Recent studies have demonstrated that prestimulus alpha-band activity substantially influences perception of near-threshold stimuli. Here, we studied the influence of prestimulus alpha power fluctuations on temporal perceptual discrimination of suprathreshold tactile stimuli and subjects' confidence regarding their perceptual decisions. We investigated how prestimulus alpha-band power influences poststimulus decision-making variables. We presented electrical stimuli with different stimulus onset asynchronies (SOAs) to human subjects, and determined the SOA for which temporal perceptual discrimination varied on a trial-by-trial basis between perceiving 1 or 2 stimuli, prior to recording brain activity with magnetoencephalography. We found that low prestimulus alpha power in contralateral somatosensory and occipital areas predicts the veridical temporal perceptual discrimination of 2 stimuli. Additionally, prestimulus alpha power was negatively correlated with confidence ratings in correctly perceived trials, but positively correlated for incorrectly perceived trials. Finally, poststimulus event-related fields (ERFs) were modulated by prestimulus alpha power and reflect the result of a decisional process rather than physical stimulus parameters around ?150 ms. These findings provide new insights into the link between spontaneous prestimulus alpha power fluctuations, temporal perceptual discrimination, decision making, and decisional confidence. The results suggest that prestimulus alpha power modulates perception and decisions on a continuous scale, as reflected in confidence ratings.
Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment.
The pathophysiology of Parkinson's disease (PD) has been related to excessive beta band oscillations in the basal ganglia. Recent recordings from the subthalamic nucleus of PD patients showed that beta oscillations show strong cross-frequency coupling with high-frequency oscillations (>200 Hz). However, little is known about the characteristics and functional properties of these oscillations. We studied the spatial distribution of high-frequency oscillations and their relation to PD motor symptoms. We included 10 PD patients in medication OFF who underwent implantation of deep brain stimulation (DBS) electrodes. Intraoperative five-channel microelectrode recordings were performed at 9 to 10 recording sites within the subthalamic nucleus and its immediate surroundings. We found a focal spatial distribution of high-frequency oscillations with highest power 2 mm below the dorsolateral border of the subthalamic nucleus. Within the subthalamic nucleus, power peaked slightly anterior to the DBS target site. In addition, contralateral akinesia/rigidity scores were negatively correlated with high-frequency oscillation power. Our results demonstrate a focal origin of high-frequency oscillations within the subthalamic nucleus and provide further evidence for their functional association with motor state.
Spike-based magnetoencephalography (MEG) source localization is an established method in the presurgical evaluation of epilepsy patients. Focal cortical dysplasias (FCDs) are associated with focal epileptic discharges of variable morphologies in the beta frequency band in addition to single epileptic spikes. Therefore, we investigated the potential diagnostic value of MEG-based localization of spike-independent beta band (12-30Hz) activity generated by epileptogenic lesions.
Alpha oscillations are a prominent electrophysiological signal measured across a wide range of species and cortical and subcortical sites. Alpha oscillations have been viewed for a long time as an "idling" rhythm, purely reflecting inactive sites. Despite earlier evidence from neurophysiology, awareness that alpha oscillations can substantially influence perception and behavior has grown only recently in cognitive neuroscience. Evidence for an active role of alpha for perception comes mainly from several visual, near-threshold experiments. In the current review, we extend this view by summarizing studies showing how alpha-defined brain states relate to illusory perception, i.e. cases of perceptual reports that are not "objectively" verifiable by distinct stimuli or stimulus features. These studies demonstrate that ongoing or prestimulus alpha oscillations substantially influence the perception of auditory, visual or multisensory illusions.
Neurons generated from pluripotent stem cells (PSCs) self-organize into functional neuronal assemblies in vitro, generating synchronous network activities. Intriguingly, PSC-derived neuronal assemblies develop spontaneous activities that are independent of external stimulation, suggesting the presence of thus far undetected intrinsically active neurons (IANs). Here, by using mouse embryonic stem cells, we provide evidence for the existence of IANs in PSC-neuronal networks based on extracellular multielectrode array and intracellular patch-clamp recordings. IANs remain active after pharmacological inhibition of fast synaptic communication and possess intrinsic mechanisms required for autonomous neuronal activity. PSC-derived IANs are functionally integrated in PSC-neuronal populations, contribute to synchronous network bursting, and exhibit pacemaker properties. The intrinsic activity and pacemaker properties of the neuronal subpopulation identified herein may be particularly relevant for interventions involving transplantation of neural tissues. IANs may be a key element in the regulation of the functional activity of grafted as well as preexisting host neuronal networks.
Deep brain stimulation of the dorsal pallidum (globus pallidus, GP) is increasingly considered as a surgical therapeutic option in Huntington's disease (HD), but there is need to identify outcome measures useful for clinical trials. Computational models consider the GP to be part of a basal ganglia network involved in cognitive processes related to the control of actions. We examined behavioural and event-related potential (ERP) correlates of action control (i.e., error monitoring) and evaluated the effects of deep brain stimulation (DBS). We did this using a standard flanker paradigm and evaluated error-related ERPs. Patients were recruited from a prospective pilot trial for pallidal DBS in HD (trial number NCT00902889). From the initial four patients with Huntington's chorea, two patients with chronic external dorsal pallidum stimulation were available for follow-up and able to perform the task. The results suggest that the external GP constitutes an important basal ganglia element not only for error processing and behavioural adaptation but for general response monitoring processes as well. Response monitoring functions were fully controllable by switching pallidal DBS stimulation on and off. When stimulation was switched off, no neurophysiological and behavioural signs of error and general performance monitoring, as reflected by the error-related negativity and post-error slowing in reaction times were evident. The modulation of response monitoring processes by GP-DBS reflects a side effect of efforts to alleviate motor symptoms in HD. From a clinical neurological perspective, the results suggest that DBS in the external GP segment can be regarded as a potentially beneficial treatment with respect to cognitive functions.
Primary dissociated brain tissue from rodents is widely used in a variety of different scientific methods to investigate cellular processes in vitro. Often, for this purpose cell cultures need to be generated just on time, requiring extensive animal lab infrastructure. We show here that cryopreservation and thawing of dissociated tissue from rat cerebral cortex at embryonic day 18 is feasible without affecting its ability to form functional neuronal networks in vitro. Vitality of fresh and re-thawed cortical cells was comparable, assessed by CellTiter-Blue-assay, CytoTox-ONE assay, immunocytochemical characterization and in vitro neuronal network activity recordings on microelectrode arrays. These findings suggest that planning and execution of experiments might be considerably facilitated by using cryo-preserved neurons instead of acutely dissociated neural cultures due to fewer logistical issues with regard to animal breeding and pregnancy timed preparations.
The neural correlates of action recognition have been widely studied in visual and sensorimotor areas of the human brain. However, the role of neuronal oscillations involved during the process of action recognition remains unclear. Here, we were interested in how the plausibility of an action modulates neuronal oscillations in visual and sensorimotor areas. Subjects viewed point-light displays (PLDs) of biomechanically plausible and implausible versions of the same actions. Using magnetoencephalography (MEG), we examined dynamic changes of oscillatory activity during these action recognition processes. While both actions elicited oscillatory activity in visual and sensorimotor areas in several frequency bands, a significant difference was confined to the beta-band (?20 Hz). An increase of power for plausible actions was observed in left temporal, parieto-occipital and sensorimotor areas of the brain, in the beta-band in successive order between 1650 and 2650 msec. These distinct spatio-temporal beta-band profiles suggest that the action recognition process is modulated by the degree of biomechanical plausibility of the action, and that spectral power in the beta-band may provide a functional interaction between visual and sensorimotor areas in humans.
Hepatic encephalopathy (HE) is associated with motor symptoms and attentional deficits, which are related to pathologically slowed oscillatory brain activity. Here, potential alterations of oscillatory activity in the somatosensory system were investigated.
