Anaesthetic Effects on the Brain Regions

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“Gentlemen! This is no humbug”

W. G. Morton, on 16th October,1846, used ether to facilitate a painless dental extraction. This, first reported, demonstration of anaesthesia, stunned the audience and led the impressed surgeon to proclaim,  “this is no humbug” (Haridas, 2016). The ground-breaking impact of this discovery was immediately obvious and it rapidly became popular for all kinds of surgeries. Ability of certain drugs to transiently, reversibly and controllably alter consciousness and provide pain relief has made surgeries safer also helped advances in surgical procedures possible; things, which could not have been contemplated without anaesthesia. General anaesthesia is given to nearly a million human beings, all over the world, every single day; yet, mechanisms of anaesthesia continue to be a ‘humbug’ in some sense.

1.1             Consciousness and anaesthesia

The basic tenets of anaesthesia include the components of unconsciousness, amnesia and immobility. A more comprehensive definition of anaesthesia, however, may include suppression of reflexes, analgesia, muscle relaxation, prevention of nausea and vomiting and even prevention of long-term side effects such as postoperative cognitive dysfunction (Urban and Bleckwenn, 2002).

Unconsciousness, for anaesthetists, means unresponsiveness to verbal command, tactile response or even painful response. While it is clear that unresponsiveness does not really mean unconsciousness, it provides a practical endpoint for anaesthetists (Sanders et al., 2012). Beyond the practicalities of anaesthesia, unconsciousness may be difficult to define as ‘consciousness’ continues to be difficult to explain and define. In philosophical terms, the subjective experience which makes one conscious continues to be a ‘hard- problem’ to define, let alone study in a systematic manner (Chalmers, 1995).

Indeed, anaesthetic drugs, producing a state of altered consciousness can be used as a neurophysiological probe, as suggested by Henry Beecher, to study consciousness (Beecher, 1947). This proposition is increasingly bearing fruit, with rapid advances in neuroimaging tools and analytic methods.

According to Baar’s ‘global workspace theory’ the human brain can been compared to a theatre, where ‘selective attention’ shines a spotlight over various competing conscious and unconscious processes (Baars et al., 2003). Various hierarchically organised networks synchronise various neuronal workspaces. For e.g the area involved in attention being the prefrontal cortices and sensory cortices may have their workspaces, while other brain regions such as the parietal cortex, doing unconscious processing provides the ‘context’. An alternative theory (Information Integration theory) by Tononi, proposes that consciousness corresponds to the capacity of  a system to integrate information (Tononi, 2004). This further depends upon two key concepts- differentiation- availability of a large number of conscious experiences and integration- the unity of each such experience. Mashour et al proposed, as an extension of the information integration theory, a ‘cognitive unbinding theory’ of anaesthesia where isolation of neural activity results in anaesthesia (Mashour, 2013). Some aspects of these theories have been able to explain the neuroimaging findings of anaesthesia, and these findings in return have helped consolidate these theories of consciousness.

1.2             Theories of anaesthesia

Early theories of anaesthetic action, presumed that all anaesthetic drugs worked in the same way and resulted in a global suppression of neural activity (wet blanket theory). However, it soon became clear that regional selectivity may exist and so some brain regions may be more crucial than others.

Meyer and Overton, showed that the lipohilicity (solubility in Olive oil) of anaesthetic drugs correlated with their anaesthetic potencies. This led to the hypothesis that the neuronal lipid bilayer was the key site of action of anaesthetic drugs and appeared to provide the basis for a ‘unitary’ site of action. This further led to numerous theories of how the anaesthetic agents may act with the lipid bilayers (Kopp Lugli et al., 2009). These theories could not explain all aspects of anaesthetic actions and so the focus shifted to alternate targets. Protein targets emerged as valid targets for anaesthetic drugs, and the rapid discovery of the range of potential protein targets meant that a unitary protein molecule as target for anaesthetic actions was unlikely.

1.2.1        Molecular targets for anaesthetic drugs

There are multiple receptors that target sites for anaesthetic drug actions.

GABA receptors are the main inhibitory receptors and are targeted by most anaesthetic drugs. GABA-A receptors are heteromeric structures with 2α, 2β and 1γ units. The γ-subunit may be replaced by variants such as δ subunits (Farrant and Nusser, 2005, Hevers and Luddens, 1998). The receptors with the γ unit are commonly located in the post-synaptic membranes while those with the δ units are heavily present in the extra-synaptic sites (Nusser et al., 1996). It is the subunit structure and their locations that determine most of the actions of the anaesthetic agents. The synaptic release of GABA in response to nerve stimuli, resulting in the fast phase synaptic inhibition is well known (phasic release). More recently, a ‘tonic’ form of inhibition resulting from extra-synaptic release and action of GABA has been identified. As the extra-synaptic receptors are not usually saturated and also because they desensitise less as compared to the post-synaptic receptors, they are more efficient targets for anaesthetic drugs to produce their ‘inhibitory’ actions (Bianchi et al., 2002, Mody et al., 1994).

