Burst suppression is an electroencephalography (EEG) pattern that is characterized by periods of high-voltage electrical activity alternating with periods of no activity in the brain. The pattern is found in patients with inactivated brain states, such as from general anesthesia, coma, or hypothermia. [1] This pattern can be physiological, as during early development, or pathological, as in diseases such as Ohtahara syndrome. [2]
The burst suppression pattern was first observed by Derbyshire et al. while studying effects of anesthetics on feline cerebral cortices in 1936, where the researchers noticed mixed slow and fast electrical activity with decreasing amplitude as anesthesia deepened. [3] In 1948, Swank and Watson coined the term "burst-suppression pattern" to describe the alternation of spikes and flatlines in electrical activity in deep anesthesia. [4] It wasn't until after the early 1960s that the burst suppression pattern began being used in medical settings; it had been primarily observed in animal studies and psychosurgeries. [5]
A paper published in 2023 showed that burst suppression and epilepsy may share the same ephaptic coupling mechanism. [6] When inhibitory control is sufficiently low, as in the case of certain general anesthetics such as sevoflurane (due to a decrease in the firing of interneurons [7] ), electric fields are able to recruit neighboring cells to fire synchronously, in a burst suppression pattern. This same mechanism also underlies epileptic bursts, but the magnitude of bursts is comparatively weaker in burst suppression, as the neuronal network still retains partial inhibitory control under the effects of anesthesia.
The pseudo-rhythmic pattern of burst suppression is dictated by extracellular calcium depletion and the ability of neurons to restore the concentration. [4] Bursts are accompanied by depletion of extracellular cortical calcium ions to levels that inhibit synaptic transmission, which leads to suppression periods. [4] During suppression, neuronal pumps restore the calcium ion concentrations to normal levels, thus causing the cortex to be subject to the process again. [4] As the brain becomes more inactive, burst periods become shorter and suppression periods become longer. [8] The shortening of bursts and lengthening of suppression is caused by the central nervous system's inability to properly regulate calcium levels due to increased blood–brain permeability. [8]
At the cellular level, hyperpolarization of the membrane potential of cortical neurons reliably precedes any overt electroencephalographic activity of burst suppression. [9] This hyperpolarization, which has been attributed to an increase in neuronal membrane potassium conductance, [9] has been hypothesized to play a major role in the induction of burst suppression, supported by the induction of burst suppression through the application of a direct acting GABAA agonist, muscimol. [5] In contrast, inhibition is diminished when burst suppression is induced through the use of isoflurane. [10] Another theory is that alterations in brain metabolism regulate activity dependent slow modulation of ATP-gated potassium channel conductance which induces burst suppression. [1] However, modulating inhibitory activity alone may not be sufficient for burst suppression, and modulation in excitatory synaptic efficiency, stemming from the depletion and subsequent recovery of interstitial calcium levels, could contribute to the induction of burst suppression. [5]
Burst episodes are associated with excitatory activity in cortical neurons. [11] Suppression is caused by the absence of synaptic activity of cortical neurons; however, some thalamocortical neurons exhibit oscillations in the delta frequency range during these periods. [9] The burst suppression pattern varies with the brain anesthetic concentration when pharmacologically inducing coma. [12] Level of suppression is adjustable by decreasing or increasing anesthetic infusion rate, thus adjusting the level of inactivation. [13]
While burst suppression has typically been viewed as a homogeneous brain state, recent studies have shown that bursts and suppressions can occur in specific regions while other regions are unaffected. [14] The fact that the burst suppression pattern persists after a patient undergoes cortical deafferentation indicates that burst suppression represents an intrinsic dynamic mode of cortex. [5] Even when a burst appears to be homogeneous across the brain, the timing of the bursts in different regions may differ. [14]
Burst suppression patterns can be classified through comparisons of burst duration and inter-burst intervals, maximum peak to peak voltage, and the ratio of power in high versus low frequencies. (Akrawi et al., 1996) [15] Burst suppression with identical bursts suggests a deterministic process of burst generation, whereas other burst suppression patterns depend on stochastic processes. [2] Burst suppression with identical bursts is a distinct pathological EEG pattern that is typical in diffuse cerebral ischemia and is associated with poor outcomes in comatose patients after cardiac arrest. [2]
Bursts are identifiable on EEG readings by their high amplitude (75-250μV), typically short period of 1–10 seconds, and have frequency ranges of 0–4 Hz (δ) and 4–7 Hz (θ). [16] Suppression episodes are identifiable by their low amplitude (< 5μV) and typically long period (> 10s). [16]
EEG recordings of burst-suppression pattern differ between adults and neonates because of diverse pattern fluctuations found in the EEG of neonates. [16] These fluctuations, along with sudden changes in synchronous neuron firing, are caused by development of the newborn's brain. [16] Burst suppression patterns also occur spontaneously during neonatal development, rather than as a characteristic of inactivated brains as in adults. [12]
In order to quantify the burst suppression pattern, the EEG signal must be subject to segmentation. [17] The first segmentation used a fixed voltage-threshold, and various methods for segmentation or burst detection have developed in time domain, [12] frequency (Fourier) domain, and both. [18] These processes separates burst and suppression episodes based on EEG features such as entropies, non-linear-energy-operator, voltage variance, or adaptation of constant false alarm rate (CFAR) algorithm, [19] etc. When the features represent distinguishable patterns of burst and suppression, a fixed threshold using ROC-curve or machine learning methods [18] are used for segmentation.
