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Infralow Frequencies and Ultradian Rhythms
Abstract
Our brain activity demonstrates amazing stability across multiple time frames ranging from a few milliseconds to several hours. The longer cycles are commonly called ultradian rhythms and they correspond to infralow frequencies (ILFs) in the milli-Hz range (0.001Hz). Ultradian rhythms between 90 minutes and 2 hours or longer are readily observed in our electroencephalogram, and they reflect periods of activity and rest, cycles of cortical excitability and plasticity followed by relative inactivity. Our nightly sleep is organized into similar stages (rapid eye movement and non-rapid eye movement sleep) as is our daily behavior (ie, the basic rest-activity cycle). Astrocytes often exhibit milli-Hz ILFs, and they play a major role in shaping neuronal plasticity and activity, and thus may organize or influence the basic rhythms of sleep and waking. The nature and importance of astrocytes in human brain functioning is subsequently reviewed.
... Tables 1 and 3 and S1, Supplemental Reference Material]. Two are geological [139,140], one is combined geological-biological [141], and the remaining thirty-eight are biological [64][65][66][67][68][69]114,122,125,. ...
... Pulsatile fuel-regulatory hormones (multiple mammalian species) are listed in an extensive review by Weigle [142]. Additional cyclic phenomena include: brain ultradian oscillations [66]; ultradian relationships among autonomic, cardiovascular and neuroendocrine systems [152]; cell cycles [149,151,156]; Ca +2 fluxes [66]; human hypnotic ultradian owl/lark synchrony [157]; and ultradian rhythms in mind-body communication [154]. At the level of microorganisms, whole populations of E. coli were genetically engineered to express a fluorescent protein in synchrony, thereby producing coordinated pulses of light [156]. ...
... Pulsatile fuel-regulatory hormones (multiple mammalian species) are listed in an extensive review by Weigle [142]. Additional cyclic phenomena include: brain ultradian oscillations [66]; ultradian relationships among autonomic, cardiovascular and neuroendocrine systems [152]; cell cycles [149,151,156]; Ca +2 fluxes [66]; human hypnotic ultradian owl/lark synchrony [157]; and ultradian rhythms in mind-body communication [154]. At the level of microorganisms, whole populations of E. coli were genetically engineered to express a fluorescent protein in synchrony, thereby producing coordinated pulses of light [156]. ...
Primary scientific literature documents frequency oscillations in both the geosphere and the biosphere arising from a host of different phenomena. At certain frequencies there are known associations between geological oscillations and biological oscillations. This raises the question as to whether these phenomena are functionally related. A compilation of the literature was undertaken, covering a spectral range of 18 orders-of-magnitude extending from 955 Ky/cycle (1.29E-14 Hz) to 0.10 ms/cycle (1.00E+4 Hz), noting those frequencies where there was geological-biological concordance. Concordance was determined for 28 frequency groupings distributed in 10 defined cycle bands within the geological-biological spectrum. The ultradian component of the circadian cycle band was the only band showing little geological-biological concordance, with concordance only at its extreme high-frequency values. Of the 384 references examined reporting geological or biological frequencies, 21 specifically mention concordances between geological and biological oscillations. Further, there are geological and biological frequencies where there are no apparent concordances between the two data sets, indicating that the histogram presented is far from a random distribution. At frequencies where there exists geological and biological concordance, a geological frequency can entrain biological frequencies and provoke a biological response. Lower frequencies affect populations; higher frequencies affect individual organisms. Frequencies of geological-biological concordance provide opportunity for the establishment of multiple interrelated zeitgebers, with disruption of these relationships potentially resulting in physiologic dysfunction, predisposing organisms toward the development of pathology and/or extinction.
Key Words:α-waves; Aristotle; Atlantic multidecadal oscillation; B-waves; β-waves; brain waves; Brunt–Väisälä; C-waves; circadian; δ-waves; Earth hum; Einstein; entrainment; frequency; geological-biological concordance; γ-waves; geomagnetic storm; glacial-interglacial; heart rate variability; hormone; hydroacoustic tremor; Kelvin waves; Lonquet-Higgins; Lunar; M-waves; Madden-Julian; microseisms; Milanković; origin of life; oscillation; populations; progenote; R-waves; Rossby waves; Schumann; solar cycle; synchrony; θ-waves; Traube-Hering waves; ultradian; V-signal; weekly; zeitgeber
Available at: https://www.researchgate.net/publication/318769341_GEOLOGICAL_AND_BIOLOGICAL_OSCILLATIONS_A_HOLISTIC_CONTINUOUS_SPECTRUM_Geological_and_Biological_Oscillations DOI: 10.13140/RG.2.2.25189.70888
... Circadian, ultradian and infradian cycles are physiological, mental and behavioural patterns of activity that exhibit approximately stable periodicity at time scales of different lengths [1][2][3][4][5][6][7][8]. A large body of evidence has been accumulated establishing a direct link between physiological systems and central and peripheral biological clocks, as well as their disturbances in disease [9]. ...
... These results show that, at the group level, daily average motion probabilities are very similar in shape, but are shifted one from the other: the control group tends to go to bed and wake up earlier than the insomniac group; and while this is true, at the interval [10][11][12][13][14][15][16][17][18][19][20] h both groups tend to exhibit qualitatively similar features, indicating that albeit small differences, both groups behave quite similar in at least some hours of the day. This is better observed with group-wise PDFs plotted against each other as in figure 1e, where it can be observed that waking up ( [6][7][8] h) and going to bed ( [22][23][24] h) are quite different processes between groups. Finally, presented in figure 1f, the Jaccard distance as a function of temporal displacement is useful to reveal the temporal shift between control and insomniac groups τ min ≈ 90 min. ...
Both parametric and non-parametric approaches to time-series analysis have advantages and drawbacks. Parametric methods, although powerful and widely used, can yield inconsistent results due to the oversimplification of the observed phenomena. They require the setting of arbitrary constants for their creation and refinement, and, although these constants relate to assumptions about the observed systems, it can lead to erroneous results when treating a very complex problem with a sizable list of unknowns. Their non-parametric counterparts, instead, are more widely applicable but present a higher detrimental sensitivity to noise and low density in the data. For the case of approximately periodic phenomena, such as human actigraphic time series, parametric methods are widely used and concepts such as acrophase are key in chronobiology, especially when studying healthy and diseased human populations. In this work, we present a non-parametric method of analysis of actigraphic time series from insomniac patients and healthy age-matched controls. The method is fully data-driven, reproduces previous results in the context of activity offset delay and, crucially, extends the concept of acrophase not only to circadian but also for ultradian spectral components.
... Information processing in the brain is not a static linear process but involves serial, parallel, and feedback pathways that are differentially activated across circadian and ultradian cycles [4][5][6][7][8][9][10][11]. This dynamic process allows, through temporal binding of neuronal activity between areas, the integration and retrieval of multimodal information [12][13][14] but also allows the formation of memory engrams through strengthening and pruning of synapses [9,15]. ...
