Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent

Cortical oscillations play a fundamental role in organizing large-scale functional brain networks. Noninvasive brain stimulation with temporally patterned waveforms such as repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) have been proposed to modulate these oscillations. Thus, these stimulation modalities represent promising new approaches for the treatment of psychiatric illnesses in which these oscillations are impaired. However, the mechanism by which periodic brain stimulation alters endogenous oscillation dynamics is debated and appears to depend on brain state. Here, we demonstrate with a static model and a neural oscillator model that recurrent excitation in the thalamo-cortical circuit, together with recruitment of cortico-cortical connections, can explain the enhancement of oscillations by brain stimulation as a function of brain state. We then performed concurrent invasive recording and stimulation of the human cortical surface to elucidate the response of cortical oscillations to periodic stimulation and support the findings from the computational models. We found that (1) stimulation enhanced the targeted oscillation power, (2) this enhancement outlasted stimulation, and (3) the effect of stimulation depended on behavioral state. Together, our results show successful target engagement of oscillations by periodic brain stimulation and highlight the role of nonlinear interaction between endogenous network oscillations and stimulation. These mechanistic insights will contribute to the design of adaptive, more targeted stimulation paradigms.     

The functional importance of rhythmic activity in the brain

Oscillations in brain activity have long been known, but many fundamental aspects of such brain rhythms, particularly their functional importance, have been unclear. As we review here, new insights into these issues are emerging from the application of intervention approaches. In these approaches, the timing of brain oscillations is manipulated by non-invasive brain stimulation, either through sensory input or transcranially, and the behavioural consequence then monitored. Notably, such manipulations have led to rapid, periodic fluctuations in behavioural performance, which co-cycle with underlying brain oscillations. Such findings establish a causal relationship between brain oscillations and behaviour, and are allowing novel tests of longstanding models about the functions of brain oscillations. VIDEO ABSTRACT:     

节律性听觉刺激下的神经振荡同步化及其应用

大脑的感觉、情绪、认知等功能与其神经振荡模式有密切的联系。通过施加节律性刺激可以调控大脑的神经振荡模式,进而影响个体感受、情绪状态和认知功能等。与近年来常见的非侵入性电刺激和磁刺激相比,同样依赖于外部刺激输入的节律性感觉刺激具有成本低、易操作等优点,被认为是一种极具潜力的神经调控手段。本文以节律性听觉刺激为例,系统综述了不同类型的节律性听觉刺激如何影响大脑的神经振荡模式,进而影响相关状态和功能;并通过总结外部节律性听觉刺激对个体感知觉、情绪与认知功能的影响,讨论其生理机制和应用前景。     

Model for receptor-controlled cytosolic calcium oscillations and for external influences on the signal pathway.

The external stimulation of many cells by a hormone, for example, often leads to an oscillating cytosolic calcium concentration. This periodic behavior is now designated the cytosolic calcium oscillator. A theoretical model is presented that describes this behavior on the basis of inositol(1,4,5)trisphosphate-induced calcium oscillations. In contrast to other models only a single positive feedback loop is taken into account to obtain oscillations. The model includes important innovations compared to other approaches. It includes the contribution of extracellular calcium and its modification after the stimulation of the cell. Furthermore, the signal pathway that leads to cytosolic calcium oscillations is described in more detail than in other models. This enables investigations on the influence of additional parameters like external electromagnetic fields on the signal transduction pathway. The model and the calculations are based on the theory of nonlinear self-sustained oscillators.     

Activity patterns in networks stabilized by background oscillations

The brain operates in a highly oscillatory environment. We investigate here how such an oscillating background can create stable organized behavior in an array of neuro-oscillators that is not observable in the absence of oscillation, much like oscillating the support point of an inverted pendulum can stabilize its up position, which is unstable without the oscillation. We test this idea in an array of electronic circuits coming from neuroengineering: we show how the frequencies of the background oscillation create a partition of the state space into distinct basins of attraction. Thus, background signals can stabilize persistent activity that is otherwise not observable. This suggests that an image, represented as a stable firing pattern which is triggered by a voltage pulse and is sustained in synchrony or resonance with the background oscillation, can persist as a stable behavior long after the initial stimulus is removed. The background oscillations provide energy for organized behavior in the array, and these behaviors are categorized by the basins of attraction determined by the oscillation frequencies. Supported in part by FENA/FCRP Grant No. 0160-G-FD211.     

Crosstalk between the peripheral nervous system and breast cancer influences tumor progression

Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as β-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.     