Importance of GABA receptor subunits is further exemplified in the hippocampal GABA receptors, with α-5 subunits, which are highly sensitive to anaesthetic drugs (Sur et al., 1999). This may be responsible for the early-amnesic effects of anaesthetic drugs. Similarly GABA-A receptors with α-4 subunits may account for the amnesic effects of volatile agents (Rao et al., 2009). Sedative effects of anaesthetic drugs are also highly dependent on the subunit structure of the GABA receptors. Replacement of the asparagine residue at position 265 in the β-2 or β-3 GABA-A receptor subunit with serine or methionine, respectively, rendered GABA-A receptors containing these subunits relatively insensitive to etomidate or propofol (Reynolds et al., 2003). Similarly, α-1 subunit’s specific constitution is essential for the sedative properties of  benzodiazepines (Rudolph et al., 1999). Gaboxodol’s sedative actions are dependent on the presence of α-4 and δ subunits in the thalamic ventrobasal neurons (Chandra et al., 2006). Hypnotic (unconsciousness) actions by anaesthetic drugs are dependent on the β-2 and β-3 subunits (Reynolds et al., 2003). Immobility, an essential component of anaesthesia, is mediated through the spinal GABA-A receptors with the β-3 subunits (Zeller et al., 2007).

Volatile anaesthetics act through multiple receptors including GABA-A. GABA receptors containing α-1 and β-3 subunits have been shown to be important binding sites for the action of volatiles (Mihic et al., 1997).

Glutamate is the major excitatory neurotransmitter in the brain. It acts on N-Methyl-D-aspartate (NMDA) and non-NMDA receptors (which include AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid and kainite receptors). These non-NMDA receptors are responsible for the fast phase of the excitatory post-synaptic potentials. Anaesthetic drugs usually have no effect on these non-NMDA receptors. NMDA receptors, however, are responsible for the slow phase of the post-synaptic potential and are affected by anaesthetic drugs such as Ketamine, Xenon and Nitrous-Oxide. Ketamine’s main actions on the NMDA receptors are thought to be of non-competitive antagonism. Xenon and Nitrous oxide also act on NMDA receptors by competing with the glycine binding subunit of the NMDA receptor (Dickinson et al., 2007).

Potassium (K+) channels may also contribute to the anaesthetic actions of the volatile agents, as they may directly activate or enhance the activity of the two-pore domain family of K+ channels (Gray et al., 1998). Other ion channels such as hyperpolarisation –activated cyclic nucleotide-gated channels which help maintain synchrony of neuronal networks and also generation of spontaneous rhythm in ‘pacemaker’ neurons may also be anaesthetic targets (Biel et al., 2009). Volatile agents, propofol and ketamine: all have been shown to inhibit the activities of these channels (Chen et al., 2009).

Through these potential molecular targets, anaesthetics may modulate neuronal function by a variety of mechanisms. They can reduce neuronal excitability and disrupt the flow of information between neurons. This may be the key mechanism of drugs acting on GABA receptor. Anaesthetic agents may also alter long-term potentiation (LTP), which normally occurs through pre- and post-synaptic firing occurring coincidentally, resulting in strengthening of the excitatory synapses. This occurs through the stabilisation of glutamate receptors in postsynaptic membrane and growth of new synapses. Finally, anaesthetic agents may alter the balance of the excitatory and inhibitory activity in neuronal networks leading to changes in network oscillatory activity (discussed further in Section 1.4).

1.3        Sleep and anaesthesia

Research into un-consciousness mechanisms can be looked into through alterations in consciousness induced during physiological conditions (such as sleep), pharmacological (such as sedation and anaesthesia) and pathological (such as epilepsy and vegetative states). Indeed, there is a fair degree of overlap among those conditions.

The phrase “now you will go off to sleep”, is commonly used by anaesthetists as they administer anaesthesia. Anaesthetic- unconsciousness is related to natural sleep, by patients and clinicians alike, as it provides a sense of comfort and reversibility. While sleep has been defined as a naturally occurring, periodic state of rest during which consciousness of one’s environment and responses to external stimuli are largely suspended (Franks and Zecharia, 2011), it cannot be completely characterised without referring to its elements such as spontaneous movements,  variations in muscle tone, response to command, self perception, mental imagery, thermodynamic control and reversibility upon external stimulation (Bonhomme et al., 2011).  While there are key differences between natural sleep and anaesthetic-induced ‘sleep’, there are enough commonalities, which has provided a substrate for further research into anaesthetic mechanisms.

1.3.1        Target brain sites for anaesthetic drug actions

Anaesthetics, in part, produce their effects by stimulating natural sleep promoting pathways. Some of the key brain regions, responsible for maintaining the sleep-wake homeostasis have been studied in detail and the effect of anaesthetic drugs on those have been evaluated. The key nuclei lie in the brainstem (forming part of the Reticular Activating System- RAS), and subcortical (hypothalamus and thalamus) regions and have been described below.