Parkinson's disease (PD) is associated with pathologically altered oscillatory activity. While synchronized oscillations between 13 and 30 Hz are increased within a cortico-subcortical network, cortico-muscular coupling (CMC) is decreased. The present study aims at investigating the effect of non-invasive transcranial alternating current stimulation (tACS) of the primary motor cortex (M1) on motor symptoms and motor-cortical oscillations in PD. In 10 PD patients and 10 healthy control subjects, static isometric contraction, dynamic fast finger tapping, and diadochokinesia of the more severely affected hand were investigated prior to and shortly after tACS of the contralateral M1 at 10 Hz vs. 20 Hz vs. sham. During isometric contraction, neuromagnetic activity was recorded using magnetoencephalography. 20 Hz tACS attenuated beta band CMC during isometric contraction and amplitude variability during finger tapping in PD patients but not in healthy control subjects. 10 Hz tACS yielded no significant after-effects. The present data suggest that PD is associated with pathophysiological alterations which abet a higher responsiveness toward frequency-specific tACS - possibly due to pathologically altered motor-cortical oscillatory synchronization at frequencies between 13 and 30 Hz.
Deep brain stimulation of the subthalamic nucleus, although highly effective for the treatment of motor impairment in Parkinson's disease (PD), can induce speech deterioration in a subgroup of patients. The aim of the current study was to survey (1) if there are distinctive stimulation effects on the different parameters of voice and speech and (2) if there is a special pattern of preexisting speech abnormalities indicating a risk for further worsening under stimulation.
The current study investigated sensorimotor involvement in the processing of verbs describing actions performed with the hands, feet, or no body part. Actual movements were used to identify neuromagnetic sources for hand and foot actions. These sources constrained the analysis of verb processing. While hand and foot sources picked up activation in all three verb conditions, peak amplitudes showed an interaction of source and verb condition at 200 ms after word onset, thereby reflecting effector-specificity. Specifically, hand verbs elicited significantly higher peak amplitudes than foot verbs in hand sources. Our results are in line with theories of embodied cognition that assume an involvement of sensorimotor areas in early stages of lexico-semantic processing, even for single words without a semantic or motor task.
Corticobasal Syndrome (CBS) is a rare neurodegenerative syndrome characterized by unilaterally beginning frontoparietal and basal ganglia atrophy. The study aimed to prove the hypothesis that there are differences in hemispheric susceptibility to disease-related changes.
The grounded cognition framework proposes that sensorimotor brain areas, which are typically involved in perception and action, also play a role in linguistic processing. We assessed oscillatory modulation during visual presentation of single verbs and localized cortical motor regions by means of isometric contraction of hand and foot muscles. Analogously to oscillatory activation patterns accompanying voluntary movements, we expected a somatotopically distributed suppression of beta and alpha frequencies in the motor cortex during processing of body-related action verbs. Magnetoencephalographic data were collected during presentation of verbs that express actions performed using the hands (H) or feet (F). Verbs denoting no bodily movement (N) were used as a control. Between 150 and 500 msec after visual word onset, beta rhythms were suppressed in H and F in comparison with N in the left hemisphere. Similarly, alpha oscillations showed left-lateralized power suppression in the H-N contrast, although at a later stage. The cortical oscillatory activity that typically occurs during voluntary movements is therefore found to somatotopically accompany the processing of body-related verbs. The combination of a localizer task with the oscillatory investigation applied to verb reading as in the present study provides further methodological possibilities of tracking language processing in the brain.
Electroencephalography (EEG) and magnetoencephalography (MEG) are the two modalities for measuring neuronal dynamics at a millisecond temporal resolution. Different source analysis methods, to locate the dipoles in the brain from which these dynamics originate, have been readily applied to both modalities alone. However, direct comparisons and possible advantages of combining both modalities have rarely been assessed during voluntary movements using coherent source analysis. In the present study, the cortical and sub-cortical network of coherent sources at the finger tapping task frequency (2-4 Hz) and the modes of interaction within this network were analysed in 15 healthy subjects using a beamformer approach called the dynamic imaging of coherent sources (DICS) with subsequent source signal reconstruction and renormalized partial directed coherence analysis (RPDC). MEG and EEG data were recorded simultaneously allowing the comparison of each of the modalities separately to that of the combined approach. We found the identified network of coherent sources for the finger tapping task as described in earlier studies when using only the MEG or combined MEG+EEG whereas the EEG data alone failed to detect single sub-cortical sources. The signal-to-noise ratio (SNR) level of the coherent rhythmic activity at the tapping frequency in MEG and combined MEG+EEG data was significantly higher than EEG alone. The functional connectivity analysis revealed that the combined approach had more active connections compared to either of the modalities during the finger tapping (FT) task. These results indicate that MEG is superior in the detection of deep coherent sources and that the SNR seems to be more vital than the sensitivity to theoretical dipole orientation and the volume conduction effect in the case of EEG.
Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by an impaired ability to inhibit unwanted behaviour. Although the presence of chronic motor and vocal tics defines Tourettes syndrome, other distinctive behavioural features like echo- and coprophenomena, and non-obscene socially inappropriate behaviour are also core features. We investigated neuronal activation during stimulus-driven execution and inhibition of prepared movements in Tourettes syndrome. To this end, we performed event-related functional magnetic resonance imaging and structural diffusion tensor imaging in 15 moderately affected uncomplicated patients with pure Tourettes syndrome and 15 healthy control participants matched for age and gender. Subjects underwent functional magnetic resonance imaging during a Go/NoGo reaction time task. They had to withhold a prepared finger movement for a variable time until a stimulus instructed them to either execute (Go) or inhibit it (NoGo). Tics were monitored throughout the experiments, combining surface electromyogram, video recording, and clinical assessment in the scanner. Patients with Tourettes syndrome had longer reaction times than healthy controls in Go trials and made more errors in total. Their functional brain activation was decreased in left primary motor cortex and secondary motor areas during movement execution (Go trials) but not during response inhibition (NoGo trials) compared with healthy control subjects. Volume of interest analysis demonstrated less task-related activation in patients with Tourettes syndrome in primary and secondary motor cortex bilaterally, but not in the basal ganglia and cortical non-motor areas. They showed reduced co-activation between the left primary sensory-motor hand area and a network of contralateral sensory-motor areas and ipsilateral cerebellar regions. There were no between-group differences in structural connectivity of the left primary sensory-motor cortex as measured by diffusion tensor imaging-based probabilistic tractography. Our results link reduced sensory-motor cortical activation during movement execution to a decreased co-activation between the sensory-motor cortex and other brain areas involved in motor processing. These functional changes in patients with Tourettes syndrome might result from adaptive reorganization in fronto-parietal brain networks engaged in motor and behavioural control, possibly triggered by abnormal processing and presumably overactivity in cortico-striato-cortical circuits. This might enable patients with Tourettes syndrome to better suppress unwanted movements but comes at a price of behavioural deficits in other domains.
Electrophysiological studies suggest that rest tremor in Parkinsons disease is associated with an alteration of oscillatory activity. Although it is well known that tremor depends on cortico-muscular coupling, it is unclear whether synchronization within and between brain areas is specifically related to the presence and severity of tremor. To tackle this longstanding issue, we took advantage of naturally occurring spontaneous tremor fluctuations and investigated cerebral synchronization in the presence and absence of rest tremor. We simultaneously recorded local field potentials from the subthalamic nucleus, the magnetoencephalogram and the electromyogram of forearm muscles in 11 patients with Parkinsons disease (all male, age: 52-74 years). Recordings took place the day after surgery for deep brain stimulation, after withdrawal of anti-parkinsonian medication. We selected epochs containing spontaneous rest tremor and tremor-free epochs, respectively, and compared power and coherence between subthalamic nucleus, cortex and muscle across conditions. Tremor-associated changes in cerebro-muscular coherence were localized by Dynamic Imaging of Coherent Sources. Subsequently, cortico-cortical coupling was analysed by computation of the imaginary part of coherency, a coupling measure insensitive to volume conduction. After tremor onset, local field potential power increased at individual tremor frequency and cortical power decreased in the beta band (13-30 Hz). Sensor level subthalamic nucleus-cortex, cortico-muscular and subthalamic nucleus-muscle coherence increased during tremor specifically at tremor frequency. The increase in subthalamic nucleus-cortex coherence correlated with the increase in electromyogram power. On the source level, we observed tremor-associated increases in cortico-muscular coherence in primary motor cortex, premotor cortex and posterior parietal cortex contralateral to the tremulous limb. Analysis of the imaginary part of coherency revealed tremor-dependent coupling between these cortical areas at tremor frequency and double tremor frequency. Our findings demonstrate a direct relationship between the synchronization of cerebral oscillations and tremor manifestation. Furthermore, they suggest the feasibility of tremor detection based on local field potentials and might thus become relevant for the design of closed-loop stimulation systems.
