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Brain responses related to auditory processing show large changes throughout infancy and childhood with some evidence that the two hemispheres might mature at different rates. Differing rates of hemispheric maturation could be linked to the proposed functional specialization of the hemispheres in which the left auditory cortex engages in analysis of precise timing information whereas the right auditory cortex focuses on analysis of sound frequency. Here the auditory change detection process for rapidly presented tone-pairs was examined in a longitudinal sample of infants at the age of 6 and 12 months using EEG. The ERP response related to change detection of a frequency contrast, its estimated source strength in the auditory areas, as well as time-frequency indices showed developmental effects. ERP amplitudes, source strength, spectral power and inter-trial phase locking decreased across age. A differential lateralization pattern emerged between 6 and 12 months as shown by inter-trial phase locking at 2–3 Hz; specifically, a larger developmental change was observed in the right as compared to the left hemisphere. Predictive relationships for the change in source strength from 6 months to 12 months were found. Six-month predictors were source strength and phase locking values at low frequencies. The results show that the infant change detection response in rapidly presented tone pairs is mainly determined by low frequency power and phase-locking with a larger phase-locking response at 6 months predicting greater change at 12 months. The ability of the auditory system to respond systematically across stimuli is suggested as a marker of maturational change that leads to more automatic and fine-tuned cortical responses.

Despite the high prevalence of mild traumatic brain injury (mTBI), current diagnostic tools to objectively assess cognitive complaints after mTBI continue to be inadequate. Our aim was to identify neuronal correlates for cognitive difficulties in mTBI patients by evaluating the possible alterations in oscillatory brain activity during a behavioral task known to be sensitive to cognitive impairment after mTBI. We compared oscillatory brain activity during rest and cognitive tasks (Paced Auditory Serial Addition Test [PASAT] and a vigilance test [VT]) with magnetoencephalography between 25 mTBI patients and 20 healthy controls. Whereas VT induced no significant differences compared with resting state in either group, patients exhibited stronger attenuation of 8-to 14-Hz oscillatory activity during PASAT than healthy controls in the left parietotemporal cortex (p ≤ 0.05). Further, significant task-related modulation in the left superior frontal gyrus and right prefrontal cortex was detected only in patients. The∼10-Hz (alpha) peak frequency declined in frontal, temporal, and parietal regions during PASAT compared with rest (p < 0.016) in patients, whereas in controls it remained the same or showed a tendency to increase. In patients, the ∼10-Hz peak amplitude was negatively correlated with behavioral performance in the Trail Making Test. The observed alterations in the cortical oscillatory activity during cognitive load may provide measurable neurophysiological correlates of cognitive difficulties in mTBI patients, even at the individual level.

Hops are a major component of beer that is added during brewing. In addition to its wide range of bioactivity, it exhibits neuroactive properties as a sedative and sleeping aid. The compounds responsible for this activity are yet to be revealed and understood in terms of their pharmacological properties. Here we evaluated the potential of several hops flavonoids in modulating the GABAergic activity and assessed their selectivity to GABAA receptors subtypes. GABA-potentiating effects were measured using [3H]ethynylbicycloorthobenzoate (EBOB) radioligand binding assay in native and recombinant α1β3γ2, α2β3γ2 and α6β3δ receptors expressed in HEK293 cells. Flumazenil sensitivity of GABA-potentiating effects and [3H]Ro 15-4513 binding assay were used to examine the flavonoids binding to benzodiazepine site. The prenylflavonoids xanthohumol (XN), isoxanthohumol (IXN) and 8-prenylnaringenin (8PN) potentiated GABA-induced displacement of [3H]EBOB binding in a concentration-dependent manner. The IC50 for this potentiation in native GABAA receptors were 29.7 µM, 11.6 µM, 7.3 µM, respectively. In recombinant receptors, the sensitivity to prenylflavonoid potentiation of GABA-induced displacement of [3H]EBOB binding followed the order α6β3δ > α2β3γ2 > α1β3γ2 with the strongest inhibition observed by 8PN in α6β3δ (IC50 = 3.6 μM). Flumazenil had no significant effect on the prenylflavonoid-induced displacement of [3H]EBOB binding and [3H]Ro 15-4513 displacement from native GABAA receptors was only detected at high micromolar concentrations (100 µM). We identified potent prenylflavonoids in hops that positively modulate GABA-induced responses in native and αβγ/δ recombinant GABAA receptors at low micromolar concentrations. These GABAergic modulatory effects were not mediated via the high-affinity benzodiazepine binding site.