Locus Coeruleus

Locus Coeruleus (LC) is situated in the brainstem and has the highest collection of noradrenergic neurons in the brain. It innervates diffusely to other parts of the brain, including directly to the cortex, thalamus, hypothalamus, basal forebrain, amygdala, hippocampus and other subcortical systems. Firing of the LC neurons promote wakefulness through actions on the medial septum, medial preoptic area and substantia innominate in the basal forebrain (Berridge, 2008). It also switches the tone of the thalamocortical neurons form a ‘burst’ pattern (as in sleep) to a ‘spiking’ pattern supporting wakefulness.

Raphe nuclei

These nuclei are the brain’s major source of serotonin. It may exert biphasic influences on arousal, such as its effect on sleep-active ventrolateral preoptic nucleus (VLPO), where it inhibits half of the neurons while it stimulates the other half (Gallopin et al., 2005).

Ventral periaqueductal gray

It has wake active dopaminergic neurons, so drugs increasing dopamine increase wakefulness. Ventral periaqueductal gray (vPAG) efferents go to arousal state regulation regions including the basal forebrain, orexinergic neurons in the perifornical hypothalamus, midline thalamic and intralaminar thalamus, laterodorsal tegmentum, as well as the sleep-active VLPO (Lu et al., 2006).

Laterodorsal tegmentum and pedunculopontine tegmentum

These nuclei constitute the major cholinergic nuclei in the brainstem and promote wakefulness or rapid-eye-movement (REM) sleep. They innervate the midline and intralaminar thalamic nuclei and thalamic reticular nuclei and alter thalamic activity from ‘bursting’ to ‘spiking’ (Steriade et al., 1990). They send projections to the pontine reticular formation and fire mainly during REM sleep. They also have GABA-ergic neurons (Fuller et al., 2007) which promote REM sleep and so may be influenced by GABAergic drugs.

Pontine reticular nucleus

Here Rapid Eye movement (REM)-ON  generating nuclei are found, however they can promote wakefulness too.  They receive cholinergic, orexinergic and GABAergic inputs. Increased GABA promotes wakefulness as demonstrated with anaesthetics (Vanini et al., 2008).

Tuberomamillary nucleus

The brain’s sole histaminergic signalling nucleus has widespread connections. Tuberomamillary nucleus (TMN) neurons display state-dependent firing patterns with maximal rates of discharge occurring during wakefulness, slower rates in NREM sleep, and minimal activity during REM sleep (John et al., 2004). Fluctuating levels of GABA modulate activity of TMN neurons and have been shown to produce hypnosis but not complete anaesthesia (Nelson et al., 2002).

Hypocretin/ orexin neurons

These are wake-promoting neurons and show maximal activity during wakefulness (Mileykovskiy et al., 2005). They project to all monoaminergic groups and basal forebrain, midline thalamic and other regions and participate in modulating emergence from anaesthetics (Kelz et al., 2008, Peyron et al., 1998).

Basal forebrain

Basal forebrain contains acetylcholinergic neurons (wake-active) and receive input from the brainstem and hypothalamic arousal-promoting nuclei and project to the cerebral cortex (Jones and Cuello, 1989). Physostigmine , an acetylcholinesterase inhibitor has been shown to reverse the effects of sevoflurane anaesthesia (Plourde et al., 2003). Basal forebrain also contains GABAergic neurons (sleep-active) which too project to the cerebral cortex, especially to the inhibitory interneurons (Freund and Meskenaite, 1992). These neurons also have α2 adrenergic receptors and are inhibited (during wakefulness) by noradrenergic projections form the LC (Modirrousta et al., 2004).

Ventrolateral preoptic nucleus (VLPO)

VLPO lies in the anterior hypothalamus and is reciprocally interconnected to wake promoting nuclei, including histaimnergic TMN, serotonergic RN, noradrenergic LC, cholinergic LDT and PPT and orexinergic neurons of hypothamaus. They contain GABA and so can reciprocally inhibit wake-active ascending Reticular Activating system (Szymusiak and McGinty, 2008).

Median preoptic nucleus

They have sleep-active GABA-ergic neurons which play a role in sleep initiation and fire before the onset of sleep (Suntsova et al., 2002). Endogenous somnogens stimulate Median Preoptic nucleus and it sends inhibitory signals to other systems such as orexinergic system or hypothalamus (Szymusiak and McGinty, 2008).

Thalamocortical system

Receive input from dorsal pathway and wake-active regions of hypothalamus. Thalamocortical (TC) system comprises of three types of neurons, which form interlocking positive and negative feedback loops. TC neurons send excitatory glutamatergic input to the other two populations: the reticular thalamic neurons and the corticothalamic (CT) neurons. The CT neurons send depolarizing glutamatergic feedback to the TC neurons (forming the positive feedback loop) and excitatory input to the reticular neurons (forming the negative feedback loop, since the reticular neurons are GABAergic and innervate the TC neurons) (Steriade, 2003). Both reticular and TC neurons receive monoaminergic and cholinergic input from the brainstem, but with opposing results. TC neurons are depolarized, while reticular neurons are hyperpolarized. During wakefulness, ongoing depolarisation of the TC neurons results in a ‘tonic’ firing pattern while during sleep they become hyperpolarised and produce a ‘bursting’ pattern of activity. During this phase they prevent transmission of sensory stimuli to the cortex (Alkire et al., 2000). Anaesthetic drugs have been shown to affect these thalamocortical systems in wide ranging sets of experiments.