Gilles de la Tourette syndrome (GTS) is a common developmental neuropsychiatric disorder characterized by tics and frequent psychiatric comorbidities, often causing significant disability. Tic generation has been linked to disturbed networks of brain areas involved in planning, controlling and execution of actions, particularly structural and functional disorders in the striatum and cortico-striato-thalamo-cortical loops. We therefore applied structural diffusion tensor imaging (DTI) to characterize changes in intrahemispheric white matter connectivity in cortico-subcortical circuits engaged in motor control in 15 GTS patients without psychiatric comorbidities. White matter connectivity was analyzed by probabilistic fiber tractography between 12 predefined cortical and subcortical regions of interest. Connectivity values were combined with measures of clinical severity rated by the Yale Global Tic Severity Scale (YGTSS). GTS patients showed widespread structural connectivity deficits. Lower connectivity values were found specifically in tracts connecting the supplementary motor areas (SMA) with basal ganglia (pre-SMA-putamen, SMA-putamen) and in frontal cortico-cortical circuits. There was an overall trend towards negative correlations between structural connectivity in these tracts and YGTSS scores. Structural connectivity of frontal brain networks involved in planning, controlling and executing actions is reduced in adult GTS patients which is associated with tic severity. These findings are in line with the concept of GTS as a neurodevelopmental disorder of brain immaturity.
The subthalamic nucleus (STN) has a pivotal role in the pathophysiology of Parkinsons disease (PD). Modulation of STN activity (by lesions, pharmacological or electrical stimulation) has been shown to improve motor parameters in PD patients and in animal models of PD. In an attempt to characterize the neurochemical bases for such antiparkinsonian action, we address specific neurotransmitter systems via local pharmacological manipulation of the STN in hemiparkinsonian rats. Here, we have focused on the GABAergic and glutamatergic receptors in the STN. In animals with unilateral 6-hydroxydopamine lesions of the nigro-striatal tract, we administered either the selective GABAA-agonist muscimol (0.5 ?g and 1.0 ?g), the non-competitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (dizocilpine; 2.5 ?g), or vehicle (0.25 ?l) into the STN. The effects of GABAergic and glutamatergic modulation of the STN on motor parameters were assessed by gauging rotational behavior and locomotion. Application of muscimol ipsilateral to the side of dopamine-depletion influenced turning behavior in a dose-dependent fashion, with the low dose re-adjusting turning behavior to a non-biased distribution, and the high dose evoking contraversive turning. The administration of MK-801 did not have such effects. These findings give evidence for the involvement of GABAergic activation in the STN in the compensation of motor asymmetries in the hemiparkinsonian rat, whereas N-methyl-d-aspartate (NMDA)-antagonism was ineffective in this model of PD.
Dynamic communication between functionally specialized, but spatially distributed areas of the brain is essential for effective brain functioning. A candidate mechanism for effective neuronal communication is oscillatory neuronal synchronization. Here, we used magnetoencephalography (MEG) to study the role of oscillatory neuronal synchronization in audio-visual speech perception. Subjects viewed congruent audio-visual stimuli of a speaker articulating the vowels /a/ or /o/. In addition, we presented modified, incongruent versions in which visual and auditory signals mismatched. We identified a left hemispheric network for processing congruent audio-visual speech as well as network interaction between areas: low frequency (4-12 Hz) power was suppressed for congruent stimuli at auditory onset around auditory cortex, while power in the high gamma (120-140 Hz)-band was enhanced in the Brocas area around auditory offset. In addition, beta-power (20-30 Hz) was suppressed in supramarginal gyrus for incongruent stimuli. Interestingly, coherence analysis revealed a functional coupling between auditory cortex and Brocas area for congruent stimuli demonstrated by an increase of coherence. In contrast, coherence decreased for incongruent stimuli, suggesting a decoupling of auditory cortex and Brocas area. In addition, the increase of coherence was positively correlated with the increase of high gamma-power. The results demonstrate that oscillatory power in several frequency bands correlates with the processing of matching audio-visual speech on a large spatio-temporal scale. The findings provide evidence that coupling of neuronal groups can be mediated by coherence in the theta/alpha band and that low frequency coherence and high frequency power modulations are correlated in audio-visual speech perception.
Expectation contributes to placebo and nocebo responses in Parkinsons disease (PD). Subthalamic nucleus (STN) deep brain stimulation (DBS) improves proximal more than distal movements whereas it impairs executive cognitive function such as verbal fluency (VF). We investigated how expectation modulates the pattern of motor improvement in STN-DBS and its interaction with VF. In a within-subject-design, expectation of 24 hypokinetic-rigid PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Motor function was assessed by Unified Parkinsons Disease Rating Scale and quantitative kinematic analysis of proximal alternating hand and distal finger tapping. VF was quantified by lexical and semantic tests. In MedOFF, expectation significantly affected proximal but not distal movements resulting in better performance in the placebo than in the nocebo condition. Placebo responders with improvement of ?25% were characterized by a trend for impaired lexical VF. These results indicate that positive motor expectations exert both motor placebo and cognitive nocebo responses by further enhancing the STN-DBS-effect on proximal movements and by impairing VF. The placebo response on motor performance resembles the clinically known STN-DBS-effect with stronger improvement in proximal than distal movements. The nocebo response on VF is likely due to implicit learning mechanisms associated with an expectation-induced placebo response on motor performance.
Parkinsons disease (PD) is a common neurodegenerative disorder owing to loss of dopaminergic cells. Akinesia - one of the core symptoms of PD - is associated with exaggerated oscillations at beta frequency (13-30 Hz) within the subthalamic nucleus (STN). Thus, enhanced oscillations below 30 Hz are assumed to represent a pathophysiological marker of PD. However, recent data suggest that OFF medication exaggerated beta oscillations within basal ganglia (BG) cortical networks may serve for the compensation of BG dysfunctions. The STN is functionally connected to mesial prefrontal areas like the supplementary motor area (SMA). But, it is still not fully understood how enhanced beta oscillations within the BG exert dominance over the primary motor cortex (M1) thereby yielding motor impairment. The present study, therefore, investigates the effect of dopaminergic state on SMA-M1 functional connectivity using Magnetoencephalography (MEG). MEG data were recorded in 7 patients suffering from PD with preponderance of akinesia during isometric contraction of the right forearm and during rest. Coherence as a measure of functional connectivity between M1 and SMA was calculated OFF and ON medication and correlated with the motor part of the Unified Parkinsons Disease Rating Scale (UPDRS III) and with disease duration. During rest a significant positive correlation between disease duration and SMA-M1 coherence was found ON but not OFF medication. Conversely, during isometric contraction SMA-M1 coherence and UPDRS III were inversely correlated OFF but not ON medication explaining more than 80% of variance. The results favor the hypothesis that OFF medication exaggerated cortical coherence at beta frequency represents a compensatory mechanism rather than a pathophysiological marker per se.
