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Background: Social anxiety disorder is characterized by intense fear and avoidance of social interactions and scrutiny by others. Although alterations in attentional control seem to play a central role in the psychopathology of social anxiety disorder, the neural underpinnings in prefrontal brain regions have not yet been fully clarified. Methods: The present study used functional MRI in participants (age 18–50 yr) with social anxiety disorder (n = 42, 31 female) and without (n = 58, 33 female). It investigated the interrelation of the effects of social anxiety disorder and early-life adversity (a main environmental risk factor of social anxiety disorder) on brain activity during an attentional control task. We applied DNA methylation analysis to determine whether epigenetic modulation in the gene encoding the glucocorticoid receptor, NR3C1, might play a mediating role in this process. Results: We identified 2 brain regions in the left and medial prefrontal cortex that exhibited an interaction effect of social anxiety disorder and early-life adversity. In participants with low levels of early-life adversity, neural activity in response to disorder-related stimuli was increased in association with social anxiety disorder. In participants with high levels of early-life adversity, neural activity was increased only in participants without social anxiety disorder. NR3C1 DNA methylation partly mediated the effect of social anxiety disorder on brain activity as a function of early-life adversity. Limitations: The absence of behavioural correlates associated with social anxiety disorder limited functional interpretation of the results. Conclusion: These findings demonstrate that the neurobiological processes that underlie social anxiety disorder might be fundamentally different depending on experiences of early-life adversity. Long-lasting effects of early-life adversity might be encoded in NR3C1 DNA methylation and entail alterations in social anxiety disorder–related activity patterns in the neural network of attentional control. [ABSTRACT FROM AUTHOR]

Use-dependent long-term changes of neuronal response properties must be gated to prevent irrelevant activity from inducing inappropriate modifications. Here we test the hypothesis that local network dynamics contribute to such gating. As synaptic modifications depend on temporal contiguity between presynaptic and postsynaptic activity, we examined the effect of synchronized gamma (ɣ) oscillations on stimulation-dependent modifications of orientation selectivity in adult cat visual cortex. Changes of orientation maps were induced by pairing visual stimulation with electrical activation of the mesencephalic reticular formation. Changes in orientation selectivity were assessed with optical recording of intrinsic signals and multiunit recordings. When conditioning stimuli were associated with strong ɣ-oscillations, orientation domains matching the orientation of the conditioning grating stimulus became more responsive and expanded, because neurons with preferences differing by less than 30° from the orientation of the conditioning grating shifted their orientation preference toward the conditioned orientation. When conditioning stimuli induced no or only weak ɣ-oscillations, responsiveness of neurons driven by the conditioning stimulus decreased. These differential effects depended on the power of oscillations in the low ɣ-band (20 Hz to 48 Hz) and not on differences in discharge rate of cortical neurons, because there was no correlation between the discharge rates during conditioning and the occurrence of changes in orientation preference. Thus, occurrence and polarity of use-dependent long-term changes of cortical response properties appear to depend on the occurrence of ɣ-oscillations during induction and hence on the degree of temporal coherence of the change-inducing network activity. [ABSTRACT FROM AUTHOR]

Alterations in the gut microbiome are associated with the pathogenesis of Alzheimer's disease (AD) and can be used as a diagnostic measure. However, longitudinal data of the gut microbiome and knowledge about its prognostic significance for the development and progression of AD are limited. The aim of the present study was to develop a reliable predictive model based on gut microbiome data for AD development. In this longitudinal study, we investigated the intestinal microbiome in 49 mild cognitive impairment (MCI) patients over a mean (SD) follow-up of 3.7 (0.6) years, using shotgun metagenomics. At the end of the 4-year follow-up (4yFU), 27 MCI patients converted to AD dementia and 22 MCI patients remained stable. The best taxonomic model for the discrimination of AD dementia converters from stable MCI patients included 24 genera, yielding an area under the receiver operating characteristic curve (AUROC) of 0.87 at BL, 0.92 at 1yFU and 0.95 at 4yFU. The best models with functional data were obtained via analyzing 25 GO (Gene Ontology) features with an AUROC of 0.87 at BL, 0.85 at 1yFU and 0.81 at 4yFU and 33 KO [Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog] features with an AUROC of 0.79 at BL, 0.88 at 1yFU and 0.82 at 4yFU. Using ensemble learning for these three models, including a clinical model with the four parameters of age, gender, body mass index (BMI) and Apolipoprotein E (ApoE) genotype, yielded an AUROC of 0.96 at BL, 0.96 at 1yFU and 0.97 at 4yFU. In conclusion, we identified novel and timely stable gut microbiome algorithms that accurately predict progression to AD dementia in individuals with MCI over a 4yFU period. [ABSTRACT FROM AUTHOR]

