Cholinergic modulation of motor sequence learning.

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.

A toolbox for decoding BCI commands based on event-related potentials.

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.

Parietal cortical alpha/beta suppression during prospective memory retrieval.

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.

Suppression of Motor Sequence Learning and Execution Through Anodal Cerebellar Transcranial Electrical Stimulation.

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.

Establishment of a teaching hospital-based dementia consultation service for rurally-based regional district general hospitals.

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.

Repetitive Anodal TDCS to the Frontal Cortex Increases the P300 during Working Memory Processing.

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.

Deep brain stimulation of the ventrointermediate nucleus of the thalamus to treat essential tremor improves motor sequence learning.

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.

Feasibility of a surveillance programme based on gargle samples and pool testing to prevent SARS-CoV-2 outbreaks in schools.

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.

Pool Testing as a Strategy for Prevention of SARS-CoV-2 Outbreaks in Schools: Protocol for a Feasibility Study.

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.

The role of the anterior nuclei of the thalamus in human memory processing.

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.

Impact of Stimulus Features on the Performance of a Gaze-Independent Brain-Computer Interface Based on Covert Spatial Attention Shifts.

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.

Neuronal oscillations of the pedunculopontine nucleus in progressive supranuclear palsy: Influence of levodopa and movement.

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.

Convolutional neural networks for decoding of covert attention focus and saliency maps for EEG feature visualization.

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.

Long-term outcomes of semi-implantable functional electrical stimulation for central drop foot.

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.

Interocular transfer of visual memory - Influence of visual impairment and abnormalities of the optic chiasm.

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.

Cortico-Muscular Coherence Is Reduced Acutely Post-stroke and Increases Bilaterally During Motor Recovery: A Pilot Study.

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.

Learning of novel semantic relationships via sudden comprehension is associated with a hippocampus-independent network.

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.

Modulation of Working Memory Using Transcranial Electrical Stimulation: A Direct Comparison Between TACS and TDCS.

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.

CSF macrophage migration inhibitory factor levels did not predict steroid treatment response after optic neuritis in patients with multiple sclerosis.

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.

Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype - a placebo controlled fMRI study.

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 ±â€¯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.