Mapping Subcortico-Cortical Coupling-A Comparison of Thalamic and Subthalamic Oscillations.

BACKGROUND: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation in tremor patients. Despite its therapeutic importance, its oscillatory coupling to cortical areas has rarely been investigated in humans. OBJECTIVES: The objective of this study was to identify the cortical areas coupled to the VIM in patients with essential tremor. METHODS: We combined resting-state magnetoencephalography with local field potential recordings from the VIM of 19 essential tremor patients. Whole-brain maps of VIM-cortex coherence in several frequency bands were constructed using beamforming and compared with corresponding maps of subthalamic nucleus (STN) coherence based on data from 19 patients with Parkinson's disease. In addition, we computed spectral Granger causality. RESULTS: The topographies of VIM-cortex and STN-cortex coherence were very similar overall but differed quantitatively. Both nuclei were coupled to the ipsilateral sensorimotor cortex in the high-beta band; to the sensorimotor cortex, brainstem, and cerebellum in the low-beta band; and to the temporal cortex, brainstem, and cerebellum in the alpha band. High-beta coherence to sensorimotor cortex was stronger for the STN (P = 0.014), whereas low-beta coherence to the brainstem was stronger for the VIM (P = 0.017). Although the STN was driven by cortical activity in the high-beta band, the VIM led the sensorimotor cortex in the alpha band. CONCLUSIONS: Thalamo-cortical coupling is spatially and spectrally organized. The overall similar topographies of VIM-cortex and STN-cortex coherence suggest that functional connections are not necessarily unique to one subcortical structure but might reflect larger frequency-specific networks involving VIM and STN to a different degree. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Slowing of Frontal ß Oscillations in Atypical Parkinsonism.

BACKGROUND: Diagnosis of atypical parkinsonian syndromes (APS) mostly relies on clinical presentation as well as structural and molecular brain imaging. Whether parkinsonian syndromes are distinguishable based on neuronal oscillations has not been investigated so far. OBJECTIVE: The aim was to identify spectral properties specific to atypical parkinsonism. METHODS: We measured resting-state magnetoencephalography in 14 patients with corticobasal syndrome (CBS), 16 patients with progressive supranuclear palsy (PSP), 33 patients with idiopathic Parkinson's disease, and 24 healthy controls. We compared spectral power as well as amplitude and frequency of power peaks between groups. RESULTS: Atypical parkinsonism was associated with spectral slowing, distinguishing both CBS and PSP from Parkinson's disease (PD) and age-matched healthy controls. Patients with atypical parkinsonism showed a shift in ß peaks (13-30 Hz) toward lower frequencies in frontal areas bilaterally. A concomitant increase in θ/α power relative to controls was observed in both APS and PD. CONCLUSION: Spectral slowing occurs in atypical parkinsonism, affecting frontal ß oscillations in particular. Spectral slowing with a different topography has previously been observed in other neurodegenerative disorders, such as Alzheimer's disease, suggesting that spectral slowing might be an electrophysiological marker of neurodegeneration. As such, it might support differential diagnosis of parkinsonian syndromes in the future. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