Simultaneous measurements of intra-cortical electrophysiology and hemodynamic signals in primates are essential for relating human neuroimaging studies with intra-cortical electrophysiology in monkeys. Previously, technically challenging and resourcefully demanding techniques such as fMRI and intrinsic-signal optical imaging have been used for such studies. Functional near-infrared spectroscopy is a relatively less cumbersome neuroimaging method that uses near-infrared light to detect small changes in concentrations of oxy-hemoglobin (HbO), deoxy-hemoglobin (HbR) and total hemoglobin (HbT) in a volume of tissue with high specificity and temporal resolution. FNIRS is thus a good candidate for hemodynamic measurements in primates to acquire local hemodynamic signals during electrophysiological recordings. To test the feasibility of using epidural fNIRS with concomitant extracellular electrophysiology, we recorded neuronal and hemodynamic activity from the primary visual cortex of two anesthetized monkeys during visual stimulation. We recorded fNIRS epidurally, using one emitter and two detectors. We performed simultaneous cortical electrophysiology using tetrodes placed between the fNIRS sensors. We observed robust and reliable responses to the visual stimulation in both [HbO] and [HbR] signals, and quantified the signal-to-noise ratio of the epidurally measured signals. We also observed a positive correlation between stimulus-induced modulation of [HbO] and [HbR] signals and strength of neural modulation. Briefly, our results show that epidural fNIRS detects single-trial responses to visual stimuli on a trial-by-trial basis, and when coupled with cortical electrophysiology, is a promising tool for studying local hemodynamic signals and neurovascular coupling. [ABSTRACT FROM AUTHOR]

Background: Many systems in nature are characterized by complex behaviour where large cascades of events, or avalanches, unpredictably alternate with periods of little activity. Snow avalanches are an example. Often the size distribution f(s) of a system's avalanches follows a power law, and the branching parameter sigma, the average number of events triggered by a single preceding event, is unity. A power law for f(s), and sigma = 1, are hallmark features of self-organized critical (SOC) systems, and both have been found for neuronal activity in vitro. Therefore, and since SOC systems and neuronal activity both show large variability, long-term stability and memory capabilities, SOC has been proposed to govern neuronal dynamics in vivo. Testing this hypothesis is difficult because neuronal activity is spatially or temporally subsampled, while theories of SOC systems assume full sampling. To close this gap, we investigated how subsampling affects f(s) and sigma by imposing subsampling on three different SOC models. We then compared f(s) and sigma of the subsampled models with those of multielectrode local field potential (LFP) activity recorded in three macaque monkeys performing a short term memory task. Results: Neither the LFP nor the subsampled SOC models showed a power law for f(s). Both, f(s) and sigma, depended sensitively on the subsampling geometry and the dynamics of the model. Only one of the SOC models, the Abelian Sandpile Model, exhibited f(s) and sigma similar to those calculated from LFP activity. Conclusion: Since subsampling can prevent the observation of the characteristic power law and sigma in SOC systems, misclassifications of critical systems as sub- or supercritical are possible. Nevertheless, the system specific scaling of f(s) and sigma under subsampling conditions may prove useful to select physiologically motivated models of brain function. Models that better reproduce f(s) and sigma calculated from the physiological recordings may be selected over alternatives. [ABSTRACT FROM AUTHOR]

Oscillatory neural activity in the gamma frequency range (>30Hz) has been shown to accompany a wide variety of cognitive processes. So far, there has been limited success in assigning a unitary basic function to these oscillations, and critics have raised the argument that they could just be an epiphenomenon of neural processing. We propose a new framework that relates gamma oscillations observed in human, as well as in animal, experiments to two underlying processes: the comparison of memory contents with stimulus-related information and the utilization of signals derived from this comparison. This model attempts to explain early gamma-band responses in terms of the match between bottom-up and top-down information. Furthermore, it assumes that late gamma-band activity reflects the readout and utilization of the information resulting from this match. [Copyright &y& Elsevier]

Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology. [ABSTRACT FROM AUTHOR]

Background: It is assumed that speech comprehension deficits in background noise are caused by age-related or acquired hearing loss. Methods: We examined young, middle-aged, and older individuals with and without hearing threshold loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (pDPOAEs), auditory brainstem responses (ABRs), auditory steady-state responses (ASSRs), speech comprehension (OLSA), and syllable discrimination in quiet and noise. Results: A noticeable decline of hearing sensitivity in extended high-frequency regions and its influence on low-frequency-induced ABRs was striking. When testing for differences in OLSA thresholds normalized for PT thresholds (PTTs), marked differences in speech comprehension ability exist not only in noise, but also in quiet, and they exist throughout the whole age range investigated. Listeners with poor speech comprehension in quiet exhibited a relatively lower pDPOAE and, thus, cochlear amplifier performance independent of PTT, smaller and delayed ABRs, and lower performance in vowel-phoneme discrimination below phase-locking limits (/o/-/u/). When OLSA was tested in noise, listeners with poor speech comprehension independent of PTT had larger pDPOAEs and, thus, cochlear amplifier performance, larger ASSR amplitudes, and higher uncomfortable loudness levels, all linked with lower performance of vowel-phoneme discrimination above the phase-locking limit (/i/-/y/). Conslusions: This study indicates that listening in noise in humans has a sizable disadvantage in envelope coding when basilar-membrane compression is compromised. Clearly, and in contrast to previous assumptions, both good and poor speech comprehension can exist independently of differences in PTTs and age, a phenomenon that urgently requires improved techniques to diagnose sound processing at stimulus onset in the clinical routine. [ABSTRACT FROM AUTHOR]

Background: Participation in multimodal leisure activities, such as playing a musical instrument, may be protective against brain aging and dementia in older adults (OA). Potential neuroprotective correlates underlying musical activity remain unclear. Objective: This cross-sectional study investigated the association between lifetime musical activity and resting-state functional connectivity (RSFC) in three higher-order brain networks: the Default Mode, Fronto-Parietal, and Salience networks. Methods: We assessed 130 cognitively unimpaired participants (≥ 60 years) from the baseline cohort of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Lifetime musical activity was operationalized by the self-reported participation in musical instrument playing across early, middle, and late life stages using the Lifetime of Experiences Questionnaire (LEQ). Participants who reported musical activity during all life stages (n = 65) were compared to controls who were matched on demographic and reserve characteristics (including education, intelligence, socioeconomic status, self-reported physical activity, age, and sex) and never played a musical instrument (n = 65) in local (seed-to-voxel) and global (within-network and between-network) RSFC patterns using pre-specified network seeds. Results: Older participants with lifetime musical activity showed significantly higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal as well as frontal regions, namely the right temporal pole and the right precentral gyrus extending into the superior frontal gyrus, compared to matched controls. There were no significant group differences in global RSFC within or between the three networks. Conclusion: We show that playing a musical instrument during life relates to higher RSFC of the medial prefrontal cortex with distant brain regions involved in higher-order cognitive and motor processes. Preserved or enhanced functional connectivity could potentially contribute to better brain health and resilience in OA with a history in musical activity. Trial registration: German Clinical Trials Register (DRKS00007966, 04/05/2015). [ABSTRACT FROM AUTHOR]

Investigates the effect of the activation of the mesencephalic reticular formation (MRF) on the occurrence and feature sensitivity of stimulus-induced response in the visual cortex. Desynchronization effect of the activation of the MRF on electroencephalographic activity.