BACKGROUND AND AIMS Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS. METHODS Forty-five BMS patients (43 women), mean age 62.5 years, and 32 healthy controls (30 women), mean age 64.8 years, participated. Patients estimated pain intensity, interference, suffering and sleep with Numeric Rating Scale. Blink reflex tests of the supraorbital (SON), mental (MN) and lingual (LN) nerves, and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C>T polymorphism was determined in 31 patients, and its effects on neurophysiologic and clinical variables were analysed. RESULTS Cool (p = 0.0090) and warm detection thresholds (p = 0.0229) of the tongue were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls (p = 0.0056). The latencies of R2 component were longer in BMS patients than in controls (p = 0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest (p = 0.0312) in homozygous patients with 957TT, who also reported most interference (p = 0.0352) and greatest suffering (p = 0.0341). Genotype 957CC associated with sleep disturbances (p = 0.0254). CONCLUSIONS Burning mouth syndrome patients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy. The DRD2 957C>T genotype influences perception and experience of BMS pain. SIGNIFICANCE The results confirm earlier findings of neuropathic pain in BMS. The DRD2 957 C>T genotype influences perception and experience of clinical pain in BMS.

Objective The study aims to develop an automatic sleep scoring method by fusing different polysomnography (PSG) signals and further to investigate PSG signals’ contribution to the scoring result. Methods Eight combinations of four modalities of PSG signals, namely electroencephalogram (EEG), electrooculogram (EOG), electromyogram (EMG), and electrocardiogram (ECG) were considered to find the optimal fusion of PSG signals. A total of 232 features, covering statistical characters, frequency characters, time-frequency characters, fractal characters, entropy characters and nonlinear characters, were derived from these PSG signals. To select the optimal features for each signal fusion, four widely used feature selection methods were compared. At the classification stage, five different classifiers were employed to evaluate the validity of the features and to classify sleep stages. Results For the database in the present study, the best classifier, random forest, realized the optimal consistency of 86.24% with the sleep macrostructures scored by the technologists trained at the Sleep Center. The optimal accuracy was achieved by fusing four modalities of PSG signals. Specifically, the top twelve features in the optimal feature set were respectively EEG features named zero-crossings, spectral edge, relative power spectral of theta, Petrosian fractal dimension, approximate entropy, permutation entropy and spectral entropy, and EOG features named spectral edge, approximate entropy, permutation entropy and spectral entropy, and the mutual information between EEG and submental EMG. In addition, ECG features (e.g. Petrosian fractal dimension, zero-crossings, mean value of R amplitude and permutation entropy) were useful for the discrimination among W, S1 and R. Conclusions Through exploring the different fusions of multi-modality signals, the present study concluded that the multi-modality of PSG signals’ fusion contributed to higher accuracy, and the optimal feature set was a fusion of multiple types of features. Besides, compared with manual scoring, the proposed automatic scoring methods were cost-effective, which would alleviate the burden of the physicians, speed up sleep scoring, and expedite sleep research.

Kinnunen, J-V, Piitulainen, H, and Piirainen, JM. Neuromuscular adaptations to short-term high-intensity interval training in female ice-hockey players. J Strength Cond Res 33(2): 479-485, 2019-High-intensity interval training (HIIT)-related neuromuscular adaptations, changes in force production, and on-ice performance were investigated in female ice-hockey players during preseason. Fourteen Finnish championship level ice-hockey players (average age 22 ± 3 years) participated in 2½-week HIIT. Both spinal (H-reflex) and supraspinal (V-wave) neuromuscular responses of the soleus muscle were recorded before and after the training period. Static jump (SJ) and countermovement jump heights, plantarflexor maximum voluntary contraction (MVC), and rate of force development (RFD) were measured. In addition, soleus and tibialis anterior muscle activations (electromyography) were measured during MVC and RFD tests. During on-ice training, skating speed and acceleration tests were performed. Subjects significantly improved their plantarflexion MVC force (11.6 ± 11.2%, p < 0.001), RFD (15.2 ± 15.9%, p < 0.01), and SJ (4.8 ± 7.6%, p ≤ 0.05). Voluntary motor drive to the soleus muscle (V-wave amplitude) increased by 16.0 ± 15.4% (p < 0.01), and coactivation of the tibialis anterior muscle during the plantarflexion RFD test was reduced by -18.9 ± 22.2% (p ≤ 0.05). No change was observed in spinal α-motoneuron excitability (H-reflex) during MVC or in on-ice performance. These results indicate that HIIT can be used to improve athletes' capability to produce maximal and explosive forces, likely through enhanced voluntary activation of their muscles and reduced antagonist coactivation. Therefore, HIIT can be recommended in preseason training to improve neuromuscular performance. However, a longer than 2½-week HIIT period is needed to improve on-ice performance in female ice-hockey players.

