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Functional electrical stimulation (FES) can support functional restoration of a paretic limb post-stroke. Hebbian plasticity depends on temporally coinciding pre- and post-synaptic activity. A tight temporal relationship between motor cortical (MC) activity associated with attempted movement and FES-generated visuo-proprioceptive feedback is hypothesized to enhance motor recovery. Using a brain-computer interface (BCI) to classify MC spectral power in electroencephalographic (EEG) signals to trigger FES-delivery with detection of movement attempts improved motor outcomes in chronic stroke patients. We hypothesized that heightened neural plasticity earlier post-stroke would further enhance corticomuscular functional connectivity and motor recovery. We compared subcortical non-dominant hemisphere stroke patients in BCI-FES and Random-FES (FES temporally independent of MC movement attempt detection) groups. The primary outcome measure was the Fugl-Meyer Assessment, Upper Extremity (FMA-UE). We recorded high-density EEG and transcranial magnetic stimulation-induced motor evoked potentials before and after treatment. The BCI group showed greater: FMA-UE improvement; motor evoked potential amplitude; beta oscillatory power and long-range temporal correlation reduction over contralateral MC; and corticomuscular coherence with contralateral MC. These changes are consistent with enhanced post-stroke motor improvement when movement is synchronized with MC activity reflecting attempted movement., (© 2024. The Author(s).)

Ventrointermediate thalamic stimulation (VIM-DBS) modulates oscillatory activity in a cortical network including primary motor cortex, premotor cortex, and parietal cortex. Here we show that, beyond the beneficial effects of VIM-DBS on motor execution, this form of invasive stimulation facilitates production of sequential finger movements that follow a repeated sequence. These results highlight the role of thalamo-cortical activity in motor learning., (© 2024. The Author(s).)

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double-blind placebo-controlled crossover design, we tested 30 healthy young participants and showed that biperiden impairs the ability to learn sequential finger movements, accompanied by widespread oscillatory broadband power changes (4-25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha and beta bands over ipsilateral motor and bilateral parietal-occipital areas. The reduced early theta power during a repeated compared with random sequence, likely reflecting disengagement of top-down attention to sensory processes, was disrupted by biperiden. Alpha synchronization during repeated sequences reflects sensory gating and lower visuospatial attention requirements compared with visuomotor responses to random sequences. After biperiden, alpha synchronization was greater, potentially reflecting excessive visuospatial attention reduction, affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing repeated sequences and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Commands in brain-computer interface (BCI) applications often rely on the decoding of event-related potentials (ERP). For instance, the P300 potential is frequently used as a marker of attention to an oddball event. Error-related potentials and the N2pc signal are further examples of ERPs used for BCI control. One challenge in decoding brain activity from the electroencephalogram (EEG) is the selection of the most suitable channels and appropriate features for a particular classification approach. Here we introduce a toolbox that enables ERP-based decoding using the full set of channels, while automatically extracting informative components from relevant channels. The strength of our approach is that it handles sequences of stimuli that encode multiple items using binary classification, such as target vs. nontarget events typically used in ERP-based spellers. We demonstrate examples of application scenarios and evaluate the performance of four openly available datasets: a P300-based matrix speller, a P300-based rapid serial visual presentation (RSVP) speller, a binary BCI based on the N2pc, and a dataset capturing error potentials. We show that our approach achieves performances comparable to those in the original papers, with the advantage that only conventional preprocessing is required by the user, while channel weighting and decoding algorithms are internally performed. Thus, we provide a tool to reliably decode ERPs for BCI use with minimal programming requirements., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Reichert, Sweeney-Reed, Hinrichs and Dürschmid.)

Cerebellum (CB) and primary motor cortex (M1) have been associated with motor learning, with different putative roles. Modulation of task performance through application of transcranial direct current stimulation (TDCS) to brain structures provides causal evidence for their engagement in the task. Studies evaluating and comparing TDCS to these structures have provided conflicting results, however, likely due to varying paradigms and stimulation parameters. Here we applied TDCS to CB and M1 within the same experimental design, to enable direct comparison of their roles in motor sequence learning. We examined the effects of anodal TDCS during motor sequence learning in 60 healthy participants, randomly allocated to CB-TDCS, M1-TDCS, or Sham stimulation groups during a serial reaction time task. Key to the design was an equal number of repeated and random sequences. Reaction times (RTs) to implicitly learned and random sequences were compared between groups using ANOVAs and post hoc t-tests. A speed-accuracy trade-off was excluded by analogous analysis of accuracy scores. An interaction was observed between whether responses were to learned or random sequences and the stimulation group. Post hoc analyses revealed a preferential slowing of RTs to implicitly learned sequences in the group receiving CB-TDCS. Our findings provide evidence that CB function can be modulated through transcranial application of a weak electrical current, that the CB and M1 cortex perform separable functions in the task, and that the CB plays a specific role in motor sequence learning during implicit motor sequence learning., (© 2022. The Author(s).)

Prospective memory (PM) impairment is among the most frequent memory complaints, yet little is known about the underlying neural mechanisms. PM for a planned intention may be achieved through strategic monitoring of the environment for cues, involving ongoing attentional processes, or through spontaneous retrieval. We hypothesized that parietal spectral power modulation accompanies prospectively encoded intention retrieval, irrespective of PM retrieval approach. A cognitively engaging arithmetic-based ongoing task (OGT) was employed to encourage spontaneous retrieval, with a focal, internally generated PM cue to eliminate OGT/PM trial differentiation based on perceptual or conceptual PM cue features. Two PM repetition frequencies were used to vary the extent of strategic monitoring. We observed a transient parietal alpha/beta spectral power reduction directly preceding the response, which was distinguishable on a single trial basis, as revealed by an OGT/PM trial classification rate exceeding 70% using linear discriminant analysis. The alpha/beta idling rhythm reflects cortical inhibition. A disengagement of task-relevant neural assemblies from this rhythm, reflected in alpha/beta power reduction, is deemed to increase information content, facilitate information integration, and enable engagement of neural assemblies in task-related cortical networks. The observed power reduction is consistent with the Dual Pathways model, where PM strategies converge at the PM retrieval stage., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: The treatment of patients with dementia poses a considerable challenge to regional district general hospitals, particularly in rural areas. Here we report the establishment and initial evaluation of a dementia-specific consultation service provided by a teaching hospital-based Psychiatry Department to regional district general hospitals in surrounding smaller towns., Methods: The consultation service was provided to patients with pre-existing or newly suspected dementia, who were in acute hospital care for concurrent conditions. An evaluation of 61 consultations - 49 on-site and 12 via telemedicine - was performed to assess the needs of the participating hospitals and the specific nature of the referrals to the consultation service., Results: Suspected dementia or cognitive dysfunction was the primary reason for consultation requests (>50% of cases). Other common requests concerned suspected delirium, behavioral symptoms, and therapeutic recommendations. During the consultations, a diagnosis of dementia was reached in 52.5% of cases, with other common diagnoses including delirium and depression. Recommendations related to pharmacotherapy were given in 54.1% of consultations. Other recommendations included referral for outpatient neurological or psychiatric follow-up, further diagnostic assessment, or assessment in a memory clinic. Geriatric psychiatric inpatient treatment was recommended in only seven cases (11.5 %)., Conclusion: Our initial evaluation demonstrates the feasibility of providing a dementia-specific consultation service in rural areas. The service has the potential to reduce acute transfers to inpatient geriatric psychiatry and enables older patients with dementia or delirium to be treated locally by helping and empowering rurally-based regional hospitals to manage these problems and associated complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schott, Voetlause, Amoah, Kratzenberg, Belz, Knipper, Timäus, Beskow, Sweeney-Reed, Wiltfang and Radenbach.)