J-difference GABA-edited MRS reveals altered cerebello-thalamo-cortical metabolism in patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a common neurological manifestation of liver cirrhosis and is characterized by an increase of ammonia in the brain accompanied by a disrupted neurotransmitter balance, including the GABAergic and glutamatergic systems. The aim of this study is to investigate metabolic abnormalities in the cerebello-thalamo-cortical system of HE patients using GABA-edited MRS and links between metabolite levels, disease severity, critical flicker frequency (CFF), motor performance scores, and blood ammonia levels. GABA-edited MRS was performed in 35 participants (16 controls, 19 HE patients) on a clinical 3 T MRI system. MRS voxels were placed in the right cerebellum, left thalamus, and left motor cortex. Levels of GABA+ and of other metabolites of interest (glutamine, glutamate, myo-inositol, glutathione, total choline, total NAA, and total creatine) were assessed. Group differences in metabolite levels and associations with clinical metrics were tested. GABA+ levels were significantly increased in the cerebellum of patients with HE. GABA+ levels in the motor cortex were significantly decreased in HE patients, and correlated with the CFF (r = 0.73; p < .05) and motor performance scores (r = -0.65; p < .05). Well-established HE-typical metabolite patterns (increased glutamine, decreased myo-inositol and total choline) were confirmed in all three regions and were closely linked to clinical metrics. In summary, our findings provide further evidence for alterations in the GABAergic system in the cerebellum and motor cortex in HE. These changes were accompanied by characteristic patterns of osmolytes and oxidative stress markers in the cerebello-thalamo-cortical system. These metabolic disturbances are a likely contributor to HE motor symptoms in HE. In patients with hepatic encephalopathy, GABA+ levels in the cerebello-thalamo-cortical loop are significantly increased in the cerebellum and significantly decreased in the motor cortex. GABA+ levels in the motor cortex strongly correlate with critical flicker frequency (CFF) and motor performance score (pegboard test tPEG), but not blood ammonia levels (NH3).

Pathomechanisms in hepatic encephalopathy.

Hepatic encephalopathy (HE) is a frequent neuropsychiatric complication in patients with acute or chronic liver failure. Symptoms of HE in particular include disturbances of sensory and motor functions and cognition. HE is triggered by heterogeneous factors such as ammonia being a main toxin, benzodiazepines, proinflammatory cytokines and hyponatremia. HE in patients with liver cirrhosis is triggered by a low-grade cerebral edema and cerebral oxidative/nitrosative stress which bring about a number of functionally relevant alterations including posttranslational protein modifications, oxidation of RNA, gene expression changes and senescence. These alterations are suggested to impair astrocyte/neuronal functions and communication. On the system level, a global slowing of oscillatory brain activity and networks can be observed paralleling behavioral perceptual and motor impairments. Moreover, these changes are related to increased cerebral ammonia, alterations in neurometabolite and neurotransmitter concentrations and cortical excitability in HE patients.

Investigation of Magnetoelectric Sensor Requirements for Deep Brain Stimulation Electrode Localization and Rotational Orientation Detection.

Correct position and orientation of a directional deep brain stimulation (DBS) electrode in the patient's brain must be known to fully exploit its benefit in guiding stimulation programming. Magnetoelectric (ME) sensors can play a critical role here. The aim of this study was to determine the minimum required limit of detection (LOD) of a ME sensor that can be used for this application by measuring the magnetic field induced by DBS. For this experiment, a commercial DBS system was integrated into a head phantom and placed inside of a state-of-the-art Superconducting Quantum Interference Device (SQUID)-based magnetoencephalography system. Measurements were performed and analyzed with digital signal processing. Investigations have shown that the minimum required detection limit depends on various factors such as: measurement distance to electrode, bandwidth of magnetic sensor, stimulation amplitude, stimulation pulse width, and measurement duration. For a sensor that detects only a single DBS frequency (stimulation frequency or its harmonics), a LOD of at least 0.04 pT/Hz0.5 is required for 3 mA stimulation amplitude and 60 µµs pulse width. This LOD value increases by an order of magnitude to 0.4 pT/Hz0.5 for a 1 kHz, and by approximately two orders to 3 pT/Hz0.5 for a 10 kHz sensor bandwidth. By averaging, the LOD can be reduced by at least another 2 orders of magnitude with a measurement duration of a few minutes.

Unilateral deep brain stimulation suppresses alpha and beta oscillations in sensorimotor cortices.

