Spontaneous Activity Fluctuations Research Articles

Spontaneous traveling waves naturally emerge from horizontal fiber time delays and travel through locally asynchronous-irregular states

Studies of sensory-evoked neuronal responses often focus on mean spike rates, with fluctuations treated as internally-generated noise. However, fluctuations of spontaneous activity, often organized as traveling waves, shape stimulus-evoked responses and perceptual sensitivity. The mechanisms underlying these waves are unknown. Further, it is unclear whether waves are consistent with the low rate and weakly correlated “asynchronous-irregular” dynamics observed in cortical recordings. Here, we describe a large-scale computational model with topographically-organized connectivity and conduction delays relevant to biological scales. We find that spontaneous traveling waves are a general property of these networks. The traveling waves that occur in the model are sparse, with only a small fraction of neurons participating in any individual wave. Consequently, they do not induce measurable spike correlations and remain consistent with locally asynchronous irregular states. Further, by modulating local network state, they can shape responses to incoming inputs as observed in vivo.

How do the blind 'see'? The role of spontaneous brain activity in self-generated perception.

Spontaneous activity of the human brain has been well documented, but little is known about the functional role of this ubiquitous neural phenomenon. It has previously been hypothesized that spontaneous brain activity underlies unprompted (internally generated) behaviour. We tested whether spontaneous brain activity might underlie internally-generated vision by studying the cortical visual system of five blind/visually-impaired individuals who experience vivid visual hallucinations (Charles Bonnet syndrome). Neural populations in the visual system of these individuals are deprived of external input, which may lead to their hyper-sensitization to spontaneous activity fluctuations. To test whether these spontaneous fluctuations can subserve visual hallucinations, the functional MRI brain activity of participants with Charles Bonnet syndrome obtained while they reported their hallucinations (spontaneous internally-generated vision) was compared to the: (i) brain activity evoked by veridical vision (externally-triggered vision) in sighted controls who were presented with a visual simulation of the hallucinatory streams; and (ii) brain activity of non-hallucinating blind controls during visual imagery (cued internally-generated vision). All conditions showed activity spanning large portions of the visual system. However, only the hallucination condition in the Charles Bonnet syndrome participants demonstrated unique temporal dynamics, characterized by a slow build-up of neural activity prior to the reported onset of hallucinations. This build-up was most pronounced in early visual cortex and then decayed along the visual hierarchy. These results suggest that, in the absence of external visual input, a build-up of spontaneous fluctuations in early visual cortex may activate the visual hierarchy, thereby triggering the experience of vision.

Challenges and future directions for representations of functional brain organization.

A key principle of brain organization is the functional integration of brain regions into interconnected networks. Functional MRI scans acquired at rest offer insights into functional integration via patterns of coherent fluctuations in spontaneous activity, known as functional connectivity. These patterns have been studied intensively and have been linked to cognition and disease. However, the field is fractionated. Diverging analysis approaches have segregated the community into research silos, limiting the replication and clinical translation of findings. A primary source of this fractionation is the diversity of approaches used to reduce complex brain data into a lower-dimensional set of features for analysis and interpretation, which we refer to as brain representations. In this Primer, we provide an overview of different brain representations, lay out the challenges that have led to the fractionation of the field and that continue to form obstacles for convergence, and propose concrete guidelines to unite the field.

Unstructured network topology begets order-based representation by privileged neurons

How spiking activity reverberates through neuronal networks, how evoked and spontaneous activity interacts and blends, and how the combined activities represent external stimulation are pivotal questions in neuroscience. We simulated minimal models of unstructured spiking networks in silico, asking whether and how gentle external stimulation might be subsequently reflected in spontaneous activity fluctuations. Consistent with earlier findings in silico and in vitro, we observe a privileged subpopulation of ‘pioneer neurons’ that, by their firing order, reliably encode previous external stimulation. We also confirm that pioneer neurons are ‘sensitive’ in that they are recruited by small fluctuations of population activity. We show that order-based representations rely on a ‘chain’ of pioneer neurons with different degrees of sensitivity and thus constitute an emergent property of collective dynamics. The forming of such representations is greatly favoured by a broadly heterogeneous connection topology—a broad ‘middle class’ in degree of connectedness. In conclusion, we offer a minimal model for the representational role of pioneer neurons, as observed experimentally in vitro. In addition, we show that broadly heterogeneous connectivity enhances the representational capacity of unstructured networks.

