Impact of sample size and regression of tissue-specific signals on effective connectivity within the core default mode network.

Interactions within brain networks are inherently directional, which are inaccessible to classical functional connectivity estimates from resting-state functional magnetic resonance imaging (fMRI) but can be detected using spectral dynamic causal modeling (DCM). The sample size and unavoidable presence of nuisance signals during fMRI measurement are the two important factors influencing the stability of group estimates of connectivity parameters. However, most recent studies exploring effective connectivity (EC) have been conducted with small sample sizes and minimally pre-processed datasets. We explore the impact of these two factors by analyzing clean resting-state fMRI data from 330 unrelated subjects from the Human Connectome Project database. We demonstrate that both the stability of the model selection procedures and the inference of connectivity parameters are highly dependent on the sample size. The minimum sample size required for stable DCM is approximately 50, which may explain the variability of the DCM results reported so far. We reveal a stable pattern of EC within the core default mode network computed for large sample sizes and demonstrate that the use of subject-specific thresholded whole-brain masks for tissue-specific signals regression enhances the detection of weak connections.

Treatment Tone Spacing and Acute Effects of Acoustic Coordinated Reset Stimulation in Tinnitus Patients.

Acoustic coordinated reset (aCR) therapy for tinnitus aims to desynchronize neuronal populations in the auditory cortex that exhibit pathologically increased coincident firing. The original therapeutic paradigm involves fixed spacing of four low-intensity tones centered around the frequency of a tone matching the tinnitus pitch, f T , but it is unknown whether these tones are optimally spaced for induction of desynchronization. Computational and animal studies suggest that stimulus amplitude, and relatedly, spatial stimulation profiles, of coordinated reset pulses can have a major impact on the degree of desynchronization achievable. In this study, we transform the tone spacing of aCR into a scale that takes into account the frequency selectivity of the auditory system at each therapeutic tone's center frequency via a measure called the gap index. Higher gap indices are indicative of more loosely spaced aCR tones. The gap index was found to be a significant predictor of symptomatic improvement, with larger gap indices, i.e., more loosely spaced aCR tones, resulting in reduction of tinnitus loudness and annoyance scores in the acute stimulation setting. A notable limitation of this study is the intimate relationship of hearing impairment with the gap index. Particularly, the shape of the audiogram in the vicinity of the tinnitus frequency can have a major impact on tone spacing. However, based on our findings we suggest hypotheses-based experimental protocols that may help to disentangle the impact of hearing loss and tone spacing on clinical outcome, to assess the electrophysiologic correlates of clinical improvement, and to elucidate the effects following chronic rather than acute stimulation.

Acoustic coordinated reset therapy for tinnitus with perceptually relevant frequency spacing and levels.

Acoustic coordinated reset (CR) therapy based on neuromodulation and neuroplasticity principles has been proposed for the treatment of tonal tinnitus. The original therapy involved periodic delivery of randomly ordered sequences of four low-level tones centered around the frequency of a tone that matched the tinnitus pitch, fT, with fixed ratios relative to fT and delivered several hours/day over several weeks. Here we transform the original CR tone selection method to a more perceptually-relevant equivalent rectangular bandwidth (ERB) frequency scale, the ERBN-number scale. Specifically, we provide a mathematical model that enables calculation of CR tones that accounts for fT- and hearing loss-related ERB widening and ERB overlaps and gaps of CR tone alignments. Further, the model ensures symmetric CR tone alignments based on modelling studies that indicate the effect is optimal if the CR stimuli are symmetrically spaced relative to the tinnitus-related population of abnormally synchronized cortical neurons to activate the adjacent sub-populations. We also present experimentally testable ERB-based CR tone alignment strategies and explain how to use the ERB-based model in experiments, clinical studies, other types of tinnitus sound treatment such as tailor-made notch music training and limitations of our approach.

Impact of acoustic coordinated reset neuromodulation on effective connectivity in a neural network of phantom sound.

Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As recently shown in a proof of concept clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms combined with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas. The objective of the present study was to analyze whether CR therapy caused an alteration of the effective connectivity in a tinnitus related network of localized EEG brain sources. To determine which connections matter, in a first step, we considered a larger network of brain sources previously associated with tinnitus. To that network we applied a data-driven approach, combining empirical mode decomposition and partial directed coherence analysis, in patients with bilateral tinnitus before and after 12 weeks of CR therapy as well as in healthy controls. To increase the signal-to-noise ratio, we focused on the good responders, classified by a reliable-change-index (RCI). Prior to CR therapy and compared to the healthy controls, the good responders showed a significantly increased connectivity between the left primary cortex auditory cortex and the posterior cingulate cortex in the gamma and delta bands together with a significantly decreased effective connectivity between the right primary auditory cortex and the dorsolateral prefrontal cortex in the alpha band. Intriguingly, after 12 weeks of CR therapy most of the pathological interactions were gone, so that the connectivity patterns of good responders and healthy controls became statistically indistinguishable. In addition, we used dynamic causal modeling (DCM) to examine the types of interactions which were altered by CR therapy. Our DCM results show that CR therapy specifically counteracted the imbalance of excitation and inhibition. CR significantly weakened the excitatory connection between posterior cingulate cortex and primary auditory cortex and significantly strengthened inhibitory connections between auditory cortices and the dorsolateral prefrontal cortex. The overall impact of CR therapy on the entire tinnitus-related network showed up as a qualitative transformation of its spectral response, in terms of a drastic change of the shape of its averaged transfer function. Based on our findings we hypothesize that CR therapy restores a silence based cognitive auditory comparator function of the posterior cingulate cortex.

Data-driven approach to the estimation of connectivity and time delays in the coupling of interacting neuronal subsystems.

One of the challenges in neuroscience is the detection of directionality between signals reflecting neural activity. To reveal the directionality of coupling and time delays between interacting multi-scale signals, we use a combination of a data-driven technique called empirical mode decomposition (EMD) and partial directed coherence (PDC) together with the instantaneous causality test (ICT). EMD is used to separate multiple processes associated with different frequency bands, while PDC and ICT allow to explore directionality and characteristic time delays, respectively. We computationally validate our approach for the cases of both stochastic and chaotic oscillatory systems with different types of coupling. Moreover, we apply our approach to the analysis of the connectivity in different frequency bands between local field potentials (LFPs) bilaterally recorded from the left and right of subthalamic nucleus (STN) in patients with Parkinson's disease (PD). We reveal a bidirectional coupling between the left and right STN in the beta-band (10-30 Hz) for an akinetic PD patient and in the tremor band (3-5 Hz) for a tremor-dominant PD patient. We detect a short time delay, most probably reflecting the inter-hemispheric transmission time. Additionally, in both patients we observe a long time delay of approximately a mean period of the beta-band activity in the akinetic PD patient or the tremor band activity in the tremor-dominant PD patient. These long delays may emerge in subcortico-thalamic loops or longer pathways, comprising reflex loops, respectively. We show that the replacement of EMD by conventional bandpass filtering complicates the detection of directionality and leads to a spurious detection of time delays.

Computational modeling of paroxysmal depolarization shifts in neurons induced by the glutamate release from astrocytes.

Recent experimental studies have shown that astrocytes respond to external stimuli with a transient increase of the intracellular calcium concentration or can exhibit self-sustained spontaneous activity. Both evoked and spontaneous astrocytic calcium oscillations are accompanied by exocytosis of glutamate caged in astrocytes leading to paroxysmal depolarization shifts (PDS) in neighboring neurons. Here, we present a simple mathematical model of the interaction between astrocytes and neurons that is able to numerically reproduce the experimental results concerning the initiation of the PDS. The timing of glutamate release from the astrocyte is studied by means of a combined modeling of a vesicle cycle and the dynamics of SNARE-proteins. The neuronal slow inward currents (SICs), induced by the astrocytic glutamate and leading to PDS, are modeled via the activation of presynaptic glutamate receptors. The dependence of the bidirectional communication between neurons and astrocytes on the concentration of glutamate transporters is analyzed, as well. Our numerical results are in line with experimental findings showing that astrocyte can induce synchronous PDSs in neighboring neurons, resulting in a transient synchronous spiking activity.