Figure 01: Figure showing sagittal view of brain demonstrating some of the key areas involved in anaesthesia.

Inset highlights key arousal systems with neurotransmitters involved in sleep or wakefulness. Sleep-active loci are shown in light blue. When wake-active systems (shown in red) are firing they antagonize the sleep-active groups. Conversely, when sleep-active neurons are active, they mutually antagonize the wake-active regions to further reinforce sleep. Anesthetic drugs are known to interact with this circuitry to produce hypnosis. 5-HT: serotonin; ACh: acetylcholine; DA: dopamine; GABA: γ-aminobutyric acid; Gal: galanin; HA: histamine; Glut: glutamate; NE: norepinephrine; BF: basal forebrain; DpME: deep mesencephalic reticular formation; LC: locus coeruleus; LDT laterodorsal tegmentum; MnPO: Median preoptic nucleus; mPFC: medial prefrontal cortex; Ox: orexin/hypocretin neurons in lateral, perifornical, and posterior hypothalamus; PnO: pontine reticular nucleus oral part; PPT pedunculopontine tegmentum; RN: raphe nuclei; SCN: suprachiasmatic nucleus; TMN: tuberomammillary nucleus; VLPO ventrolateral preoptic nucleus; vPAG: ventral periaqueductal gray. Adapted from (Moore and Kelz, 2011)

1.4             Cortical cytoarchitecture and cell assemblies: generation of brain rhythms

The human neocortex is a thin, extended, convoluted sheet of tissue with a surface area of ~2600 cm2, and thickness 3–4 mm. It contains up to 28 x109 neurons and approximately the same number of glial cells. Cortical neurons are connected with each other and with cells in other parts of the brain by a vast number of synapses, of the order of 1012 (Mountcastle, 1997). The neurons in the neocortex are structured in relatively well-defined horizontal layers (6 laminae) and vertical columns. The basic unit of the neocortex is a ‘minicolumn’, a narrow chain of neurons extending through the layers, perpendicular to the pial surface. Each minicolum contains 80-100 neurons (a lot more in the striate cortex). Cortical columns are formed by minicolumns bound together by short-range horizontal connections. Putting these columns in macroscopic perspective, assuming that a column with a diameter of 40μm contains 100 cells, the cortical surface that would correspond to 50,000 cells (which is the number expected to produce the weakest magnetic current of 10nAm) should form a patch with about 0.63 mm2 in area. If this cortical patch had a circular form, then its diameter would be about 0.9 mm (Lopes da Silva, 2010).

While the neocortex contains hundreds of types of cells, they may, broadly, be classified as ‘projection neurons’ and ‘interneurons’. Projection neurons are glutamatergic, pyramidal neurons that project to other cortical, subcortical and subcerebral regions (Figure 0‑1). Interneurons are GABA-ergic and make local, short-distance connections (Molyneaux et al., 2007). The basis of the columnar arrangement, in sensory cortices, is that each column receives selective input from the relay thalamic nuclei. Activities, both excitatory and inhibitory, in these cortical pyramidal cells is observed on EEG (Kirschstein and Kohling, 2009). Pyramidal cells in different layers may have further differentiation of roles depending on the inputs ending in those and the afferent sources (Figure 0‑2). For e.g. the visual evoked potentials are generated from the activity of the layer IV (Kraut et al., 1985) while the visual gamma band responses result from the activities of layers II, III and IV (Xing et al., 2012).

Figure 02: Cortical laminar structure: basic circuits.

Blue and grey fibres are afferents, interneurons are green and efferents are red. Adapted from Lynch, 2013 (Lynch, 2013)

Inhibitory interneurons, typically, have short ranges and influence neurons close-by. They also have short latencies and faster action potentials than pyramidal cells. These cells, thus, prevent runaway excitation of pyramidal cells. There is feed-forward inhibition, such that a rapidly occurring inhibitory potential limits the time window for summation of excitatory inputs to generate action potentials. There is feedback inhibition too, where excitation of the pyramidal cell excites the interneuron which inhibits the pyramidal cell (Figure 0‑3) (Mohler, 2002). This mechanism results in the oscillatory action potentials, which are then recorded as the EEG/ MEG rhythms.

Figure 03: Scheme of feedforward and feedback inhibition

Pyr: Pyramidal cells. Adapted from Mohler, 2002 (Mohler, 2002)

1.5             Using advances in neuroimaging techniques

As is clear from the previous sections that neuronal assemblies, in microscopic scale, interact with each other, in microsecond time scales, to produce the behavioural changes associated with anaesthesia. In-vivo study of such changes in humans is close to impossible. Advances in neuroimaging techniques have provided a non-invasive window in to such neuronal changes, albeit, occurring at a macroscopic, large scale, network-level. The advantages and strengths of different neuroimaging techniques are discussed in more detail in Chapter 2.