Transcranial direct current stimulation (TDCS) is a technique with which neuronal activity, and therefore potentially behavior, is modulated by applying weak electrical currents to the scalp. Application of TDCS to enhance working memory (WM) has shown promising but also contradictory results, and little emphasis has been placed on repeated stimulation protocols, in which effects are expected to be increased. We aimed to characterize potential behavioral and electrophysiological changes induced by TDCS during WM training and evaluate whether repetitive anodal TDCS has a greater modulatory impact on the processes underpinning WM than single-session stimulation. We examined the effects of single-session and repetitive anodal TDCS to the dorsolateral prefrontal cortex (DLPFC), targeting the frontal-parietal network, during a WM task in 20 healthy participants. TDCS had no significant impact on behavioral measures, including reaction time and accuracy. Analyzing the electrophysiological response, the P300 amplitude significantly increased following repetitive anodal TDCS, however, positively correlating with task performance. P300 changes were identified over the parietal cortex, which is known to engage with the frontal cortex during WM processing. These findings support the hypothesis that repetitive anodal TDCS modulates electrophysiological processes underlying WM.

The network of brain structures engaged in motor sequence learning comprises the same structures as those involved in tremor, including basal ganglia, cerebellum, thalamus, and motor cortex. Deep brain stimulation (DBS) of the ventrointermediate nucleus of the thalamus (VIM) reduces tremor, but the effects on motor sequence learning are unknown. We investigated whether VIM stimulation has an impact on motor sequence learning and hypothesized that stimulation effects depend on the laterality of electrode location. Twenty patients (age: 38-81 years; 12 female) with VIM electrodes implanted to treat essential tremor (ET) successfully performed a serial reaction time task, varying whether the stimuli followed a repeating pattern or were selected at random, during which VIM-DBS was either on or off. Analyses of variance were applied to evaluate motor sequence learning performance according to reaction times (RTs) and accuracy. An interaction was observed between whether the sequence was repeated or random and whether VIM-DBS was on or off (F[1,18] = 7.89, p = .012). Motor sequence learning, reflected by reduced RTs for repeated sequences, was greater with DBS on than off (T[19] = 2.34, p = .031). Stimulation location correlated with the degree of motor learning, with greater motor learning when stimulation targeted the lateral VIM (n = 23, ρ = 0.46; p = .027). These results demonstrate the beneficial effects of VIM-DBS on motor sequence learning in ET patients, particularly with lateral VIM electrode location, and provide evidence for a role for the VIM in motor sequence learning., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

School closures have a negative impact on physical and mental well-being, and education, of children and adolescents. A surveillance programme to detect asymptomatic SARS-CoV-2 infection could allow schools to remain open, while protecting the vulnerable. We assessed the feasibility of a programme employing gargle samples and pool testing of individually extracted RNA using rRT-qPCR in a primary and a secondary school in Germany, based on programme logistics and acceptance. Twice a week, five participants per class were selected to provide samples, using an algorithm weighted by a risk-based priority score to increase likelihood of case detection. The positive response rate was 54.8% (550 of 1003 pupils). Logistics evaluation revealed the rate-limiting steps: completing the regular pre-test questionnaire and handing in the samples. Acceptance questionnaire responses indicated strong support for research into developing a surveillance programme and a positive evaluation of gargle tests. Participation was voluntary. As not all pupils participated, individual reminders could lead to participant identification. School-wide implementation of the programme for infection monitoring purposes would enable reminders to be given to all school pupils to address these steps, without compromising participant anonymity. Such a programme would provide a feasible means to monitor asymptomatic respiratory tract infection in schools., (© 2021. The Author(s).)

Extensive neuroanatomical connectivity between the anterior thalamic nuclei (ATN) and hippocampus and neocortex renders them well-placed for a role in memory processing, and animal, lesion, and neuroimaging studies support such a notion. The deep location and small size of the ATN have precluded their real-time electrophysiological investigation during human memory processing. However, ATN electrophysiological recordings from patients receiving electrodes implanted for deep brain stimulation for pharmacoresistant focal epilepsy have enabled high temporal resolution study of ATN activity. Theta frequency synchronization of ATN and neocortical oscillations during successful memory encoding, enhanced phase alignment, and coupling between ATN local gamma frequency activity and frontal neocortical and ATN theta oscillations provide evidence of an active role for the ATN in memory encoding, potentially integrating information from widespread neocortical sources. Greater coupling of a broader gamma frequency range with theta oscillations at rest than during memory encoding provides additional support for the hypothesis that the ATN play a role in selecting local, task-relevant high frequency activity associated with particular features of a memory trace., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: School closures are a widely implemented strategy for limiting infection spread in the current COVID-19 pandemic. The negative impact of school closures on children and young people is increasingly apparent, however., Objective: We aim to evaluate the feasibility of an infection monitoring program in schools to enable targeted quarantining to replace school closures. The program is currently being implemented in two model schools in Magdeburg, Germany, within the framework of the Study of Coronavirus Outbreak Prevention in Magdeburg Schools (Studie zur Ausbruchsvermeidung von Corona an Magdeburger Schulen [STACAMA])., Methods: Five pupils per class are pseudorandomly selected twice a week and asked to provide a gargle sample over a 16-week evaluation period. RNA is extracted from each sample individually in a laboratory and pooled according to school class for real-time reverse transcription polymerase chain reaction (rRT-PCR) analysis. Immediate individual sample testing will be carried out in the case of a positive pool test. Individual RNA extraction prior to pooling and application of rRT-PCR result in high test sensitivity. Testing will be performed in strict adherence to data protection standards. All participating pupils will receive a 16-digit study code, which they will be able to use to access their test., Results: When the study commenced on December 2, 2020, 520 (52%) pupils and their families or guardians had consented to study participation. The study was suspended after four test rounds due to renewed school closures resulting from rising regional infection incidence. Testing resumed when schools reopened on March 8, 2021, at which time consent to participation was provided for 54% of pupils. We will quantitatively and qualitatively evaluate the logistics and acceptability of the program., Conclusions: The findings from this study should inform the design of infection surveillance programs in schools based on gargle samples and a PCR-based pool testing procedure, enabling the identification of aspects that may require adaptation before large-scale implementation. Our focus on each step of the logistics and on the experiences of families should enable a robust assessment of the feasibility of such an approach., International Registered Report Identifier (irrid): DERR1-10.2196/28673., (©Catherine M Sweeney-Reed, Doreen Wolff, Jakob Niggel, Michael Kabesch, Christian Apfelbacher. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.05.2021.)