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 ± 6.09 years; 48.7 % female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memory's mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95 % confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated – and, thus, explained – that association (95 % CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults. [Display omitted] • Adherence to the Mediterranean diet (MeDiAd) can benefit verbal memory in older age. • White matter properties can help explain the relation between MeDiAd and cognition. • Baseline MeDiAd was associated with (latent) verbal episodic memory four years later. • Baseline fornix fractional anisotropy mediated that association. • Fornix mediation was independent of the known mediation by hippocampal volume. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation–inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of BdnfPax2 KO mice. These mice develop an autism‐like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of BdnfPax2 KOs, connected to maturation deficits of high‐spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation–inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high‐spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is often preceded by stages of cognitive impairment, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI). While cerebrospinal fluid (CSF) biomarkers are established predictors of AD, other non‐invasive candidate predictors include personality traits, anxiety, and depression, among others. These predictors offer non‐invasive assessment and exhibit changes during AD development and preclinical stages. Methods: In a cross‐sectional design, we comparatively evaluated the predictive value of personality traits (Big Five), geriatric anxiety and depression scores, resting‐state functional magnetic resonance imaging activity of the default mode network, apoliprotein E (ApoE) genotype, and CSF biomarkers (tTau, pTau181, Aβ42/40 ratio) in a multi‐class support vector machine classification. Participants included 189 healthy controls (HC), 338 individuals with SCD, 132 with amnestic MCI, and 74 with mild AD from the multicenter DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Results: Mean predictive accuracy across all participant groups was highest when utilizing a combination of personality, depression, and anxiety scores. HC were best predicted by a feature set comprised of depression and anxiety scores and participants with AD were best predicted by a feature set containing CSF biomarkers. Classification of participants with SCD or aMCI was near chance level for all assessed feature sets. Conclusion: Our results demonstrate predictive value of personality trait and state scores for AD. Importantly, CSF biomarkers, personality, depression, anxiety, and ApoE genotype show complementary value for classification of AD and its at‐risk stages. Key points: Multi‐class support vector machine classification was used to compare the predictive value of well‐established and non‐invasive, easy‐to‐assess candidate variables for classifying participants with healthy cognition, subjective cognitive decline, amnestic mild cognitive impairment, and mild Alzheimer's disease.Personality traits, geriatric anxiety and depression scores, resting‐state functional magnetic resonance imaging activity of the default mode network, ApoE genotype, and CSF biomarkers were comparatively evaluated.A combination of personality, anxiety, and depression scores provided the highest predictive accuracy, comparable to CSF biomarkers, indicating complementary value.Established and candidate predictors had limited success in classifying SCD and aMCI, underscoring the heterogeneity of these cognitive states and emphasizing the need for standardizing terminology and diagnostic criteria. [ABSTRACT FROM AUTHOR]

Background: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer's disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. Objective: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. Methods: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Results: Group differences approached significance for BF total volume (p = 0.061) and the Ch4 subregion (p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. Conclusions: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at "grey zone" levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert. [ABSTRACT FROM AUTHOR]

Background: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies.Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum.Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum.Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small.Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples. [ABSTRACT FROM AUTHOR]

Abstract: The present work investigates instantaneous synchronization in multivariate signals. It introduces a new method to detect subsets of synchronized time series that do not consider any baseline information. The method is based on a Bayesian Gaussian mixture model applied at each location of a time–frequency map. The work assesses the relevance of detected subsets by a stability measure. The application to Local Field Potentials measured during a visuo-motor experiment in monkeys reveals a subset of synchronized time series measured in the visual cortex. [Copyright &y& Elsevier]

Simultaneous spike-counts of neural populations are typically modeled by a Gaussian distribution. On short time scales, however, this distribution is too restrictive to describe and analyze multivariate distributions of discrete spike-counts. We present an alternative that is based on copulas and can account for arbitrary marginal distributions, including Poisson and negative binomial distributions as well as second and higher-order interactions. We describe maximum likelihood-based procedures for fitting copula-based models to spike-count data, and we derive a so-called flashlight transformation which makes it possible to move the tail dependence of an arbitrary copula into an arbitrary orthant of the multivariate probability distribution. Mixtures of copulas that combine different dependence structures and thereby model different driving processes simultaneously are also introduced. First, we apply copula-based models to populations of integrate-and-fire neurons receiving partially correlated input and show that the best fitting copulas provide information about the functional connectivity of coupled neurons which can be extracted using the flashlight transformation. We then apply the new method to data which were recorded from macaque prefrontal cortex using a multi-tetrode array. We find that copula-based distributions with negative binomial marginals provide an appropriate stochastic model for the multivariate spike-count distributions rather than the multivariate Poisson latent variables distribution and the often used multivariate normal distribution. The dependence structure of these distributions provides evidence for common inhibitory input to all recorded stimulus encoding neurons. Finally, we show that copula-based models can be successfully used to evaluate neural codes, e.g., to characterize stimulus-dependent spike-count distributions with information measures. This demonstrates that copula-based models are not only a versatile class of models for multivariate distributions of spike-counts, but that those models can be exploited to understand functional dependencies. [ABSTRACT FROM AUTHOR]