Quantifying the burst suppression pattern allows for calculation of the burst suppression ratio (BSR) by assigning binary values of 0 to bursts and 1 to suppression episodes. [17] Thus, a burst suppression ratio of 1 is associated with a state of the brain that shows no electrical activity, while a ratio of 0 indicates that the brain is active. The burst suppression ratio measures the amount of time within an interval spent in the suppressed state. [12] This ratio increases as the brain becomes increasingly inactive until the brain's EEG signal flatlines, represented by a burst suppression ratio equal to 1. [20] Because of the direct relationship between burst suppression ratio and brain inactivity, the ratio is an indicator of suppression intensity. [12]
Using the same binary assignments to the burst suppression pattern, another measure of the depth of burst suppression, the burst suppression probability (BSP), can be determined. [12] Mathematically, the instantaneous probability of being suppressed, is
BSR = (Total time of suppression/epoch length) × 100%. [20] where xi is the brain's suppression state at time iΔ, with Δ representing intervals for analysis, and ranges across all real numbers. [17]
Because the burst suppression pattern is characteristic of inactivated brains, the pattern can be used as a marker for the level of coma a patient is in, with persistence of the pattern commonly associated with poor prognosis. [17] Note, however, that there is evidence linking sedation-induced burst suppression with positive outcomes in patients recovering from coma following traumatic brain injury, suggesting a neuroprotective effect. [21] When inducing coma to protect the brain post trauma, the pattern assists in maintaining the necessary level of coma so that no further damage occurs to the brain. [13] The pattern is also used to test the ability of anesthetic arousal agents to induce emergence from comas. [17] The burst suppression pattern can also be used to track ascent into and descent out of hypothermia through observing changes in the pattern. [17]
Monitoring the burst suppression ratio aids medical personnel in adjusting suppression intensity for therapeutic purposes; however, medical personnel currently rely on visually monitoring the EEG and arbitrarily assessing the depth of burst suppression. [12] Not only is the evaluation of the EEG signal for burst suppression done manually, but also the infusion rate of anesthetic to adjust suppression intensity. [13] The introduction of machines makes maintaining proper levels of inactivity more precise through the use of algorithms. This is done through the use of measures such as burst suppression probability [12] for real-time tracking of burst suppression or brain–machine interfaces to automate maintaining proper levels of inactivity. [13]
General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.
Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.
Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.
An induced coma – also known as a medically induced coma (MIC), barbiturate-induced coma, or drug-induced coma – is a temporary coma brought on by a controlled dose of an anesthetic drug, often a barbiturate such as pentobarbital or thiopental. Other intravenous anesthetic drugs such as midazolam or propofol may be used.
Enflurane is a halogenated ether. Developed by Ross Terrell in 1963, it was first used clinically in 1966. It was increasingly used for inhalational anesthesia during the 1970s and 1980s but is no longer in common use.
A gamma wave or gamma rhythm is a pattern of neural oscillation in humans with a frequency between 25 and 140 Hz, the 40 Hz point being of particular interest. Gamma rhythms are correlated with large-scale brain network activity and cognitive phenomena such as working memory, attention, and perceptual grouping, and can be increased in amplitude via meditation or neurostimulation. Altered gamma activity has been observed in many mood and cognitive disorders such as Alzheimer's disease, epilepsy, and schizophrenia.
The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animals. The brain's sleep-promoting nuclei, together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states. The VLPO is active during sleep, particularly during non-rapid eye movement sleep, and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal. The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the endogenous sleep-promoting substances adenosine and prostaglandin D2. The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.
Alpha waves, or the alpha rhythm, are neural oscillations in the frequency range of 8–12 Hz likely originating from the synchronous and coherent electrical activity of thalamic pacemaker cells in humans. Historically, they are also called "Berger's waves" after Hans Berger, who first described them when he invented the EEG in 1924.
Neural oscillations, or brainwaves, are rhythmic or repetitive patterns of neural activity in the central nervous system. Neural tissue can generate oscillatory activity in many ways, driven either by mechanisms within individual neurons or by interactions between neurons. In individual neurons, oscillations can appear either as oscillations in membrane potential or as rhythmic patterns of action potentials, which then produce oscillatory activation of post-synaptic neurons. At the level of neural ensembles, synchronized activity of large numbers of neurons can give rise to macroscopic oscillations, which can be observed in an electroencephalogram. Oscillatory activity in groups of neurons generally arises from feedback connections between the neurons that result in the synchronization of their firing patterns. The interaction between neurons can give rise to oscillations at a different frequency than the firing frequency of individual neurons. A well-known example of macroscopic neural oscillations is alpha activity.
