Partial Directed Coherence and the Vector Autoregressive Modelling Myth and a Caveat.

Here we dispel the lingering myth that Partial Directed Coherence is a Vector Autoregressive (VAR) Modelling dependent concept. In fact, our examples show that it is spectral factorization that lies at its heart, for which VAR modelling is a mere, albeit very efficient and convenient, device. This applies to Granger Causality estimation procedures in general and also includes instantaneous Granger effects. Care, however, must be exercised for connectivity between multivariate data generated through nonminimum phase mechanisms as it may possibly be incorrectly captured.

Functional Changes in Cortical Activity of Patients Submitted to Knee Osteoarthritis Treatment: An Exploratory Pilot Study.

INTRODUCTION: There is evidence that brain plasticity is the central mechanism involved in the functional recovery process of patients with knee osteoarthritis. Studies involving the analysis of central nervous system mechanisms of pain control and recovery could provide more data on future therapeutic approaches. OBJECTIVE: The aim of the study was to explore possible functional changes in cortical activity of patients submitted to knee osteoarthritis standardized pain treatment using electroencephalography. METHODOLOGY: Ten patients with clinical and radiological diagnosis of painful knee unilateral or bilateral osteoarthritis were recruited to participate in clinical (Pain's Visual Analog Scale), radiological (Kellgren-Lawrence Scale), and neurophysiological (electroencephalography) assessments to evaluate cortical activity during cortical pain modulation activity. The clinical and neurophysiological analyses were performed before and after standardized pain treatment. RESULTS: Eight patients participated in this study. A significant improvement in pain perception and relative increase in interhemispheric connectivity after therapies was observed. In electroencephalography analysis, tests with real movement showed a relative increase in density directed at Graph's analysis. CONCLUSIONS: Relative increase density directed measures at connectivity analysis in electroencephalography after pain treatment can be possible parameters to be explored in future research with a larger number of patients.

Frequency Domain Repercussions of Instantaneous Granger Causality.

Using directed transfer function (DTF) and partial directed coherence (PDC) in the information version, this paper extends the theoretical framework to incorporate the instantaneous Granger causality (iGC) frequency domain description into a single unified perspective. We show that standard vector autoregressive models allow portraying iGC's repercussions associated with Granger connectivity, where interactions mediated without delay between time series can be easily detected.

Partial directed coherence: twenty years on some history and an appraisal.

Here while we reminisce about how partial directed coherence was proposed, its motivation and evolution, we take the opportunity to relate it to some of its kin quantities and some of its offspring. Emphasis is placed on our development of asymptotic criteria to place it as a reliable investigation tool, where the connectivity detection problem is completely solved as opposed to what we call the characterization problem. We end by musing over some points now on our wishlist.

Pitch and Duration Pattern Sequence Tests in 7- to 11-Year-Old Children: Results Depend on Response Mode.

BACKGROUND: Pitch pattern sequence (PPS) and duration pattern sequence (DPS) tests are frequently used in the assessment of auditory processing disorder. Current recommendations suggest alternate, interchangeable modes for responding to stimuli. PURPOSE: The objective of the study is to evaluate the influence of response mode (i.e., humming, pointing, and labeling) and age on PPS and DPS performance of 7- to 11-year-old children. RESEARCH DESIGN: Laboratory-based testing of school children. Cross-sectional comparison of age, with repeated measures of age, test, ear, and response mode. STUDY SAMPLE: From 452 children recruited, 228 right-handed children (109 girls) aged 7 years to 11 years 11 months (mean age 9 years 4 months) completed at least one test (PPS: 211, DPS: 198), and 181 children completed both tests. Audiology inclusion criteria include normal hearing thresholds (≤15 dB HL at octave frequencies 250-8000 Hz); word recognition in quiet ≥92%; tympanogram peak compensated static acoustic compliance 0.4-1.6 mmhos; and tympanometric peak pressure -100 to +50 daPa, all in both ears. Other inclusion criteria were Portuguese as first language; right handed; no musical training; no related, known, or observed phonological, learning, neurologic, psychiatric, or behavioral disorder; otologic history; and delayed neuropsychomotor or language development. DATA COLLECTION AND ANALYSIS: PPS: 30 trials per ear and response condition of three consecutive 500 msec duration intermixed high (1430 Hz) or low (880 Hz) frequency tones presented monaurally at 50 dB HL. The first response condition was humming followed by labeling (naming: high or low). DPS: As per PPS except 1000 Hz tones of intermixed 500 (long) and 250 msec (short) duration. First response was pointing (at a symbolic object) followed by labeling. Trends across age and between tests were assessed using repeated measures generalized linear mixed models. Correlation coefficients were calculated to assess relations among test scores. The two-sided significance level was 0.05. RESULTS: Older children performed better than younger children in all tasks. Humming the tone pattern (PPS humming) produced generally better performance than either articulating the attributes of the tones (labeling) or pointing to objects representing tone duration. PPS humming produced ceiling performance for many children of all ages. For both labeling tasks and DPS pointing, performance was better on the PPS than on the DPS, for stimulation of the right than the left ear, and in boys than girls. Individual performance on the two tasks was highly correlated. CONCLUSIONS: Response mode does matter in the PPS and DPS. Results from humming should not be combined with or be a substitute for results obtained from a labeling response. Tasks that rely on labeling a tonal stimulus should be avoided in testing hearing in children or other special populations.