Neurons can engage in synchronized oscillatory activity in the gamma-frequency range when responding to sensory stimuli. Both the oscillatory patterning and the synchronization of responses are enhanced with arousal and attention or when the electroencephalogram is activated by electrical stimulation of the mesencephalic reticular formation. Here we show with intracortical application of cholinergic antagonists that the enhancement of gamma oscillations and response synchronization is mediated by acetylcholine and muscarinic receptors. We demonstrate further that coapplication of cholinergic agonists with synchrony-inducing light stimuli causes a lasting increase in the probability that the stimulated cells engage in gamma oscillations and response synchronization. These changes develop slowly over tens of minutes and then persist for many hours. Thus, cholinergic modulation plays a crucial role both in the fast, state-dependent facilitation of gamma oscillations and response synchronization and in use-dependent long-term modifications of cortical dynamics that favor synchronization of responses in the gamma-frequency range. [ABSTRACT FROM AUTHOR]

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV) intemeurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ intemeuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV+ intemeuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous y oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies. [ABSTRACT FROM AUTHOR]

Functional brain development is not well understood. In the visual system, neurophysiological studies in nonhuman primates show quite mature neuronal properties near birth although visual function is itself quite immature and continues to develop over many months or years after birth. Our goal was to assess the relative development of two main visual processing streams, dorsal and ventral, using BOLD fMRI in an attempt to understand the global mechanisms that support the maturation of visual behavior. Seven infant macaque monkeys (Macaca mulatta) were repeatedly scanned, while anesthetized, over an age range of 102 to 1431 days. Large rotating checkerboard stimuli induced BOLD activation in visual cortices at early ages. Additionally we used static and dynamic Glass pattern stimuli to probe BOLD responses in primary visual cortex and two extrastriate areas: V4 and MT-V5. The resulting activations were analyzed with standard GLM and multivoxel pattern analysis (MVPA) approaches. We analyzed three contrasts: Glass pattern present/absent, static/dynamic Glass pattern presentation, and structured/random Glass pattern form. For both GLM and MVPA approaches, robust coherent BOLD activation appeared relatively late in comparison to the maturation of known neuronal properties and the development of behavioral sensitivity to Glass patterns. Robust differential activity to Glass pattern present/absent and dynamic/static stimulus presentation appeared first in V1, followed by V4 and MT-V5 at older ages; there was no reliable distinction between the two extrastriate areas. A similar pattern of results was obtained with the two analysis methods, although MVPA analysis showed reliable differential responses emerging at later ages than GLM. Although BOLD responses to large visual stimuli are detectable, our results with more refined stimuli indicate that global BOLD activity changes as behavioral performance matures. This reflects an hierarchical development of the visual pathways. Since fMRI BOLD reflects neural activity on a population level, our results indicate that, although individual neurons might be adult-like, a longer maturation process takes place on a population level. [ABSTRACT FROM AUTHOR]

Self-organized critical (SOC) systems are complex dynamical systems that may express cascades of events, called avalanches. The SOC state was proposed to govern brain function, because of its activity fluctuations over many orders of magnitude, its sensitivity to small input and its long term stability. In addition, the critical state is optimal for information storage and processing. Both hallmark features of SOC systems, a power law distribution f(s) for the avalanche size s and a branching parameter (bp) of unity, were found for neuronal avalanches recorded in vitro. However, recordings in vivo yielded contradictory results. Electrophysiological recordings in vivo only cover a small fraction of the brain, while criticality analysis assumes that the complete system is sampled. We hypothesized that spatial subsampling might influence the observed avalanche statistics. In addition, SOC models can have different connectivity, but always show a power law for f(s) and bp = 1 when fully sampled. This may not be the case under subsampling, however. Here, we wanted to know whether a state change from awake to asleep could be modeled by changing the connectivity of a SOC model without leaving the critical state. We simulated a SOC model and calculated f(s) and bp obtained from sampling only the activity of a set of 4 x 4 sites, representing the electrode positions in the cortex. We compared these results with results obtained from multielectrode recordings of local field potentials (LFP) in the cortex of behaving monkeys. We calculated f(s) and bp for the LFP activity recorded while the monkey was either awake or asleep and compared these results to results obtained from two subsampled SOC model with different connectivity. f(s) and bp were very similar for both the experiments and the subsampled SOC model, but in contrast to the fully sampled model, f(s) did not show a power law and bp was smaller than unity. With increasing the distance between the sampling sites, f(s) changed from "apparently supercritical" to "apparently subcritical" distributions in both the model and the LFP data. f(s) and bp calculated from LFP recorded during awake and asleep differed. These changes could be explained by altering the connectivity in the SOC model. Our results show that subsampling can prevent the observation of the characteristic power law and bp in SOC systems, and misclassifications of critical systems as sub- or supercritical are possible. In addition, a change in f(s) and bp for different states (awake/asleep) does not necessarily imply a change from criticality to sub- or super-criticality, but can also be explained by a change in the effective connectivity of the network without leaving the critical state. [ABSTRACT FROM AUTHOR]