Timescales of spontaneous fMRI fluctuations relate to structural connectivity in the brain.

Intrinsic timescales of activity fluctuations vary hierarchically across the brain. This variation reflects a broad gradient of functional specialization in information storage and processing, with integrative association areas displaying slower timescales that are thought to reflect longer temporal processing windows. The organization of timescales is associated with cognitive function, distinctive between individuals, and disrupted in disease, but we do not yet understand how the temporal properties of activity dynamics are shaped by the brain’s underlying structural connectivity network. Using resting-state fMRI and diffusion MRI data from 100 healthy individuals from the Human Connectome Project, here we show that the timescale of resting-state fMRI dynamics increases with structural connectivity strength, matching recent results in the mouse brain. Our results hold at the level of individuals, are robust to parcellation schemes, and are conserved across a range of different timescale- related statistics. We establish a comprehensive BOLD dynamical signature of structural connectivity strength by comparing over 6,000 time series features, highlighting a range of new temporal features for characterizing BOLD dynamics, including measures of stationarity and symbolic motif frequencies. Our findings indicate a conserved property of mouse and human brain organization in which a brain region’s spontaneous activity fluctuations are closely related to their surrounding structural scaffold.

Cortical Statistical Correlation Tomography of EEG Resting State Networks.

Resting state networks (RSNs) have been found in human brains during awake resting states. RSNs are composed of spatially distributed regions in which spontaneous activity fluctuations are temporally and dynamically correlated. A new computational framework for reconstructing RSNs with human EEG data has been developed in the present study. The proposed framework utilizes independent component analysis (ICA) on short-time Fourier transformed inverse source maps imaged from EEG data and statistical correlation analysis to generate cortical tomography of electrophysiological RSNs. The proposed framework was evaluated on three sets of resting-state EEG data obtained in the comparison of two conditions: (1) healthy controls with eyes closed and eyes open; (2) healthy controls and individuals with a balance disorder; (3) individuals with a balance disorder before and after receiving repetitive transcranial magnetic stimulation (rTMS) treatment. In these analyses, the same group of five RSNs with similar spatial and spectral patterns were successfully reconstructed by the proposed framework from each individual EEG dataset. These EEG RSN tomographic maps showed significant similarity with RSN templates derived from functional magnetic resonance imaging (fMRI). Furthermore, significant spatial and spectral differences of RSNs among compared conditions were observed in tomographic maps as well as their spectra, which were consistent with findings reported in the literature. Beyond the success of reconstructing EEG RSNs spatially on the cortical surface as in fMRI studies, this novel approach defines RSNs further with spectra, providing a new dimension in understanding and probing basic neural mechanisms of RSNs. The findings in patients' data further demonstrate its potential in identifying biomarkers for the diagnosis and treatment evaluation of neuropsychiatric disorders.

Spontaneous activity forms a foundation for odor-evoked activation maps in the rat olfactory bulb

Fluctuations in spontaneous activity have been observed by many neuroimaging techniques, but because these resting-state changes are not evoked by stimuli, it is difficult to determine how they relate to task-evoked activations. We conducted multi-modal neuroimaging scans of the rat olfactory bulb, both with and without odor, to examine interaction between spontaneous and evoked activities. Independent component analysis of spontaneous fluctuations revealed resting-state networks, and odor-evoked changes revealed activation maps. We constructed simulated activation maps using resting-state networks that were highly correlated to evoked activation maps. Simulated activation maps derived by intrinsic optical signal (IOS), which covers the dorsal portion of the glomerular sheet, significantly differentiated one odor's evoked activation map from the other two. To test the hypothesis that spontaneous activity of the entire glomerular sheet is relevant for representing odor-evoked activations, we used functional magnetic resonance imaging (fMRI) to map the entire glomerular sheet. In contrast to the IOS results, the fMRI-derived simulated activation maps significantly differentiated all three odors' evoked activation maps. Importantly, no evoked activation maps could be significantly differentiated using simulated activation maps produced using phase-randomized resting-state networks. Given that some highly organized resting-state networks did not correlate with any odors' evoked activation maps, we posit that these resting-state networks may characterize evoked activation maps associated with odors not studied. These results emphasize that fluctuations in spontaneous activity form a foundation for active processing, signifying the relevance of resting-state mapping to functional neuroimaging.