BACKGROUND AND PURPOSE: The relationship between brain β-amyloid and regional atrophy is still incompletely understood in elderly individuals at risk of dementia. Here, we studied the associations between brain β-amyloid load and regional GM and WM volumes in older adults who were clinically evaluated as being at increased risk of cognitive decline based on cardiovascular risk factors. MATERIALS AND METHODS: Forty subjects (63–81 years of age) were recruited as part of a larger study, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. Neuroimaging consisted of PET using (11)C Pittsburgh compound-B and T1-weighted 3D MR imaging for the measurement of brain β-amyloid and GM and WM volumes, respectively. All subjects underwent clinical, genetic, and neuropsychological evaluations for the assessment of cognitive function and the identification of cardiovascular risk factors. RESULTS: Sixteen subjects were visually evaluated as showing cortical β-amyloid (positive for β-amyloid). In the voxel-by-voxel analyses, no significant differences were found in GM and WM volumes between the samples positive and negative for β-amyloid. However, in the sample positive for β-amyloid, increases in (11)C Pittsburgh compound-B uptake were associated with reductions in GM volume in the left prefrontal (P = .02) and right temporal lobes (P = .04). CONCLUSIONS: Our results show a significant association between increases in brain β-amyloid and reductions in regional GM volume in individuals at increased risk of cognitive decline. This evidence is consistent with a model in which increases in β-amyloid incite neurodegeneration in memory systems before cognitive impairment manifests.

In early life auditory discrimination ability can be enhanced by passive sound exposure. In contrast, in adulthood passive exposure seems to be insufficient to promote discrimination ability, but this has been tested only with a single short exposure session in humans. We tested whether passive exposure to unfamiliar auditory stimuli can result in enhanced cortical discrimination ability and change detection in adult humans, and whether the possible learning effect generalizes to different stimuli. To address these issues, we exposed adult Finnish participants to Chinese lexical tones passively for 2 h per day on 4 consecutive days. Behavioral responses and the brain's event-related potentials (ERPs) were measured before and after the exposure for the same stimuli applied in the exposure phase and to sinusoidal sounds roughly mimicking the frequency contour in speech sounds. Passive exposure modulated the ERPs to speech sound changes in both ignore (mismatch negativity latency, P3a amplitude and P3a latency) and attend (P3b amplitude) test conditions, but not the behavioral responses. Furthermore, effect of passive exposure transferred to the processing of the sinusoidal sounds as indexed by the latency of the mismatch negativity. No corresponding effects in the ERPs were found in a control group that participated to the test measurements, but received no exposure to the sounds. The results show that passive exposure to foreign speech sounds in adulthood can enhance cortical discrimination ability and attention orientation toward changes in speech sounds and that the learning effect can transfer to non-speech sounds. peerReviewed

Neurofeedback requires a direct translation of neuronal brain activity to sensory input given to the user or subject. However, decoding certain states, e.g., mindfulness or wandering thoughts, from ongoing brain activity remains an unresolved problem. In this study, we used magnetoencephalography (MEG) to acquire brain activity during mindfulness meditation and thought-inducing tasks mimicking wandering thoughts. We used a novel real-time feature extraction to decode the mindfulness, i.e., to discriminate it from the thought-inducing tasks. The key methodological novelty of our approach is usage of MEG power spectra and functional connectivity of independent components as features underlying mindfulness states. Performance was measured as the classification accuracy on a separate session but within the same subject. We found that the spectral- and connectivity-based classification approaches allowed discriminating mindfulness and thought-inducing tasks with an accuracy around 60% compared to the 50% chance-level. Both classification approaches showed similar accuracy, although the connectivity approach slightly outperformed the spectral one in a few cases. Detailed analysis showed that the classification coefficients and the associated independent components were highly individual among subjects and a straightforward transfer of the coefficients over subjects provided near chance-level classification accuracy. Thus, discriminating between mindfulness and wandering thoughts seems to be possible, although with limited accuracy, by machine learning, especially on the subject-level. Our hope is that the developed spectral- and connectivity-based decoding methods can be utilized in real-time neurofeedback to decode mindfulness states from ongoing neuronal activity, and hence, provide a basis for improved, individualized mindfulness training.