Deep brain stimulation (DBS) is an established therapy to treat motor symptoms in movement disorders such as Parkinson's disease (PD). The mechanisms leading to the high therapeutic effectiveness of DBS are poorly understood so far, but modulation of oscillatory activity is likely to play an important role. Thus, investigating the effect of DBS on cortical oscillatory activity can help clarifying the neurophysiological mechanisms of DBS. Here, we aimed at scrutinizing changes of cortical oscillatory activity by DBS at different frequencies using magnetoencephalography (MEG). MEG data from 17 PD patients were acquired during DBS of the subthalamic nucleus (STN) the day after electrode implantation and before implanting the pulse generator. We stimulated the STN unilaterally at two different stimulation frequencies, 130 Hz and 340 Hz using an external stimulator. Data from six patients had to be discarded due to strong artefacts and two other datasets were excluded since these patients were not able to finalize the paradigm. After DBS artefact removal, power spectral density (PSD) values of MEG were calculated for each individual patient and averaged over the group. DBS at both 130 Hz and 340 Hz led to a widespread suppression of cortical alpha/beta band activity (8-22 Hz) specifically over bilateral sensorimotor cortices. No significant differences were observed between the two stimulation frequencies. Our finding of a widespread suppression of cortical alpha/beta band activity is particularly interesting as PD is associated with pathologically increased levels of beta band activity in the basal ganglia-thalamo-cortical circuit. Therefore, suppression of such oscillatory activity might be an essential effect of DBS for relieving motor symptoms in PD and can be achieved at different stimulation frequencies above 100 Hz.

Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal ganglia.

OBJECTIVE: Freezing of gait is a poorly understood symptom of Parkinson disease, and can severely disrupt the locomotion of affected patients. However, bicycling ability remains surprisingly unaffected in most patients suffering from freezing, suggesting functional differences in the motor network. The purpose of this study was to characterize and contrast the oscillatory dynamics underlying bicycling and walking in the basal ganglia. METHODS: We present the first local field potential recordings directly comparing bicycling and walking in Parkinson disease patients with electrodes implanted in the subthalamic nuclei for deep brain stimulation. Low (13-22Hz) and high (23-35Hz) beta power changes were analyzed in 22 subthalamic nuclei from 13 Parkinson disease patients (57.5 ± 5.9 years old, 4 female). The study group consisted of 5 patients with and 8 patients without freezing of gait. RESULTS: In patients without freezing of gait, both bicycling and walking led to a suppression of subthalamic beta power (13-35Hz), and this suppression was stronger for bicycling. Freezers showed a similar pattern in general. Superimposed on this pattern, however, we observed a movement-induced, narrowband power increase around 18Hz, which was evident even in the absence of freezing. INTERPRETATION: These results indicate that bicycling facilitates overall suppression of beta power. Furthermore, movement leads to exaggerated synchronization in the low beta band specifically within the basal ganglia of patients susceptible to freezing. Abnormal ∼18Hz oscillations are implicated in the pathophysiology of freezing of gait, and suppressing them may form a key strategy in developing potential therapies. Ann Neurol 2017;82:592-601.

Ammonia-weighted imaging by chemical exchange saturation transfer MRI at 3 T.

Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT-weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations.

Parkinsonian Rest Tremor Is Associated With Modulations of Subthalamic High-Frequency Oscillations.

BACKGROUND: High frequency oscillations (>200 Hz) have been observed in the basal ganglia of PD patients and were shown to be modulated by the administration of levodopa and voluntary movement. OBJECTIVE: The objective of this study was to test whether the power of high-frequency oscillations in the STN is associated with spontaneous manifestation of parkinsonian rest tremor. METHODS: The electromyogram of both forearms and local field potentials from the STN were recorded in 11 PD patients (10 men, age 58 [9.4] years, disease duration 9.2 [6.3] years). Patients were recorded at rest and while performing repetitive hand movements before and after levodopa intake. High-frequency oscillation power was compared across epochs containing rest tremor, tremor-free rest, or voluntary movement and related to the tremor cycle. RESULTS: We observed prominent slow (200-300 Hz) and fast (300-400 Hz) high-frequency oscillations. The ratio between slow and fast high-frequency oscillation power increased when tremor became manifest. This increase was consistent across nuclei (94%) and occurred in medication ON and OFF. The ratio outperformed other potential markers of tremor, such as power at individual tremor frequency, beta power, or low gamma power. For voluntary movement, we did not observe a significant difference when compared with rest or rest tremor. Finally, rhythmic modulations of high-frequency oscillation power occurred within the tremor cycle. CONCLUSIONS: Subthalamic high-frequency oscillation power is closely linked to the occurrence of parkinsonian rest tremor. The balance between slow and fast high-frequency oscillation power combines information on motor and medication state. © 2016 International Parkinson and Movement Disorder Society.

