic procedures and of more specialized research. The purpose of the present report is to establish that the use of histo- and cytochemical technics combined with light microscopy is also an essential aspect of both types of investigation. Substantiating evidence is presented in the form of 6 examples, chosen from recent studies, of cytopathologic changes in neuromuscular disease as demonstrated by these technics. Two fundamental types of abnormalities in skeletal muscle are detectable with histo- and cytochemical technics: (a) a generalized change of a given reaction, for example, loss of phosphorylase activity, and (b) a localized change of activity confined either to a specific type of muscle fiber (as in the new myopathy with rod-shaped structures) or to certain regions of individual muscle fibers (as in target fibers and central core disease). Further, if the cytochemical technics are sufficiently refined, they may be used to demonstrate the functional activity of fine structural components of the muscle cell. On the basis of such data, predictions can often be made as to the fine structural changes which electron-microscopy will reveal. It must be understood, though, that some cytochemical changes might not be accompanied by changes of fine structure and vice versa. Cytochemistry combined with electron-microscopy would give even more detailed information, but this approach has 2 major limitations: (a) only a very few cytochemical reactions are as yet refined enough to be used with electron-microscopy and(b) study of a large …

Autosomal-recessive and autosomal-dominant hereditary inclusion-body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibres containing paired helical filaments. We immunostained muscle biopsy specimens from quadriceps-sparing autosomal-recessive and autosomal-dominant inclusion-body myopathy subjects, disease-control subjects and normal patients, utilizing isoform-specific antibodies against the neuronal and inducible forms of nitric oxide synthase, and antibodies against nitrotyrosine. Approximately 75% of the vacuolated muscle fibres in all recessive and dominant inclusion-body myopathy patients contained inclusions strongly immunoreactive with antibodies against neuronal and inducible nitric oxide synthase which, by immunoelectron microscopy, were colocalized to clusters of tubulofilaments (previously shown, by us, to be paired helical filaments). Strong nitrotyrosine immunoreactivity was in the form of multiple dots and large granular patches, which ultrastructurally did not immunolocalize to tubulofilaments. Excess intracellular nitric oxide can combine with superoxide to produce highly toxic peroxynitrite, which can nitrate tyrosines of proteins. The presence of nitrotyrosine is indicative of nitric oxide-induced oxidative stress. Our data suggest that oxidative stress plays a role in the pathogenic cascade of hereditary inclusion-body myopathies.

There is a paucity of reports on structural brain differences comparing alcohol dependent subjects with and without comorbid affective pathology. 3-T MRI (Siemens MAGNETOM Trio) scans of 115 alcohol dependent subjects with or without affective comorbid diagnoses that underwent qualified detoxification inpatient treatment were evaluated using a T1-weighted, 3D-MPRAGE sequence. Variables for severity of dependence were analysed. Alcohol dependent subjects compared to alcohol dependent subjects with comorbid affective pathology showed a higher level of cerebral atrophy in the entire brain. Distinct areas in the frontal, parietal, cerebellar, rigth temporal, and left insular region showed specific atrophy patterns. Patients without affective comorbidity had significantly higher Gamma-GT levels and higher MCH, however, no differences in alcohol intake, duration of addiction and CDT. Alcohol addicted subjects without comorbid affective disorder display a significantly greater cerebral atrophy compared to comorbid patients. The results suggest that affective comorbidity may have a protective role for cerebral atrophy in patients with alcohol dependence. Higher atrophy and GGT values combined with comparable alcohol intake and duration of addiction may hint on a higher sensitivity for alcoholtoxic effects in non-comorbid subjects. This study was supported by EUSARNAD (Marie Curie International Research Staff Exhange Scheme Program).

When viewing the needle of a syringe approaching your skin, anticipation of a painful prick may lead to increased arousal. How this anticipation is reflected in neural oscillatory activity and how it relates to activity within the autonomic nervous system is thus far unknown. Recently, we found that viewing needle pricks compared with Q-tip touches increases the pupil dilation response (PDR) and perceived unpleasantness of electrical stimuli. Here, we used high-density electroencephalography to investigate whether anticipatory oscillatory activity predicts the unpleasantness of electrical stimuli and PDR while viewing a needle approaching a hand that is perceived as one's own. We presented video clips of needle pricks and Q-tip touches, and delivered spatiotemporally aligned painful and nonpainful intracutaneous electrical stimuli. The perceived unpleasantness of electrical stimuli and the PDR were enhanced when participants viewed needle pricks compared with Q-tip touches. Source reconstruction using linear beamforming revealed reduced alpha-band activity in the posterior cingulate cortex (PCC) and fusiform gyrus before the onset of electrical stimuli when participants viewed needle pricks compared with Q-tip touches. Moreover, alpha-band activity in the PCC predicted PDR on a single trial level. The anticipatory reduction of alpha-band activity in the PCC may reflect a neural mechanism that serves to protect the body from forthcoming harm by facilitating the preparation of adequate defense responses.

article i nfo In our environment, acute pain is often accompanied by input from other sensory modalities, like visual stimuli, which can facilitate pain processing. To date, it is not well understood how these inputs influence the perception and processing of pain. Previous studies on integrative processing between sensory modalities other than pain haveshownthatmultisensoryresponse gains are strongest whentheconstituent unimodalstimuli are minimal- ly effective in evoking responses. This finding has been termed the principle of inverse effectiveness (IE). In this high-densityelectroencephalographystudy,weinvestigated theinfluence of Gaborpatchesoflowand high con- trast levels on the perception and processing of spatially and temporally aligned painful electrical stimuli of low and high intensities. Subjective pain ratings, event-related potentials (ERPs) and oscillatory responses served as dependent measures. In line with the principle of IE, stronger crossmodal biasing effects of visual input on sub- jective pain ratings were found for low compared to high intensity painful stimuli. This effect was paralleled by stronger bimodal interactions in right-central ERPs (150-200 ms) for low compared to high intensity pain stim- uli.Moreover,anenhancedsuppressionofmedio-centralbeta-bandactivity (12-24 Hz,200-400 ms)wasfound for low compared to high intensity pain stimuli. Our findings possibly reflect a facilitation of stimulus processing that serves to enhance response readiness of the sensorimotor system following painful stimulation. Taken to- gether, our study demonstrates that multisensory processing between visual and painful stimuli follows the principle of IE and suggests a role for beta-band oscillations in the crossmodal modulation of pain.