... This frontohippocampal reciprocal communication allows for memory consolidation by strengthening synaptic engrams and pruning irrelevant synapses, thus economically optimizing brain function. Such a state-dependent pattern seems to also exist during wakefulness, with ultradian rhythms showing a similar duration to sleep cycles [4,32,33], although the lack of clear state separation makes individual state contributions to learning and memory consolidation less clear. Nonetheless, studies indicate that learning and memory consolidation, encephalographic activity, brainstem neurophysiological activity, and molecular pathways of long-term potentiation also abide to ultradian modulation during wakefulness [34][35][36][37][38]. ...
This perspective binds emerging evidence on the bidirectional relationship between Alzheimer's disease (AD) and sleep disorders through a model of brain rhythm attractor breakdown. This approach explains behavioral-cognitive changes in AD across the sleep-wake cycle and supports a causal association between early brainstem tau pathology and subsequent cortical amyloid-β accumulation. Specifically, early tau dysregulation within brainstem-hypothalamic nuclei leads to breakdown of sleep-wake attractor networks, with patients displaying an attenuated range of behavioral and electrophysiological activity patterns, a “twilight zone” of constant activity between deep rest and full alertness. This constant cortical activity promotes activity-dependent amyloid-β accumulation in brain areas that modulate their activity across sleep-wake states, especially the medial prefrontal cortex. In addition, the accompanying breakdown of hippocampal–medial prefrontal cortex interplay across sleep stages could explain deficient memory consolidation through dysregulation of synaptic plasticity. Clinical implications include the potential therapeutic benefit of attractor consolidation (e.g., slow-wave sleep enhancers) in delaying AD progression.
... Episodic ultradian rhythms, which ordinarily last 90-120 minutes but can take place over up to 6 hours, are readily observed on electroencephalographic measures (18). These include the classic 90-to 120-minute basic rest-activity cycles (BRACs) initially described decades ago by Kleitman (19). ...
Objective:
Numerous therapist variables and cognitive biases can affect the quality of the therapeutic alliance and the conduct and outcomes of psychotherapy. This article aims to examine factors that potentially affect clinician performance, including chronobiological variables of clinicians and patients.
Methods:
The author reviewed literature pertaining to biological influences on human cognitive performance and considered how these factors may apply to the practice of psychotherapy.
Results:
Biological factors potentially affecting the conduct and quality of psychotherapy were identified. These factors include decision fatigue, hunger, sleep deficit, shift work, and several chronobiological issues related to circadian rhythms and episodic ultradian rhythms. In addition, misaligned scheduling of psychotherapy sessions in relation to therapist and patient evening-morning chronotypes may impede the effectiveness of psychotherapy.
Conclusions:
The practice of psychotherapy is cognitively demanding, requiring that clinicians remain constantly alert and in command of their executive functions. Decreases in clinician alertness resulting from homeostatic depletion, chronobiologically misaligned schedules, and illness-associated factors may reduce the quality and benefit of psychotherapy sessions. Mitigation strategies are available. Investigations of these factors are needed.
... 4,7,8 A similar pattern of recursive activity with modulation of brain rhythms exists during wakefulness, although in an attenuated manner, giving rise to ultradian rhythms across the sleepwake cycle. [9][10][11][12][13] It is through such a recursive interplay between cortical areas that . Sleep-wake cycle regulation: homeostatic and circadian processes. ...
A growing body of evidence shows the bidirectional relationship between sleep disorders and dementia. Sleep disorders often precede cognitive impairment by many years, in keeping with evidence that certain degenerative diseases originate from the brainstem and hypothalamus. Such selective vulnerability is associated with sleep fragmentation, daytime napping, sleep phase disorders, insufficient or excessive sleep duration, and sleep-disordered breathing. However, recent research indicates that sleep disorders accentuate neuropathology, such as decreased slow-wave sleep (SWS) promoting amyloid aggregation. This bidirectional relationship makes for a self-promoting feedback loop that accelerates both processes, highlighting the need for early interventions in elderly patients without dementia. Behavioral interventions, such as sleep hygiene, daytime exercise, and avoidance of alcohol and coffee after a certain time of day, are important first steps. Equally important are interventions that promote sleep consolidation, enhance SWS, or correct sleep-disordered breathing. Finally, optimizing medication timing, such as daytime-only use of cholinesterase inhibitors, can improve sleep and memory consolidation.
... For instance, cortical spreading depression, which involves systematic depolarization of expanding regions of cortex, lasts several minutes [32]. At even longer time scales, ultradian rhythms are associated with a periodic waxing and waning of global cortical activity [33]. Although it is not known whether these ultradian rhythms show any sequential patterning in the deactivation and activation of cortical regions, they clearly affect the propagation of activity in ways that are analogous to extremely low frequency (< 2 mHz) cortical waves. ...
Electrical waves propagate across sensory and motor cortices in stereotypical patterns. These waves have been described as potentially facilitating sensory processing when they travel through sensory cortex, as guiding movement preparation and performance when they travel across motor cortex, and as possibly promoting synaptic plasticity and the consolidation of memory traces, especially during sleep. Here, an alternative theoretical framework is suggested that integrates Pavlovian hypotheses about learning and cortical function with concepts from contemporary proceduralist theories of memory. The proposed framework postulates that sensory-evoked cortical waves are gradually modified across repeated experiences such that the waves more effectively differentiate sensory events, and so that the waves are more likely to reverberate. It is argued that the qualities of cortical waves—their origins, form, intensity, speed, periodicity, extent, and trajectories —are a function of both the structural organization of neural circuits and ongoing reverberations resulting from previously experienced events. It is hypothesized that experience-dependent cortical plasticity, both in the short- and long-term, modulates the qualities of cortical waves, thereby enabling individuals to make progressively more precise distinctions between complex sensory events, and to reconstruct components of previously experienced events. Unlike most current neurobiological theories of learning and memory mechanisms, this hypothesis does not assume that synaptic plasticity, or any other form of neural plasticity, serves to store physical records of previously experienced events for later reactivation. Rather, the reorganization of cortical circuits may alter the potential for certain wave patterns to arise and persist. Understanding what factors determine the spatiotemporal dynamics of cortical waves, how structural changes affect their qualities, and how wave dynamics relate to both mental experiences and memory-based performances, may provide new insights into the nature of learning and memory.
... Meanwhile, Parri and Crunelli [63] reported calcium oscillations as slow as 0.003 Hz (corresponding to a wavelength approaching 6 minutes) generated by thalamic astrocytes. Kaiser [64] suggests that, since the astrocyte network manages energy and excitability in the thalamus, this thalamic process may influence the thalamocortical network and allow detection of corresponding infraslow frequencies in the EEG. While the oscillatory behaviour observed in Sensitivity and S1-score in Figures 7 and 8 may be partly artefact, it could arise in part from a combination of infraslow oscillatory processes (known to have large amplitude [61]), in at least some of the patients, that interact to cause complex low-frequencydominated oscillations in the salience of signal patterns that are discriminative in the context of the predictive models. ...