Visual experience sculpts whole-cortex spontaneous infraslow activity patterns through an Arc-dependent mechanism

Decades of work in experimental animals has established the importance of visual experience during critical periods for the development of normal sensory-evoked responses in the visual cortex. However, much less is known concerning the impact of early visual experience on the systems-level organization of spontaneous activity. Human resting-state fMRI has revealed that infraslow fluctuations in spontaneous activity are organized into stereotyped spatiotemporal patterns across the entire brain. Furthermore, the organization of spontaneous infraslow activity (ISA) is plastic in that it can be modulated by learning and experience, suggesting heightened sensitivity to change during critical periods. Here we used wide-field optical intrinsic signal imaging in mice to examine whole-cortex spontaneous ISA patterns. Using monocular or binocular visual deprivation, we examined the effects of critical period visual experience on the development of ISA correlation and latency patterns within and across cortical resting-state networks. Visual modification with monocular lid suturing reduced correlation between left and right cortices (homotopic correlation) within the visual network, but had little effect on internetwork correlation. In contrast, visual deprivation with binocular lid suturing resulted in increased visual homotopic correlation and increased anti-correlation between the visual network and several extravisual networks, suggesting cross-modal plasticity. These network-level changes were markedly attenuated in mice with genetic deletion of Arc, a gene known to be critical for activity-dependent synaptic plasticity. Taken together, our results suggest that critical period visual experience induces global changes in spontaneous ISA relationships, both within the visual network and across networks, through an Arc-dependent mechanism.

Ultrasensitivity and fluctuations in the Barkai-Leibler model of chemotaxis receptors in Escherichia coli.

A stochastic version of the Barkai-Leibler model of chemotaxis receptors in Escherichia coli is studied here with the goal of elucidating the effects of intrinsic network noise in their conformational dynamics. The model was originally proposed to explain the robust and near-perfect adaptation of E. coli observed across a wide range of spatially uniform attractant/repellent (ligand) concentrations. In the model, a receptor is either active or inactive and can stochastically switch between the two states. The enzyme CheR methylates inactive receptors while CheB demethylates active receptors and the probability for a receptor to be active depends on its level of methylation and ligand occupation. In a simple version of the model with two methylation sites per receptor (M = 2), we show rigorously, under a quasi-steady state approximation, that the mean active fraction of receptors is an ultrasensitive function of [CheR]/[CheB] in the limit of saturating receptor concentration. Hence the model shows zero-order ultrasensitivity (ZOU), similar to the classical two-state model of covalent modification studied by Goldbeter and Koshland (GK). We also find that in the limits of extremely small and extremely large ligand concentrations, the system reduces to two different two-state GK modules. A quantitative measure of the spontaneous fluctuations in activity is provided by the variance in the active fraction, which is estimated mathematically under linear noise approximation (LNA). It is found that peaks near the ZOU transition. The variance is a non-monotonic, but weak function of ligand concentration and a decreasing function of receptor concentration. Gillespie simulations are also performed in models with M = 2, 3 and 4. For M = 2, simulations show excellent agreement with analytical results obtained under LNA. Numerical results for M = 3 and M = 4 are qualitatively similar to our mathematical results in M = 2; while all the models show ZOU in mean activity, the variance is found to be smaller for larger M. The magnitude of receptor noise deduced from available experimental data is consistent with our predictions. A simple analysis of the downstream signaling pathway shows that this noise is large enough to affect the motility of the organism, and may have a beneficial effect on it. The response of mean receptor activity to small time-dependent changes in the external ligand concentration is computed within linear response theory, and found to have a bilobe form, in agreement with earlier experimental observations.

Spontaneous population activity fluctuations boost sensory tuning curves and gate information processing

Background Sensory cortex often undergoes population activity fluctuations due to attentional modulations and arousal changes, but activity fluctuations can also be generated intrinsically. The mechanisms that underlie these spontaneous activity fluctuations are unknown, in particular whether they arise from common inputs or more active neuronal processes. We measured the activity of tens of V1 neurons simultaneously in monkeys stimulated with oriented visual stimuli, and found that the tuning curves (TCs) of orientation selective neurons spontaneously underwent shifts and multiplicative scalings proportional to population activity while their widths remained constant Based on this observed TC activity dependence, we constructed a precise statistical model featuring Poissonlike firing, shifts and gain modulation. The model not only accounted for neuronal co-variability but also approached the performance of state-of-art decoding methods. Surprisingly, we found that decoding performance on sensory stimuli increased with population activity, despite the fact that the stimulus was identical. Therefore, spontaneous population activity fluctuations display highly non-random features, boosting TCs by shifts and multiplicative factors that gate information processing.