Covert hepatic encephalopathy: elevated total glutathione and absence of brain water content changes.

Recent pathophysiological models suggest that oxidative stress and hyperammonemia lead to a mild brain oedema in hepatic encephalopathy (HE). Glutathione (GSx) is a major cellular antioxidant and known to be involved in the interception of both. The aim of this work was to study total glutathione levels in covert HE (minimal HE and HE grade 1) and to investigate their relationship with local brain water content, levels of glutamine (Gln), myo-inositol (mI), neurotransmitter levels, critical flicker frequency (CFF), and blood ammonia. Proton magnetic resonance spectroscopy ((1)H MRS) data were analysed from visual and sensorimotor cortices of thirty patients with covert HE and 16 age-matched healthy controls. Total glutathione levels (GSx/Cr) were quantified with respect to creatine. Furthermore, quantitative MRI brain water content measures were evaluated. Data were tested for links with the CFF and blood ammonia. GSx/Cr was elevated in the visual (mHE) and sensorimotor (mHE, HE 1) MRS volumes and correlated with blood ammonia levels (both P < 0.001). It was further linked to Gln/Cr and mI/Cr (P < 0.01 in visual, P < 0.001 in sensorimotor) and to GABA/Cr (P < 0.01 in visual). Visual GSx/Cr correlated with brain water content in the thalamus, nucleus caudatus, and visual cortex (P < 0.01). Brain water measures did neither show group effects nor correlations with CFF or blood ammonia. Elevated total glutathione levels in covert HE (< HE 2) correlate with blood ammonia and may be a regional-specific reaction to hyperammonemia and oxidative stress. Brain water content is locally linked to visual glutathione levels, but appears not to be associated with changes of clinical parameters. This might suggest that cerebral oedema is only marginally responsible for the symptoms of covert HE.

Low visual cortex GABA levels in hepatic encephalopathy: links to blood ammonia, critical flicker frequency, and brain osmolytes.

The pathogenesis of hepatic encephalopathy (HE) is not fully understood yet. Hyperammonemia due to liver failure and subsequent disturbance of cerebral osmolytic balance is thought to play a pivotal role in the emergence of HE. The aim of this in-vivo MR spectroscopy study was to investigate the levels of γ-aminobutyric acid (GABA) and its correlations with clinical symptoms of HE, blood ammonia, critical flicker frequency, and osmolytic levels. Thirty patients with minimal HE or HE1 and 16 age-matched healthy controls underwent graduation of HE according to the West-Haven criteria and including the critical flicker frequency (CFF), neuropsychometric testing and blood testing. Edited proton magnetic resonance spectroscopy ((1)H MRS) was used to non-invasively measure the concentrations of GABA, glutamate (Glu), glutamine (Gln), and myo-inositol (mI) - all normalized to creatine (Cr) - in visual and sensorimotor cortex. GABA/Cr in the visual area was significantly decreased in mHE and HE1 patients and correlated both to the CFF (r = 0.401, P = 0.013) and blood ammonia levels (r = -0.434, P = 0.006). Visual GABA/Cr was also strongly linked to mI/Cr (r = 0.720, P < 0.001) and Gln/Cr (r = -0.699, P < 0.001). No group differences or correlations were found for GABA/Cr in the sensorimotor area. Hepatic encephalopathy is associated with a regional specific decrease of GABA levels in the visual cortex, while no changes were revealed for the sensorimotor cortex. Correlations of visual GABA/Cr with CFF, blood ammonia, and osmolytic regulators mI and Gln indicate that decreased visual GABA levels might contribute to HE symptoms, most likely as a consequence of hyperammonemia.