Epilepsy is the second most common neurological disorder, affecting 0.6-0.8% of the world's population. In this neurological disorder, abnormal activity of the brain causes seizures, the nature of which tend to be sudden. Antiepileptic Drugs (AEDs) are used as long-term therapeutic solutions that control the condition. Of those treated with AEDs, 35% become resistant to medication. The unpredictable nature of seizures poses risks for the individual with epilepsy. It is clearly desirable to find more effective ways of preventing seizures for such patients. The automatic detection of oncoming seizures, before their actual onset, can facilitate timely intervention and hence minimize these risks. In addition, advance prediction of seizures can enrich our understanding of the epileptic brain. In this study, drawing on the body of work behind automatic seizure detection and prediction from digitised Invasive Electroencephalography (EEG) data, a prediction algorithm, ASPPR (Advance Seizure Prediction via Pre-ictal Relabeling), is described. ASPPR facilitates the learning of predictive models targeted at recognizing patterns in EEG activity that are in a specific time window in advance of a seizure. It then exploits advanced machine learning coupled with the design and selection of appropriate features from EEG signals. Results, from evaluating ASPPR independently on 21 different patients, suggest that seizures for many patients can be predicted up to 20 minutes in advance of their onset. Compared to benchmark performance represented by a mean S1-Score (harmonic mean of Sensitivity and Specificity) of 90.6% for predicting seizure onset between 0 and 5 minutes in advance, ASPPR achieves mean S1-Scores of: 96.30% for prediction between 1 and 6 minutes in advance, 96.13% for prediction between 8 and 13 minutes in advance, 94.5% for prediction between 14 and 19 minutes in advance, and 94.2% for prediction between 20 and 25 minutes in advance.
Implant Destekli Sabit Protezlerde Protetik Başarısızlık Nedenleri (Derleme)
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Die 24/7 Mentalität des „rund um die Uhr verfügbar sein“ ignoriert fundamentale biologische Grundsätze wie die menschlichen Bedürfnisse nach Erholung, Ruhe und ausreichendem Schlaf. Schichtarbeit, Jetlag und das Phänomen Sekundenschlaf veranschaulichen mit aller Deutlichkeit die gesundheitlichen Risiken, die sich daraus entwickeln: Nachtarbeit und Jetlag entkoppeln chronobiologische Rhythmen von äußeren, natürlichen Zeitzyklen (z. B. Hell- Dunkelwechsel). Über Jahre entstehen so schwerwiegende gesundheitliche Risiken. Die Folgen, wie Müdigkeit und Erschöpfung wirken anfänglich harmlos. Denn dagegen helfen starker Kaffee und die Wachmacher Angebote aus dem Internet. Stimulantien und Amphetamine schaffen jedoch hypervigilante Zustände und steigern nicht die Leistungsfähigkeit, wie Krankheitsbilder mit der Kernsymptomatik Hypervigilanz zeigen. Um fit und leistungsfähig zu sein, helfen einfache und natürliche Dinge: ausreichender Schlaf und eine effiziente Pausengestaltung.
Abstract
This monograph recounts the development history of the Othmer Method of neurofeedback over more than 30 years. With beginnings in the standard EEG-band protocols developed by neurofeedback pioneers Sterman and Lubar, the method migrated in successive stages from fixed protocols, implemented in an operant conditioning design, to a systematic, sequential, but non-prescriptive approach that is organized according to the developmental hierarchy.
This method places initial reliance on training on the tonic slow cortical potential, in the infra-low frequency regime, as the developmental hierarchy maps directly into a frequency hierarchy. The training has to be done in a frequency-specific manner, at frequencies referred to as optimal response frequencies that are unique to each individual. Thus, while the training approach is nomothetic in design, it is idiopathic in execution.
The absence of any reinforcers in the training places the brain in charge of the particulars of its journey to functional recovery. The reliance on endogenous neuromodulation to target critical frequencies yields an efficient process with a comprehensive scope. The Infra-Low Frequency (ILF) neurofeedback is complemented by more conventional EEG-band protocols for specific objectives.
Major depressive disorder is a debilitating condition with a lifetime risk of ten percent. Most treatments take several weeks to achieve clinical efficacy, limiting the ability to bring instant relief needed in psychiatric emergencies. One intervention that rapidly alleviates depressive symptoms is sleep deprivation; however, its mechanism of action is unknown. Astrocytes regulate responses to sleep deprivation, raising the possibility that glial signaling mediates antidepressive-like actions of sleep deprivation. Here, we found that astrocytic signaling to adenosine (A1) receptors was required for the robust reduction of depressive-like behaviors following 12 hours of sleep deprivation. As sleep deprivation activates synaptic A1 receptors, we mimicked the effect of sleep deprivation on depression phenotypes by administration of the A1 agonist CCPA. These results provide the first mechanistic insight into how sleep deprivation impacts mood, and provide a novel pathway for rapid antidepressant development by modulation of glial signaling in the brain.
Metabotropic glutamate receptor (mGluR)-dependent calcium ion (Ca²+) signaling in astrocytic processes regulates synaptic transmission and local blood flow essential for brain function. However, because of difficulties in imaging astrocytic processes, the subcellular spatial organization of mGluR-dependent Ca²+ signaling is not well characterized and its regulatory mechanism remains unclear. Using genetically encoded Ca²+ indicators, we showed that despite global stimulation by an mGluR agonist, astrocyte processes intrinsically exhibited a marked enrichment of Ca²+ responses. Immunocytochemistry indicated that these polarized Ca²+ responses could be attributed to increased density of surface mGluR5 on processes relative to the soma. Single-particle tracking of surface mGluR5 dynamics revealed a membrane barrier that blocked the movement of mGluR5 between the processes and the soma. Overexpression of mGluR or expression of its carboxyl terminus enabled diffusion of mGluR5 between the soma and the processes, disrupting the polarization of mGluR5 and of mGluR-dependent Ca²+ signaling. Together, our results demonstrate an mGluR5-selective diffusion barrier between processes and soma that compartmentalized mGluR Ca²+ signaling in astrocytes and may allow control of synaptic and vascular activity in specific subcellular domains.
Trends in alternative medicine use by American health care consumers are rising substantially. Extensive literature exists reporting on the effectiveness of neurofeedback in the treatment of autism, closed head injury, insomnia, migraine, depression, attention deficit hyperactivity disorder, epilepsy, and posttraumatic stress disorder. We speculated that neurofeedback might serve as a therapeutic modality for patients with medically refractory neurological disorders and have begun referring patients to train with clinical neurofeedback practitioners. The modality is not always covered by insurance. Confident their child's medical and neurological needs would continue to be met, the parents of 3 children with epilepsy spectrum disorder decided to have their child train in the modality. The children's individual progress following neurofeedback are each presented here. A proposed mechanism and practice implications are discussed.