1.6             Insights into anaesthetic action from neuroimaging research

Neuroimaging techniques, in humans, have been used to confirm the findings of animal (in vivo/ in vitro) research; but also to generate testable hypotheses. Some of the earliest neuroimaging studies used PET to study pharmacodynamics effects on the brain and also to study cerebral perfusion changes, especially in terms of their usefulness for neuro-anaesthesia, or in patients with a raised intracranial pressure. PET was therefore, naturally, used to study perfusion and metabolic changes to study anaesthetic mechanisms. The neuroimaging literature may be divided into specific questions, in relation to different consciousness levels and different anaesthetic drugs, which the neuroimaging researchers have attempted to answer.

1.6.1        Is the anaesthetic effect global or regional?

Some of the early theories of anaesthetic mechanism suggested a ‘global suppression’ by drugs resulting in unconsciousness. However, neuroimaging studies demonstrated that there was not only a global reduction in cerebral metabolism and perfusion, but also that different anaesthetics affect different regions preferentially. In one of the first studies of its kind, Alkire et al, during propofol anaesthesia, showed reduced global metabolism along with some regions more depressed than others (Alkire et al., 1995). Inhalational anaesthetic agents isoflurane and halothane revealed a significant global suppression of neuronal activity (Alkire et al., 1997, Alkire et al., 1999). There was a greater global suppression and regional suppression of cortical metabolism with less effect on basal ganglia and midbrain with propofol as compared to the inhalational agents. Sedative doses of propofol and sevoflurane reduced perfusion in the cuneus, precuneus, posterior limbic system and the thalamus or midbrain, with propofol causing additional reduction in frontal and parietal regions (Kaisti et al., 2002). Jeong et al described the changes as propofol affecting the neocortex more while sevoflurane affected the paleocortex and telencephalon more (Jeong et al., 2006).

Halothane and isoflurane, drugs with similar chemical structure, appeared to have different effects on perfusion in different regions (Reinstrup et al., 1995). Even within GABAergic intravenous anaesthetic drugs, different molecules may have different actions on the brain. Propofol at sedative doses decrease CBF in the right-sided anterior brain whereas thiopental decreased CBF mainly in the left cerebellum. At hypnotic concentrations both drugs decrease CBF in the posterior cortical regions. Also, at these concentrations propofol reduces thalamic blood flow but thiopental did not (Veselis et al., 2004).

These studies demonstrated the regional effects of anaesthetic agents and pointed towards mechanistic differences between propofol and inhalational group of drugs.

1.6.2        Relating molecular mechanisms to neuroimaging findings

The key differences in propofol and the commonly used inhalational anaesthetic agents is that while propofol has mainly GABA-ergic activity, inhalational drugs work through a number of other receptors. Cerebral metabolic changes with propofol correlated with the GABA receptor density (i.e. areas with greater GABA receptors, showed greater reduction in activity) but not with isoflurane, which produced metabolic changes correlating with the muscarinic (acetylcholinergic) receptor density (Alkire and Haier, 2001). These findings further provided proof of different receptor mechanisms of the two main groups of anaesthetic agents.

1.6.3        Neural correlates of suppression of sensations and cognition

Anaesthetic unconsciousness includes reversible, cognitive and sensorimotor failure. Neuroimaging studies have been done during specific tasks to investigate changes in brain activity and the effect of anaesthetic drugs on the regions involved with escalating doses.

During isoflurance anaesthesia, blunting of noxious and normal sensory stimuli were shown while some sensory cortical and thalamic activity persisted during lower (sedative) doses (Antognini et al., 1997). Similarly, at sub-anaesthetic doses, isoflurane was shown to affect specific areas including the right anterior insular and intraparietal sulcus while performing a visual search task while the sensory cortical and subcortical regions were unaffected (Heinke and Schwarzbauer, 2001). With propofol, brain responses to a vibrotactile stimulus decreased in a dose-dependent manner in the cortical and subcortical regions (Bonhomme et al., 2001). Thalamic activity was lost completely only at the doses producing unconsciousness. Propofol related dose-dependent suppression of primary cortical activity has been shown by multiple groups (Dueck et al., 2005, Heinke et al., 2004, Veselis et al., 2005). Similarly, dose related suppression of brain activity in higher-order regions has been shown by most of these studies. Thalamic activity is lost later as sedative depth progresses; however, it stays unclear if thalamic suppression is a cause or consequence of cortical suppression. While some of these studies supported the concept of a ‘thalamic switch of consciousness’, other neuroimaging modalities have revealed other contenders as the key anatomical sites for switching consciousness on-off, or a lack of any such specific brain site (See Section 1.6.7).

1.6.4        Neural correlates of amnesia

Amnesia is a key component of anaesthesia and has therefore been an area of interest. The focus has been on studying anaesthetic effect on brain regions known to be involved in memory and the sequence of amnesia induced as a part of anaesthetic process.