The effect of conscious intention to act on the Bereitschaftspotential.

The current study investigated the effect of conscious intention to act on the Bereitschaftspotential. Situations in which the awareness of acting is minimally expressed were generated by asking 16 participants to press a button after performing a mental imagery task based on animal pictures (automatic condition). The affective responses induced by the pictures were controlled by selecting the animals according to different valences, threatening and neutral. The Bereitschaftspotential associated with the button presses was compared to the observed when similar movements were performed under the basic instructions of the self-paced movement paradigm (willed condition). Enhanced Bereitschaftspotential amplitudes were observed in the willed condition with respect to the automatic condition. This effect was manifested as a negative slope at medial frontocentral sites during the last 500 ms before movement onset. The valence of the pictures did not affect the motor preparatory potentials. The results suggest that significant part of the NS' subcomponent of the readiness potential is associated with the attention to-and, presumably, awareness of-intention to move, possibly reflecting cortical activation from supplementary motor areas. Secondarily, our findings supports that the feeling of threat does not influence the Bereitschaftspotential associated with automatic movements. Regarding methodological issues, the behavioural model of spontaneous voluntary movements proposed in automatic condition can benefit investigations on purely motor (or non-cognitive) subcomponents of the Bereitschaftspotential.

Directed Transfer Function: Unified Asymptotic Theory and Some of Its Implications.

OBJECTIVE: To present a unified mathematical derivation of the frequency-dependent asymptotic behavior of the three main forms of directed transfer function (DTF). METHODS: A synthesis of the results (proved in an extended Appendix) is followed by a series of Monte Carlo simulations of representative examples. RESULTS: DTF estimators are asymptotically normal when the true values are different from zero. Under the null hypothesis H0: DTF=0, the estimator is distributed as a linear combination of independent χ21 variables. CONCLUSIONS: Null DTF rejection is shown to be achievable with identical performance irrespective of which DTF form is adopted. SIGNIFICANCE: Together with recent allied partial directed coherence results, this paper rounds up connectivity inference tools for a class of frequency-domain connectivity estimators.

Deep Brain Stimulation: More Complex than the Inhibition of Cells and Excitation of Fibers.

High-frequency deep brain stimulation (DBS) is an effective treatment for some movement disorders. Though mechanisms underlying DBS are still unclear, commonly accepted theories include a "functional inhibition" of neuronal cell bodies and the excitation of axonal projections near the electrodes. It is becoming clear, however, that the paradoxical dissociation "local inhibition" and "distant excitation" is far more complex than initially thought. Despite an initial increase in neuronal activity following stimulation, cells are often unable to maintain normal ionic concentrations, particularly those of sodium and potassium. Based on currently available evidence, we proposed an alternative hypothesis. Increased extracellular concentrations of potassium during DBS may change the dynamics of both cells and axons, contributing not only to the intermittent excitation and inhibition of these elements but also to interrupt abnormal pathological activity. In this article, we review mechanisms through which high extracellular potassium may mediate some of the effects of DBS.

Source and sink nodes in absence seizures.

As opposed to focal epilepsy, absence seizures do not exhibit a clear seizure onset zone or focus since its ictal activity rapidly engages both brain hemispheres. Yet recent graph theoretical analysis applied to absence seizures EEG suggests the cortical focal presence, an unexpected feature for this type of epilepsy. In this study, we explore the characteristics of absence seizure by classifying the nodes as to their source/sink natures via weighted directed graph analysis based on connectivity direction and strength estimation using information partial directed coherence (iPDC). By segmenting the EEG signals into relatively short 5-sec-long time windows we studied the evolution of coupling strengths from both sink and source nodes, and the network dynamics of absence seizures in eight patients.