Oscillatory activity of the human brain has received growing interest as a key mechanism of large-scale integration across different brain regions. Besides a crucial role of oscillatory activity in the emergence of other neurological and psychiatric diseases, recent evidence indicates a key role in the pathophysiology of hepatic encephalopathy (HE). This review summarizes the current knowledge on pathological alterations of oscillatory brain activity in association with liver dysfunction and HE in the context of spontaneous brain activity, motor symptoms, sensory processing, and attention. The existing literature demonstrates a prominent slowing of the frequency of oscillatory activity as shown for spontaneous brain activity at rest, with respect to deficits of motor behavior and motor symptoms, and in the context of visual attention processes. The observed slowing extends across different subsystems of the brain and has been confirmed across different frequency bands, providing evidence for ubiquitous changes of oscillatory activity in HE. For example, the frequency of cortico-muscular coherence in HE patients appears at the frequency of the mini-asterixis (?12Hz), while cirrhotics without overt signs of HE show coherence similar to healthy subjects, i.e. at 13-30Hz. Interestingly, the so-called critical flicker frequency (CFF) as a measure of the processing of an oscillating visual stimulus has emerged as a useful tool to quantify HE disease severity, correlating with behavioral and neurophysiological alterations. Moreover, the CFF reliably distinguishes patients with manifest HE from cirrhotics without any signs of HE and healthy controls using a cut-off frequency of 39Hz. In conclusion, oscillatory activity is globally slowed in HE in close association with HE symptoms and disease severity. Although the underlying causal mechanisms are not yet understood, these results indicate that pathological changes of oscillatory activity play an important role in the pathophysiology of HE.
Expectation contributes to placebo and nocebo responses in Parkinsons disease (PD). While there is evidence for expectation-induced modulations of bradykinesia, little is known about the impact of expectation on resting tremor. Subthalamic nucleus (STN) deep brain stimulation (DBS) improves cardinal PD motor symptoms including tremor whereas impairment of verbal fluency (VF) has been observed as a potential side-effect. Here we investigated how expectation modulates the effect of STN-DBS on resting tremor and its interaction with VF. In a within-subject-design, expectation of 24 tremor-dominant PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Resting tremor was recorded by accelerometry and bradykinesia of finger tapping and diadochokinesia were assessed by a 3D ultrasound motion detection system. VF was quantified by lexical and semantic tests. In a subgroup of patients, the effect of STN-DBS on tremor was modulated by expectation, i.e. tremor decreased (placebo response) or increased (nocebo response) by at least 10% as compared to the control condition while no significant effect was observed for the overall group. Interestingly, nocebo responders in MedON were additionally characterized by significant impairment in semantic verbal fluency. In contrast, bradykinesia was not affected by expectation. These results indicate that the therapeutic effect of STN-DBS on tremor can be modulated by expectation in a subgroup of patients and suggests that tremor is also among the parkinsonian symptoms responsive to placebo and nocebo interventions. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of tremor, negative expectations counteracted the therapeutic effect and at the same time exacerbated a side-effect often associated with STN-DBS. The present findings underscore the potency of patients expectation and its relevance for therapeutic outcomes.
Synchronous oscillatory activity at alpha (8-12 Hz), beta (13-30 Hz), and gamma (30-90 Hz) frequencies is assumed to play a key role for motor control. Corticomuscular coherence (CMC) represents an established measure of the pyramidal systems integrity. Transcranial alternating current stimulation (tACS) offers the possibility to modulate ongoing oscillatory activity. Behaviorally, 20 Hz tACS in healthy subjects has been shown to result in movement slowing. However, the neurophysiological changes underlying these effects are not entirely understood yet. The present study aimed at ascertaining the effects of tACS at 10 and 20 Hz in healthy subjects on CMC and local power of the primary sensorimotor cortex. Neuromagnetic activity was recorded during isometric contraction before and at two time points (2-10 min and 30-38 min) after tACS of the left primary motor cortex (M1), using a 306 channel whole head magnetoencephalography (MEG) system. Additionally, electromyography (EMG) of the right extensor digitorum communis (EDC) muscle was measured. TACS was applied at 10 and 20 Hz, respectively, for 10 min at 1 mA. Sham stimulation served as control condition. The data suggest that 10 Hz tACS significantly reduced low gamma band CMC during isometric contraction. This implies that tACS does not necessarily cause effects at stimulation frequency. Rather, the findings suggest cross-frequency interplay between alpha and low gamma band activity modulating functional interaction between motor cortex and muscle.
Oscillatory activity is modulated by sensory stimulation but can also fluctuate in the absence of sensory input. Recent studies have demonstrated that such fluctuations of oscillatory activity can have substantial influence on the perception of subsequent stimuli. In the present study, we employed a simultaneity task in the somatosensory domain to study the role of prestimulus oscillatory activity on the temporal perception of 2 events. Subjects received electrical stimulations of the left and right index finger with varying stimulus onset asynchronies (SOAs) and reported their subjective perception of simultaneity, while brain activity was recorded with magnetoencephalography. With intermediate SOAs (30 and 45 ms), subjects frequently misperceived the stimulation as simultaneously. We compared neuronal oscillatory power in these conditions and found that power in the high beta band (?20 to 40 Hz) in primary and secondary somatosensory cortex prior to the electrical stimulation predicted subjects reports of simultaneity. Additionally, prestimulus alpha-band power influenced perception in the condition SOA 45 ms. Our results indicate that fluctuations of ongoing oscillatory activity in the beta and alpha bands shape subjective perception of physically identical stimulation.
Cortico-muscular coherence (CMC) at beta frequency (13-30 Hz) occurs particularly during weak to moderate isometric contraction. It is a well-established measure of communication between the primary motor cortex (M1) and corresponding muscles revealing information about the integrity of the pyramidal system. Although the slowing of brain and muscle dynamics during healthy aging has been evidenced, functional communication as determined by CMC has not been investigated so far. Since decline of motor functions at higher age is likely to be associated with CMC changes, the present study aims at shedding light on the functionality of the motor system from a functional interaction perspective. To this end, CMC was investigated in 27 healthy subjects aging between 22 and 77 years during isometric contraction of their right forearm. Neuromagnetic activity was measured using whole-head magnetoencephalography (MEG). Muscle activity was measured by means of surface electromyography (EMG) of the right extensor digitorum communis (EDC) muscle. Additionally, MEG-EMG phase lags were calculated in order to estimate conducting time. The analysis revealed CMC and M1 power amplitudes to be increased with age accompanied by slowing of M1, EMG, and CMC. Frequency changes were particularly found in subjects aged above 40 years suggesting that at this middle age, neurophysiological changes occur, possibly reflecting an early neurophysiological marker of seniority. Since MEG-EMG phase lags did not vary with age, changes cannot be explained by alterations of nerve conduction. We argue that the M1 power amplitude increase and the shift towards lower frequencies might represent a neurophysiological marker of healthy aging which is possibly compensated by increased CMC amplitude.
The mechanism and time course of emotional side effects of subthalamic deep brain stimulation in Parkinsons disease are a matter for discussion. We report a 53-month follow-up of a patient with affective lability. Postoperative lesion plus bilateral stimulation strongly influenced mood in the first week in terms of laughing behavior, while voltage changes had only minor long-term impact up to 37 months on negative emotion, possibly caused by the right electrode stimulating the subthalamic nucleus and adjacent fiber tracts involving the internal capsule. Thus we conclude that affective lability can occur with different temporal dynamics of microlesion, and early and chronic stimulation.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in PD. However, QoL fails to improve in a relevant proportion of patients. We studied clinical baseline and progression parameters associated with improvement in QoL after DBS. Data from a German randomized, controlled study comparing DBS (60 patients) with best medical treatment (59 patients) were analyzed. Changes in patients QoL were assessed using the Parkinsons Disease Questionnaire (PDQ-39) at baseline and at the 6-month follow-up. For the STN-DBS patients, the changes in PDQ-39 were correlated with predefined clinical preoperative and progression parameters. Scores for QoL improved after STN-DBS for 57% of the patients, and for 43% patients, they did not improve. Patients with improvement in QoL showed significantly higher cumulative daily "off" time. Changes in the PDQ-39 showed a significant positive correlation with the cumulative daily off time at baseline. Logistic regression analysis revealed that 1 additional hour off time at baseline increases the odds for improvement on PDQ-39 by a factor of 1.33 (odds ratio). In the postoperative course, changes in the PDQ-39 significantly correlated with the reduction of cumulative daily off time, an improvement on the UPDRS (UPDRS III off), and positive mood changes. Among the baseline parameters, the cumulative daily off time is the strongest predictor for improvement in disease-related QoL after DBS. Improvement in QoL after STN-DBS is also correlated with changes in motor functions and changes in depression and anxiety.