Regaining communication abilities in patients who are unable to speak or move is one of the main goals in decoding brain waves for brain-computer interface (BCI) control. Many BCI approaches designed for communication rely on attention to visual stimuli, commonly applying an oddball paradigm, and require both eye movements and adequate visual acuity. These abilities may, however, be absent in patients who depend on BCI communication. We have therefore developed a response-based communication BCI, which is independent of gaze shifts but utilizes covert shifts of attention to the left or right visual field. We recorded the electroencephalogram (EEG) from 29 channels and coregistered the vertical and horizontal electrooculogram. Data-driven decoding of small attention-based differences between the hemispheres, also known as N2pc, was performed using 14 posterior channels, which are expected to reflect correlates of visual spatial attention. Eighteen healthy participants responded to 120 statements by covertly directing attention to one of two colored symbols (green and red crosses for "yes" and "no," respectively), presented in the user's left and right visual field, respectively, while maintaining central gaze fixation. On average across participants, 88.5% (std: 7.8%) of responses were correctly decoded online. In order to investigate the potential influence of stimulus features on accuracy, we presented the symbols with different visual angles, by altering symbol size and eccentricity. The offline analysis revealed that stimulus features have a minimal impact on the controllability of the BCI. Hence, we show with our novel approach that spatial attention to a colored symbol is a robust method with which to control a BCI, which has the potential to support severely paralyzed people with impaired eye movements and low visual acuity in communicating with their environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Reichert, Tellez Ceja, Sweeney-Reed, Heinze, Hinrichs and Dürschmid.)

Objective: The pedunculopontine nucleus (PPN) has been proposed as a new deep brain stimulation (DBS) target for the treatment in idiopathic Parkinson's syndrome (IPS) and progressive supranuclear palsy (PSP). In IPS, levodopa has been shown to induce alpha activity in the PPN, indicating a possible physiological role for these oscillations in movement control. Despite shared clinical features, the PPN is more severely affected in PSP than IPS. Here we investigated neuronal oscillations in the PPN in PSP and the influence of levodopa and movement., Methods: Local field potentials were recorded bilaterally from the PPN of 4 PSP patients at rest, with levodopa and during self-paced leg movements., Results: During rest, levodopa administration was associated with significantly increased alpha and reduced gamma activity in the PPN. Without levodopa, continuous movements were associated with reduced alpha and beta power. These differences between oscillatory power during movement and resting state were not observed with levodopa administration., Conclusion: In PSP the changes in neuronal oscillations in the PPN region on levodopa administration are similar to those reported in IPS. The enhancement of lower frequency oscillations in the PPN is possibly influenced by a dopaminergic activation of the striatal pathway and a reduced pallidal inhibition., Significance: Levodopa influences neuronal oscillations at low and high frequencies in the PPN region in Parkinsonian disorders., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Convolutional neural networks (CNNs) have proven successful as function approximators and have therefore been used for classification problems including electroencephalography (EEG) signal decoding for brain-computer interfaces (BCI). Artificial neural networks, however, are considered black boxes, because they usually have thousands of parameters, making interpretation of their internal processes challenging. Here we systematically evaluate the use of CNNs for EEG signal decoding and investigate a method for visualizing the CNN model decision process., Approach: We developed a CNN model to decode the covert focus of attention from EEG event-related potentials during object selection. We compared the CNN and the commonly used linear discriminant analysis (LDA) classifier performance, applied to datasets with different dimensionality, and analyzed transfer learning capacity. Moreover, we validated the impact of single model components by systematically altering the model. Furthermore, we investigated the use of saliency maps as a tool for visualizing the spatial and temporal features driving the model output., Main Results: The CNN model and the LDA classifier achieved comparable accuracy on the lower-dimensional dataset, but CNN exceeded LDA performance significantly on the higher-dimensional dataset (without hypothesis-driven preprocessing), achieving an average decoding accuracy of 90.7% (chance level  =  8.3%). Parallel convolutions, tanh or ELU activation functions, and dropout regularization proved valuable for model performance, whereas the sequential convolutions, ReLU activation function, and batch normalization components reduced accuracy or yielded no significant difference. Saliency maps revealed meaningful features, displaying the typical spatial distribution and latency of the P300 component expected during this task., Significance: Following systematic evaluation, we provide recommendations for when and how to use CNN models in EEG decoding. Moreover, we propose a new approach for investigating the neural correlates of a cognitive task by training CNN models on raw high-dimensional EEG data and utilizing saliency maps for relevant feature extraction.

The pedunculopontine nucleus (PPN) is engaged in posture and gait control, and neuronal degeneration in the PPN has been associated with Parkinsonian disorders. Clinical outcomes of deep brain stimulation of the PPN in idiopathic Parkinson's disease (IPD) and progressive supranuclear palsy (PSP) differ, and we investigated whether the PPN is differentially affected in these conditions. We had the rare opportunity to record continuous electrophysiological data intraoperatively in 30 s blocks from single microelectrode contacts implanted in the PPN in six PSP patients and three IPD patients during rest, passive movement, and active movement. Neuronal spikes were sorted according to shape using a wavelet-based clustering approach to enable comparisons between individual neuronal firing rates in the two disease states. The action potential widths showed a bimodal distribution consistent with previous findings, suggesting spikes from noncholinergic (likely glutamatergic) and cholinergic neurons. A higher PPN spiking rate of narrow action potentials was observed in the PSP than in the IPD patients when pooled across all three conditions (Wilcoxon rank sum test: p = 0.0141). No correlation was found between firing rate and disease severity or duration. The firing rates were higher during passive movement than rest and active movement in both groups, but the differences between conditions were not significant. PSP and IPD are believed to represent distinct disease processes, and our findings that the neuronal firing rates differ according to disease state support the proposal that pathological processes directly involving the PPN may be more pronounced in PSP than IPD.