A simple rule for dendritic spine and axonal bouton formation can account for cortical reorganization after focal retinal lesions.

Lasting alterations in sensory input trigger massive structural and functional adaptations in cortical networks. The principles governing these experience-dependent changes are, however, poorly understood. Here, we examine whether a simple rule based on the neurons' need for homeostasis in electrical activity may serve as driving force for cortical reorganization. According to this rule, a neuron creates new spines and boutons when its level of electrical activity is below a homeostatic set-point and decreases the number of spines and boutons when its activity exceeds this set-point. In addition, neurons need a minimum level of activity to form spines and boutons. Spine and bouton formation depends solely on the neuron's own activity level, and synapses are formed by merging spines and boutons independently of activity. Using a novel computational model, we show that this simple growth rule produces neuron and network changes as observed in the visual cortex after focal retinal lesions. In the model, as in the cortex, the turnover of dendritic spines was increased strongest in the center of the lesion projection zone, while axonal boutons displayed a marked overshoot followed by pruning. Moreover, the decrease in external input was compensated for by the formation of new horizontal connections, which caused a retinotopic remapping. Homeostatic regulation may provide a unifying framework for understanding cortical reorganization, including network repair in degenerative diseases or following focal stroke.

A direct relationship between oscillatory subthalamic nucleus-cortex coupling and rest tremor in Parkinson's disease.

Electrophysiological studies suggest that rest tremor in Parkinson's 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 Parkinson's 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.

The slowed brain: cortical oscillatory activity in hepatic encephalopathy.

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.

Sustained gamma band synchronization in early visual areas reflects the level of selective attention.

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.

Lowered frequency and impaired modulation of gamma band oscillations in a bimodal attention task are associated with reduced critical flicker frequency.

Visual attention is associated with occipital gamma band activity. While gamma band power can be modulated by attention, the frequency of gamma band activity is known to decrease with age. The present study tested the hypothesis that reduced visual attention is associated with a change in induced gamma band activity. To this end, 26 patients with liver cirrhosis and 8 healthy controls were tested. A subset of patients showed symptoms of hepatic encephalopathy (HE), a frequent neuropsychiatric complication in liver disease, which comprises a gradual increase of cognitive dysfunction including attention deficits. All participants completed a behavioral task requiring shifts of attention between simultaneously presented visual and auditory stimuli. Brain activity was recorded using magnetoencephalography (MEG). The individual critical flicker frequency (CFF) was assessed as it is known to reliably reflect the severity of HE. Results showed correlations of behavioral data and HE severity, as indexed by CFF. Individual visual gamma band peak frequencies correlated positively with the CFF (r=0.41). Only participants with normal, but not with pathological CFF values showed a modulation of gamma band power with attention. The present results suggest that CFF and attentional performance are related. Moreover, a tight relation between the CFF and occipital gamma band activity both in frequency and power is shown. Thus, the present study provides evidence that a reduced CFF in HE, a disease associated with attention deficits, is closely linked to a slowing of gamma band activity and impaired modulation of gamma band power in a bimodal attention task.

Pre- and post-stimulus alpha activity shows differential modulation with spatial attention during the processing of pain.

