When and How to Interpret Null Results in NIBS: A Taxonomy Based on Prior Expectations and Experimental Design

Experiments often challenge the null hypothesis that an intervention, for instance application of non-invasive brain stimulation (NIBS), has no effect on an outcome measure. In conventional statistics, a positive result rejects that hypothesis, but a null result is meaningless. Informally, however, researchers often do find null results meaningful to a greater or lesser extent. We present a model to guide interpretation of null results in NIBS research. Along a “gradient of surprise,” from Replication nulls through Exploration nulls to Hypothesized nulls, null results can be less or more surprising in the context of prior expectations, research, and theory. This influences to what extent we should credit a null result in this greater context. Orthogonal to this, experimental design choices create a “gradient of interpretability,” along which null results of an experiment, considered in isolation, become more informative. This is determined by target localization procedure, neural efficacy checks, and power and effect size evaluations. Along the latter gradient, we concretely propose three “levels of null evidence.” With caveats, these proposed levels C, B, and A, classify how informative an empirical null result is along concrete criteria. Lastly, to further inform, and help formalize, the inferences drawn from null results, Bayesian statistics can be employed. We discuss how this increasingly common alternative to traditional frequentist inference does allow quantification of the support for the null hypothesis, relative to support for the alternative hypothesis. It is our hope that these considerations can contribute to the ongoing effort to disseminate null findings alongside positive results to promote transparency and reduce publication bias

Oscillatory delta and theta frequencies differentially support multiple items encoding to optimize memory performance during the digit span task

The human brain has limited storage capacity often challenging the encoding and recall of a long series of multiple items. Different encoding strategies are therefore employed to optimize performance in memory processes such as chunking where particular items are ‘grouped’ to reduce the number of items to store artificially. Additionally, related to the position of an item within a series, there is a tendency to remember the first and last items on the list better than the middle ones, which calls the “serial position effect”. Although relatively well-established in behavioral research, the neuronal mechanisms underlying such encoding strategies and memory effects remain poorly understood. Here, we used event-related EEG oscillation analyses to unravel the neuronal substrates of serial encoding strategies and effects during the behaviorally controlled execution of the digit span task. We recorded EEG in forty-four healthy young-adult participants during a backward digit span (ds) task with two difficulty levels (i.e., 3-ds and 5-ds). Participants were asked to recall the digits in reverse order after the presentation of each set. We analyzed the pattern of event-related delta and theta oscillatory power in the time-frequency domain over fronto-central and parieto-occipital areas during the item (digit) list encoding, focusing on how these oscillatory responses changed with each subsequent digit being encoded in the series. Results showed that the development of event-related delta power evoked by digits in each series matched the ‘serial position curve’, with higher delta power being present during the first, and especially last, digits as compared to digits presented in the middle of a set, for both difficulty levels. Event-related theta power, in contrast, rather resembled a neural correlate of a chunking pattern where, during the 5-ds encoding, a clear change in event-related theta occurred around the third/fourth positions, with decreasing power values for later digits. This suggests that different oscillatory mechanisms linked to different frequency bands may code for the different encoding strategies and effects in serial item presentation. Furthermore, recall-EEG correlations suggested that participants with higher fronto-central delta responses during digit encoding showed also higher recall scores. The here presented findings contribute to our understanding of the neural oscillatory mechanisms underlying multiple item encoding, directly informing recent efforts towards memory enhancement through targeted oscillation-based neuromodulation.Türkiye Bilimsel ve Teknolojik Araştırma Kurum