Although astrocytes are increasingly recognized as important modulators of neuronal excitability and information transfer at the synapse, whether these cells regulate neuronal network activity has only recently started to be investigated. In this article, we highlight the role of astrocytes in the modulation of circuit function with particular focus on sleep-related rhythmogenesis. We discuss recent data showing that these glial cells regulate slow oscillations, a specific thalamocortical activity that characterizes non-REM sleep, and sleep-associated behaviors. Based on these findings, we predict that our understanding of the genesis and tuning of thalamocortical rhythms will necessarily go through an integrated view of brain circuits in which non-neuronal cells can play important neuromodulatory roles.
Gliotransmission, the release of molecules from astrocytes, regulates neuronal excitability and synaptic transmission in situ. Whether this process affects neuronal network activity in vivo is not known. Using a combination of astrocyte-specific molecular genetics, with in vivo electrophysiology and pharmacology, we determined that gliotransmission modulates cortical slow oscillations, a rhythm characterizing nonrapid eye movement sleep. Inhibition of gliotransmission by the expression of a dominant negative SNARE domain in astrocytes affected cortical slow oscillations, reducing the duration of neuronal depolarizations and causing prolonged hyperpolarizations. These network effects result from the astrocytic modulation of intracortical synaptic transmission at two sites: a hypofunction of postsynaptic NMDA receptors, and by reducing extracellular adenosine, a loss of tonic A1 receptor-mediated inhibition. These results demonstrate that rhythmic brain activity is generated by the coordinated action of the neuronal and glial networks.
Defining the microanatomic differences between the human brain and that of other mammals is key to understanding its unique computational power. Although much effort has been devoted to comparative studies of neurons, astrocytes have received far less attention. We report here that protoplasmic astrocytes in human neocortex are 2.6-fold larger in diameter and extend 10-fold more GFAP (glial fibrillary acidic protein)-positive primary processes than their rodent counterparts. In cortical slices prepared from acutely resected surgical tissue, protoplasmic astrocytes propagate Ca(2+) waves with a speed of 36 microm/s, approximately fourfold faster than rodent. Human astrocytes also transiently increase cystosolic Ca(2+) in response to glutamatergic and purinergic receptor agonists. The human neocortex also harbors several anatomically defined subclasses of astrocytes not represented in rodents. These include a population of astrocytes that reside in layers 5-6 and extend long fibers characterized by regularly spaced varicosities. Another specialized type of astrocyte, the interlaminar astrocyte, abundantly populates the superficial cortical layers and extends long processes without varicosities to cortical layers 3 and 4. Human fibrous astrocytes resemble their rodent counterpart but are larger in diameter. Thus, human cortical astrocytes are both larger, and structurally both more complex and more diverse, than those of rodents. On this basis, we posit that this astrocytic complexity has permitted the increased functional competence of the adult human brain.
An increasing number of EEG and resting state fMRI studies in both humans and animals indicate that spontaneous low frequency fluctuations in cerebral activity at <0.1 Hz (infra-slow oscillations, ISOs) represent a fundamental component of brain functioning, being known to correlate with faster neuronal ensemble oscillations, regulate behavioural performance and influence seizure susceptibility. Although these oscillations have been commonly indicated to involve the thalamus their basic cellular mechanisms remain poorly understood. Here we show that various nuclei in the dorsal thalamus in vitro can express a robust ISO at approximately 0.005-0.1 Hz that is greatly facilitated by activating metabotropic glutamate receptors (mGluRs) and/or Ach receptors (AchRs). This ISO is a neuronal population phenomenon which modulates faster gap junction (GJ)-dependent network oscillations, and can underlie epileptic activity when AchRs or mGluRs are stimulated excessively. In individual thalamocortical neurons the ISO is primarily shaped by rhythmic, long-lasting hyperpolarizing potentials which reflect the activation of A1 receptors, by ATP-derived adenosine, and subsequent opening of Ba(2+)-sensitive K(+) channels. We argue that this ISO has a likely non-neuronal origin and may contribute to shaping ISOs in the intact brain.
Whereas glia were once thought to be passive structural elements in the brain, they have more recently been revealed to be active players in providing metabolic support for and regulating activity of the neurons they surround. Notably, it was discovered that glia can be activated by neurotransmitters released from adjacent excitatory synapses and can in turn release chemical transmitters to act back upon those neurons through gliotransmission (Figure 1) (Haydon and Carmignoto, 2006). The primary chemicals released from astrocytes are glutamate (Glu) and ATP, which can act to facilitate neural transmission (not shown). Yet, ATP is also rapidly hydrolyzed by ectonucleotidase enzymes to adenosine (AD), which accumulates in the extracellular space and can act upon adenosine 1 receptors (A1R) on local neurons to tonically depress synaptic activity. This neuron-glia-neuron feedback results in activity-dependent attenuation of neural excitability, which could be relevant for sleep and its homeostatic regulation.
Our ability to perceive weak signals is correlated among consecutive trials and fluctuates slowly over time. Although this "streaking effect" has been known for decades, the underlying neural network phenomena have remained largely unidentified. We examined the dynamics of human behavioral performance and its correlation with infraslow (0.01-0.1 Hz) fluctuations in ongoing brain activity. Full-band electroencephalography revealed prominent infraslow fluctuations during the execution of a somatosensory detection task. Similar fluctuations were predominant also in the dynamics of behavioral performance. The subjects' ability to detect the sensory stimuli was strongly correlated with the phase, but not with the amplitude of the infraslow EEG fluctuations. These data thus reveal a direct electrophysiological correlate for the slow fluctuations in human psychophysical performance. We then examined the correlation between the phase of infraslow EEG fluctuations and the amplitude of 1-40 Hz neuronal oscillations in six frequency bands. Like the behavioral performance, the amplitudes in these frequency bands were robustly correlated with the phase of the infraslow fluctuations. These data hence suggest that the infraslow fluctuations reflect the excitability dynamics of cortical networks. We conclude that ongoing 0.01-0.1 Hz EEG fluctuations are prominent and functionally significant during execution of cognitive tasks.