Synchronous spike discharge of cortical neurons is thought to be a fingerprint of neuronal cooperativity. Because neighboring neurons are more densely connected to one another than neurons that are located further apart, near-synchronous spike discharge can be expected to be prevalent and it might provide an important basis for cortical computations. Using microelectrodes to record local groups of neurons does not allow for the reliable separation of synchronous spikes from different cells, because available spike sorting algorithms cannot correctly resolve the temporally overlapping waveforms. We show that high spike sorting performance of in vivo recordings, including overlapping spikes, can be achieved with a recently developed filter-based template matching procedure. Using tetrodes with a three-dimensional structure, we demonstrate with simulated data and ground truth in vitro data, obtained by dual intracellular recording of two neurons located next to a tetrode, that the spike sorting of synchronous spikes can be as successful as the spike sorting of nonoverlapping spikes and that the spatial information provided by multielectrodes greatly reduces the error rates. We apply the method to tetrode recordings from the prefrontal cortex of behaving primates, and we show that overlapping spikes can be identified and assigned to individual neurons to study synchronous activity in local groups of neurons. [ABSTRACT FROM AUTHOR]

The analysis of neuronal processes distributed across multiple cortical areas aims at the identification of interactions between signals recorded at different sites. Such interactions can be described by measuring the stability of phase angles in the case of oscillatory signals or other forms of signal dependencies for less regular signals. Before, however, any form of interaction can be analyzed at a given time and frequency, it is necessary to assess whether all potentially contributing signals are present. We have developed a new statistical procedure for the detection of coincident power in multiple simultaneously recorded analog signals, allowing the classification of events as 'non-accidental co-activation'. This method can effectively operate on single trials, each lasting only for a few seconds. Signals need to be transformed into time-frequency space, e.g. by applying a short-time Fourier transformation using a Gaussian window. The discrete wavelet transform (DWT) is used in order to weight the resulting power patterns according to their frequency. Subsequently, the weighted power patterns are binarized via applying a threshold. At this final stage, significant power coincidence is determined across all subgroups of channel combinations for individual frequencies by selecting the maximum ratio between observed and expected duration of co-activation as test statistic. The null hypothesis that the activity in each channel is independent from the activity in every other channel is simulated by independent, random rotation of the respective activity patterns. We applied this procedure to single trials of multiple simultaneously sampled local field potentials (LFPs) obtained from occipital, parietal, central and precentral areas of three macaque monkeys. Since their task was to use visual cues to perform a precise arm movement, coactivation of numerous cortical sites was expected. In a data set with 17 channels analyzed, up to 13 sites expressed simultaneous power in the range between 5 and 240 Hz. On average, more than 50% of active channels participated at least once in a significant power co-activation pattern (PCP). Because the significance of such PCPs can be evaluated at the level of single trials, we are confident that this procedure is useful to study single trial variability with sufficient accuracy that much of the behavioral variability can be explained by the dynamics of the underlying distributed neuronal processes. [ABSTRACT FROM AUTHOR]