Brain enabled by next-generation neurotechnology: using multiscale and multimodal models

As many articles in this issue of IEEE Pulse demonstrate, interfacing directly with the brain presents several fundamental challenges. These challenges reside at multiple levels and span many disciplines, ranging from the need to understand brain states at the level of neural circuits to creating technological innovations to facilitate new therapeutic options. The goal of our multiuniversity research team, composed of researchers from Stanford University, Brown University, the University of California at San Francisco (UCSF), and the University College London (UCL), is to substantially elevate the fundamental understanding of brain information processing and its relationship with sensation, behavior, and injury. Our team was assembled to provide expertise ranging from neuroscience to neuroengineering and to neurological and psychiatric clinical guidance, all of which are critical to the overarching research goal. By employing a suite of innovative experimental, computational, and theoretical approaches, the Defense Advanced Research Projects Agency (DARPA) Reorganization and Plasticity to Accelerate Injury Recovery (REPAIR) team has set its sights on learning how the brain and its microcircuitry react (e.g., to sudden physiological changes) and what can be done to encourage recovery from such (reversible) injury. In this article, we summarize some of the team's technical goals, approaches, and early illustrative results.     

Methods for parameter identification in oscillatory networks and application to cortical and thalamic 600 Hz activity.

Directed information transfer in the human brain occurs presumably by oscillations. As of yet, most approaches for the analysis of these oscillations are based on time-frequency or coherence analysis. The present work concerns the modeling of cortical 600 Hz oscillations, localized within the Brodmann Areas 3b and 1 after stimulation of the nervus medianus, by means of coupled differential equations. This approach leads to the so-called parameter identification problem, where based on a given data set, a set of unknown parameters of a system of ordinary differential equations is determined by special optimization procedures. Some suitable algorithms for this task are presented in this paper. Finally an oscillatory network model is optimally fitted to the data taken from ten volunteers.     

极低频磁场对激动剂诱发钙振荡的影响

从激动剂诱发钙振荡的非线性动力学模型出发, 通过数值计算分析极低频磁场对胞内游离钙离子浓度［Ｃａ２ ＋ ］ｉ 的影响。研究结果表明：只有当外加磁场的频率与胞内钙振荡的特征频率相近时,极低频磁场才会对该细胞的［Ｃａ２ ＋］ｉ 产生影响;由于激动剂诱发钙振荡的动力学模型中的许多参数是因细胞而异的,因此极低频磁场对［Ｃａ２ ＋ ］ｉ 的影响具有显著的个体差异     

Electrifying rhythms in plant cells

Physiological oscillations (or rhythms) pervade all spatiotemporal scales of biological organization, either because they perform critical functions or simply because they can arise spontaneously and may be difficult to prevent. Regardless of the case, they reflect regulatory relationships between control points of a given system and offer insights as read-outs of the concerted regulation of a myriad of biological processes. Here we review recent advances in understanding ultradian oscillations (period < 24h) in plant cells, with a special focus on single-cell oscillations. Ion channels are at the center stage due to their involvement in electrical/excitabile phenomena associated with oscillations and cell-cell communication. We highlight the importance of quantitative approaches to measure oscillations in appropriate physiological conditions, which are essential strategies to deal with the complexity of biological rhythms. Future development of optogenetics techniques in plants will further boost research on the role of membrane potential in oscillations and waves across multiple cell types.     

Somatic evoked high-frequency magnetic oscillations reflect activity of inhibitory interneurons in the human somatosensory cortex

High-frequency potential oscillations in the range of 300–900 Hz have recently been shown to concur with the primary response (N20) of the somatosensory cortex in awake humans. However, the physiological mechanisms of the high-frequency oscillations remained undetermined. We addressed the issue by analyzing magnetic fields during wakefulness and sleep over the left hemisphere to right median nerve stimulation with a wide bandpass (0.1–2000 Hz) recording with subsequent high-pass (> 300 Hz) and low-pass (< 300 Hz) filtering. With wide bandpass recordings, high-frequency magnetic oscillations with the main signal energy at 580–780 Hz were superimposed on the N20m during wakefulness. Isofield mapping at each peak of the high-pass filtered and isolated high-frequency oscillations showed a dipolar pattern and the estimated source for these peaks was the primary somatosensory cortex (area 3b) very close to that for the N20m peak. During sleep, the high-frequency oscillations showed dramatic diminution in amplitude while the N20m amplitude exhibited a moderate increment. This reciprocal relation between the high-frequency oscillations and the N20m during a wake-sleep cycle suggests that they represent different generator substrates. We speculate that the high-frequency oscillations represent a localized activity of the GABAergic inhibitory interneurons of layer 4, which have been shown in animal experiments to respond monosynaptically to thalamo-cortical input with a high-frequency (600–900 Hz) burst of short duration spikes. On the other hand, the underlying N20m represents activity of pyramidal neurons which receive monosynaptic excitatory input from the thalamus as well as a feed-forward inhibition from the interneurons.     