Clinical manifestations of Alzheimer's disease (AD) are associated with a breakdown in large-scale communication, such that AD may be considered as a "disconnection syndrome." An established method to test effective connectivity is the combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) because the TMS-induced cortical response propagates to distant anatomically connected regions. To investigate whether prefrontal connectivity alterations may predict disease severity, we explored the relationship of dorsolateral prefrontal cortex connectivity (derived from TMS-EEG) with cognitive decline (measured with Mini Mental State Examination and a face-name association memory task) in 26 patients with AD. The amplitude of TMS-EEG evoked component P30, which was found to be generated in the right superior parietal cortex, predicted Mini Mental State Examination and face-name memory scores: higher P30 amplitudes predicted poorer cognitive and memory performances. The present results indicate that advancing disease severity might be associated with effective connectivity increase involving long-distance frontoparietal connections, which might represent a maladaptive pathogenic mechanism reflecting a damaged excitatory-inhibitory balance between anterior and posterior regions.

Spatial source phase, the phase information of spatial maps extracted from functional magnetic resonance imaging (fMRI) data by data-driven methods such as independent component analysis (ICA), has rarely been studied. While the observed phase has been shown to convey unique brain information, the role of spatial source phase in representing the intrinsic activity of the brain is yet not clear. This study explores the spatial source phase for identifying spatial differences between patients with schizophrenia (SZs) and healthy controls (HCs) using complex-valued resting-state fMRI data from 82 individuals. ICA is first applied to preprocess fMRI data, and post-ICA phase de-ambiguity and denoising are then performed. The ability of spatial source phase to characterize spatial differences is examined by the homogeneity of variance test (voxel-wise F-test) with false discovery rate correction. Resampling techniques are performed to ensure that the observations are significant and reliable. We focus on two components of interest widely used in analyzing SZs, including the default mode network (DMN) and auditory cortex. Results show that the spatial source phase exhibits more significant variance changes and higher sensitivity to the spatial differences between SZs and HCs in the anterior areas of DMN and the left auditory cortex, compared to the magnitude of spatial activations. Our findings show that the spatial source phase can potentially serve as a new brain imaging biomarker and provide a novel perspective on differences in SZs compared to HCs, consistent with but extending previous work showing increased variability in patient data.

Brain structure and many brain functions are known to be genetically controlled, but direct links between neuroimaging measures and their underlying cellular‐level determinants remain largely undiscovered. Here, we adopt a novel computational method for examining potential similarities in high‐dimensional brain imaging data between siblings. We examine oscillatory brain activity measured with magnetoencephalography (MEG) in 201 healthy siblings and apply Bayesian reduced‐rank regression to extract a low‐dimensional representation of familial features in the participants' spectral power structure. Our results show that the structure of the overall spectral power at 1–90 Hz is a highly conspicuous feature that not only relates siblings to each other but also has very high consistency within participants' own data, irrespective of the exact experimental state of the participant. The analysis is extended by seeking genetic associations for low‐dimensional descriptions of the oscillatory brain activity. The observed variability in the MEG spectral power structure was associated with SDK1 (sidekick cell adhesion molecule 1) and suggestively with several other genes that function, for example, in brain development. The current results highlight the potential of sophisticated computational methods in combining molecular and neuroimaging levels for exploring brain functions, even for high‐dimensional data limited to a few hundred participants.

Muscimol, the major psychoactive ingredient in the mushroom Amanita muscaria, has been regarded as a universal non-selective GABA-site agonist. Deletion of the GABAA receptor (GABAA R) δ subunit in mice (δKO) leads to a drastic reduction in high-affinity muscimol binding in brain sections and to a lower behavioral sensitivity to muscimol than their wild type counterparts. Here, we use forebrain and cerebellar brain homogenates from WT and δKO mice to show that deletion of the δ subunit leads to a > 50% loss of high-affinity 5 nM [3 H]muscimol-binding sites despite the relatively low abundance of δ-containing GABAA Rs (δ-GABAA R) in the brain. By subtracting residual high-affinity binding in δKO mice and measuring the slow association and dissociation rates we show that native δ-GABAA Rs in WT mice exhibit high-affinity [3 H]muscimol-binding sites (KD ~1.6 nM on α4βδ receptors in the forebrain and ~1 nM on α6βδ receptors in the cerebellum at 22°C). Co-expression of the δ subunit with α6 and β2 or β3 in recombinant (HEK 293) expression leads to the appearance of a slowly dissociating [3 H]muscimol component. In addition, we compared muscimol currents in recombinant α4β3δ and α4β3 receptors and show that δ subunit co-expression leads to highly muscimol-sensitive currents with an estimated EC50 of around 1-2 nM and slow deactivation kinetics. These data indicate that δ subunit incorporation leads to a dramatic increase in GABAA R muscimol sensitivity. We conclude that biochemical and behavioral low-dose muscimol selectivity for δ-subunit-containing receptors is a result of low nanomolar-binding affinity on δ-GABAA Rs.