Background: Central drop foot is a common problem in patients with stroke or multiple sclerosis (MS). For decades, it has been treated with orthotic devices, keeping the ankle in a fixed position. It has been shown recently that semi-implantable functional electrical stimulation (siFES) of the peroneal nerve can lead to a greater gait velocity increase than orthotic devices immediately after being switched on. Little is known, however, about long-term outcomes over 12 months, and the relationship between quality of life (QoL) and gait speed using siFES has never been reported applying a validated tool. We provide here a report of short (3 months) and long-term (12 months) outcomes for gait speed and QoL., Methods: Forty-five consecutive patients (91% chronic stroke, 9% MS) with central drop foot received siFES (Actigait®). A 10 m walking test was carried out on day 1 of stimulation (T1), in stimulation ON and OFF conditions, and repeated after 3 (T2) and 12 (T3) months. A 36-item Short Form questionnaire was applied at all three time points., Results: We found a main effect of stimulation on both maximum (p < 0.001) and comfortable gait velocity (p < 0.001) and a main effect of time (p = 0.015) only on maximum gait velocity. There were no significant interactions. Mean maximum gait velocity across the three assessment time points was 0.13 m/s greater with stimulation ON than OFF, and mean comfortable gait velocity was 0.083 m/s faster with stimulation ON than OFF. The increase in maximum gait velocity over time was 0.096 m/s, with post hoc testing revealing a significant increase from T1 to T2 (p = 0.012), which was maintained but not significantly further increased at T3. QoL scores showed a main effect of time (p < 0.001), with post hoc testing revealing an increase from T1 to T2 (p < 0.001), which was maintained at T3 (p < 0.001). Finally, overall absolute QoL scores correlated with the absolute maximum and comfortable gait speeds at T2 and T3, and the increase in overall QoL scores correlated with the increase in comfortable gait velocity from T1 to T3. Pain was reduced at T2 (p < 0.001) and was independent of gait speed but correlated with overall QoL (p < 0.001)., Conclusions: Peroneal siFES increased maximal and comfortable gait velocity and QoL, with the greatest increase in both over the first three months, which was maintained at one year, suggesting that 3 months is an adequate follow-up time. Pain after 3 months correlated with QoL and was independent of gait velocity, suggesting pain as an independent outcome measure in siFES for drop foot.

Due to an increased crossing of the optic nerve fibers at the optic chiasm in albinism, the visual cortex receives largely monocular input from the contralateral eye. Here we investigated whether this obstruction of binocular integration at the cortical input stage also impacts on interocular information exchange at the high processing level of visual memory. Interocular transfer (IOT) of visual memory retrieval was tested psychophysically after monocular encoding in 8 albinotic participants and 24 healthy controls. The retrieval performance (hit rate, reaction time, d') was determined when using the same or different eye at encoding. To assess the effect of reduced visual acuity (VA) on recognition, we simulated interocular acuity differences (IOA) in two healthy control groups (each n = 8), i.e., with large (VA: 0.89 vs. 0.12) and small simulated interocular difference (VA: 0.25 vs. 0.12), with the latter matched to that observed in the albinotic participants (VA: 0.20 vs. 0.15). A significant decrease in retrieval performance was observed in controls with simulated strongly reduced VA in one eye (p < 0.0001). For the other conditions and groups, including the albinotic participants, no dependence on VA and no significant difference between using the same or different eye was observed. This indicates interocular transfer and hence interocular information exchange in human albinism. These findings thus provide insights into the scope of plasticity of binocular information processing and inter-hemispherical information flow., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Sudden comprehension-or insight-during problem-solving can enhance learning, but the underlying neural processes are largely unknown. We investigated neural correlates of learning from sudden comprehension using functional magnetic resonance imaging and a verbal problem-solving task. Solutions and "solutions" to solvable and unsolvable verbal problems, respectively, were presented to induce sudden comprehension or continued incomprehension. We found activations of the hippocampus, medial prefrontal cortex (mPFC), amygdala, and striatum during sudden comprehension. Notably, however, mPFC and temporo-parietal neocortical structures rather than the hippocampus were associated with later learning of suddenly comprehended solutions. Moreover, difficult compared to easy sudden comprehension elicited midbrain activations and was associated with successful learning, pointing to learning via intrinsic reward. Sudden comprehension of novel semantic associations may constitute a special case of long-term memory formation primarily mediated by the mPFC, expanding our knowledge of its role in prior-knowledge-dependent memory., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Motor recovery following stroke is believed to necessitate alteration in functional connectivity between cortex and muscle. Cortico-muscular coherence has been proposed as a potential biomarker for post-stroke motor deficits, enabling a quantification of recovery, as well as potentially indicating the regions of cortex involved in recovery of function. We recorded simultaneous EEG and EMG during wrist extension from healthy participants and patients following ischaemic stroke, evaluating function at three time points post-stroke. EEG-EMG coherence increased over time, as wrist mobility recovered clinically, and by the final evaluation, coherence was higher in the patient group than in the healthy controls. Moreover, the cortical distribution differed between the groups, with coherence involving larger and more bilaterally scattered areas of cortex in the patients than in the healthy participants. The findings suggest that EEG-EMG coherence has the potential to serve as a biomarker for motor recovery and to provide information about the cortical regions that should be targeted in rehabilitation therapies based on real-time EEG.

Background: Cerebrospinal fluid (CSF) markers of disease in patients with radiologically isolated syndrome (RIS) are the subject of intense investigation, because they have the potential to enhance our understanding of the natural disease course and provide insights into similarities and differences between RIS and other multiple sclerosis (MS) disease identities. Methods: Here we compared neurofilament light chain (NFL) and progranulin (PGRN) levels in the CSF in RIS patients with levels in patients with different subtypes of MS and healthy controls (HC) using Kruskal-Wallis one-way analysis of variance. Results: Median CSF NFL concentrations in RIS patients did not differ to those in HC and clinically isolated syndrome (CIS) patients, but were significantly lower than in relapsing remitting (RRMS) and primary progressive (PPMS) MS patients. In contrast, RIS patients exhibited higher median CSF PGRN levels than HC and showed no significant differences compared with CIS, RRMS, and PPMS cases. Conclusion: We postulate that elevated PGRN values in the CSF of RIS patients might indicate inflammatory and repair activity prior to axonal disintegration.