Sustained neural rhythms reveal endogenous oscillations supporting speech perception

Rhythmic sensory or electrical stimulation will produce rhythmic brain responses. These rhythmic responses are often interpreted as endogenous neural oscillations aligned (or “entrained”) to the stimulus rhythm. However, stimulus-aligned brain responses can also be explained as a sequence of evoked responses, which only appear regular due to the rhythmicity of the stimulus, without necessarily involving underlying neural oscillations. To distinguish evoked responses from true oscillatory activity, we tested whether rhythmic stimulation produces oscillatory responses which continue after the end of the stimulus. Such sustained effects provide evidence for true involvement of neural oscillations. In Experiment 1, we found that rhythmic intelligible, but not unintelligible speech produces oscillatory responses in magnetoencephalography (MEG) which outlast the stimulus at parietal sensors. In Experiment 2, we found that transcranial alternating current stimulation (tACS) leads to rhythmic fluctuations in speech perception outcomes after the end of electrical stimulation. We further report that the phase relation between electroencephalography (EEG) responses and rhythmic intelligible speech can predict the tACS phase that leads to most accurate speech perception. Together, we provide fundamental results for several lines of research—including neural entrainment and tACS—and reveal endogenous neural oscillations as a key underlying principle for speech perception.

Just as a child on a swing continues to move after the pushing stops, this study reveals similar entrained rhythmic echoes in brain activity after hearing speech and electrical brain stimulation; perturbation with tACS shows that these brain oscillations help listeners to understand speech.     

Alpha-Band Rhythms in Visual Task Performance: Phase-Locking by Rhythmic Sensory Stimulation

Oscillations are an important aspect of neuronal activity. Interestingly, oscillatory patterns are also observed in behaviour, such as in visual performance measures after the presentation of a brief sensory event in the visual or another modality. These oscillations in visual performance cycle at the typical frequencies of brain rhythms, suggesting that perception may be closely linked to brain oscillations. We here investigated this link for a prominent rhythm of the visual system (the alpha-rhythm, 8–12 Hz) by applying rhythmic visual stimulation at alpha-frequency (10.6 Hz), known to lead to a resonance response in visual areas, and testing its effects on subsequent visual target discrimination. Our data show that rhythmic visual stimulation at 10.6 Hz: 1) has specific behavioral consequences, relative to stimulation at control frequencies (3.9 Hz, 7.1 Hz, 14.2 Hz), and 2) leads to alpha-band oscillations in visual performance measures, that 3) correlate in precise frequency across individuals with resting alpha-rhythms recorded over parieto-occipital areas. The most parsimonious explanation for these three findings is entrainment (phase-locking) of ongoing perceptually relevant alpha-band brain oscillations by rhythmic sensory events. These findings are in line with occipital alpha-oscillations underlying periodicity in visual performance, and suggest that rhythmic stimulation at frequencies of intrinsic brain-rhythms can be used to reveal influences of these rhythms on task performance to study their functional roles.     

综述: 知觉相关的神经振荡-外界节律同步化现象

具有特定频率的节律性刺激能同步大脑内相应频率的神经振荡,使神经活动与外界刺激发生相位锁定,称之为神经振荡-外界节律同步化(neural entrainment).这种同步化的现象伴随着大脑内神经元集群兴奋水平的周期性波动,并与节律信息加工、知觉及注意等认知过程存在关联.得益于其非侵入、易操作以及能有效调控神经活动的特性,神经振荡-外界节律同步化成为了研究神经振荡与知觉和认知功能关系的有力手段,也为认知障碍诊断及干预提供了新的思路和方法.     

Dihydroxyacetone-induced oscillations in cytoplasmic free Ca2+ and the ATP/ADP ratio in pancreatic beta-cells at substimulatory glucose

Glucose stimulation of pancreatic beta-cells causes oscillatory influx of Ca2+, leading to pulsatile insulin secretion. We have proposed that this is due to oscillations of glycolysis and the ATP/ADP ratio, which modulate the activity of ATP-sensitive K+ channels. We show here that dihydroxyacetone, a secretagogue that feeds into glycolysis below the putative oscillator phosphofructokinase, could cause a single initial peak in cytoplasmic free Ca2+ ([Ca2+]i) but did not by itself cause repeated oscillations in [Ca2+]i in mouse pancreatic beta-cells. However, in the presence of a substimulatory concentration of glucose (4 mm), dihydroxyacetone induced [Ca2+]i oscillations. Furthermore, these oscillations correlated with oscillations in the ATP/ADP ratio, as seen previously with glucose stimulation. Insulin secretion in response to dihydroxyacetone was transient in the absence of glucose but was considerably enhanced and somewhat prolonged in the presence of a substimulatory concentration of glucose, in accordance with the enhanced [Ca2+]i response. These results are consistent with the hypothesized role of phosphofructokinase as the generator of the oscillations. Dihydroxyacetone may affect phosphofructokinase by raising the free concentration of fructose 1,6-bisphosphate to a critical level at which it activates the enzyme autocatalytically, thereby inducing the pulses of phosphofructokinase activity that cause the metabolic oscillations.     