A number of previous studies have implicated regions in posterior auditory cortex (AC) in auditory-motor integration during speech production. Other studies, in turn, have shown that activation in AC and adjacent regions in the inferior parietal lobule (IPL) is strongly modulated during active listening and depends on task requirements. The present fMRI study investigated whether auditory-motor effects interact with those related to active listening tasks in AC and IPL. In separate task blocks, our subjects performed either auditory discrimination or 2-back memory tasks on phonemic or nonphonemic vowels. They responded to targets by either overtly repeating the last vowel of a target pair, overtly producing a given response vowel, or by pressing a response button. We hypothesized that the requirements for auditory-motor integration, and the associated activation, would be stronger during repetition than production responses and during repetition of nonphonemic than phonemic vowels. We also hypothesized that if auditory-motor effects are independent of task-dependent modulations, then the auditory-motor effects should not differ during discrimination and 2-back tasks. We found that activation in AC and IPL was significantly modulated by task (discrimination vs. 2-back), vocal-response type (repetition vs. production), and motor-response type (vocal vs. button). Motor-response and task effects interacted in IPL but not in AC. Overall, the results support the view that regions in posterior AC are important in auditory-motor integration. However, the present study shows that activation in wide AC and IPL regions is modulated by the motor requirements of active listening tasks in a more general manner. Further, the results suggest that activation modulations in AC associated with attention-engaging listening tasks and those associated with auditory-motor performance are mediated by independent mechanisms.

The auditory dorsal stream has been implicated in sensorimotor integration and concatenation of sequential sound events, both being important for processing of speech and music. The auditory ventral stream, by contrast, is characterized as subserving sound identification and recognition. We studied the respective roles of the dorsal and ventral streams, including recruitment of basal ganglia and medial temporal lobe structures, in the processing of tone sequence elements. A sequence was presented incrementally across several runs during functional magnetic resonance imaging in humans, and we compared activation by sequence elements when heard for the first time (“novel”) versus when the elements were repeating (“familiar”). Our results show a shift in tone-sequence-dependent activation from posterior-dorsal cortical areas and the basal ganglia during the processing of less familiar sequence elements towards anterior and ventral cortical areas and the medial temporal lobe after the encoding of highly familiar sequence elements into identifiable auditory objects.

Neurocognition in Childhood Epilepsy: Impact on Mortality and Complete Seizure Remission 50 Years Later Sillanpää M, Saarinen MM, Karrasch M, Schmidt D, Hermann BP. Epilepsia. 2019;60(1):131-138. doi:10.1111/epi.14606. Epub 2018 Nov 22.Objective:To study associations of the severity of impairment in childhood neurocognition (NC) with long-term mortality and complete seizure remission.Methods:A population-based cohort of 245 subjects with childhood-onset epilepsy was followed up for 50 years (median = 45, range = 2-50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, Tenth Revision (R41.83, F70-F73). The outcome variables, defined as all-cause mortality and 10-year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models.Results:Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50-year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2-9.2], 4.2 [1.2-14.2], and 5.5 [2.4-12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment.Significance:The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood-onset epilepsy.

Consciousness and working memory (WM) have been thought to be closely related, but their exact relationship has remained unclear. The present study focused on the question whether visual awareness, the subjective experience of seeing, depends on resources of WM. Three dual-task experiments were run. The participants were asked to report their awareness of a low-contrast target stimulus while their WM was loaded by a requirement to concurrently maintain verbal information (Experiment 1) or visuo-spatial information (Experiment 2) in WM, or by a concurrent executive task (Experiment 3). Behavioral responses and event-related brain potential (ERP) correlates of visual awareness in response to the targets were examined. Experiments 1 and 2 revealed that maintenance of information in WM did not have any effect on reported visual awareness and its electrophysiological correlates. Experiment 3 found that executive load decreased reported visual awareness, which was reflected in ERPs around 350–550 ms after stimulus onset as a reduction in the amplitudes of P3 to detected stimuli. The earlier, posterior correlate of visual awareness in N200 time window (180–280 ms) was not affected by load in any of the conditions. The results suggest that visual consciousness and WM share resources at a relatively late stage of conscious processing, which involves active manipulation of contents. The findings are in line with a recent view suggesting that a posterior “hot zone” is responsible for visual awareness, while frontal regions contribute to higher-level cognitive processes that occur after visual awareness has arisen.