Glucocorticoid (GC) refractory relapses in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS), who are in potential need of treatment escalation, are a key challenge in routine clinical practice. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be an endogenous counter-regulator of GC, and potentiates autoimmune-mediated neuroinflammation. In order to evaluate whether MIF levels are elevated in the cerebrospinal fluid (CSF) of MS patients (CSF-MIF), and whether they are higher still during a GC refractory relapse, we compared CSF-MIF concentrations of CIS/MS patients with acute optic neuritis as their first inflammatory episode (ON, n = 20), CIS/MS patients with a stable disease progression/without relapse (CIS/MS w/o, n = 18), and healthy controls (HC, n = 20) using ANOVA. Mean CSF-MIF concentrations in CIS/MS w/o patients were significantly higher than in ON patients and HCs, whereas ON patients and HCs did not differ. A subgroup analysis of the ON group revealed 10 patients to be responsive to GC-treatment (GC-ON) and 10 patients refractory under GC-treatment (rGC-ON). However, mean CSF-MIF concentrations did not differ between GC-ON and rGC-ON cases. We therefore conclude that MIF is not suitable for distinguishing GC responders from non-responders in a group of patients with acute optic neuritis, but it rather mirrors the ongoing inflammation in long-term MS disease progression., Competing Interests: MP received speaker honoraria from Roche, Genzyme and Novartis as well as travel/accommodation/meeting expenses from Novartis, Biogen Idec, Genzyme and MERCK Serono. CS has no competing interests to declare. SGM receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. DR has no competing interests to declare. JN has no competing interests to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Transcranial electrical stimulation (TES) has been considered a promising tool for improving working memory (WM) performance. Recent studies have demonstrated modulation of networks underpinning WM processing through application of transcranial alternating current (TACS) as well as direct current (TDCS) stimulation. Differences between study designs have limited direct comparison of the efficacy of these approaches, however. Here we directly compared the effects of theta TACS (6 Hz) and anodal TDCS on WM, applying TACS to the frontal-parietal loop and TDCS to the dorsolateral prefrontal cortex (DLPFC). WM was evaluated using a visual 2-back WM task. A within-subject, crossover design was applied ( N = 30) in three separate sessions. TACS, TDCS, and sham stimulation were administered in a counterbalanced order, and the WM task was performed before, during, and after stimulation. Neither reaction times for hits (RT-hit) nor accuracy differed according to stimulation type with this study design. A marked practice effect was noted, however, with improvement in RT-hit irrespective of stimulation type, which peaked at the end of the second session. Pre-stimulation RT-hits in session three returned to the level observed pre-stimulation in session two, irrespective of stimulation type. The participants who received sham stimulation in session one and had therefore improved their performance due to practice alone, had thus reached a plateau by session two, enabling us to pool RT-hits from sessions two and three for these participants. The pooling allowed implementation of a within-subject crossover study design, with a direct comparison of the effects of TACS and TDCS in a subgroup of participants ( N = 10), each of whom received both stimulation types, in a counterbalanced order, with pre-stimulation performance the same for both sessions. TACS resulted in a greater improvement in RT-hits than TDCS ( F (2,18) = 4.31 p = 0.03). Our findings suggest that future work optimizing the application of TACS has the potential to facilitate WM performance.

Objective: Diminished blood levels of zinc have been reported to be associated with T-cell-mediated autoimmunity, which has been implicated in multiple sclerosis (MS). We aimed to compare the distribution of serum zinc status in MS patients with that in healthy controls (HCs) and to investigate a potential correlation with clinical state, through analysis of serum zinc concentration in MS patients suffering from different disease subtypes., Methods: Serum zinc concentrations of 133 patients with relapsing (RMS) and 18 patients with the progressive form of MS (PMS), according to the McDonald criteria of 2010, were measured. Clinical status was quantified using the Expanded Disability Status Scale (EDSS). Zinc concentrations were also determined in the sera of 50 HCs, matched for age and sex at a group level., Results: MS patients showed significantly lower zinc concentrations (mean (SD)) than HCs (12.5 (2.1) µmol/L vs. 14.6 (2.3) µmol/L, p < 0.001). In contrast, we did not find any difference between RMS (12.4 (2.0) µmol/L) and PMS (13.0 (3.0) µmol/L) cases ( p = 0.8). Patients receiving disease-modifying treatment showed lower mean (SD) serum zinc levels than untreated cases (12.3 (1.9) µmol/L vs. 13.5 (3.2) µmol/L, p < 0.03). Zinc levels were not related to disease duration, EDSS, annual relapse rate, or the median number of relapses., Conclusions: The data suggest that a diagnosis of MS is related to lower serum zinc concentrations than in HCs, and concentrations were lower still under disease-modifying therapy. However, zinc levels did not predict disease subtypes or disability status.

Background: Affective stimulation entails changes in brain network patterns at rest, but it is unknown whether exogenous emotional stimulation has a prolonged effect on the temporal dynamics of endogenous cortical arousal. We therefore investigated differences in cortical arousal in the listener following stimulation with different attachment-related narratives., Methods: Resting-state EEG was recorded from sixteen healthy subjects for ten minutes each with eyes closed: first at baseline and then after passively listening to three affective narratives from strangers about their early childhood experiences (prototypical for insecure-dismissing, insecure-preoccupied, and secure attachment). Using the VIGALL 2.1 algorithm, low or high vigilance stages in consecutive EEG segments were classified, and their dynamic profile was analyzed. Questionnaires assessed the listeners' emotional response to the content of the narrative., Results: As a general effect of preceding affective stimulation, vigilance following the stimulation was significantly elevated compared to baseline rest, and carryover effects in dynamic vigilance profiles were observed. A difference between narrative conditions was revealed for the insecure-dismissing condition, in which the decrease in duration of high vigilance stages was fastest compared to the other two conditions. The behavioral data supported the observation that especially the insecure narratives induced a tendency in the listener to affectively disengage from the narrative content., Discussion: This study revealed carryover effects in endogenous cortical arousal evoked by preceding affective stimulation and provides evidence for attachment-specific dynamic alterations of brain states and individual differences in emotional reactivity., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Ketamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI., Methods: Fifty-nine healthy participants (mean age 25.57 ± 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840)., Results: A significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers., Conclusions: We demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects., Methods: Blood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 [A-3081T]) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX)., Results: Systolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 [T] carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than [A] homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005)., Conclusions: Subanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