Midazolam (a benzodiazepine- another GABA-ergic drug), commonly used for procedural sedation provides good anterograde amnesia. Decreased CBF in the left middle temporal gyrus, left dorsolateral prefrontal cortex and bilateral orbitofrontal cortex were shown during midazolam infusion (Reinsel et al., 2000), however activity on prefrontal cortex was not associated with amnesia (Bagary et al., 2000). Lorazepam (another BZD) and scopolamine (anticholinergic drug) produced amnesia and suppressed activity in the hippocampus, fusiform gyrus and inferior prefrontal cortex (Sperling et al., 2002).

Right sided prefrontal and parietal areas were involved in the amnesic effects of propofol sedation, while medial temporal lobes were more resistant, suggesting an indirect effect of propofol on centres known to be key for memory (Veselis et al., 2002). During an auditory recall task it was shown that primary and association auditory cortical areas remain active during propofol anaesthesia but the regions associated with processing and recall, bilateral planum temporale, were suppressed at sedative doses (Plourde et al., 2006). Davis et al studied the brain responses to different states of speech, comprehension and recall (Davis et al., 2007). They showed that superior and middle temporal gyri were related to speech perception and active during the mild sedation stage but not during deep sedation. Activation of the inferior frontal posterior temporal responses corresponded to comprehension and was absent even during mild sedation.

These studies have therefore helped understand some of the key steps in the anaesthetic cascade with specific effects on key brain regions involved in memory and recall.

1.6.5        Atypical anaesthetic drugs

Anaesthetic drugs with different (non-GABAergic) actions, such as ketamine, nitrous oxide, xenon and dexmedetomidine are associated with quite different behavioural and central effects. Most of these drugs are not useful as sole anaesthetics (except ketamine) but they are useful as sedatives and as a component of multimodal anaesthesia. Neuroimaging studies of the altered consciousness induced by these drugs have also provided a valuable insight into the mechanisms of anaesthesia and the differences with typical anaesthetic drugs.

Ketamine is an NMDA anatagonist and produces a state of ‘dissociative’ anaesthesia where patients are immobile, amnesic and do not experience pain. However, they appear awake, but detached from the surroundings and may also be able to talk. PET demonstrated a dose dependent CBF increase in the anterior cingulate, thalamus, putamen and frontal cortex while the greatest relative increase occurred the ACC, insula and frontal cortex (Langsjo et al., 2003).This increase in perfusion was associated with an in crease in neuronal metabolism (Langsjo et al., 2005, Langsjo et al., 2004). BOLD-fMRI studies also demonstrated task related deactivations in specific brain regions with ketamine (Abel et al., 2003a, Abel et al., 2003b) while its analgesic effects were correlated with a reduced activity in the insular cortex and thalamus (Rogers et al., 2004).

Like ketamine, nitrous oxide has been shown to increase cerebral metabolism. Inhalation of nitrous oxide (20%) was associated with significant activation in the anterior cingulate cortex while deactivation was found in the posterior cingulate, hippocampus, para hippocampal gyrus, and visual association cortices (Gyulai et al., 1996). Unlike ketamine and nitrous oxide, xenon was shown not to increase metabolism. Xenon resulted in a metabolic suppression and also cortical and sub-cortical CBF (Rex et al., 2008, Rex et al., 2006)

Dexmedetomidine is an α-2 adrenergic agonist, which produces characteristic sedation wherein patients are easily arousable even from deeper stages. PET showed a dose dependent global and regional decrease in CBF with dexmedetomidine (Prielipp et al., 2002). Clonidine, another alpha 2 adrenergic agonist, was shown to reduce acts on the prefrontal, orbital and parietal association cortex, precuneus, posterior cingulate and thalamus (Bonhomme et al., 2008).

These neuroimaging findings show how different receptor mechanisms affecting different brain regions may produce the same behavioural outcomes, i.e. altered consciousness.  While this does not completely shift the focus away from having a single common final pathway of anaesthetic unconsciousness, it shows that there may be a number of different paths in terms of approaching it.

1.6.6        Connectivity- functional and effective

As the understanding of the anaesthetic effects on the brain regions (and their metabolism and perfusion) has improved, the focus has moved on to the interaction of different brain regions underlying anaesthesia. This has been facilitated by discovery of the temporal coherence in the activity of various brain regions- resting state networks and the advances in mathematical modelling, being able to predict the influence of one region over the others.

Network connectivity studies have studied higher-state (those serving higher cognitive functions) and basic-state (those serving primary sensory functions) functional networks and consistently demonstrated a disruption of higher state networks earlier in the anaesthetic cascade while the lower-state (primary function) maintained their activities even during deeper stages of sedation and anaesthesia.

While functional connectivity provides a useful measure of potential relationship between different brain regions, efforts have been made to identify more direct measures and to be able to demonstrate causal influence of one site on the other to establish the sequence of effects. EEG changes following TMS induced stimulation showed that during midazolam sedation the spread of cortical activity was much limited to the stimulation site (Ferrarelli et al., 2010). This demonstrated a direct measure of loss of cortical connectivity from the stimulation site, associated with midazolam. The direction of connectivity within the frontoparietal networks has also been of interest. The feedforward connections relay incoming sensory information while the feedback projections help select and interpret those. During the anaesthetic state the feedforward information transfer may continue however the feedback gets reduced and may be responsible for the unconsciousness (Imas et al., 2005). Computational modelling has shown this directional suppression of feedback activity as a common step between different classes of anaesthetics including ketamine, sevoflurane and porpoofol (Lee et al., 2013). During propofol induced anaesthesia feed forward connectivity persists suggesting that sensory information continues to flow (Ku et al., 2011).