Oscillatory Correlates of Visual Consciousness

Conscious experiences are linked to activity in our brain: the neural correlates of consciousness (NCC). Empirical research on these NCCs covers a wide range of brain activity signals, measures, and methodologies. In this paper, we focus on spontaneous brain oscillations; rhythmic fluctuations of neuronal (population) activity which can be characterized by a range of parameters, such as frequency, amplitude (power), and phase. We provide an overview of oscillatory measures that appear to correlate with conscious perception. We also discuss how increasingly sophisticated techniques allow us to study the causal role of oscillatory activity in conscious perception (i.e., ‘entrainment’). This review of oscillatory correlates of consciousness suggests that, for example, activity in the alpha-band (7–13 Hz) may index, or even causally support, conscious perception. But such results also showcase an increasingly acknowledged difficulty in NCC research; the challenge of separating neural activity necessary for conscious experience to arise (prerequisites) from neural activity underlying the conscious experience itself (substrates) or its results (consequences)

Phase of beta-frequency tACS over primary motor cortex modulates corticospinal excitability

The assessment of corticospinal excitability by means of transcranial magnetic stimulation-induced motor evoked potentials is an established diagnostic tool in neurophysiology and a widely used procedure in fundamental brain research. However, concern about low reliability of these measures has grown recently. One possible cause of high variability of MEPs under identical acquisition conditions could be the influence of oscillatory neuronal activity on corticospinal excitability. Based on research showing that transcranial alternating current stimulation can entrain neuronal oscillations we here test whether alpha or beta frequency tACS can influence corticospinal excitability in a phase-dependent manner. We applied tACS at individually calibrated alpha- and beta-band oscillation frequencies, or we applied sham tACS. Simultaneous single TMS pulses time locked to eight equidistant phases of the ongoing tACS signal evoked MEPs. To evaluate offline effects of stimulation frequency, MEP amplitudes were measured before and after tACS. To evaluate whether tACS influences MEP amplitude, we fitted one-cycle sinusoids to the average MEPs elicited at the different phase conditions of each tACS frequency. We found no frequency-specific offline effects of tACS. However, beta-frequency tACS modulation of MEPs was phase-dependent. Post hoc analyses suggested that this effect was specific to participants with low (<19 Hz) intrinsic beta frequency. In conclusion, by showing that beta tACS influences MEP amplitude in a phase-dependent manner, our results support a potential role attributed to neuronal oscillations in regulating corticospinal excitability. Moreover, our findings may be useful for the development of TMS protocols that improve the reliability of MEPs as a meaningful tool for research applications or for clinical monitoring and diagnosis

Where Are the fMRI Correlates of Phosphene Perception?

Pulses of transcranial magnetic stimulation (TMS) over occipital cortex can induce transient visual percepts called phosphenes. Phosphenes are an interesting stimulus for the study of the human visual system, constituting conscious percepts without visual inputs, elicited by neural activation beyond retinal and subcortical processing stages in the visual hierarchy. The same TMS pulses, applied at threshold intensity phosphene threshold (PT), will prompt phosphene reports on half of all trials (“P-yes”) but not on the other half (“P-no”). Contrasting brain activity (P-yes &gt; P-no) can provide unique information on neural mechanisms underlying conscious percepts, as has been demonstrated by published EEG studies. Yet to our knowledge no articles reporting analogous contrasts with functional magnetic resonance imaging (fMRI) have been published. Since it seems unlikely that such studies have never been performed, this straightforward and technically feasible idea may have been explored in multiple failed, and unpublished, attempts. Here, we argue why such unsuccessful attempts, even small-scale, best be shared. We also report our own failed attempt to find phosphene-related activity in fMRI. Threshold phosphenes are weak percepts, and their detection subjective and difficult. If fMRI correlates of phosphenes are obtainable with this contrast, small-scale (‘pilot’) measurements may not be sufficiently powerful to detect them. At the same time, due to the challenges and costs involved in TMS-fMRI, attempts might not often get beyond the piloting stage. We propose that the only way out of this quandary is the communication and sharing of such unsuccessful attempts and associated data

Stimulus Presentation at Specific Neuronal Oscillatory Phases Experimentally Controlled with tACS: Implementation and Applications