The relation of ongoing brain activity, evoked neural responses, and cognition.

Ongoing brain activity has been observed since the earliest neurophysiological recordings and is found over a wide range of temporal and spatial scales. It is characterized by remarkably large spontaneous modulations. Here, we review evidence for the functional role of these ongoing activity fluctuations and argue that they constitute an essential property of the neural architecture underlying cognition. The role of spontaneous activity fluctuations is probably best understood when considering both their spatiotemporal structure and their functional impact on cognition. We first briefly argue against a “segregationist” view on ongoing activity, both in time and space, which would selectively associate certain frequency bands or levels of spatial organization with specific functional roles. Instead, we emphasize the functional importance of the full range, from differentiation to integration, of intrinsic activity within a hierarchical spatiotemporal structure. We then highlight the flexibility and context-sensitivity of intrinsic functional connectivity that suggest its involvement in functionally relevant information processing. This role in information processing is pursued by reviewing how ongoing brain activity interacts with afferent and efferent information exchange of the brain with its environment. We focus on the relationship between the variability of ongoing and evoked brain activity, and review recent reports that tie ongoing brain activity fluctuations to variability in human perception and behavior. Finally, these observations are discussed within the framework of the free-energy principle which – applied to human brain function – provides a theoretical account for a non-random, coordinated interaction of ongoing and evoked activity in perception and behavior.

So Many Choices: What Computational Models Reveal about Decision-Making Mechanisms

Is decision making in the brain (a) optimal, (b) stochastic, (c) probabilistic, or (d) all of the above? Two papers in this issue of Neuron by Beck et al. and Furman and Wang address these questions by constructing model neural circuits capable of picking one option given multiple perceptual choices.

Sensory Memory for Odors Is Encoded in Spontaneous Correlated Activity Between Olfactory Glomeruli

Sensory memory is a short-lived persistence of a sensory stimulus in the nervous system, such as iconic memory in the visual system. However, little is known about the mechanisms underlying olfactory sensory memory. We have therefore analyzed the effect of odor stimuli on the first odor-processing network in the honeybee brain, the antennal lobe, which corresponds to the vertebrate olfactory bulb. We stained output neurons with a calcium-sensitive dye and measured across-glomerular patterns of spontaneous activity before and after a stimulus. Such a single-odor presentation changed the relative timing of spontaneous activity across glomeruli in accordance with Hebb's theory of learning. Moreover, during the first few minutes after odor presentation, correlations between the spontaneous activity fluctuations suffice to reconstruct the stimulus. As spontaneous activity is ubiquitous in the brain, modifiable fluctuations could provide an ideal substrate for Hebbian reverberations and sensory memory in other neural systems.

Spontaneous activity and electrical coupling in human detrusor smooth muscle: implications for detrusor overactivity?

Large uncontrollable detrusor contractions, decreased compliance that increases luminal pressures during filling, and detrusor underactivity are all examples of abnormal bladder function. Studies of the nervous control of lower urinary tract function and measurement of the cellular properties of the component tissues of the bladder wall have been performed to deepen our knowledge of these problems. The resultant data have suggested that lower urinary tract smooth muscle should not be regarded solely as a collection of independent cellular contractile units that are each activated by separate neural inputs, but also as a syncytium of cells. Although this syncytial arrangement may not be as well developed as in other tissues, it should impose a new layer of activity that will affect overall bladder function. Recent studies have addressed this issue through investigation of spontaneous contractile activity, the cellular basis of syncytial function, and their normal and abnormal functional consequences. The results suggest that individual detrusor cells possess membrane properties that may lead to spontaneous activity fluctuations, which can affect adjacent cells and, thus, produce multicellular aberrant responses. It remains unclear whether these responses manifest themselves as dysfunctional activity in the whole bladder defects because the extent of local multicellular abnormalities is not known at present. The data do imply that myogenic defects can contribute to abnormal bladder function and, thus, suggest several new targeted drug models that should be explored.

Is state-dependent alternation of slow dynamics in central single neurons during sleep present in the rat ventroposterior thalamic nucleus?