Corticokinematic coherence (CKC) between limb kinematics and magnetoencephalographic (MEG) signals reflects cortical processing of proprioceptive afference. However, it is unclear whether strength of CKC is reproducible across measurement sessions. We thus examined reproducibility of CKC in a follow-up study. Thirteen healthy right-handed volunteers (7 females, 21.7 +/- 4.3 yrs) were measured using MEG in two separate sessions 12.6 +/- 1.3 months apart. The participant was seated and relaxed while his/her dominant or non-dominant index finger was continuously moved at 3 Hz (4 min for each hand) using a pneumatic movement actuator. Finger kinematics were recorded with a 3-axis accelerometer. Coherence was computed between finger acceleration and MEG signals. CKC strength was defined as the peak coherence value at 3 Hz form a single sensor among 40 pre-selected Rolandic gradiometers contralateral to the movement. Pneumatic movement actuator provided stable proprioceptive stimuli and significant CKC responses peaking at the contralateral Rolandic sensors. In the group level, CKC strength did not differ between the sessions in dominant (Day-1 0.40 +/- 0.19 vs. Day-2 0.41 +/- 0.17) or non-dominant (0.35 +/- 0.16 vs. 0.36 +/- 0.17) hand, nor between the hands. Intraclass-correlation coefficient (ICC) values indicated excellent inter-session reproducibility for CKC strength for both dominant (0.86) and non-dominant (0.97) hand. However, some participants showed pronounced inter-session variability in CKC strength, but only for the dominant hand. CKC is a promising tool to study proprioception in long-term longitudinal studies in the group level to follow, e.g., integrity of cortical proprioceptive processing with motor functions after stroke.

The popular framework of cortical entrainment postulates that speech comprehension crucially depends on the continuous alignment of low-frequency cortical oscillatory activity with the amplitude en...

Here we review the literature assessing the roles of the brain dopaminergic and serotonergic systems in the modulation of pain as revealed by in vivo human studies using positron emission tomography. In healthy subjects, dopamine D-2/D-3 receptor availability particularly in the striatum and serotonin 5-HT1A and 5-HT2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D-2/D-3 or serotonin 5-HT2A receptors is associated with high pain intensity, whereas high availability of 5-HT1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D-2/D-3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D-2/D-3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D-2/D-3 receptors. In healthy subjects, brain serotonin 5-HT1A as well as dopamine D-2/D-3 receptor availabilities associate with the subject's response criterion rather than the capacity to discriminate painful thermal stimuli suggesting that these neurotransmitter systems act mainly on non-sensory rather than sensory factors of thermally induced pain experience. Additionally, 5-HT1A receptor availability predicts the subject's discriminative ability but not response criterion for non-painful tactile test stimuli, while no such correlation is observed with dopamine D-2/D-3 receptors. These findings suggest that dopamine acting on striatal dopamine D-2/D-3 receptors and serotonin acting on cortical 5-HT1A and 5-HT2A receptors contribute to top-down pain regulation in humans.

Objective Our goal was to discover attention- and inhibitory control-related differences in the main oscillations of the brain of children who stutter (CWS) compared to typically developed children (TDC). Methods We performed a time-frequency analysis using wavelets, fast Fourier transformation (FFT) and the Alpha/Theta power ratio of EEG data collected during a visual Go/Nogo task in 7–9 year old CWS and TDC, including also the time window between consecutive tasks. Results CWS showed significantly reduced occipital alpha power and Alpha/Theta ratio in the “resting” or preparatory period between visual stimuli especially in the Nogo condition. Conclusions The CWS demonstrate reduced inhibition of the visual cortex and information processing in the absence of visual stimuli, which may be related to problems in attentional gating. Significance Occipital alpha oscillation is elementary in the control and inhibition of visual attention and the lack of occipital alpha modulation indicate fundamental differences in the regulation of visual information processing in CWS. Our findings support the view of stuttering as part of a wide-ranging brain dysfunction most likely involving also attentional and inhibitory networks.

Receptive field (RF) models are an important tool for deciphering neural responses to sensory stimuli. The two currently popular RF models are multifilter linear-nonlinear (LN) models and context models. Models are, however, never correct, and they rely on assumptions to keep them simple enough to be interpretable. As a consequence, different models describe different stimulus-response mappings, which may or may not be good approximations of real neural behavior. In the current study, we take up two tasks: 1) we introduce new ways to estimate context models with realistic nonlinearities, that is, with logistic and exponential functions, and 2) we evaluate context models and multifilter LN models in terms of how well they describe recorded data from complex cells in cat primary visual cortex. Our results, based on single-spike information and correlation coefficients, indicate that context models outperform corresponding multifilter LN models of equal complexity (measured in terms of number of parameters), with the best increase in performance being achieved by the novel context models. Consequently, our results suggest that the multifilter LN-model framework is suboptimal for describing the behavior of complex cells: the context-model framework is clearly superior while still providing interpretable quantizations of neural behavior. NEW & NOTEWORTHY We used data from complex cells in primary visual cortex to estimate a wide variety of receptive field models from two frameworks that have previously not been compared with each other. The models included traditionally used multifilter linear-nonlinear models and novel variants of context models. Using mutual information and correlation coefficients as performance measures, we showed that context models are superior for describing complex cells and that the novel context models performed the best.