In recent years it has become increasingly clear that both the power and phase of oscillatory brain activity can influence the processing and perception of sensory stimuli. Transcranial alternating current stimulation (tACS) can phase-align and amplify endogenous brain oscillations and has often been used to control and thereby study oscillatory power. Causal investigation of oscillatory phase is more difficult, as it requires precise real-time temporal control over both oscillatory phase and sensory stimulation. Here, we present hardware and software solutions allowing temporally precise presentation of sensory stimuli during tACS at desired tACS phases, enabling causal investigations of oscillatory phase. We developed freely available and easy to use software, which can be coupled with standard commercially available hardware to allow flexible and multi-modal stimulus presentation (visual, auditory, magnetic stimuli, etc.) at pre-determined tACS-phases, opening up a range of new research opportunities. We validate that stimulus presentation at tACS phase in our setup is accurate to the sub-millisecond level with high inter-trial consistency. Conventional methods investigating the role of oscillatory phase such as magneto-/electroencephalography can only provide correlational evidence. Using brain stimulation with the described methodology enables investigations of the causal role of oscillatory phase. This setup turns oscillatory phase into an independent variable, allowing innovative and systematic studies of its functional impact on perception and cognition

A chronometric exploration of high-resolution ‘sensitive TMS masking’ effects on subjective and objective measures of vision

Transcranial magnetic stimulation (TMS) can induce masking by interfering with ongoing neural activity in early visual cortex. Previous work has explored the chronometry of occipital involvement in vision by using single pulses of TMS with high temporal resolution. However, conventionally TMS intensities have been high and the only measure used to evaluate masking was objective in nature. Recent studies have begun to incorporate subjective measures of vision, alongside objective ones. The current study goes beyond previous work in two regards. First, we explored both objective vision (an orientation discrimination task) and subjective vision (a stimulus visibility rating on a four-point scale), across a wide range of time windows with high temporal resolution. Second, we used a very sensitive TMS-masking paradigm: stimulation was at relatively low TMS intensities, with a figure-8 coil, and the small stimulus was difficult to discriminate already at baseline level. We hypothesized that this should increase the effective temporal resolution of our paradigm. Perhaps for this reason, we are able to report a rather interesting masking curve. Within the classical-masking time window, previously reported to encompass broad SOAs anywhere between 60 and 120 ms, we report not one, but at least two dips in objective performance, with no masking in-between. The subjective measure of vision did not mirror this pattern. These preliminary data from our exploratory design suggest that, with sensitive TMS masking, we might be able to reveal visual processes in early visual cortex previously unreported

Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances

Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances

Frequency-controlled electrophoretic mobility of a particle within a porous, hollow shell

The unique properties of yolk-shell or rattle-type particles make them promising candidates for applications ranging from switchable photonic crystals, to catalysts, to sensors. To realize many of these applications it is important to gain control over the dynamics of the core particle independently of the shell. Hypothesis: The core particle may be manipulated by an AC electric field with rich frequency-dependent behavior. Experiments: Here, we explore the frequency-dependent dynamic electrophoretic mobility of a charged core particle within a charged, porous shell in AC electric fields both experimentally using liquid-phase electron microscopy and numerically via the finite-element method. These calculations solve the Poisson-Nernst-Planck-Stokes equations, where the core particle moves according to the hydrodynamic and electric forces acting on it. Findings: In experiments the core exhibited three frequency-dependent regimes of field-driven motion: (i) parallel to the field, (ii) diffusive in a plane orthogonal to the field, and (iii) unbiased random motion. The transitions between the three observed regimes can be explained by the level of matching between the time required to establish ionic gradients in the shell and the period of the AC field. We further investigated the effect of shell porosity, ionic strength, and inner-shell radius. The former strongly impacted the core's behavior by attenuating the field inside the shell. Our results provide physical understanding on how the behavior of yolk-shell particles may be tuned, thereby enhancing their potential for use as building blocks for switchable photonic crystals