Transcranial electrical currents to probe EEG brain rhythms and memory consolidation during sleep in humans

Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (～0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8-12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25-45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies.     

Cytosolic Ca2+ oscillations in REF52 fibroblasts: Ca(2+)-stimulated IP3 production or voltage-dependent Ca2+ channels as key positive feedback elements.

Oscillations in cytosolic free calcium concentrations ([Ca2+]i) can be elicited in REF52 fibroblasts by three different modes of stimulation. We have previously demonstrated that [Ca2+]i oscillations result when these cells are simultaneously depolarized and stimulated with a hormone linked to phosphoinositide breakdown. Further evidence is now presented that such oscillations are linked to fluctuations in the concentration of IP3 and the Ca2+ content of an IP3-sensitive Ca2+ store. [Ca2+]i oscillations can also be generated in REF52 cells either by direct stimulation of G-proteins with GTP gamma S or AlF4- or by destabilizing the membrane potential and opening voltage-dependent calcium channels. This report compares the different types of oscillations and their mechanisms.     

Brain stimulation competes with ongoing oscillations for control of spike timing in the primate brain

Transcranial alternating current stimulation (tACS) is a popular method for modulating brain activity noninvasively. In particular, tACS is often used as a targeted intervention that enhances a neural oscillation at a specific frequency to affect a particular behavior. However, these interventions often yield highly variable results. Here, we provide a potential explanation for this variability: tACS competes with the brain’s ongoing oscillations. Using neural recordings from alert nonhuman primates, we find that when neural firing is independent of ongoing brain oscillations, tACS readily entrains spiking activity, but when neurons are strongly entrained to ongoing oscillations, tACS often causes a decrease in entrainment instead. Consequently, tACS can yield categorically different results on neural activity, even when the stimulation protocol is fixed. Mathematical analysis suggests that this competition is likely to occur under many experimental conditions. Attempting to impose an external rhythm on the brain may therefore often yield precisely the opposite effect.

Transcranial alternating current stimulation (tACS) is a popular method for modulating brain activity noninvasively; however, tACS can often yield highly variable results. This study shows that when neurons are strongly entrained to ongoing oscillations, tACS often causes a decrease in entrainment instead of the expected enhancement.     

A mathematical model of oxygen transport in intact muscle with imposed surface oscillations

A one-dimensional (1D) reaction-diffusion equation is presented to model oxygen delivery by the microcirculation and oxygen diffusion and consumption in intact muscle. This model is motivated by in vivo experiments in which oscillatory boundary conditions are used to study the mechanisms of local blood flow regulation in response to changes in the tissue oxygen environment. An exact periodic solution is presented for the 1D 'in vivo' model and shown to agree with experimental data for the case where the blood flow regulation system is not activated. Approximate low- and high-frequency solutions are presented, and the latter is shown to agree with the pure diffusion solution in the absence of sources or sinks. For the low frequencies considered experimentally, the 1D in vivo model shows that as depth increases: (i) the mean of tissue O(2) oscillations changes exponentially, (ii) the amplitude of oscillations decreases very rapidly, and (iii) the phase of oscillations remains nearly the same as that of the imposed surface oscillations. The 1D in vivo model also shows that the dependence on depth of the mean, amplitude, and phase of tissue O(2) oscillations is nearly the same for all stimulation periods >30s, implying that experimentally varying the forcing period in this range will not change the spatial distribution of the O(2) stimulation.     

Characteristic features of electron-ion collisions in strong electric fields

The classical motion of an electron in the Coulomb field of an ion and in a uniform external electric field is analyzed. A nondimensionalization method that makes it possible to study electron motion in arbitrarily strong electric fields is proposed. The possible electron trajectories in the plane of motion in a static field are classified. It is noted that, from a practical standpoint, the most interesting trajectories are snakelike trajectories, which are absent in the problem with a weak external field. An adiabatic approximation for transverse electron motions in quasistatic (strong) fields is constructed. A one-dimensional equation of motion is derived that accounts for transverse electron oscillations and the increase in the effective electron mass as an electron approaches an ion. An analytic model is used to calculate the spectra of bremsstrahlung generated by individual electrons. The calculated results are shown to agree well with the results of direct numerical integration of the basic equations. It is predicted that, at frequencies higher than the frequency of the incident light, pronounced peaks can appear in the spectrum of the transverse dipole moment of an electron; as a result, an electron is expected to effectively emit radiation at these frequencies in the direction of the external field.