Stroke like episodes can occur by cortical compression due to changes in intracranial pressure. We report a patient after left hemicraniectomy who presented transient speech arrest after sleeping on the left side. We propose that mechanical compression of the left inferior or superior frontal gyrus led to this episode similar to a major mass effect due to an unprotected brain surface after hemicraniectomy.
In vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration and sympathetic cardiac innervation with SPECT is used to distinguish idiopathic Parkinson disease (PD) from atypical parkinsonian disorder (APD). However, the diagnostic accuracy of these imaging approaches as stand-alone procedures is often unsatisfying. The aim of this study was therefore to evaluate to which extent diagnostic accuracy can be increased by their combined use together with a multidimensional statistical algorithm.
Recent studies have observed the ubiquity of phase-amplitude coupling (PAC) phenomenon in human and animal brain recordings. While various methods were performed to quantify it, a rigorous analytical definition of PAC is lacking. This paper yields an analytical definition and accordingly offers theoretical insights into some of the current methods. A direct PAC estimator based on the given definition is presented and shown theoretically to be superior to some of the previous methods such as general linear model (GLM) estimator. It is also shown that the proposed PAC estimator is equivalent to GLM estimator when a constant term is removed from its formulation. The validity of the derivations is demonstrated with simulated data of varying noise levels and local field potentials recorded from the subthalamic nucleus of a Parkinsons disease patient.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in Parkinsons disease (PD). Dementia is considered as a contraindication for STN-DBS. However, no controlled study assessed the impact of STN-DBS on the QoL and motor outcome in PD patients with a borderline global cognitive impairment. We studied clinical baseline and progression parameters in a cohort of STN-DBS patients with a global cognitive score still in the non-demented range but scoring in the lowest quartile of the Mattis Dementia Rating Scale (MDRS), a measure of global cognitive functioning. Data from a German randomised controlled study comparing DBS (60 patients) with best medical treatment (BMT, 59 patients) were analysed. Changes in patients QoL scores were assessed using the Parkinsons disease questionnaire (PDQ-39) at baseline and at the 6 months follow up. Patients were split into four groups according to their MDRS performance at baseline and these groups were compared in the context of motor outcome and QoL. Twelve out of sixty patients of the STN-DBS group scored in the lowest quartile of the MDRS (range between one hundred thirty and one hundred thirty seven points). An individual analysis revealed that 3 of 12 patients showed a clinical relevant improvement in QoL whereas the group statistics did not reveal any significant improvement in QoL measures after STN-DBS compared to the BMT group. Since this failure to improve in QoL cannot be explained by a failure to improve in motor functions, stimulation settings and psychiatric scales after STN-DBS, the failure to improve in QoL in patients with a borderline global cognitive score might be specifically related to lower cognitive functioning.
Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinso?s disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ? 130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ? 130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds.
Dopaminergic treatments are associated with impulse control disorders such as pathological gambling in a subset of patients with Parkinsons Disease. While deep brain stimulation of the subthalamic nucleus has been reported to reduce symptoms of impulse control disorders in some Parkinsons Disease patients, little is known about its specific effects on gambling behaviour. In this experiment, we investigated the effects of deep brain stimulation of the subthalamic nucleus on one of the central features of pathological gambling: the tendency to chase losses. Loss-chasing is associated with impaired control over gambling behaviour and it is one of the most salient features of pathological gambling as it presents in the clinic. Twenty two patients with advanced idiopathic Parkinsons Disease and chronically implanted subthalamic nucleus electrodes for deep brain stimulation completed a simple laboratory model of loss-chasing behaviour twice: once with and once without stimulation. Exploratory analysis indicated that deep brain stimulation of the subthalamic nucleus increased the value of losses chased by patients with Parkinsons Disease when shifting from off- to on-stimulation. These effects were not attributable to changes in state affect or to the motor impairments produced by the withdrawal of deep brain stimulation of the subthalamic nucleus. The effects of the stimulation on the value of losses chased were more pronounced in female than in male patients and reduced in patients taking dopamine receptor agonists. Collectively, these results suggest that deep brain stimulation of the subthalamic nucleus can transiently alter the evaluation of accumulated losses during gambling episodes in idiopathic Parkinsons Disease.
Cortical gamma band synchronization is associated with attention. Accordingly, directing attention to certain visual stimuli modulates gamma band activity in visual cortical areas. However, gradual effects of attention and behavior on gamma band activity in early visual areas have not yet been reported. In the present study, the degree of selective visual attention was gradually varied in a cued bimodal reaction time paradigm using audio-visual stimuli. Brain activity was recorded with magnetoencephalography (MEG) and analyzed with respect to time, frequency, and location of strongest response. Reaction times to visual and auditory stimuli reflected three presumed graded levels of visual attention (high, medium, and low). MEG data showed sustained gamma band synchronization in all three conditions in early visual areas (V1 and V2), while the intensity of gamma band synchronization increased with the level of visual attention (from low to high). Differences between conditions were seen for up to 1600 ms. The current results show that in early visual areas the level of gamma band synchronization is related to the level of attention directed to a visual stimulus. These gradual and long-lasting effects highlight the key role of gamma band synchronization in early visual areas for selective attention.
It has been proposed that the workings of the brain are mainly intrinsically generated recurrent neuronal activity, with sensory inputs as modifiers of such activity in both sensory and higher order modality non-specific regions. This is supported by the demonstration of recurrent neuronal activity in the visual system as a response to visual stimulation. In contrast recurrent activity has never been demonstrated before in higher order modality non-specific regions. Using magneto-encephalography and Granger causality analysis, we tested in a paralimbic network the hypothesis that stimulation may enhance causal recurrent interaction between higher-order, modality non-specific regions. The network includes anterior cingulate/medial prefrontal and posterior cingulate/medial parietal cortices together with pulvinar thalami, a network known to be effective in autobiographic memory retrieval and self-awareness. Autobiographic memory retrieval of previous personal judgments of visually presented words was used as stimuli. It is demonstrated that the prestimulus condition is characterized by causal, recurrent oscillations which are maximal in the lower gamma range. When retrieving previous judgments of visually presented adjectives, this activity is dramatically increased during the stimulus task as ascertained by Granger causality analysis. Our results confirm the hypothesis that stimulation may enhance causal interaction between higher order, modality non-specific brain regions, exemplified in a network of autobiographical memory retrieval.