Extensive work using magneto- and electroencephalography (M/EEG) suggests that cortical alpha activity represents a top-down controlled gating mechanism employed by processes like attention across different modalities. However, it is not yet clear to what extent this presumed gating function of alpha activity also applies to the processing of pain. In the current study, a spatial attention paradigm was employed requiring subjects to attend to painful laser stimuli on one hand while ignoring stimuli on the other hand. Simultaneously, brain activity was recorded with MEG. In order to disentangle pre- and post-stimulus effects of attention, alpha activity was analyzed during time windows in anticipation of and in response to painful laser stimulation. Painful laser stimuli led to a suppression of alpha activity over both ipsi- and contralateral primary somatosensory areas irrespective if they were attended or ignored. Spatial attention was associated with a lateralization of anticipatory pre-stimulus alpha activity. Alpha activity was lower over primary somatosensory areas when the contralateral hand was attended compared to when the ipsilateral hand was attended, in line with the notion that oscillatory alpha activity regulates the flow of incoming information by engaging and/or disengaging early sensory areas. On the contrary, post-stimulus alpha activity, for stimuli on either hand, was consistently decreased with attention over contralateral areas. Most likely, this finding reflects an increased cortical activation and enhanced alerting if a painful stimulus is attended. The present results show that spatial attention results in a modulation of both pre- and post-stimulus alpha activity associated with pain. This flexible regulation of alpha activity matches findings from other modalities. We conclude that the assumed functional role of alpha activity as a top-down controlled gating mechanism includes pain processing and most likely represents a unified mechanism used throughout the brain.

MaDoPO: Magnetic Detection of Positions and Orientations of Segmented Deep Brain Stimulation Electrodes: A Radiation-Free Method Based on Magnetoencephalography.

BACKGROUND: Current approaches to detect the positions and orientations of directional deep brain stimulation (DBS) electrodes rely on radiative imaging data. In this study, we aim to present an improved version of a radiation-free method for magnetic detection of the position and the orientation (MaDoPO) of directional electrodes based on a series of magnetoencephalography (MEG) measurements and a possible future solution for optimized results using emerging on-scalp MEG systems. METHODS: A directional DBS system was positioned into a realistic head-torso phantom and placed in the MEG scanner. A total of 24 measurements of 180 s each were performed with different predefined electrode configurations. Finite element modeling and model fitting were used to determine the position and orientation of the electrode in the phantom. Related measurements were fitted simultaneously, constraining solutions to the a priori known geometry of the electrode. Results were compared with the results of the high-quality CT imaging of the phantom. RESULTS: The accuracy in electrode localization and orientation detection depended on the number of combined measurements. The localization error was minimized to 2.02 mm by considering six measurements with different non-directional bipolar electrode configurations. Another six measurements with directional bipolar stimulations minimized the orientation error to 4°. These values are mainly limited due to the spatial resolution of the MEG. Moreover, accuracies were investigated as a function of measurement time, number of sensors, and measurement direction of the sensors in order to define an optimized MEG device for this application. CONCLUSION: Although MEG introduces inaccuracies in the detection of the position and orientation of the electrode, these can be accepted when evaluating the benefits of a radiation-free method. Inaccuracies can be further reduced by the use of on-scalp MEG sensor arrays, which may find their way into clinics in the foreseeable future.

Self-organized criticality in developing neuronal networks.

Recently evidence has accumulated that many neural networks exhibit self-organized criticality. In this state, activity is similar across temporal scales and this is beneficial with respect to information flow. If subcritical, activity can die out, if supercritical epileptiform patterns may occur. Little is known about how developing networks will reach and stabilize criticality. Here we monitor the development between 13 and 95 days in vitro (DIV) of cortical cell cultures (n = 20) and find four different phases, related to their morphological maturation: An initial low-activity state (≈19 DIV) is followed by a supercritical (≈20 DIV) and then a subcritical one (≈36 DIV) until the network finally reaches stable criticality (≈58 DIV). Using network modeling and mathematical analysis we describe the dynamics of the emergent connectivity in such developing systems. Based on physiological observations, the synaptic development in the model is determined by the drive of the neurons to adjust their connectivity for reaching on average firing rate homeostasis. We predict a specific time course for the maturation of inhibition, with strong onset and delayed pruning, and that total synaptic connectivity should be strongly linked to the relative levels of excitation and inhibition. These results demonstrate that the interplay between activity and connectivity guides developing networks into criticality suggesting that this may be a generic and stable state of many networks in vivo and in vitro.