The newly described slow cortical rhythm (approximately 0.3 Hz), whose depolarizing-hyperpolarizing components are analyzed in the preceding article, is now investigated from the standpoint of its relations with delta (1-4 Hz) and spindle (7-14 Hz) rhythmicity. Regular-spiking and intrinsically bursting cortical neurons were mostly recorded from association suprasylvian areas 5 and 7; fewer neurons were also recorded from pericruciate motor and posterolateral visual areas. Although most cells were investigated under various anesthetics, a similar slow cortical rhythm was found in animals with brainstem transection at the low- or high-collicular levels. These cerveau isolé (isolated forebrain) preparations display the major sleep rhythms of the EEG in the absence of general anesthetics. In 38% of recorded cortical neurons (n = 105), the slow rhythm was combined with delta oscillation. Both cellular rhythms were phase locked to the slow and delta oscillations in the surface- and depth-recorded EEG. In a group of this cell sample (n = 47), delta activity occurred as stereotyped, clock-like action potentials during the interdepolarization lulls of the slow rhythm. In another neuronal subsample (n = 58), delta events were grouped in sequences superimposed upon the depolarizing envelope of the slow rhythm, with such sequences recurring rhythmically at approximately 0.3-0.4 Hz. The associations between the two cellular and EEG rhythms (1-4 Hz and 0.3-0.4 Hz) were quantified by means of autocorrelograms, cross-correlograms, and spike-triggered averages. In 26% of recorded neurons (n = 72), the slow rhythm was combined with spindle oscillations. Regular-spiking cortical neurons fully reflected the whole frequency range of thalamically generated spindles (7-14 Hz). However, during similar patterns of EEG spindling, intrinsically bursting cells fired grouped action potentials (with intraburst frequencies of 100-200 Hz) at only 2-4 Hz. The dependence of the slow cortical oscillation upon the thalamus was studied by lesions and stimulation. The slow rhythm survived extensive ipsilateral thalamic destruction by means of electrolytic lesions or kainate-induced loss of perikarya in thalamic nuclei that were input sources to the recorded cortical neurons. To further prevent the possibility of a thalamic role in the genesis of the slow rhythm, through the contralateral thalamocortical systems and callosal projections, we also transected the corpus callosum in thalamically lesioned animals, and still recorded the slow rhythm in cortical neurons. These data indicate that the thalamus is not essentially implicated in the genesis of the slow rhythm.(ABSTRACT TRUNCATED AT 400 WORDS)
Forced expression of gap junction proteins, connexins, enables gap junction-deficient cell lines to propagate intercellular calcium waves. Here, we show that ATP secretion from the poorly coupled cell lines, C6 glioma, HeLa, and U373 glioblastoma, is potentiated 5- to 15-fold by connexin expression. ATP release required purinergic receptor-activated intracellular Ca2+ mobilization and was inhibited by Cl- channel blockers. Calcium wave propagation also was reduced by purinergic receptor antagonists and by Cl- channel blockers but insensitive to gap junction inhibitors. These observations suggest that cell-to-cell signaling associated with connexin expression results from enhanced ATP release and not, as previously believed, from an increase in intercellular coupling.
A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
Animal models of epilepsy have shown that synchronous burst firing is associated with epileptogenesis, yet the evidence from human studies linking neuronal synchrony and burst firing to epileptogenesis remains equivocal. Sleep-wake states have been shown to differentially modulate the generation of epileptiform EEG spikes between brain regions of greater and lesser seizure-generating potential, providing information that helps to identify the primary epileptogenic region. Using these state-dependent mechanisms to assist us in identifying neuronal correlates of human epilepsy, we recorded interictal neuronal activity from mesial temporal lobe (MTL) areas in epileptic patients implanted with depth electrodes required for medical diagnosis during polysomnographically defined sleep-wake states. Results show that single neurons recorded ipsilateral to seizure-initiating MTL ("epileptic") areas had significantly higher firing rates (p = 0.01) and burst propensity (p = 0.01) and greater synchrony of discharges (p = 0.003) compared with neurons recorded from contralateral non-seizure-generating MTL ("non-epileptic") areas. In particular, during episodes of slow wave sleep (SWS) and rapid eye movement (REM) sleep, epileptic hippocampal neurons had significantly higher burst rates compared with non-epileptic hippocampal neurons (both p = 0.01). In contrast, during episodes of wakefulness (Aw), no difference in burst firing between epileptic and non-epileptic hippocampal neurons was observed. Furthermore, synchronous firing was significantly higher between epileptic MTL neurons compared with non-epileptic MTL neurons during SWS (p = 0.04) and REM sleep (p = 0.02), but no difference in neuronal synchrony was found between epileptic and non-epileptic neurons during Aw. These results provide evidence that sleep states differentially modulate abnormal epileptogenic neuronal discharge properties within human MTL and confirm that neuronal burst firing and enhanced neuronal synchrony observed in experimental animal models of epilepsy characterizes human epilepsy as well.
The cellular mechanisms underlying functional hyperemia--the coupling of neuronal activation to cerebral blood vessel responses--are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation--by patch pipette--of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
Human cortical activity has been intensively examined at frequencies ranging from 0.5 Hz to several hundred Hz. Recent studies have, however, reported also infraslow fluctuations in neuronal population activity, magnitude of electroencephalographic oscillations, discrete sleep events, as well as in the occurrence of interictal events. Here we use direct current electroencephalography to demonstrate large-scale infraslow oscillations in the human cortex at frequencies ranging from 0.02 to 0.2 Hz. These oscillations, which are not detectable in conventional electroencephalography because of its limited recording bandwidth (typical lower limit 0.5 Hz), were observed in widespread cortical regions. Notably, the infraslow oscillations were strongly synchronized with faster activities, as well as with the interictal epileptic events and K complexes. Our findings suggest that the infraslow oscillations represent a slow, cyclic modulation of cortical gross excitability, providing also a putative mechanism for the as yet enigmatic aggravation of epileptic activity during sleep.
• epilepsy
• slow cortical oscillations
• phase synchrony
• direct current electroencephalography
• full-band electroencephalography
While enormous resources have been recently invested into the development of a variety of neuroimaging techniques, the bandwidth of the clinical EEG, originally set by trivial technical limitations, has remained practically unaltered for over 50 years. An increasing amount of evidence shows that salient EEG signals are observed beyond the bandwidth of the routine clinical EEG, which is typically around 0.5-50 Hz. Physiological and pathological EEG activity ranges at least from 0.01 Hz to several hundred Hz, as demonstrated in recordings of spontaneous activity in the immature human brain, as well as during epileptic seizures, or various kinds of cognitive tasks and states in the adult brain. In the present paper, we will review several arguments leading to the conclusion that elimination of the lower (infraslow) or higher (ultrafast) bands of the EEG frequency spectrum in routine EEG leads to situations where salient and physiologically meaningful features of brain activity are ignored. Recording the full, physiologically relevant range of frequencies is readily attained with commercially available direct-current (DC) coupled amplifiers, which have a wide dynamic range and a high sampling rate. Such amplifiers, combined with appropriate DC-stable electrode-skin interface, provide a genuine full-band EEG (FbEEG). FbEEG is mandatory for a faithful, non-distorted and non-attenuated recording, and it does not have trade-offs that would favor any frequency band at the expense of another. With the currently available electrode, amplifier and data acquisition technology, FbEEG is likely to become the standard approach for a wide range of applications in both basic science and in the clinic.
To investigate the role of astrocytes in regulating synaptic transmission, we generated inducible transgenic mice that express a dominant-negative SNARE domain selectively in astrocytes to block the release of transmitters from these glial cells. By releasing adenosine triphosphate, which accumulates as adenosine, astrocytes tonically suppressed synaptic transmission, thereby enhancing the dynamic range for long-term potentiation and mediated activity-dependent, heterosynaptic depression. These results indicate that astrocytes are intricately linked in the regulation of synaptic strength and plasticity and provide a pathway for synaptic cross-talk.