Adaptive behavior relies on the ability of the brain to form predictions and monitor action outcomes. In the human brain, the same system is thought to monitor action outcomes regardless of whether the information originates from internal (e.g., proprioceptive) and external (e.g., visual) sensory channels. Neural signatures of processing motor errors and action outcomes communicated by external feedback have been studied extensively; however, the existence of such a general action-monitoring system has not been tested directly. Here, we use concurrent EEG-MEG measurements and a probabilistic learning task to demonstrate that event-related responses measured by electroencephalography and magnetoencephalography display spatiotemporal patterns that allow an effective transfer of a multivariate statistical model discriminating the outcomes across the following conditions: (a) erroneous versus correct motor output, (b) negative versus positive feedback, (c) high- versus low-surprise negative feedback, and (d) erroneous versus correct brain-computer-interface output. We further show that these patterns originate from highly-overlapping neural sources in the medial frontal and the medial parietal cortices. We conclude that information about action outcomes arriving from internal or external sensory channels converges to the same neural system in the human brain, that matches this information to the internal predictions.

Background Experiences during anaesthetic-induced unresponsiveness have previously been investigated by interviews after recovery. To explore whether experiences occur during drug administration, we interviewed participants during target-controlled infusion (TCI) of dexmedetomidine or propofol and after recovery. Methods Healthy participants received dexmedetomidine (n=23) or propofol (n=24) in stepwise increments until loss of responsiveness (LOR1). During TCI we attempted to arouse them for interview (return of responsiveness, ROR1). After the interview, if unresponsiveness ensued with the same dose (LOR2), the procedure was repeated (ROR2). Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness (LOC), infusion terminated, and the participants interviewed upon recovery (ROR3). An emotional sound stimulus was presented during LORs and LOC, and memory for stimuli was assessed with recognition task after recovery. Interview transcripts were content analysed. Results Of participants receiving dexmedetomidine, 18/23 were arousable from LOR1 and LOR2. Of participants receiving propofol, 10/24 were arousable from LOR1 and two of four were arousable from LOR2. Of 93 interviews performed, 84% included experiences from periods of unresponsiveness (dexmedetomidine 90%, propofol 74%). Internally generated experiences (dreaming) were present in 86% of reports from unresponsive periods, while externally generated experiences (awareness) were rare and linked to brief arousals. No within drug differences in the prevalence or content of experiences during infusion vs after recovery were observed, but participants receiving dexmedetomidine reported dreaming and awareness more often. Participants receiving dexmedetomidine recognised the emotional sounds better than participants receiving propofol (42% vs 15%), but none reported references to sounds spontaneously. Conclusion Anaesthetic-induced unresponsiveness does not induce unconsciousness or necessarily even disconnectedness. Clinical trial registration NCT01889004.

Background There has been growing interest towards naturalistic neuroimaging experiments, which deepen our understanding of how human brain processes and integrates incoming streams of multifaceted sensory information, as commonly occurs in real world. Music is a good example of such complex continuous phenomenon. In a few recent fMRI studies examining neural correlates of music in continuous listening settings, multiple perceptual attributes of music stimulus were represented by a set of high-level features, produced as the linear combination of the acoustic descriptors computationally extracted from the stimulus audio. New method fMRI data from naturalistic music listening experiment were employed here. Kernel principal component analysis (KPCA) was applied to acoustic descriptors extracted from the stimulus audio to generate a set of nonlinear stimulus features. Subsequently, perceptual and neural correlates of the generated high-level features were examined. Results The generated features captured musical percepts that were hidden from the linear PCA features, namely Rhythmic Complexity and Event Synchronicity. Neural correlates of the new features revealed activations associated to processing of complex rhythms, including auditory, motor, and frontal areas. Comparison with existing method Results were compared with the findings in the previously published study, which analyzed the same fMRI data but applied linear PCA for generating stimulus features. To enable comparison of the results, methodology for finding stimulus-driven functional maps was adopted from the previous study. Conclusions Exploiting nonlinear relationships among acoustic descriptors can lead to the novel high-level stimulus features, which can in turn reveal new brain structures involved in music processing.