Theta waves generate the theta rhythm, a neural oscillation in the brain that underlies various aspects of cognition and behavior, including learning, memory, and spatial navigation in many animals. It can be recorded using various electrophysiological methods, such as electroencephalogram (EEG), recorded either from inside the brain or from electrodes attached to the scalp.
Electrocorticography (ECoG), a type of intracranial electroencephalography (iEEG), is a type of electrophysiological monitoring that uses electrodes placed directly on the exposed surface of the brain to record electrical activity from the cerebral cortex. In contrast, conventional electroencephalography (EEG) electrodes monitor this activity from outside the skull. ECoG may be performed either in the operating room during surgery or outside of surgery. Because a craniotomy is required to implant the electrode grid, ECoG is an invasive procedure.
The sensorimotor mu rhythm, also known as mu wave, comb or wicket rhythms or arciform rhythms, are synchronized patterns of electrical activity involving large numbers of neurons, probably of the pyramidal type, in the part of the brain that controls voluntary movement. These patterns as measured by electroencephalography (EEG), magnetoencephalography (MEG), or electrocorticography (ECoG), repeat at a frequency of 7.5–12.5 Hz, and are most prominent when the body is physically at rest. Unlike the alpha wave, which occurs at a similar frequency over the resting visual cortex at the back of the scalp, the mu rhythm is found over the motor cortex, in a band approximately from ear to ear. People suppress mu rhythms when they perform motor actions or, with practice, when they visualize performing motor actions. This suppression is called desynchronization of the wave because EEG wave forms are caused by large numbers of neurons firing in synchrony. The mu rhythm is even suppressed when one observes another person performing a motor action or an abstract motion with biological characteristics. Researchers such as V. S. Ramachandran and colleagues have suggested that this is a sign that the mirror neuron system is involved in mu rhythm suppression, although others disagree.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
The preBötzinger complex, often abbreviated as preBötC, is a functionally and anatomically specialized site in the ventral-lateral region of the lower medulla oblongata. The preBötC is part of the ventral respiratory group of respiratory related interneurons. Its foremost function is to generate the inspiratory breathing rhythm in mammals. In addition, the preBötC is widely and paucisynaptically connected to higher brain centers that regulate arousal and excitability more generally such that respiratory brain function is intimately connected with many other rhythmic and cognitive functions of the brain and central nervous system. Further, the preBötC receives mechanical sensory information from the airways that encode lung volume as well as pH, oxygen, and carbon dioxide content of circulating blood and the cerebrospinal fluid.
Emery Neal Brown is an American statistician, computational neuroscientist, and anesthesiologist. He is the Warren M. Zapol Professor of Anesthesia at Harvard Medical School and at Massachusetts General Hospital (MGH), and a practicing anesthesiologist at MGH. At MIT he is the Edward Hood Taplin Professor of Medical Engineering and professor of computational neuroscience, the associate director of the Institute for Medical Engineering and Science, and the Director of the Harvard–MIT Program in Health Sciences and Technology.
Recurrent thalamo-cortical resonance or Thalamocortical oscillation is an observed phenomenon of oscillatory neural activity between the thalamus and various cortical regions of the brain. It is proposed by Rodolfo Llinas and others as a theory for the integration of sensory information into the whole of perception in the brain. Thalamocortical oscillation is proposed to be a mechanism of synchronization between different cortical regions of the brain, a process known as temporal binding. This is possible through the existence of thalamocortical networks, groupings of thalamic and cortical cells that exhibit oscillatory properties.
Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.
Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex and allocortex. It is typically non-invasive, with the EEG electrodes placed along the scalp using the International 10–20 system, or variations of it. Electrocorticography, involving surgical placement of electrodes, is sometimes called "intracranial EEG". Clinical interpretation of EEG recordings is most often performed by visual inspection of the tracing or quantitative EEG analysis.
Patrick Lee Purdon is an American biomedical engineer whose research focuses on neuroscience, neuroengineering, and clinical applications. He holds the Nathaniel M. Sims Endowed Chair in Anesthesia Innovation and Bioengineering at Massachusetts General Hospital and is an associate professor of anaesthesia at Harvard Medical School. Purdon received his Ph.D. in biomedical engineering from Massachusetts Institute of Technology in 2005. His research in neuroengineering encompasses the mechanisms of anesthesia, Alzheimer’s disease and brain health, anesthesia and the developing brain, neural signal processing, and the development of novel technologies for brain monitoring. He has published over 90 peer-reviewed publications, is an inventor on 16 pending patents, and is a Fellow of the American Institute for Medical and Biological Engineering. Purdon has won many awards, including the prestigious National Institutes of Health Director’s New Innovator Award, and his work has been covered in the popular media, including programs on Radiolab and NPR.