Combining information from neuroimaging tools (as is the focus of this thesis) has also provided valuable information about the temporal and spatial sequence of changes in the anaesthetic cascade. Slow wave EEG-activity (1Hz) of cortical neurons emerged at the point of loss of consciousness with propofol and was associated with thalamocortical dissociation (Ni Mhuircheartaigh et al., 2013).

1.6.7        Consciousness switch

A great deal of research has focused on identifying a key brain area which results in consciousness, a so called ‘consciousness switch’. Neuroimging techniques have provided a tool to investigate if indeed there is such a brain region.

Thalamus had been known to be the gateway to the cortex and therefore naturally appeared to be a contender. Thalamic microinjection of nicotine was able to reverese sevoflurane induced unconsciousness in mice (Alkire et al., 2007). Selective lesion of the medial thalamus can produce coma while stimulation of the central thalamus can restore consciousness (Schiff, 2008, Schiff, 2009). Most neuroimaging literature, as discussed above, shows thalamus to be more resistant to anaesthetic effects than the cortical areas, suggesting that thalamic suppression is related to anaesthetic unconsciousness. However, more detailed analyses and recent anaesthetic literature has challenged this view. It is unclear whether thalamic suppression is a cause of unconsciousness, or the consequence of cortical suppression (and therefore unconsciousness) or an equal participant (Mashour and Alkire, 2013).

Precuneus, which forms a key node of the default mode network has also been suggested by some as the key region maintaining consciousness. As one of the brain areas with highest resting metabolism, it is one of the commonly affected areas in sedation/ anaesthesia (Cavanna and Trimble, 2006). Physostigmine induced reversal of propofol sedation was associated with increased perfusion of thalamus and precuneus (Xie et al., 2011). More recently the right dorsal anterior insular cortex has been proposed as the cortical gate associated with anaesthesia (Warnaby et al., 2016).

These neuroimaging studies have certainly contributed to the understanding of anaesthetic mechanisms, the similarities and differences between different anaesthetic compounds and the value of using the strengths of different neuroimaging modalitites. These have informed some of the experimental designs used in this thesis.

1.7             Need for understanding mechanisms of sedation and anaesthesia

While anaesthetic drugs may be used a consciousness probe to understand consciousness better, there are other obvious and pressing needs for this area of research. The bench to bedside translation of this area of research holds promise for clinicians in some of these areas.

1.7.1        Disorders of consciousness

Coma has been defined as a state of profound unconsciousness associated with markedly depressed cerebral activity, a loss of the ability to maintain awareness of self and environment combined with markedly reduced responsiveness to environmental stimuli, and a loss of the ability to perceive and respond. This essentially means a lack of wakefulness and awareness. Coma, for most people, leads on to irreversible loss of brain stem function or brain death. If only wakefulness returns, patients may be in a state of unresponsive wakefulness syndrome (earlier called vegetative state). When patients show return of limited signs of awareness without consistent communication with the environment, they are called to be In a state of minimal conscious state. These states are different from the locked-in syndrome, where patients have all cognitive functions, but an inability to perform movements except with their eyes (Kirsch et al., 2016).

These conditions are not just challenging for clinical management but also pose a diagnostic challenge. Wrong diagnosis and classification of altered consciousness states can be as high as 40 % (Schnakers et al., 2009). Owen et al demonstrated presence of consciousness in a young woman, who was believed to be in a vegetative state, by using activation of relevant brain regions on fMRI on verbal commands (Owen et al., 2006). This not only exposed the limited understanding of brain function but also challenged the commonly held behaviour-driven definitions of ‘awareness’. Further neuroimaging testing revealed awareness and also potentially communicate in a small group of patients with MCS (Monti et al., 2010). Similar to pharmacological sedation, neuroimaging has revealed disruption of functional connectivity in DMN and other frontoparietal resting state networks in patients with UWS/MCS (Noirhomme et al., 2010, MacDonald et al., 2015). Recovery from UWS/MCS has also been shown to correlate strongly with functional connectivity strength of the PCC/ precuneus (Wu et al., 2015).

Differentiating MCS from UWS has implications in terms of prognosis, but also ethical and legal in terms of care and decision making. Indeed, it has been suggested that neuroimaging could be used to facilitate neurorehabilitaiton in such group of patients (Laureys et al., 2006).

It is clear that differentiating the different conditions of pathological alterations in consciousness is critical in terms of prognosis and overall better quality of care of these patients. Neuroimaging techniques have shown value where explicit behaviour has been unable to help. It is expected that better understanding of the neurophysiology of consciousness will help this particular group of patients.