Stroke occurrence shows strong correlations with sleep disorders and even subtle sleep disturbances have been shown to affect ischemic stroke (IS) occurrence. Chronobiology also exerts effects, like the morning surge in IS occurrence. Lunar cycles have also been shown to affect sleep and other physiological processes, but studies on moon phases and its possible association with occurrence of stroke are rare and nonconclusive. Therefore, we studied the effects of moon phases on stroke hospitalizations and in-hospital mortality nationwide in Finland in 2004-2014. All patients aged ≥18 years with IS or intracerebral hemorrhage (ICH) as primary discharge diagnosis were included. Daily number of admissions was treated as a response variable while moon phase, year and astronomical season were independent variables in Poisson regression modeling. We found no association between moon phases and stroke occurrence. The overall occurrence rates did not vary between different moon phases for IS or ICH (p = 0.61 or higher). There were no differences between moon phases in daily admission rates among men, women, young and old patients for any of the stroke subtypes. There was no difference in in-hospital mortality with regard to moon phase for IS or ICH overall (p = 0.19 or higher), nor in subgroup analyses. There were no significant interactions between moon phase and astronomical season for stroke occurrence or in-hospital mortality. To conclude, in this over a decade-long nationwide study including a total of 46 million person years of follow-up, we found no association between moon phases and occurrence or in-hospital mortality rates of IS or intracerebral hemorrhage.

Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.

Motivation The collective and co-ordinated synaptic activity of large neuronal populations is relevant to neuronal development as well as a range of neurological diseases. Quantification of synaptically-mediated neuronal signalling permits further downstream analysis as well as potential application in target validation and in vitro screening assays. Our aim is to develop a phenotypic quantification for neuronal activity imaging data of large populations of neurons, in particular relating to the spatial component of the activity. Results We extend the use of Markov random field (MRF) models to achieve this aim. In particular, we consider Bayesian posterior densities of model parameters in Gaussian MRFs to directly model changes in calcium fluorescence intensity rather than using spike trains. The basis of our model is defining neuron ‘neighbours’ by the relative spatial positions of the neuronal somata as obtained from the image data whereas previously this has been limited to defining an artificial square grid across the field of view and spike binning. We demonstrate that our spatial phenotypic quantification is applicable for both in vitro and in vivo data consisting of thousands of neurons over hundreds of time points. We show how our approach provides insight beyond that attained by conventional spike counting and discuss how it could be used to facilitate screening assays for modifiers of disease-associated defects of communication between cells. Availability and implementation We supply the MATLAB code and data to obtain all of the results in the paper. Supplementary information Supplementary data are available at Bioinformatics online.

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6. Here we introduce electroretinography-based methods for determining the inhibition constants of PDE inhibitors towards the naturally occurring light-activated and spontaneously activated forms of PDE6. We compare our results to earlier biochemical determinations with trypsin-activated PDE6 with disintegrated PDE6 γ-subunit. The potencies of PDE inhibitors were determined by stimulating the photoreceptors of isolated mouse retinas with light and tracking the inhibitor-induced changes in their electrical responses. The methods were tested with three PDE inhibitors, 3-isobutyl-1-methylxanthine (IBMX), sildenafil, and zaprinast. The inhibition constants towards light-activated, spontaneously activated, and trypsin-activated PDE6 differed significantly from each other for sildenafil and zaprinast but were closely similar for IBMX. We hypothesize that this is due to the ability of the PDE6 γ-subunit to compete with sildenafil and zaprinast from the same binding sites near the catalytic domain of PDE6. The introduced methods are beneficial both for selecting potent molecules for PDE6 inhibition and for testing the drugs targeted at other PDE isoforms against adverse effects on visual function.

Introduction We describe a new nerve conduction study technique with reference values for the 3 branches of the supraclavicular nerve (SCN) in young healthy subjects and application of it in 2 patients. Methods The recording electrode was placed on the posterior border of the sternocleidomastoid muscle, 6-7 cm from the sternoclavicular joint. SCN branches were stimulated below the clavicle, 2.5, 7, and 10.5 cm lateral to the sternoclavicular joint. Results Twenty healthy volunteers (10 men), 19-38 years, mean 25.9 years (SD 6.3), and 2 patients with SCN lesions were studied. The mean conduction velocities of the SCN branches were 70-78 m/s (SD 8-10 m/s), and amplitudes 3-4 µV (SD 0.9-2.0 µV). There were no side-to-side or gender differences. Discussion The 3 SCN branches could be studied in all subjects. We provide reference values for young subjects. This new method was useful in verifying SCN lesions in 2 patients. Muscle Nerve 58: 300-303, 2018.