A salience network (SN) anchored in the anterior insula (AI) and dorsal anterior cingulate cortex (dACC) plays a key role in switching between brain networks during salience detection and attention regulation. Previous fMRI studies have associated expectancy behaviors and SN activation with novelty seeking (NS) and reward dependence (RD) personality traits. To address the question of how functional connectivity (FC) in the SN is modulated by internal (expectancy-related) salience assignment and different personality traits, 68 healthy participants performed a salience expectancy task using functional magnetic resonance imaging, and psychophysiological interaction analysis (PPI) was conducted to determine salience-related connectivity changes during these anticipation periods. Correlation was then evaluated between PPI and personality traits, assessed using the temperament and character inventory of 32 male participants. During high salience expectancy, SN-seed regions showed reduced FC to visual areas and parts of the default mode network, but increased FC to the central executive network. With increasing NS, participants showed significantly increasing disconnection between right AI and middle cingulate cortex when expecting high-salience pictures as compared to low-salience pictures, while increased RD also predicted decreased right dACC and caudate FC for high salience expectancy. Our findings suggest a direct link between personality traits and internal salience processing mediated by differential network integration of the SN. SN activity and coordination may therefore be moderated by novelty seeking and reward dependency personality traits, which are associated with risk of addiction. Hum Brain Mapp 38:4064-4077, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Cross-frequency coupling (CFC) between slow and fast brain rhythms, in the form of phase-amplitude coupling (PAC), is proposed to enable the coordination of neural oscillatory activity required for cognitive processing. PAC has been identified in the neocortex and mesial temporal regions, varying according to the cognitive task being performed and also at rest. PAC has also been observed in the anterior thalamic nucleus (ATN) during memory processing. The thalamus is active during the resting state and has been proposed to be involved in switching between task-free cognitive states such as rest, in which attention is internally-focused, and externally-focused cognitive states, in which an individual engages with environmental stimuli. It is unknown whether PAC is an ongoing phenomenon during the resting state in the ATN, which is modulated during different cognitive states, or whether it only arises during the performance of specific tasks. We analyzed electrophysiological recordings of ATN activity during rest from seven patients who received thalamic electrodes implanted for treatment of pharmacoresistant focal epilepsy. PAC was identified between theta (4-6 Hz) phase and high frequency band (80-150 Hz) amplitude during rest in all seven patients, which diminished during engagement in tasks involving an external focus of attention. The findings are consistent with the proposal that theta-gamma coupling in the ATN is an ongoing phenomenon, which is modulated by task performance.

The measurement of autoregulatory delay by near-infrared spectroscopy (NIRS) has been proposed as an alternative technique to assess cerebral autoregulation, which is routinely assessed via transcranial Doppler sonography (TCD) in most centers. Comparitive studies of NIRS and TCD, however, are largely missing. We investigated whether cerebrovascular reserve (CVR), as assessed via TCD, correlates with the delay of the autoregulatory response to changes in arterial blood pressure (ABP) as assessed by NIRS, i.e., if impaired upstream vasomotor reactivity is reflected by downstream cortical autoregulation. Twenty patients with unilateral high-grade steno-occlusion of the middle cerebral artery (MCA) underwent bilateral multichannel NIRS of the cortical MCA distributions over a period of 6 min while breathing at a constant rate of 6 cycles/min to induce stable oscillations in ABP. The phase shift φ between ABP and cortical blood oxygenation was calculated as a measure of autoregulatory latency. In a subgroup of 13 patients, CO 2 reactivity of the MCAs was determined by TCD to assess CVR in terms of normalized autoregulatory response (NAR). Mean phase shift between ABP and blood oxygenation was significantly increased over the hemisphere ipsilateral to the steno-occlusion (n = 20, p = 0.042). The interhemispheric difference Δφ in phase shift was significantly larger in patients with markedly diminished or exhausted CVR (NAR < 10) than in patients with normal NAR values (NAR ≥ 10) (p = 0.007). Within the MCA core distribution territory, a strong correlation existed between Δφ and CO 2 reactivity of the affected MCA (n = 13, r = -0.78, p = 0.011). NIRS may provide an alternative or supplementary approach to evaluate cerebral autoregulation in risk assessment of ischemic events in steno-occlusive disease of cerebral arteries, especially in patients with insufficient bone windows for TCD.

The relationships between interictal epileptiform discharges (IEDs) in the anterior (ANT) and dorsomedial nuclei (DMNT) of the thalamus and electro-clinical parameters in pharmacoresistant focal epilepsy patients receiving intrathalamic electrodes for deep brain stimulation (DBS) were investigated. Thalamus-localized IEDs (LIEDs) and surface EEG (sEEG)-IEDs were evaluated in eight patients who underwent ANT-DBS. Occurrence and frequency of ANT- and DMNT-LIEDs and pre-operative sEEG-IEDs were examined with respect to seizure onset location and seizure outcome following ANT-DBS. LIEDs were identified in all eight patients, in the ANT, DMNT, or both. ANT-LIEDs were observed in all patients with an unequivocal temporal seizure onset zone. The ANT-LIED frequency correlated with pre-surgical sEEG-IED frequency (ρ = 0.76, p = 0.033) and predicted ANT-DBS responsiveness (T = -2.6; p = 0.0428). Of the five patients with bilateral sEEG-IEDs, all had ANT-LIEDs, but only one patient had DMNT-LIEDs. All patients with no or unilateral sEEG-IEDs had DMNT-LIEDs. Observation of LIEDS in the ANT and DMNT supports the hypothesis that these nuclei are involved in propagation of focal epileptic activity. Their correspondence with differing electro-clinical features suggests that these nuclei are functionally distinguishable nodes within the epileptic networks of individual patients.

Purpose: Aim of the present study was to investigate potential impairment of non-motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non-motor associated cortical areas correlates with clinical parameters and disease-specific degeneration of the corpus callosum (CC) in ALS., Material and Methods: Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains., Results: ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs ( p  = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (ρ = - 0.85, p  = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI ( p  < 0.05)., Conclusions: The present study further supports involvement of non-motor areas in ALS. Our results render homotopic rs-FC as assessed by NIRS a potential clinical marker for disease progression rate in ALS patients without executive dysfunction and a potential anatomical marker for ALS-specific degeneration of the CC and CSTs.