1.7.2        Complications of anaesthesia and sedation

Critically ill patients, being managed in Intensive Care units, experience a number of traumatic experiences during their stay. These include activities such as airway instrumentations, placing intravenous / arterial lines, catheterisation and nursing care. Most critically ill patients are kept sedated to help them cope with being bed-bound, dependent and to tolerate mechanical ventilation. PTSD is fairly common in ICU survivors and while the causes could be many, use of be benzodiazepine sedative and ‘frightening’ ICU experiences can contribute to those.

The trauma of their clinical condition is compounded by other neurological consequences, such as delirium. Delirium, is an acute and fluctuating disturbance of consciousness and cognition, a common manifestation of acute brain dysfunction in critically ill patients, occurring in up to 80% of the sickest of these patients (Girard et al., 2008). This delirium makes the stay distressing; it also has long-term consequences including dementia death. This forms one of the key elements of the ‘triad’ of ICU management- pain, agitation and delirium. It has been proposed that sedation should be used only after this triad has been managed. Sedation itself can cause delirium and different sedatives have been shown to affect the incidence and outcomes of delirium (Reade and Finfer, 2014). Dexmedetomidine has been shown to reduce the incidence of ICU delirium when compared with midazolam. It has been suggested that dexmedetomidine’s non-GABAergic actions, in promoting the natural sleep pathways, helps avoid this complication (Pandharipande et al., 2007).

Similar delirium may occur following surgery (post anaesthesia delirium) and has been reported to be as common as upto 54% in patients undergoing major elective non-cardiac surgery (Sanders et al., 2011). Certain anaesthetic drugs such as benzodiazepines, opioids and inhalational agents are more likely to be associated with delirium (Hernandez et al., 2017).

It is likely that a better neurophysiologic understanding of delirium and development of cleaner anaesthetic drugs will benefit a large group of surgical and critically ill patients.

1.7.3        Awareness during anaesthesia

During general anaesthesia, patients expect to be unconscious and amnesic to their surgical experience. Clinically, ensuring amnesia and immobility (which Is easily achievable by giving high enough doses) needs to be balanced against overdosing patients, which may cause cardiovascular compromise or delayed recovery. This is where anaesthesia becomes an ‘art’. A better understanding of brain function which anaesthetic drugs are meant to block can support this art.

The consequences of accidental awareness during anaesthesia include experiencing excruciating pain during the procedure and have long term neuropsychiatric sequelae like post-traumatic stress disorder (Ghoneim, 2000). National Audit Project-5, one of the largest surveys of its kind identified the incidence of accidental awareness under general anaesthesia (AAGA), its consequences and the factors related to it (Cook et al., 2014). They found that although the incidence of AAGA was low, its impact can be substantial with patients experiencing long term distress and psychological consequences including post traumatic stress disorder. This was commoner and worse in those patients who experienced paralysis (due to the neuromuscular drugs administered) during AAGA. NAP recently reported a high degree of awareness during procedures carried out under sedation. This report reflects a failure of explanation on the part of the anaesthetist rather than the failure of sedation; while amnesia is not always a goal of procedural sedation it would be useful to provide that with reliability and be able to monitor that.

Co-relational depth of anaesthesia monitors have been developed for use during anaesthesia and sedation. These are usually indices derived from EEG activity. These monitoring systems have however not been widely popular due partly to the unfamiliarity of anaesthetists with the underlying EEG, but, mainly due to a  lack of clear understanding of the mechanistic link between anaesthetic drugs and their mechanisms of activity. Also, failure of such monitors (and indeed EEG indices) to reflect the effects of certain drugs (which increase EEG activity as opposed to decrease it, with increasing drug effect). Therefore, a reliable depth of unconsciousness/ anaesthesia monitor which would work with all types of anaesthetic drugs would improve the safety and quality of anaesthetic practice. Indeed, it has been suggested that a comprehensive understanding of the mechanisms of pharmacological, physiological and pathological consciousness may result in development of a ‘consciousness-meter’ (Boly et al., 2013).

With increasing pressures on anaesthetic departments providing clinical cover in non-operating areas in increasingly difficult. Sedation, when administered by non-anaesthetists is associated with a much higher morbidity and mortality (Quine et al., 1995). If a reliable, responsive sedation monitoring system could be developed, it is envisaged that the safety profile of sedatives in non-anaesthetic hands may increase thus widening the safe practice patients enjoy in the hands of anaesthetists.

1.8        Conclusions

The contents of this chapter provide the relevant background for the experiments in thesis. Understanding of the complexities of some of the receptor mechanisms and targets of anaesthesia, brain regions and current neuroimaging literature is required to formulate the hypotheses in the following chapters. The focus of this thesis is on mild sedation, which is clearly distinct from anaesthetic unconsciousness. While mild sedation is the first step towards the loss of consciousness in response to anaesthetic drugs and it may also have more in common with other disorders where cognition and memory is affected. A range of advanced neuroimaging tools are used in this thesis in an attempt to bring together the metabolic, haemodynamic and neurophysiologic characteristics of mild sedation to understand its neural correlates. This will undeniably assist in understanding the mechanisms of consciousness and making sedation safer in clinical practice.

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