Increasing evidence suggests that abnormal oscillatory activity in basal ganglia and cortex plays a pivotal role in the pathophysiology of Parkinsons disease. Recordings of local field potentials from subthalamic nucleus of patients undergoing deep brain stimulation have focused on oscillations occurring at frequencies below 100 Hz in the alpha, beta and gamma range and suggested that, in particular, an increase of beta band oscillations underlies slowing of movement in Parkinsons disease. Recent findings showing that the amplitude of high frequency oscillations (>200 Hz) couples with the phase of beta activity have raised the important question about the role of subthalamic high frequency oscillations in Parkinsons disease. To investigate functional characteristics and clinical relevance of high frequency oscillations, we recorded local field potentials from 18 subthalamic nuclei of 9 akinetic-rigid Parkinsonian patients with implanted deep brain stimulation electrodes and still externalised leads before and after intake of levodopa. We identified two distinct bands of high frequency oscillations, one centred around 250 Hz and another one around 350 Hz that show characteristic levodopa dependent amplitude and coupling behaviours. Administration of levodopa changed the power ratio between the two high frequency bands towards the component centred around 350 Hz in all 18 nuclei under study (p<10(-4)). Moreover, this power ratio correlated significantly with the Unified Parkinsons Disease Rating Scale hemibody akinesia/rigidity subscore (r=0.3618, p=0.015), but interestingly not with beta peak power (p=0.1) suggesting that levodopa induced changes in high frequency and beta oscillations are at least potentially independent of each other. Accordingly, a combined parameter composed of power ratio of high frequency oscillations and beta peak power significantly increased the correlation with the motor state (r=0.45, p=0.004). These results indicate that a shift from slower to faster frequencies of the spectrum greater than 200 Hz represents a prokinetic neurophysiological marker underlying levodopa induced motor improvement in Parkinsons disease.
The posterior subthalamic area (PSA), ventral to the intercommissural line (ICL) and the ventral intermediate nucleus (VIM), has been suggested as a promising target for deep brain stimulation (DBS) in patients suffering from essential tremor (ET). In this study the clinical benefit of VIM and PSA DBS on postural tremor suppression was systematically evaluated in a two step approach with a 3D ultrasound kinematic analysis tool.
Brain imaging has shown altered corpus callosum (CC) morphology in patients with Gilles de la Tourette syndrome (GTS). Yet it is unclear whether these morphological changes are associated with altered interhemispheric interactions. Here, we combined transcranial magnetic stimulation (TMS) with diffusion tensor magnetic resonance imaging (DTI) to explore functional and structural interhemispheric connections between the left and right motor hand areas. We studied 14 unmedicated GTS patients without psychiatric comorbidity (2 women, mean age 35.5 years) and 15 healthy volunteers (3 women, mean age 35 years). Left-to-right and right-to-left interhemispheric inhibitions (IHIs) were measured in hand muscles with TMS. In 13 GTS patients and all healthy controls, we measured fractional anisotropy (FA) with DTI to examine the relation between functional measures of interhemispheric connectivity as derived by TMS and structural properties of the CC region that carries fibers interconnecting both motor cortices. In GTS patients, left-to-right IHI was weaker than right-to-left IHI. Left-to-right IHI in GTS patients was also reduced compared with healthy controls. Voxel-based morphometric analysis revealed that FA in the motor region of the CC did not differ between groups. However, there was a significant interaction between groups and the relation between regional FA and left-to-right IHI in the motor region of the CC. A negative linear relation between FA and left-to-right IHI was present in control subjects but not in patients. Our combined TMS-DTI approach demonstrates abnormal functional interhemispheric connectivity in GTS accompanied by an altered structure-function relationship in the motor CC.
Implantation of electrodes in the subthalamic nucleus (STN) for deep brain stimulation is a well-established method to ameliorate motor symptoms in patients suffering from Parkinsons disease (PD). This study investigated the pathophysiology of rest and postural tremor in PD. In 14 patients with PD, we recorded intraoperatively local field potentials (LFPs) in the STN (at different recording depths) and electromyographic signals (EMGs) of the contralateral forearm. Using coherence analysis we analysed tremor epochs both at rest and hold conditions in patients of the akinetic-rigid or of the tremor-dominant PD subtype. Data analysis revealed significant LFP-EMG coherence during periods of rest and postural tremor. However, strong differences between both tremor types were observed: local maxima (cluster) of rest and postural tremor did not match. Additionally, during rest tremor coherence occurred significantly more frequently at single tremor frequency than at double tremor frequency in tremor-dominant as well as in akinetic-rigid patients. In contrast, during postural tremor in patients with akinetic-rigid PD coherence was predominantly at double tremor frequency. The data suggest a specific topography of tremor clusters for rest and postural tremor. Furthermore, we presume that the same tremor mechanisms exist in patients with tremor-dominant and akinetic-rigid PD, but to different degrees.
In healthy subjects repeated tactile stimulation in a conditioning test stimulation paradigm yields attenuation of primary (S1) and secondary (S2) somatosensory cortical activation, whereas a preceding painful stimulus results in facilitation.
In patients with essential tremor (ET) already treated with chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius (VIM) we investigated whether optimization of stimulation parameters could improve clinical tremor suppression, and whether this putative effect could be sustained over time. Twenty-three ET patients with VIM-DBS participated in the prospective study. All electrode contacts were tested systematically and stimulation parameters were optimized over the course of 2 days. Clinical tremor rating scale (TRS) was videotaped before, directly after the optimization and at a 10 weeks follow-up and evaluated blindly and independently by two clinicians. For stimulation effect optimization we increased the number of active contacts whereas the total charge applied to the tissue was kept constant. TRS hemi-body scores decreased significantly after optimization. At the 10 weeks follow-up, however, the improvement had faded and was no longer significant. The activities of daily living (ADL) remained significantly improved. Systematic optimization of VIM-DBS parameters in ET patients leads to a short term improvement which habituates over time. Our results provide further evidence for a tolerance effect in chronic VIM stimulation thereby suggesting that frequently alternating stimulation protocols should be tested in future studies of ET patients treated with VIM-DBS.
In patients with Gilles de la Tourette syndrome (GTS) alterations of motor cortex (M1) excitability at rest have been evidenced. In contrast, there has so far been little research into changes of motor cortical reactivity during the time course of voluntary movements in GTS patients. The present study investigates neuromagnetic event-related desynchronization (ERD) and event-related synchronization (ERS) of bilateral M1 in 11 GTS patients and 11 healthy control subjects. ERD represents motor cortical activation, whereas ERS most likely indicates its inhibition. Subjects performed a self-paced finger movement task while magnetoencephalography was used to record neuromagnetic activity. In GTS patients, ERD at beta frequency was significantly increased in the contralateral hemisphere before and during movements, whereas ERS following movement termination was increased in M1 ipsilateral. Ipsilateral ERS was inversely correlated with tic severity as determined by the Yale Global Tic Severity Rating Scale. The data of the present study support the hypothesis that during voluntary movements, motor cortical reactivity is pathologically altered in GTS patients. The observed pattern of increased activation (ERD) prior to and during movement execution followed by increased inhibition (ERS) after movement termination at beta frequency suggests abnormally increased motor cortical activation, possibly driving stronger inhibition. The stronger this inhibition is, the better symptoms appear to be controlled.
The current study aimed to investigate predictive markers for acute symptoms of depression and mania following deep brain stimulation (DBS) surgery of the subthalamic nucleus for the treatment of motor symptoms in Parkinsons disease (PD). Fourteen patients with PD (7 males) were included in a prospective longitudinal study. Neuropsychological tests, psychopathology scales and tests of motor functions were administered at several time points prior to and after neurosurgery. Pre-existing psychopathological and motor symptoms predicted postoperative affective side effects of DBS surgery. As these can easily be assessed, they should be considered along with other selection criteria for DBS surgery.
A slight decline in cognitive functions and especially in executive functioning after deep brain stimulation (DBS) of the nucleus subthalamicus (STN) in patients with Parkinsons disease (PD) has been described. This study evaluated baseline parameters that contribute to a deterioration of cognitive functioning after DBS. We analyzed data from the neuropsychological protocol in a randomized controlled study comparing DBS with best medical treatment (BMT). Change scores were calculated for the cognitive domains "global cognitive functioning," "memory," "working memory," "attention," and "executive function." These domain-specific change scores were correlated with previously defined preoperative parameters. Compared with the BMT group (63 patients), the STN-DBS group (60 patients) showed a significant decline only in the domain executive function 6 months after DBS, which was significantly correlated with age, levodopa-equivalence dosage (LED) and axial subscore of the UPDRS in the off-medication state at baseline. Multiple regression analysis showed that these three factors explained, however, only about 23% of the variance. Patients with higher age, higher baseline LED, and/or higher axial subscore of the UPDRS at baseline have an increased risk for worsening of executive function after STN-DBS. High scores of these factors might reflect an advanced stage of disease progression. As these baseline factors explained the variance of the change score executive function only to a minor proportion, other factors including the surgical procedure, the exact placement of the electrode or postsurgical management might be more relevant for a decline in executive functioning after STN-DBS.