Mice lacking epidermal growth factor receptor (EGFR) develop a neurodegeneration of unknown etiology affecting exclusively the frontal cortex and olfactory bulbs. Here, we show that EGFR signaling controls cortical degeneration by regulating cortical astrocyte apoptosis. Whereas EGFR(-/-) midbrain astrocytes are unaffected, mutant cortical astrocytes display increased apoptosis mediated by an Akt-caspase-dependent mechanism and are unable to support neuronal survival. The expression of many neurotrophic factors is unaltered in EGFR(-/-) cortical astrocytes suggesting that neuronal loss occurs as a consequence of increased astrocyte apoptosis rather than impaired secretion of trophic factors. Neuron-specific expression of activated Ras can compensate for the deficiency of EGFR(-/-) cortical astrocytes and prevent neuronal death. These results identify two functionally distinct astrocyte populations, which differentially depend on EGFR signaling for their survival and also for their ability to support neuronal survival. These spatial differences in astrocyte composition provide a mechanism for the region-specific neurodegeneration in EGFR(-/-) mice.
Chronobiology has identified a multitude of rhythms within our body as well as within each living cell. Some of these rhythms, such as the circadian and circannual, interact with our environment, while others run on their own, but are often coupled to the circadian or to other body rhythms. Recent evidence shows that these rhythms might be more important for our health than expected: Disturbance of the circadian rhythms by jet lag or shift work not only evokes autonomic disturbances but also increases the incidence of cancer, as shown in this issue of Cancer Causes and Control. The occurrence of rhythms in the organism obviously bears several advantages: (1) It increases organismic stability by calibrating the system's characteristics: Regulation curves in time and space are crucial for controlling physiological long-term stability. To determine its properties continuously the system varies its parameters slightly over several time scales at different frequencies-akin to what our body does, e.g. in heart-rate variability. (2) Tuning and synchronization of rhythms saves energy: It was Huygens who observed that clocks on a wall tend to synchronize their beats. It turned out later that synchronisation is a very common phenomenon observed in bodies' rhythms and can be found, for example, when we relax or sleep. At such times energy consumption is minimal, our body working most efficiently. (3) Temporal compartmentalization allows polar events to occur in the same space unit: there are polarities in the universe of our body, which cannot happen simultaneously. Systole and diastole, inspiration and expiration, work and relaxation, wakefulness and sleep, reductive and oxidative states cannot be performed efficiently at the same time and place. Temporal compartmentalization is probably the most efficient way to mediate between these polarities. Chronobiology and chronomedicine are opening a new and very exciting understanding of our bodies' regulation. The biological time and its oscillations gain more attention and importance as these interrelations are understood.
Rapidly accumulating experimental data over the past two decades discloses extremely complex neuro-glial interactions and provides new insights regarding novel roles of glial cells, particularly astrocytes, in complex functions. Widespread astrocytic processes, interconnected by gap junctions, form an extremely large physiological syncytium. This structure in conjunction with neuronal activity, very likely contributes to cognitive functions. Based on electrophysiological and neuroanatomical data, the present hypothesis proposes a self-organised, iterative and reciprocal magnetic interaction between neurones and astrocytes to explain neurocomputation, including memory processing, in the human neocortex.
Mammalian circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), and current dogma holds that the SCN is required for the expression of circadian rhythms in peripheral tissues. Using a PERIOD2::LUCIFERASE fusion protein as a real-time reporter of circadian dynamics in mice, we report that, contrary to previous work, peripheral tissues are capable of self-sustained circadian oscillations for >20 cycles in isolation. In addition, peripheral organs expressed tissue-specific differences in circadian period and phase. Surprisingly, lesions of the SCN in mPer2(Luciferase) knockin mice did not abolish circadian rhythms in peripheral tissues, but instead caused phase desynchrony among the tissues of individual animals and from animal to animal. These results demonstrate that peripheral tissues express self-sustained, rather than damped, circadian oscillations and suggest the existence of organ-specific synchronizers of circadian rhythms at the cell and tissue level.
Nathaniel Kleitman, the author of the pioneering volume Sleep and wakefulness, (1963)1 is lively and well at 96, living alone in his apartment in Southern California where I have interviewed him a number of times over the past few years. His general appearance and élan is so reminiscent of the American humorist George Burns that it was all I could do to suppress a laugh each time I saw him. His daughter, Esther, who lives nearby, was present at some of the interviews and helped in the preparation of this material for publication. Kleitman has been in retirement for 30 years since he left his faculty position at the University of Chicago at the age of 65. Perhaps his personal experience with the ageing process reported here can serve as a necessary corrective to many of the misconceptions that currently distort our understanding of sleep, wakefulness and well-being in senior citizens.
A major ideal of science is to integrate apparently different phenomena into a general theory of nature. The more widely divergent the phenomena that we can bring together in a meaningful way, the greater the beauty, scope and potential utility of the theory. We admire the simple elegance whereby Newton’s theory of gravitation proposed a grand unification of celestial mechanics — the orbits of the sun, moon and planets — with the humble fall of an apocryphal apple here on earth.
The synchronization of neuronal assemblies during cortical UP states has been implicated in computational and homeostatic processes, but the mechanisms by which this occurs remain unknown. To investigate potential roles of astrocytes in synchronizing cortical circuits, we electrically activated astrocytes while monitoring the activity of the surrounding network with electrophysiological recordings and calcium imaging. Stimulating a single astrocyte activates other astrocytes in the local circuit and can trigger UP state synchronizations of neighboring neurons. Moreover, interfering with astrocytic activity with intracellular injections of a calcium chelator into individual astrocytes inhibits spontaneous and stimulated UP states. Finally, both astrocytic activity and neuronal UP states are regulated by purinergic signaling in the circuit. These results demonstrate that astroglia can play a causal role in regulating the synchronized activation of neuronal ensembles.
We examined fluctuations in band-limited power (BLP) of local field potential (LFP) signals recorded from multiple electrodes in visual cortex of the monkey during different behavioral states. We asked whether such signals demonstrated coherent fluctuations over time-scales of seconds and minutes, and would thus serve as good candidates for direct comparison with data obtained from functional magnetic resonance imaging (fMRI). We obtained the following results. (i) The BLP of the local field displayed fluctuations at many time-scales, with particularly large amplitude at very low frequencies (<0.1 Hz). (ii) These fluctuations exhibited high coherence between electrode pairs, particularly for BLP signals derived from the gamma (γ) frequency range. (iii) Coherence in the BLP, unlike that in the raw LFP, did not fall off sharply as a function of cortical distance. (iv) The structure and coherence of BLP changes were highly similar under distinctly different behavioral states. These results demonstrate the existence of widespread coherent activity fluctuations in the brain of the awake monkey over very long time-scales. We propose that such signals may make a significant contribution to the high variability observed in the time course of physiological signals, including those measured with functional imaging techniques. The results are discussed in the context of combined fMRI/electrophysiological recordings.