Pre-stimulus theta (4-8Hz) power in the hippocampus and neocortex predicts whether a memory for a subsequent event will be formed. Anatomical studies reveal thalamus-hippocampal connectivity, and lesion, neuroimaging, and electrophysiological studies show that memory processing involves the dorsomedial (DMTN) and anterior thalamic nuclei (ATN). The small size and deep location of these nuclei have limited real-time study of their activity, however, and it is unknown whether pre-stimulus theta power predictive of successful memory formation is also found in these subcortical structures. We recorded human electrophysiological data from the DMTN and ATN of 7 patients receiving deep brain stimulation for refractory epilepsy. We found that greater pre-stimulus theta power in the right DMTN was associated with successful memory encoding, predicting both behavioral outcome and post-stimulus correlates of successful memory formation. In particular, significant correlations were observed between right DMTN theta power and both frontal theta and right ATN gamma (32-50Hz) phase alignment, and frontal-ATN theta-gamma cross-frequency coupling. We draw the following primary conclusions. Our results provide direct electrophysiological evidence in humans of a role for the DMTN as well as the ATN in memory formation. Furthermore, prediction of subsequent memory performance by pre-stimulus thalamic oscillations provides evidence that post-stimulus differences in thalamic activity that index successful and unsuccessful encoding reflect brain processes specifically underpinning memory formation. Finally, the findings broaden the understanding of brain states that facilitate memory encoding to include subcortical as well as cortical structures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The data presented here comprise clinical, neuropsychological, and intrathalamic electrophysiological data from 7 patients with pharmacoresistant focal epilepsy and are related to the article "Pre-stimulus thalamic theta power predicts human memory formation" C.M. Sweeney-Reed, T. Zaehle, J. Voges, F.C. Schmitt, L. Buentjen, K. Kopitzki, et al. (2016) [1]. The patients participated in a memory paradigm after receiving electrodes implanted in the DMTN due to the surgical approach taken in electrode insertion for deep brain stimulation of the anterior thalamic nucleus. Epilepsy duration and pre-operative neuropsychological tests provide an indication of the profile of patients receiving intrathalamic electrode implantation and the memory capabilities in such a patient group. The electrophysiological data were recorded from the right DMTN preceding stimulus presentation during intentional memory encoding. The patients viewed a series of photographic scenes, which they judged as indoors or outdoors. The 900 ms epochs prior to stimulus presentation were labeled as preceding successful or unsuccessful subsequent memory formation according to a subsequent memory test for the items. The difference between theta power preceding successful versus unsuccessful subsequent memory formation is shown against time for each patient individually.

Background: Gait dysfunction due to lower limb central paralysis, frequently involving drop foot, is a common cause of disability in multiple sclerosis and has been treated with transcutaneous functional electrical stimulation (FES). We provide here the first report of 4-channel semi-implantable FES of the peroneal nerve which has been successfully used for rehabilitation in patients following stroke., Methods: FES was implemented via a 4-channel semi-implantable closed-loop system (ActiGait(®), ©Ottobock), generating dorsiflexion in drop foot. Walking distance, gait symmetry (temporospatial gait analyses, Vicon Motion Systems(®)), gait velocity (10 m walking test) and quality of life (SF-36 questionnaire) were measured to evaluate the therapeutic benefit of this system in two patients with progressive MS., Results: Walking distance increased from 517 to 1884 m in Patient 1 and from 52 to 506 m in Patient 2. Gait velocity did not change significantly in Patient 1 and increased from 0.6 to 0.8 m/s in Patient 2. Maximum deviations of center of mass from the midline to each side changed significantly after 3 months of stimulation compared to baseline, decreasing from 15 to 12 mm in Patient 1 and from 47 to 37 mm in Patient 2. Both patients experienced reduced pain and fatigue and benefits to quality of life. Adverse events did not occur during the observation period., Conclusion: We conclude that implantable 4-channel FES systems are not only feasible but present a promising new alternative for treating central drop foot in MS patients.

Introduction: To understand the interplay between affective social information processing and its influence on mental states we investigated changes in functional connectivity (FC) patterns after audio exposure to emotional biographic narratives., Methods: While lying in the 7T MR scanner, 23 male participants listened to narratives of early childhood experiences of three persons, each having either a secure, dismissing, or preoccupied attachment representation. Directly after having listened to each of the prototypical narratives, participants underwent a 10-minute resting-state fMRI scan. To study changes in FC patterns between experimental conditions, three post-task conditions were compared to a baseline condition. Specific local alterations, as well as differences in connectivity patterns between distributed brain regions, were quantified using Network-based statistics (NBS) and graph metrics., Results: Using NBS, a nine-region subnetwork showing reduced FC after having listened to the dismissing narrative was identified. Of this subnetwork, only the left Supplementary Motor Area (SMA) exhibited a decrease in the nodal graph metrics degree and strength exclusively after listening to the dismissing narrative. No other region showed post-task changes in nodal metrics. A post hoc analysis of dynamic characteristics of FC of the left SMA showed a significant decrease in the dismissing condition when compared with the other conditions in the first three minutes of the scan, but faded away in the two subsequent intervals the differences., Conclusions: Nodal metrics and NBS converge on reduced connectivity measures exclusively in left SMA in the dismissing condition, which may specifically reflect ongoing network changes underlying prolonged emotional reactivity to attachment-related processing.

Previously we reported electrophysiological evidence for a role for the anterior thalamic nucleus (ATN) in human memory formation (Sweeney-Reed et al., 2014). Theta-gamma cross-frequency coupling (CFC) predicted successful memory formation, with the involvement of gamma oscillations suggesting memory-relevant local processing in the ATN. The importance of the theta frequency range in memory processing is well-established, and phase alignment of oscillations is considered to be necessary for synaptic plasticity. We hypothesized that theta phase alignment in the ATN would be necessary for memory encoding. Further analysis of the electrophysiological data reveal that phase alignment in the theta rhythm was greater during successful compared with unsuccessful encoding, and that this alignment was correlated with the CFC. These findings support an active processing role for the ATN during memory formation.