Echophenomena in Gilles de la Tourette syndrome (GTS) may relate to deficient processing of observed biological movements. This would be reflected in altered effects of movement observation on motor responses in these patients. We studied reaction times in 11 unmedicated GTS patients without psychiatric comorbidity and healthy subjects. In experiment 1, participants imitated single biological finger movement stimuli or nonbiological dot movement stimuli immediately. In experiment 2, participants responded to a tone while viewing biological or nonbiological movement stimuli that were either compatible (identical) or incompatible (different) with their response. In experiment 1, both patients and healthy subjects responded faster to single biological than to nonbiological stimuli. In experiment 2, biological stimuli caused a larger compatibility-effect in responses than nonbiological stimuli in both groups, provided stimulus presentation and response initiation coincided. Healthy subjects responded faster to compatible biological than nonbiological stimuli. In contrast, GTS patients responded slower to incompatible biological than nonbiological stimuli. Patients mean reaction time in experiment 2 correlated with phonic tic-frequency. Motor facilitation by observing biological movements appears to rely on concomitance of stimuli and responses in GTS patients and healthy individuals. Differing behavioral effects of movement observation in GTS might reflect altered activation of an action observation-execution matching system. To avoid unwanted movements GTS patients probably have to inhibit motor activation induced by observed movement automatically. Thus, movement stimuli may facilitate similar motor responses less but interfere more with different responses in these patients.
The non-ergot dopamine agonist rotigotine has been formulated in a once-daily transdermal patch for 24-h application which ensures continuous rotigotine release over 24 h. This open, prospective, non-interventional study investigated compliance with the patch under clinical practice conditions.
We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinsons disease (PD) patients. Thirty-five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinsons Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off-stimulation, regardless of the sequence of stimulation. In open assessment, both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group.
Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid-cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain-induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole-brain coverage. In this study, we thought to investigate the spatio-temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference-free measure of event-related EEG activity) in a time window 0-400 ms poststimulus were used to model trial-to-trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG-derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG-time windows suggests largely parallel signal processing in the bilateral operculo-insular and mid-cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG.
Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional mu-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI), PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD) response to painful laser stimulation.
Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinsons disease, although its precise mechanisms remain poorly understood. To gain further insight into the mechanisms underlying deep brain stimulation, we analysed the causal relationship between forearm muscle activity and local field potentials derived from the subthalamic nucleus. In 19 patients suffering from Parkinsons disease of the akinetic-rigid subtype, we calculated the squared partial directed coherence between muscles of the contralateral forearm and the subthalamic nucleus or zona incerta during both a rest and a hold condition of the arm. For both recording regions, data analysis revealed that, during the rest condition, electromyographic activity was significantly more often Granger-causal for the local field potentials than the opposite causation. In contrast, during the hold condition, no significant difference was found in the occurrence of causalities. Contrary to the existing basal ganglia model and the current concept of Parkinsons disease pathophysiology, we found the subthalamic nucleus to receive more afferences than it emitted efferences, suggesting that its role is more complex than a simple driving nucleus in the basal ganglia loop. Therefore, the effect of deep brain stimulation in the subthalamic nucleus could, at least in part, result from a blockade of pathological afferent input.
Precise timing as determined by sensorimotor synchronization is crucial for a wide variety of activities. Although it is well-established that musicians show superior timing as compared to non-musicians, the neurophysiological foundations - in particular the underlying functional brain network - remain to be characterized. To this end, drummers, professional pianists and non-musicians performed an auditory synchronization task while neuromagnetic activity was measured using a 122-channel whole-head magnetoencephalography (MEG) system. The underlying functional brain network was determined using the beamformer approach Dynamic Imaging of Coherent Sources (DICS). Behaviorally, drummers performed less variably than non-musicians. Neuromagnetic analysis revealed a cerebello-thalamo-cortical network in all subjects comprising bilateral primary sensorimotor cortices (S1/M1), contralateral supplementary motor and premotor regions (SMA and PMC), thalamus, posterior parietal cortex (PPC), ipsilateral cerebellum and bilateral auditory cortices. Stronger PMC-thalamus and PPC-thalamus interactions at alpha and beta frequencies were evident in drummers as compared to non-musicians. In professional pianists stronger PMC-thalamus interaction as compared to non-musicians at beta frequency occurred. The present data suggest that precise timing is associated with increased functional interaction within a PMC-thalamus-PPC network. The PMC-thalamus connectivity at beta frequency might be related to musical expertise, whereas the PPC-thalamus interaction might have specific relevance for precise timing.
Neurological diseases frequently induce pathological changes of cerebrospinal fluid (CSF) that might secondarily influence brain activity, as the CSF-brain barrier is partially permeable. However, functional effects of CSF on neuronal network activity have not been specified to date. Here, we report that CSF specimens from patients with reduced Glasgow Coma Scale values caused by severe traumatic brain injury suppress synchronous activity of in vitro-generated neuronal networks in comparison with controls. We present evidence that underlying mechanisms include increased N-methyl-D-aspartate receptor activity mediated by a CSF fraction containing elevated amino acid concentrations. These proof-of-principle data suggest that determining effects of CSF specimens on neuronal network activity might be of diagnostic value.
The diagnostic and prognostic value of critical flicker frequency (CFF) analysis for assessment of severity and dynamics of hepatic encephalopathy (HE) was studied before and after implantation of a transjugular intrahepatic portosystemic shunt (TIPS).
The present study aimed at investigating to what extent sensorimotor synchronization is related to (i) musical specialization, (ii) perceptual discrimination, and (iii) the movements trajectory. To this end, musicians with different musical expertise (drummers, professional pianists, amateur pianists, singers, and non-musicians) performed an auditory and visual synchronization and a cross-modal temporal discrimination task. During auditory synchronization drummers performed less variably than amateur pianists, singers and non-musicians. In the cross-modal discrimination task drummers showed superior discrimination abilities which were correlated with synchronization variability as well as with the trajectory. These data suggest that (i) the type of specialized musical instrument affects synchronization abilities and (ii) synchronization accuracy is related to perceptual discrimination abilities as well as to (iii) the movements trajectory. Since particularly synchronization variability was affected by musical expertise, the present data imply that the type of instrument improves accuracy of timekeeping mechanisms.
By studying neuronal activity through neuronal electrogenesis, neurophysiological investigations provide a functional assessment of the nervous system and, therefore, has been used for quantitative assessment and follow-up of hepatic encephalopathy (HE). The different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are those that reflect cortical function, i.e., cognitive-evoked potentials (EPs) (P300 paradigm), electroencephalogram (EEG), visual EPs (latency>100 ms) and somatosensory EPs (SEPs) (latency between 25 and 100 ms). Short-latency EPs (brainstem acoustic EPs, SEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and motor EPs can disclose myelopathies. Because of its parallelism to the clinical examination, clinical neurophysiology can complement the neurological examination: (i) to provide evidence of HE in patients who have normal consciousness; (ii) to rule out, at least under some conditions, disturbances of consciousness due to other causes (e.g. drug-induced disturbances, non-convulsive status epilepticus) with the reservation that the mildest degrees of encephalopathy might be associated with an EEG pattern similar to that induced by drugs; and (iii) to demonstrate the worsening or, conversely improvement, of HE in the follow-up period.