Many studies have shown the existence of cycles of approximately 90 to 100 minutes (corresponding to Kleitman's basic rest-activity cycle) and several hours ('slow ultradian rhythm' cycles). EEG power spectra, mood, performance, and self-evaluation of performance were measured every 15 minutes for 9 hours for 10 male university students. Principal component analysis was applied to extracted ultradian fluctuations in EEG activity, task performance, and the subjective variables. The analysis indicated that two common temporal fluctuations were present, one in the behavioral and subjective variables, and the other in EEG activity. Spectral analysis indicated that the former fluctuated at a rate of 12 cycles per day (corresponding to basic rest-activity cycle), and the latter was comprised of both a slower (6 cycles per day) and a faster (10 to 18 cycles per day) cycle, thereby supporting the multioscillator hypothesis of ultradian rhythm.
In this chapter we first define ultradian rhythms and offer a brief tutorial on spectroscopic methods to extract them from
data, including some cautionary comments regarding false positive identifications. We then contrast features of ultradian
rhythms with those of circadian rhythms and conjecture that the former are the basic rhythmic signature of life. To justify
that conjecture we introduce a physical heuristic – homeodynamics – that presents quantized, cyclic action (the product of energy × time) as an essential thermodynamic characteristic of open
systems that persist over times that are long compared to their internal process times. From that perspective we argue that
the start-up of terrestrial life began with energetics (metabolism) as dynamics manifested by ultradian rhythms, only later
acquiring informational molecular memories and constraints as relatively static codes.
The synchronization of neuronal assemblies during cortical UP states has been implicated in computational and homeostatic processes, but the mechanisms by which this occurs remain unknown. To investigate potential roles of astrocytes in synchronizing cortical circuits, we electrically activated astrocytes while monitoring the activity of the surrounding network with electrophysiological recordings and calcium imaging. Stimulating a single astrocyte activates other astrocytes in the local circuit and can trigger UP state synchronizations of neighboring neurons. Moreover, interfering with astrocytic activity with intracellular injections of a calcium chelator into individual astrocytes inhibits spontaneous and stimulated UP states. Finally, both astrocytic activity and neuronal UP states are regulated by purinergic signaling in the circuit. These results demonstrate that astroglia can play a causal role in regulating the synchronized activation of neuronal ensembles.
Astrocytes exhibit spontaneous calcium fluctuations. These activities have not been captured by large-scale recordings, and little is known about their collective dynamics. In situ and in vivo calcium imaging from hundreds (up to 2195) of astrocytes in the mouse hippocampus and neocortex revealed that neighboring astrocytes spontaneously exhibited synchronous calcium elevations and formed locally correlated cell groups ("clusters" of 2 to 5 astrocytes within a diameter of 81 ± 45 μm). Cluster activity accounted for approximately 10% of the astrocytic calcium events, and 44% of the clusters appeared repetitively during our observation period of 60 min. Astrocytic clusters emerged through metabotropic glutamate receptor activation, independently of neuronal activity. Neurons were depolarized by 1.5 mV when clusters appeared near their dendrites. This depolarization was mediated by non-N-methyl-D-aspartate (NMDA) glutamate receptor channels and was replicated by calcium uncaging activation of multiple astrocytes. Importantly, the activation of single astrocytes alone could not depolarize neurons but readily elicited NMDA-dependent slow inward currents in depolarized neurons. Thus, these novel ensemble dynamics of astrocytes, which cannot be captured by conventional small-scale imaging techniques, play a different role in neuronal modulation than does the sporadic activity of single astrocytes.
Astrocytes modulate neuronal activity by releasing chemical transmitters via a process termed gliotransmission. The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation. Inhibiting gliotransmission attenuated the accumulation of sleep pressure, assessed by measuring the slow wave activity of the EEG during NREM sleep, and prevented cognitive deficits associated with sleep loss. Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wild-type mice mimicked the transgenic phenotype, we conclude that astrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors.
The purpose of this work was to investigate the presence of ultradian rhythms in: 1. levels of electroencephalographic activation; 2. interhemispheric correlation and 3. the performance of two cognitive tasks, and the correlation between these variables. Eight volunteers, aged 20 to 30, participated in the experiment. Two sessions were carried out: one from 0800 to 1400 on one day and the other from 1400 to 2000 another day. Samples of EEG activity were taken every 15 min at rest with eyes open in left and right temporal, central, parietal and occipital derivations referred to the ipsilateral earlobe the performance on two tasks, one logico-analytical (left hemisphere functions) and one spatial test (right hemisphere functions) was assessed. As control, body and environmental temperature were recorded. To test for the presence of ultradian rhythms, the data were subjected to a Fourier analysis. Different EEG variables showed rhythmicity throughout the sessions, principally with slow oscillation periods (3 and 6h); ultradian rhythms with 3h periods were also found in body temperature, while task performance showed no significant rhythmic patterns during sessions. Finally, no significant correlations were found between physiological variables evaluated and task performance.
Neuron:glial ratios were determined in specific regions of Albert Einstein's cerebral cortex to compare with samples from 11 human male cortices. Cell counts were made on either 6- or 20-micron sections from areas 9 and 39 from each hemisphere. All sections were stained with the Klüver-Barrera stain to differentiate neurons from glia, both astrocytes and oligodendrocytes. Cell counts were made under oil immersion from the crown of the gyrus to the white matter by following a red line drawn on the coverslip. The average number of neurons and glial cells was determined per microscopic field. The results of the analysis suggest that in left area 39, the neuronal: glial ratio for the Einstein brain is significantly smaller than the mean for the control population (t = 2.62, df 9, p less than 0.05, two-tailed). Einstein's brain did not differ significantly in the neuronal:glial ratio from the controls in any of the other three areas studied.
This review furnishes data in support of the suggestion that an ultradian basic rest-activity cycle is involved in the functioning of the central nervous system and manifests itself in the alternation of non-REM and REM sleep and a similar periodicity in wakefulness.
Astroglial cells in primary culture release factors into the medium that promote the growth and prolong the survival of rat
hippocampal neurons in vitro.
The ultradian dynamics of the human waking EEG was studied using a short visual fixation task repeated every 10 min throughout the daytime. The EEG spectra obtained from the tasks were assessed for time effect and ultradian periodicity. Fronto-central EEG high frequency powers (22.5-44.5 Hz) decreased at the time of the midafternoon vigilance dip (14.00-17.00 h) along with slight concomitant increases in parietal alpha (7.5-13.5 Hz) and delta (1-3 Hz) powers. A slow ultradian rhythm with a 3-4 h periodicity strongly modulated EEG power in all frequency bands between 1 and 44.5 Hz. The high frequency waking EEG may well reflect the activity of a brain arousal process underlying maintenance of the waking state probably throughout the 24 h cycle.