Background: Analysis of cerebrospinal fluid (CSF) has improved over the last few years; thus specific markers for different diseases have emerged, e.g., amyloid-β (Aβ) for Alzheimer's disease (AD) and progranulin for frontotemporal dementia (FTD)., Objective: Evaluation of correlation between biomarkers in CSF and cognitive performance in populations with AD and FTD., Methods: 27 patients with AD and 16 with FTD were included. CSF tau, P-tau(181P), Aβ₄₂, and progranulin (PGRN) were measured and a standardized neuropsychological test battery applied. Olfactory testing was additionally included where available., Results: For all patients across both groups, an association between PGRN and categoric (p = 0.016) and letter fluency (p = 0.029), naming (p = 0.003), and overall cognition (Mini-Mental State Examination: p = 0.04) was observed. Aβ42 was strongly associated with memory function (learning: p = 0.001; recall: p = 0.002). A correlation between Aβ₄₂ and memory performance was moreover found for each group separately, while PGRN also showed a correlation with recognition memory (p = 0.04) in AD. Furthermore, an association between reduced PGRN and olfactory dysfunction was revealed (p = 0.01)., Conclusions: CSF-levels of PGRN and Aβ₄₂ levels express deficits in cognition differentially, with PGRN being predominantly associated with frontal and Aβ₄₂ with temporal dysfunction. This mirrors the cerebral occurrence of these proteins. These associations appear to be consistent across both disease groups. The relationship between PGRN and olfaction further underpins the association between PRGN and frontal dysfunction.

The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding.

Cerebral palsy (CP) includes a broad range of disorders, which can result in impairment of posture and movement control. Brain-computer interfaces (BCIs) have been proposed as assistive devices for individuals with CP. Better understanding of the neural processing underlying motor control in affected individuals could lead to more targeted BCI rehabilitation and treatment options. We have explored well-known neural correlates of movement, including event-related desynchronization (ERD), phase synchrony, and a recently-introduced measure of phase dynamics, in participants with CP and healthy control participants. Although present, significantly less ERD and phase locking were found in the group with CP. Additionally, inter-group differences in phase dynamics were also significant. Taken together these findings suggest that users with CP exhibit lower levels of motor cortex activation during motor imagery, as reflected in lower levels of ongoing mu suppression and less functional connectivity. These differences indicate that development of BCIs for individuals with CP may pose additional challenges beyond those faced in providing BCIs to healthy individuals.

A number of tests exist to check for statistical significance of phase synchronisation within the Electroencephalogram (EEG); however, the majority suffer from a lack of generality and applicability. They may also fail to account for temporal dynamics in the phase synchronisation, regarding synchronisation as a constant state instead of a dynamical process. Therefore, a novel test is developed for identifying the statistical significance of phase synchronisation based upon a combination of work characterising temporal dynamics of multivariate time-series and Markov modelling. We show how this method is better able to assess the significance of phase synchronisation than a range of commonly used significance tests. We also show how the method may be applied to identify and classify significantly different phase synchronisation dynamics in both univariate and multivariate datasets.

The goal of this research was to investigate the changes in neural processing in mild cognitive impairment. We measured phase synchrony, amplitudes, and event-related potentials in veridical and false memory to determine whether these differed in participants with mild cognitive impairment compared with typical, age-matched controls. Empirical mode decomposition phase locking analysis was used to assess synchrony, which is the first time this analysis technique has been applied in a complex cognitive task such as memory processing. The technique allowed assessment of changes in frontal and parietal cortex connectivity over time during a memory task, without a priori selection of frequency ranges, which has been shown previously to influence synchrony detection. Phase synchrony differed significantly in its timing and degree between participant groups in the theta and alpha frequency ranges. Timing differences suggested greater dependence on gist memory in the presence of mild cognitive impairment. The group with mild cognitive impairment had significantly more frontal theta phase locking than the controls in the absence of a significant behavioural difference in the task, providing new evidence for compensatory processing in the former group. Both groups showed greater frontal phase locking during false than true memory, suggesting increased searching when no actual memory trace was found. Significant inter-group differences in frontal alpha phase locking provided support for a role for lower and upper alpha oscillations in memory processing. Finally, fronto-parietal interaction was significantly reduced in the group with mild cognitive impairment, supporting the notion that mild cognitive impairment could represent an early stage in Alzheimer's disease, which has been described as a 'disconnection syndrome'.

Transient episodes of synchronisation of neuronal activity in particular frequency ranges are thought to underlie cognition. Empirical mode decomposition phase locking (EMDPL) analysis is a method for determining the frequency and timing of phase synchrony that is adaptive to intrinsic oscillations within data, alleviating the need for arbitrary bandpass filter cut-off selection. It is extended here to address the choice of reference electrode and removal of spurious synchrony resulting from volume conduction. Spline Laplacian transformation and independent component analysis (ICA) are performed as pre-processing steps, and preservation of phase synchrony between synthetic signals, combined using a simple forward model, is demonstrated. The method is contrasted with use of bandpass filtering following the same pre-processing steps, and filter cut-offs are shown to influence synchrony detection markedly. Furthermore, an approach to the assessment of multiple EEG trials using the method is introduced, and the assessment of statistical significance of phase locking episodes is extended to render it adaptive to local phase synchrony levels. EMDPL is validated in the analysis of real EEG data, during finger tapping. The time course of event-related (de)synchronisation (ERD/ERS) is shown to differ from that of longer range phase locking episodes, implying different roles for these different types of synchronisation. It is suggested that the increase in phase locking which occurs just prior to movement, coinciding with a reduction in power (or ERD) may result from selection of the neural assembly relevant to the particular movement.

Transient neural assemblies mediated by synchrony in particular frequency ranges are thought to underlie cognition. We propose a new approach to their detection, using empirical mode decomposition (EMD), a data-driven approach removing the need for arbitrary bandpass filter cut-offs. Phase locking is sought between modes. We explore the features of EMD, including making a quantitative assessment of its ability to preserve phase content of signals, and proceed to develop a statistical framework with which to assess synchrony episodes. Furthermore, we propose a new approach to ensure signal decomposition using EMD. We adapt the Hilbert spectrum to a time-frequency representation of phase locking and are able to locate synchrony successfully in time and frequency between synthetic signals reminiscent of EEG. We compare our approach, which we call EMD phase locking analysis (EMDPL) with existing methods and show it to offer improved time-frequency localisation of synchrony.

The identification and visualization of clusters formed by motor unit action potentials (MUAPs) is an essential step in investigations seeking to explain the control of the neuromuscular system. This work introduces the generative topographic mapping (GTM), a novel machine learning tool, for clustering of MUAPs, and also it extends the GTM technique to provide a way of visualizing MUAPs. The performance of GTM was compared to that of three other clustering methods: the self-organizing map (SOM), a Gaussian mixture model (GMM), and the neural-gas network (NGN). The results, based on the study of experimental MUAPs, showed that the rate of success of both GTM and SOM outperformed that of GMM and NGN, and also that GTM may in practice be used as a principled alternative to the SOM in the study of MUAPs. A visualization tool, which we called GTM grid, was devised for visualization of MUAPs lying in a high-dimensional space. The visualization provided by the GTM grid was compared to that obtained from principal component analysis (PCA).