Based upon our previous results in cats, we hypothesized that neurons in the central processor systems of the brain generally exhibit state-dependent dynamics alternation of slow fluctuations in spontaneous activity during sleep. To test the validity of this hypothesis across species, we recorded single neuronal activity during sleep from the ventroposterior (VP) thalamic nucleus in unanesthetized, head-restrained rats. Spectral analysis was performed on successive spike-counts of neuronal activity recorded during three stages of the sleep-wakefulness cycle: wakefulness (W, n=6), slow-wave sleep (SWS, n=20), and paradoxical sleep (PS, n=32). We found that firing of VP neurons displayed white-noise-like dynamics over the range of 0.04–1.0 Hz during SWS and 1/ f-noise-like dynamics over the same range during PS. We also demonstrated for the first time that the slow dynamics of neuronal activity during quiet wakefulness (but not drowsiness) are white-noise-like. These results suggest that our hypothesis is true across species. During W and SWS, the brain may be considered as under global inhibition. Conversely, PS may represent a state of global disinhibition in the brain, where neuronal activity exhibits 1/ f-noise-like dynamics. Fluctuations observed in living organisms may be involved in essential processes in generation and function of sleep states.

Neoplastic Cell Activation And Proliferative Response To CD40-Ligand Characterize Recurrent Leukemic Bouts In An Unusual Case Of Low Grade Lymphoma

Spontaneous fluctuations in activity of low-grade B cell lymphomas are common but not understood. An explanation may be offered by studying an atypical SLL/CLL case characterized by recurrent cycles of leukemic phase alternating with spontaneous remission (1). During remissions, residual IgMK+ leukemic cells exhibited resting phenotype, low proliferative response to CD40-ligand and delayed apoptosis. In contrast, the acute phase counterparts were phenotypically activated, underwent rapid apoptosis in culture and proliferated extensively in response to membrane-anchored CD40-ligand. Transient bursts of serum TNFa and IL-10 preceded the acute phases, which were characterized by the co-existence of CD40-ligand+ T lymphocytes and lymphoma cells in the bone marrow. Based on ex-vivo and in-vitro data, we suggest that changes in the lymphoma milieu affect the neoplastic cell activation status, rate of proliferation in response to activated T cells and rate of apoptosis. These responses may underlie both the induction and spontaneous regression of the acute phases in this unique lymphoma. Our findings raise the possibility that part of this mechanism may have evolved during transformation of indolent common CLL to its more aggressive form.

Response properties of chemosensory peg sensilla on the pectines of scorpions.

By behavioral and anatomical criteria, the pectinal sensory appendages of scorpions appear to be chemoreceptive organs specialized for detection of substances on substrates. These comb-like, midventral appendages contain tens of thousands of minute (< 5 microns), truncated setae, called pegs, arranged in dense, two-dimensional arrays on the ventral surface. In this study we used extracellular recording techniques to examine spontaneous and stimulated activity of sensory neurons within individual pegs. Chronic recordings lasting several days showed long-term fluctuations in spontaneous activity of sensory units in single peg sensilla, with peak activity coinciding with the animal's normal period of foraging. Several units were identified by the stereotypical waveforms of action potentials they elicit. Near-range olfactory stimulation of peg sensilla by volatile alcohols, aldehydes, ketones, esters, and carboxylic acids produced dose-dependent patterns of neural response. Contact stimulation with these chemicals, or water, or mechanical deflection of the peg tip also evoked activity in identifiable units. The peg sensilla appear to be broadly sensitive to odorants and tastants, suggesting they function similarly to the antennae of mandibulate arthropods.

Responses of on and off cells in the rostral ventral medulla to stimulation of vagal afferents and changes in mean arterial blood pressure in intact and cardiopulmonary deafferented rats