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable yet clinically heterogeneous syndrome associated with hypocatecholamine function in subcortical and prefrontal cortical regions and clinical response to medications that enhance catecholamine function. The goal of this article is to present a hypothesis about the etiology of ADHD by synthesizing these findings with recent experiments indicating that activity-dependent neuronal energy consumption is regulated by cortical astrocytes. The scientific literature was searched from 1966 to the present using MEDLINE and relevant key words. Inattention and impulsivity may be related to hypofunctionality of catecholamine projection pathways to prefrontal cortical areas, resulting in decreased neuronal energy availability. This may be mediated by astrocyte catecholamine receptors that normally regulate energy availability during neuronal activation. At least some forms of ADHD may be viewed as cortical, energy-deficit syndromes secondary to catecholamine-mediated hypofunctionality of astrocyte glucose and glycogen metabolism, which provides activity-dependent energy to cortical neurons. Several tests of this hypothesis are proposed.
During development, astrocytes in the ventrobasal thalamus display spontaneous intracellular calcium [Ca(2+)](i) oscillations, that can lead to the excitation of adjacent thalamocortical neurons via an NMDA receptor-mediated mechanism. In this study, we show that while astrocytes usually exhibit oscillations of irregular amplitude and frequency, a subset of spontaneously active thalamic astrocytes exhibits rhythmic, i.e. pacemaker, [Ca(2+)](i) oscillations with an average frequency of 0.019 Hz. This frequency of the pacemaker oscillations is close to the modal frequency of the irregularly oscillating astrocytes, suggesting that there is a preferred frequency for astrocytic [Ca(2+)](i) oscillations. If pacemaker [Ca(2+)](i) oscillations underlie excitatory signaling to neurons, the result would be rhythmic activation of thalamocortical neurons and astrocyte-driven synchronized oscillations within neurons of the thalamocortical loop.
Recent studies in the ventrobasal (VB) thalamus have shown that astrocytes display spontaneous intracellular calcium [Ca(2+)](i) oscillations early postnatally. [Ca(2+)](i) oscillations are correlated in groups of up to five astrocytes, and propagate between cells. NMDA receptor-mediated, long lasting inward currents in thalamocortical (TC) neurons of the VB complex are correlated to [Ca(2+)](i) increases in neighbouring astrocytes, and stimulation of astrocytic [Ca(2+)](i) increases also lead to inward currents in neurons. These findings suggest that astrocytes are spontaneously active and can induce neuronal activity, a reversal of the previously held view of neuron-glia interactions in the central nervous system. This activity occurs at an important period in the development of the thalamus and therefore suggests a potential functional role in a variety of processes. Along with data on the neurotransmitter receptor repertoire of thalamic astrocytes these findings enlarge the body of knowledge on astrocytes in the thalamus, and further contribute to the emerging field of astrocyte-neuron and neuron-astrocyte interactions in the central nervous system.
We examined fluctuations in band-limited power (BLP) of local field potential (LFP) signals recorded from multiple electrodes in visual cortex of the monkey during different behavioral states. We asked whether such signals demonstrated coherent fluctuations over time-scales of seconds and minutes, and would thus serve as good candidates for direct comparison with data obtained from functional magnetic resonance imaging (fMRI). We obtained the following results. (i) The BLP of the local field displayed fluctuations at many time-scales, with particularly large amplitude at very low frequencies (<0.1 Hz). (ii) These fluctuations exhibited high coherence between electrode pairs, particularly for BLP signals derived from the gamma frequency range. (iii) Coherence in the BLP, unlike that in the raw LFP, did not fall off sharply as a function of cortical distance. (iv) The structure and coherence of BLP changes were highly similar under distinctly different behavioral states. These results demonstrate the existence of widespread coherent activity fluctuations in the brain of the awake monkey over very long time-scales. We propose that such signals may make a significant contribution to the high variability observed in the time course of physiological signals, including those measured with functional imaging techniques. The results are discussed in the context of combined fMRI/electrophysiological recordings.
To study whether hemodynamic changes in human brain generate scalp-EEG responses.
Direct current EEG (DC-EEG) was recorded from 12 subjects during 5 non-invasive manipulations that affect intracranial hemodynamics by different mechanisms: bilateral jugular vein compression (JVC), head-up tilt (HUT), head-down tilt (HDT), Valsalva maneuver (VM), and Mueller maneuver (MM). DC shifts were compared to changes in cerebral blood volume (CBV) measured by near-infrared spectroscopy (NIRS).
DC shifts were observed during all manipulations with highest amplitudes (up to 250 microV) at the midline electrodes, and the most pronounced changes (up to 15 microV/cm) in the DC voltage gradient around vertex. In spite of inter-individual variation in both amplitude and polarity, the DC shifts were consistent and reproducible for each subject and they showed a clear temporal correlation with changes in CBV.
Our results indicate that hemodynamic changes in human brain are associated with marked DC shifts that cannot be accounted for by intracortical neuronal or glial currents. Instead, the data are consistent with a non-neuronal generator mechanism that is associated with the blood-brain barrier.
These findings have direct implications for mechanistic interpretation of slow EEG responses in various experimental paradigms.
Circadian clocks influence most aspects of physiology and behavior, so perhaps it is not surprising that circadian oscillators exist in nearly all mammalian cells. These cells remain synchronized to the outside world in hierarchical fashion, with a "master clock" tissue in the suprachiasmatic nucleus of the hypothalamus receiving light input from the retina and then conveying timing information to "slave" clocks in peripheral tissues. Recent research has highlighted both the similarities and differences between central and peripheral clocks and provided new insight into their communication. Above all, however, this parallelism of clockwork has provided a unique opportunity to study at the cellular level a regulatory mechanism that affects complex behaviors.
Astrocytes have long been thought to act as a support network for neurons, with little role in information representation
or processing. We used two-photon imaging of calcium signals in the ferret visual cortex in vivo to discover that astrocytes,
like neurons, respond to visual stimuli, with distinct spatial receptive fields and sharp tuning to visual stimulus features
including orientation and spatial frequency. The stimulus-feature preferences of astrocytes were exquisitely mapped across
the cortical surface, in close register with neuronal maps. The spatially restricted stimulus-specific component of the intrinsic
hemodynamic mapping signal was highly sensitive to astrocyte activation, indicating that astrocytes have a key role in coupling
neuronal organization to mapping signals critical for noninvasive brain imaging. Furthermore, blocking astrocyte glutamate
transporters influenced the magnitude and duration of adjacent visually driven neuronal responses.
The Psychobiology of Mind-Body Healing, Revised Edition
- E Rossi
Rossi E: The Psychobiology of Mind-Body Healing, Revised Edition.
New York: W. W. Norton Professional Books, 1986/1993
- S Othmer
- F S Othmer
- S B Legarda
Othmer S, Othmer FS, Legarda SB: Clinical neurofeedback: Training
brain behavior, Treatment Strategies-Pediatric Neurology and Psychiatry, 2;67-73, 2011