Experience-dependent upregulation of multiple plasticity factors in the hippocampus during early REM sleep.

Sleep is beneficial to learning, but the underlying mechanisms remain controversial. The synaptic homeostasis hypothesis (SHY) proposes that the cognitive function of sleep is related to a generalized rescaling of synaptic weights to intermediate levels, due to a passive downregulation of plasticity mechanisms. A competing hypothesis proposes that the active upscaling and downscaling of synaptic weights during sleep embosses memories in circuits respectively activated or deactivated during prior waking experience, leading to memory changes beyond rescaling. Both theories have empirical support but the experimental designs underlying the conflicting studies are not congruent, therefore a consensus is yet to be reached. To advance this issue, we used real-time PCR and electrophysiological recordings to assess gene expression related to synaptic plasticity in the hippocampus and primary somatosensory cortex of rats exposed to novel objects, then kept awake (WK) for 60 min and finally killed after a 30 min period rich in WK, slow-wave sleep (SWS) or rapid-eye-movement sleep (REM). Animals similarly treated but not exposed to novel objects were used as controls. We found that the mRNA levels of Arc, Egr1, Fos, Ppp2ca and Ppp2r2d were significantly increased in the hippocampus of exposed animals allowed to enter REM, in comparison with control animals. Experience-dependent changes during sleep were not significant in the hippocampus for Bdnf, Camk4, Creb1, and Nr4a1, and no differences were detected between exposed and control SWS groups for any of the genes tested. No significant changes in gene expression were detected in the primary somatosensory cortex during sleep, in contrast with previous studies using longer post-stimulation intervals (>180 min). The experience-dependent induction of multiple plasticity-related genes in the hippocampus during early REM adds experimental support to the synaptic embossing theory.

Partial directed coherence statistical performance characteristics in frequency domain.

In this work we show the asymptotic behavior of information partial directed coherence estimator via the Monte Carlo simulation of a particular toy model taken from the literature. We show that the control of false positive rate tends to the chosen significance level if detection decision is made at specific frequency values.

On neural connectivity estimation problems.

After briefly recapping and reframing the problem of neural connectivity and its implications for today's brain mapping efforts, we argue that supplementing/replacing traditional conservative correlation based analysis methods requires active user understanding of the aims and limitations of the newly proposed multivariate analysis frameworks before the new methods can gain general acceptance and full profit can be made from the expanded descriptive opportunities they offer.

On the statistical performance of Granger-causal connectivity estimators.

In this article, we extend the statistical detection performance evaluation of linear connectivity from Sameshima et al. (in: Slezak et al. (eds.) Lecture Notes in Computer Science, 2014) via brand new Monte Carlo simulations of three widely used toy models under different data record lengths for a classic time domain multivariate Granger causality test, information partial directed coherence, information directed transfer function, and include conditional multivariate Granger causality whose behaviour was found to be anomalous.

Canonical information flow decomposition among neural structure subsets.

Partial directed coherence (PDC) and directed coherence (DC) which describe complementary aspects of the directed information flow between pairs of univariate components that belong to a vector of simultaneously observed time series have recently been generalized as bPDC/bDC, respectively, to portray the relationship between subsets of component vectors (Takahashi, 2009; Faes and Nollo, 2013). This generalization is specially important for neuroscience applications as one often wishes to address the link between the set of time series from an observed ROI (region of interest) with respect to series from some other physiologically relevant ROI. bPDC/bDC are limited, however, in that several time series within a given subset may be irrelevant or may even interact opposingly with respect to one another leading to interpretation difficulties. To address this, we propose an alternative measure, termed cPDC/cDC, employing canonical decomposition to reveal the main frequency domain modes of interaction between the vector subsets. We also show bPDC/bDC and cPDC/cDC are related and possess mutual information rate interpretations. Numerical examples and a real data set illustrate the concepts. The present contribution provides what is seemingly the first canonical decomposition of information flow in the frequency domain.

Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1)H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8)) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44)) and lysine (rs8101881, P = 1.2×10(-33)), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics.