The relationships between mean arterial blood pressure (MAP) and the activity of putative pain modulatory neurons of the rostroventral medulla (ON and OFF cells) were determined in intact and cardiopulmunary deafferented rats. A total of 173 neurons were recorded from 97 rats as follows: 32 ON cells and 25 OFF cells from 39 intact rats; 32 ON cells and 20 OFF cells from 24 rats with bilateral sino-aortic deafferentation (SAD); 12 ON cells and 20 OFF cells from 19 rats with bilateral cervical vagotomy (CVAG); and 20 ON cells and 12 OFF cells from 15 rats with both SAD and CVAG. ON and OFF cells showed spontaneous fluctuations in activity such that ON cell activity was negatively correlated with MAP whereas OFF cell activity was positively correlated with MAP under conditions of no applied stimuli. These correlations were present in both intact and cardiopulmonary deafferented rats. Further, experimentally induced increases in MAP decreased ON cell activity and increased OFF cell activity in intact rats, but not in rats with SAD, CVAG, or the combination of SAD and CVAG. Experimentally induced decreases in MAP decreased OFF cell activity in intact rats and rats with CVAG, but not in rats with SAD or the combination of SAD and CVAG. These findings indicate that ON and OFF cells are modulated by baroreceptor activity, but baroreceptor input is not necessary for the spontaneous fluctuations in ON and OFF cell activity. Electrical stimulation of vagal afferents (VAS) inhibited 60% of the OFF cells studied, excited 4%, and produced biphasic effects consisting of excitation at low intensities and inhibition at greater intensities in 28% of all OFF cells. In general, VAS excited the majority of the ON cells studied, although there were significant differences between effects in intact and cardiopulmonary deafferented rats. Greater intensities of VAS that inhibited OFF cells and excited ON cells also inhibited the tail flick. Thus, inhibition of OFF cells and excitation of ON cells was correlated with antinociception. The effects of intravenous (i.v.) administration of 1.0 mg/kg morphine on neuronal activity did not differ between intact and cardiopulmonary deafferented rats. Intravenous administration of morphine produced a sustained inhibition of 20.7% of all ON cells studied, produced a biphasic effect consisting of a brief excitation followed by a sustained inhibition in 62.1% of the ON cells, and had no effect on the activity of 17.2% of the ON cells. Morphine-produced inhibition of ON cell activity was reversed by i.v. administration of naloxone HCl, but was not affected by i.v. administration of naloxone methobromide (NMB). However, pre-treatment with NMB attenuated the initial morphine-produced excitation of ON cells. In studies of OFF cells, i.v. administration of morphine excited 40.0% of the OFF cells, produced a biphasic effect consisting of an initial inhibition followed by excitation in 33.3% of the OFF cells, and had no effect on the activity of 26.7% of the OFF cells. Naloxone HCl reversed the effects of morphine within 1 min after administration, whereas NMB had no effect on the morphine-produced excitation of OFF cells. Intravenous administration of morphine following pre-treatment with NMB excited the 2 OFF cells studied. These data suggest that ON and OFF cells in the rostroventral medulla not only receive converging input from cardiopulmonary and somatic afferents, but may also function in the regulation of both systems. Specifically, the excitation of ON cells and inhibition of OFF cells may decrease MAP and nociception, whereas the inhibition of ON cells and excitation of OFF cells may increase MAP and nociception. This hypothesis contradicts previous hypotheses suggesting that inhibition of ON cells and excitation of OFF cells attenuates nociception indicating that current hypotheses on the function of ON and OFF cells require further analyses.

Functioning of catfish electroreceptors: Statistical distribution of sensitivity and fluctuations of spontaneous activity

1. Properties of electroreceptors (small pits) in the dorsal skin of the head of catfish,Ictalurus nebulosus, were determined by recording the impulse activity from the lumen of individual receptors in intact fish. 2. The sensitivity of a small pit to sinusoidal current was defined as the difference of the maximum and minimum average impulse frequency during the stimulus period, divided by the stimulus current. 3. The statistical distribution of the sensitivity was found to be unimodal, with a modus at 0.5 Hz/nA. The sensitivity of 96% of the small pits is between 0.04 and 1.6 Hz/nA (Fig. 1). 4. The input/output relation of the small pits (impulse frequency versus stimulus current) is sigmoidal, but has a nearly linear segment at small stimulus amplitudes (Fig. 3). 5. The statistical distribution of the mean spontaneous impulse frequency has a modus at 40 Hz. The spontaneous activity of 95% of the small pits is between 15 and 70 Hz (Fig. 2). 6. The frequency of the spontaneous activity of individual small pits fluctuates considerably. The standard deviation (RMS value) of this “frequency noise” is between 6 and 35 Hz, and varies little with sensitivity (Fig. 5). 7. Both the sensitivity and the frequency noise are reduced by an outward current of 0.5 to 6 μA, and by exposition to a calcium free medium. 8. The origin of these phenomena in the receptor structures is discussed.