Abstract: Event-related potentials (ERPs) are widely used in basic neuroscience and in clinical diagnostic procedures. In contrast, neurophysiological insights from ERPs have been limited, as several different mechanisms lead to ERPs. Apart from stereotypically repeated responses (additive evoked responses), these mechanisms are asymmetric amplitude modulations and phase-resetting of ongoing oscillatory activity. Therefore, a method is needed that differentiates between these mechanisms and moreover quantifies the stability of a response. We propose a constrained subspace independent component analysis that exploits the multivariate information present in the all-to-all relationship of recordings over trials. Our method identifies additive evoked activity and quantifies its stability over trials. We evaluate identification performance for biologically plausible simulation data and two neurophysiological test cases: Local field potential (LFP) recordings from a visuo-motor-integration task in the awake behaving macaque and magnetoencephalography (MEG) recordings of steady-state visual evoked fields (SSVEFs). In the LFPs we find additive evoked response contributions in visual areas V2/4 but not in primary motor cortex A4, although visually triggered ERPs were also observed in area A4. MEG-SSVEFs were mainly created by additive evoked response contributions. Our results demonstrate that the identification of additive evoked response contributions is possible both in invasive and in non-invasive electrophysiological recordings. [Copyright &y& Elsevier]

Sustained activity in prefrontal cortex is associated with the maintenance of information during short-term memory (STM). We have used impurity reduction criteria of classification trees to investigate how the behavioral performance of a monkey during STM is reflected in the information content of three features of recorded signals: rates of individual neurons, oscillations in the LFP, and oscillations in the spiking activity. The LFP power in all bands, but in the and bands in particular, is more informative than the firing rate of neurons and the spike power with respect to the monkey''s performance. [Copyright &y& Elsevier]

Abstract: Hyperoxia is present in many anaesthesia protocols used in animal blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. However, little data exist on the influence of hyperoxia on the magnitude of stimulus-induced relative changes in BOLD fMRI signal (ΔBOLD%). No study to date has investigated these effects in a time-resolved manner, although cerebral vasoregulation offers sites for a time-dependent interaction of hyperoxia and ΔBOLD%. Here we investigated time-dependent effects of an inspiratory oxygen fraction of 90%. We tightly clamped end tidal CO2 and body temperature and recorded physiological parameters relevant to rCBF in (fentanyl/isoflurane) anaesthetized monkeys while using visual stimulation to elicit ΔBOLD%. To clarify whether changes in ΔBOLD% arose from changes in baseline blood oxygenation or rather altered neuronal or vascular reactivity, we directly measured changes in rCBV using monocrystalline ion oxide nanoparticles (MION) as contrast agent. In visual cortex we found a biphasic modulation of stimulus-induced ΔBOLD% under hyperoxia: We observed first a significant decrease in ΔBOLD% by −24% for data averaged over the time interval of 0–180 min post onset of hyperoxia followed by a subsequent recovery to baseline. rCBV response amplitudes were decreased by 21% in the same time interval (0–180 min). In the LGN, we neither found a significant modulation of ΔBOLD% nor of MION response amplitude. The cerebrovascular effects of hyperoxia may, therefore, be regionally specific and cannot be explained by a deoxyhemoglobin dilution model accounting for plasma oxygenation without assuming altered neuronal activity or altered neurovascular coupling. [Copyright &y& Elsevier]

Working memory (WM) capacity limitations and their neurophysiological correlates are of special relevance for the understanding of higher cognitive functions. Evidence from behavioral studies suggests that restricted attentional resources contribute to these capacity limitations. In an event-related functional magnetic resonance imaging (fMRI) study, we probed the capacity of the human visual WM system for up to four complex nonnatural objects using a delayed discrimination task. A number of prefrontal and parietal areas bilaterally showed increased blood oxygen level-dependent activity, relative to baseline, throughout the task when more than one object had to be held in memory. Monotonic increases in response to memory load were observed bilaterally in the dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (pre-SMA). Conversely, activity in the frontal eye fields (FEFs) and in areas along the intraparietal sulcus (IPS) peaked when subjects had to maintain only two or three objects and decreased in the highest load condition. This dissociation of memory load effects on cortical activity suggests that the cognitive operations subserved by the IPS and FEF, which are most likely related to attention, fail to support visual WM when the capacity limit is approached. The correlation of brain activity with performance implies that only the operations performed by the DLPFC and pre-SMA, which support an integrated representation of visual information, helped subjects to maintain a reasonable level of performance in the highest load condition. These results indicate that at least two distinct cortical subsystems are recruited for visual WM, and that their interplay changes when the capacity limit is reached. [Copyright &y& Elsevier]

Background: Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. Methods: We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. Results: The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996–1.000, p <.05). Conclusion: These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline. Trial registration: German Clinical Trials Register DRKS00007966. Registered 4 May 2015. [ABSTRACT FROM AUTHOR]