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10(-13), r(2) = 8.9%, ß = -0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with-but is statistically distinct from-the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10(-37), r(2) = 23.2%, ß = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.

Spectral characteristics of the hippocampal LFP during contextual fear conditioning.

OBJECTIVE: The hippocampus has an important role in the acquisition and recall of aversive memories. The objective of this study was to investigate the relationship among hippocampal rhythms. METHODS: Microeletrodes arrays were implanted in the hippocampus of Wistar rats. The animals were trained and tested in a contextual fear conditioning task. The training consisted in applying shocks in the legs. The memory test was performed 1 day (recent memory) or 18 days (remote memory) after training. We proposed a measure based on the FFT power spectrum, denominated "delta-theta ratio", to characterize the different behaviors (active exploration and freezing) and the memories types. RESULTS: The delta-theta ratio was able to distinguish recent and remote memories. In this study, the ratio for the 18-day group was smaller than for the 1-day group. Moreover, this measure was useful to distinguish the different behavior states - active exploration and freezing. CONCLUSIONS: The results suggest delta-theta oscillations could reflect the demands on information processing during recent and remote memory recalls.

Spectral characteristics of the hippocampal LFP during contextual fear conditioning / Características espectrais da atividade elétrica hipocampal durante o medo condicionado ao contexto

Objective: The hippocampus has an important role in the acquisition and recall of aversive memories. The objective of this study was to investigate the relationship among hippocampal rhythms. Methods: Microeletrodes arrays were implanted in the hippocampus of Wistar rats. The animals were trained and tested in a contextual fear conditioning task. The training consisted in applying shocks in the legs. The memory test was performed 1 day (recent memory) or 18 days (remote memory) after training. We proposed a measure based on the FFT power spectrum, denominated "delta-theta ratio", to characterize the different behaviors (active exploration and freezing) and the memories types. Results: The delta-theta ratio was able to distinguish recent and remote memories. In this study, the ratio for the 18-day group was smaller than for the 1-day group. Moreover, this measure was useful to distinguish the different behavior states - active exploration and freezing. Conclusions: The results suggest delta-theta oscillations could reflect the demands on information processing during recent and remote memory recalls.

Objetivo: O hipocampo tem um importante papel na aquisição e evocação das memórias aversivas. Pretendeu-se, neste trabalho, investigar a dinâmica entre os ritmos hipocampais durante a evocação das memórias aversivas recente e remota. Métodos: Foram implantadas matrizes de microeletrodos em ratos Wistar. Os animais foram treinados e testados numa tarefa de condicionamento contextual de medo. O treino consistiu em aplicações de choques nas patas. O teste de memória foi realizado 1 dia (memória recente) ou 18 dias (memória remota) após o treino. Nesse trabalho, foi proposta uma medida baseada no espectro de potências, denominada "razão delta-theta", para caracterização dos diferentes comportamentos observados (vigília exploratória e congelamento) e tipos de memórias. Resultados: A razão delta-theta mostrou-se capaz de distinguir os grupos testados para as memórias recente e remota. Neste caso, observou-se, para o grupo testado 18 dias após, um valor menor do que para o grupo testado 1 dia após. Além disso, essa medida mostrou-se útil para distinguir os diferentes estados comportamentais. Conclusões: Os resultados sugerem que a dinâmica entre os ritmos delta e theta pode refletir o processamento da informação durante a evocação das memórias recente e remota.

Sensitivity of genome-wide-association signals to phenotyping strategy: the PROP-TAS2R38 taste association as a benchmark.

Natural genetic variation can have a pronounced influence on human taste perception, which in turn may influence food preference and dietary choice. Genome-wide association studies represent a powerful tool to understand this influence. To help optimize the design of future genome-wide-association studies on human taste perception we have used the well-known TAS2R38-PROP association as a tool to determine the relative power and efficiency of different phenotyping and data-analysis strategies. The results show that the choice of both data collection and data processing schemes can have a very substantial impact on the power to detect genotypic variation that affects chemosensory perception. Based on these results we provide practical guidelines for the design of future GWAS studies on chemosensory phenotypes. Moreover, in addition to the TAS2R38 gene past studies have implicated a number of other genetic loci to affect taste sensitivity to PROP and the related bitter compound PTC. None of these other locations showed genome-wide significant associations in our study. To facilitate further, target-gene driven, studies on PROP taste perception we provide the genome-wide list of p-values for all SNPs genotyped in the current study.