Despite the fact that essential tremor (ET) is the most prevalent movement disorder, the underlying pathological mechanisms are not fully understood. There is accumulating evidence that this specific type of tremor is mainly of central origin, in particular involving inferior olive, cerebellum, thalamus, and primary motor cortex. We studied 8 patients with ET recording simultaneously neural activity with a whole-scalp neuromagnetometer and tremor activity with surface electromyography (EMG). Subjects performed an isometric contraction of the left forearm. Tremor frequency of 5 to 7 Hz and its first harmonic were clearly evident in power spectra of EMG recordings. We used the localization technique dynamic imaging of coherent sources (DICS) to identify cerebral areas coherent to the EMG signal at tremor frequency and its first harmonic. All subjects showed coherence to the contralateral primary motor cortex. In a further step, DICS was used to identify areas of significant cerebro-cerebral coherence. The analysis revealed a network of areas consisting of contralateral primary motor cortex, premotor cortex, thalamus, brainstem, and ipsilateral cerebellum. These results are consistent with the view that in ET, a network of cerebral areas including brainstem shows oscillatory interactions, which lead to a rhythmic modulation of muscle activity becoming apparent as tremor.
Resting tremor in idiopathic Parkinsons disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor-dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122-channel whole-head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast-acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro-cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus-premotor-motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas.
Pain is a complex experience subserved by an extended network of brain areas. However, the functional integration among these brain areas, i.e., how they interact and communicate to generate a coherent pain percept and an adequate behavioral response is largely unknown. Here, we used magnetoencephalography to investigate functional integration among pain-related cortical activations in terms of Granger causality and compared it with tactile-related activations. The results show causal influences of primary somatosensory cortex on secondary somatosensory cortex for tactile-related but not for pain-related activations, which supports the proposition of a partially parallel organization of pain processing in the human brain. Furthermore, during a simple reaction time task, the strength of causal influences between somatosensory areas but not the latencies between activations correlated significantly with the speed of reaction times. These findings show how the analysis of functional integration complements traditional analyses of electrophysiological data and provides novel and behaviorally relevant information about the organization of the human pain system.
We assessed the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) or internal pallidum (GPi-DBS) on health-related quality of life (HrQoL) in patients with advanced Parkinsons disease participating in a previously reported multicenter trial. Sickness Impact Profile (SIP) questionnaires were available for analysis in a subgroup of n = 20/20 patients with GPi-DBS and n = 45/49 patients with STN-DBS at baseline, 6 and 36 months. The SIP provides a physical dimension and a psychosocial dimension sum score and 12 category scores: Alertness/Intellectual Behavior (AIB), Ambulation (A), Body Care and Movement (BCM), Communication (C), Eating (E), Emotional Behavior (EB), Home Management (HM), Mobility (M), Recreation and Pastimes (RP), Sleep and Rest (SR), Social Interaction (SI), and Work (W). Motor functioning was assessed by means of the Unified Parkinsons Disease Rating Scale and diaries. At 6 months significant improvements in off-period motor symptoms and activities of daily living were paralleled by significant reductions in the total, physical, and psychosocial SIP score in both treatment groups. At 3 years, sustained improvements were observed in the physical dimension score, BCM, E, M, RP after STN-DBS and M, SI after GPi-DBS. All other SIP subscores approached baseline values, but were still the same or better (except C) whereas motor functioning remained stable after 36 months. STN-DBS and GPi-DBS led to significant early improvements in HrQoL. Despite sustained motor improvements many of these initial benefits were lost after 3 years. This may reflect either progression of the disease or adaptive changes in the subjective perception of health-related wellbeing over time.
Movement execution strongly relies on precise sensorimotor synchronization. In a finger-tapping task that requires subjects to synchronize their finger taps to regular pacing signal synchronization accuracy varies with respect to pacing signals modality. This study aimed at elucidating functional brain dynamics associated with modality specific behavioral synchronization accuracy. To this end, 10 right-handed subjects performed a finger-tapping task with respect to regular auditory and visual pacing, respectively, whereas neuromagnetic activity was recorded using a 122-channel whole-head neuromagnetometer. Visual pacing was associated with significantly reduced tap-to-pacer asynchrony and increased intertap variability as compared to auditory pacing. The brain dynamics associated with task execution were analyzed using the frequency domain beamformer approach dynamic imaging of coherent sources (DICS). Both tasks were shown to be associated with comparable networks. However, during visual pacing involvement of the ventral premotor cortex (PMv) was shown, whereas during auditory pacing the dorsal premotor cortex (PMd) was concerned with task execution. Synchronization with respect to visual pacing was associated with significantly increased functional interaction between thalamus and PMv at beta frequency as compared to functional interplay between thalamus and PMd during auditory pacing. Auditory synchronization was associated with increased functional interaction between left superior temporal gyrus and PMd at alpha frequency. Furthermore, functional interaction between thalamus and premotor cortex at beta frequency was significantly correlated with synchronization accuracy. All in all the present data suggest that modality specific synchronization differences are associated with frequency and connectivity specific changes of functional interaction in distinct brain networks.
We simultaneously recorded local field potentials (LFPs) in the subthalamic nucleus (STN) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm in eight patients with idiopathic tremor-dominant Parkinsons disease (resting tremor) during the bilateral implantation of deep brain stimulation electrodes. Recordings were made at different heights (in 0.5- to 2.0-mm steps beginning outside the STN) using up to five concentrically configured macroelectrodes (2 mm apart). The patients were instructed to relax their contralateral forearm (rest condition). We analysed the coherence between tremor EMGs and STN LFPs, which showed significant tremor-associated coupling at single tremor and double tremor frequencies. Moreover, the EMG-LFP coherences were characterised by differences between antagonistic muscles (flexor, extensor) and by the spatial distribution of LFPs within the STN. Coherence at single and double tremor frequencies occurred significantly more frequently within STN than above STN (in the zona incerta). In this study, we were able to show that, within STN, tremor-associated LFP activity varied with spatial distribution and with the contralateral antagonistic forearm muscles. These findings suggest the existence of distribution- and muscle-specific tremor-associated LFP activity at different tremor frequencies and an organisation of tremor-related subloops within the STN.
Under rest condition, beta-band (13-30Hz) activity in patients with Parkinsons disease (PD) is prominent in the subthalamic nucleus (STN). However, the beta-band coupling between STN and muscle activity, its distribution and relation to motor symptoms remains unclear.
Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Previous structural MRI studies have identified regional abnormalities in grey matter, especially in the basal ganglia. These findings are consistent with the assumption of alterations in cortico-striato-thalamo-cortical circuits and dopaminergic neurotransmission playing a major role in the pathophysiology of GTS. Additionally, recent imaging studies suggested an involvement of sensory-motor cortices in the pathophysiology of GTS. However, little is known about the role of white matter changes in GTS. In this study, we aimed to examine whether GTS is associated with abnormalities in white matter microstructure and whether these changes are correlated with tic severity. In a morphometric study based on diffusion tensor MRI of the whole brain, we compared brain tissue diffusion characteristics between 15 unmedicated adults with GTS without psychiatric co-morbidity and 15 healthy age- and sex-matched controls. We performed voxel-based morphometry (VBM) of regional fractional anisotropy (FA) values to identify regional differences in white matter microstructure between the groups. We also tested for a linear relationship between regional FA values and clinical scores of tic severity. Probabilistic fibre tracking was applied to characterize anatomical connectivity of those areas showing differences in regional FA. Compared with healthy controls, GTS patients showed bilateral FA increases in white matter underlying the post- and precentral gyrus, below the left supplementary motor area, and in the right ventro-postero-lateral part of the thalamus. The peak increase in FA was located below the left postcentral gyrus. Probabilistic tractography identified transcallosal and ipsilateral cerebello-thalamo-cortical pathways of the somatosensory system passing through this subcortical region. In patients, regional FA in this region showed an inverse linear relationship with tic severity. These findings demonstrate, for the first time, structural alterations in somatosensory pathways in GTS. Changes of water diffusion characteristics point towards reduced branching in somatosensory pathways in GTS patients. The negative correlation between higher regional FA values and fewer tics suggests that these alterations of white matter microstructure represent adaptive reorganization of somatosensory processing in GTS.
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