Cortical synaptic basis of consciousness

Consciousness is one of final questions for humans to tackle in neuroscience. Due to a lack of understanding of basic brain networks and mechanisms of functions, our knowledge of consciousness mainly stays at a theoretical level. Recent studies using brain imaging in humans and modern neuroscience techniques in animal studies reveal the basic brain network for consciousness. The projection from the thalamus to different cortical regions forms a network of activities to maintain consciousness in humans and animals. These feedback and feedforward circuits maintain consciousness even in certain brain injury conditions. Pterions and ion channels that contribute to these circuit neural activities are targets for drugs and manipulations that affect consciousness such as anesthetic agents. Synaptic plasticity that trains synapses during learning and information recall modified the circuits and contributes to a high level of consciousness in a certain population.


| INTRODUCTION
Consciousness is the status that humans and animals can feel and detect the environment, and are capable to make appropriate responses to changed stimuli.In recent years, neuroscientists have taken difficult experimental approaches to investigate the consciousness, or neuronal correlates of consciousness (NCC).This is the minimal neuronal mechanism that supports any specific consciousness experience (Koch, 2018;Koch et al., 2016;Seth & Bayne, 2022).Different experimental approaches have been used to investigate such neuronal mechanisms, including brain imaging, and animal experiments with brain injury or anesthesia.Pain and pleasure, are two major types of emotion affecting the brain.Consciousness of pain is a key type of sensory consciousness.It has been proposed to use to evaluate the level of consciousness as well as the recovery of consciousness during anesthesia.
The studies of consciousness have recently advanced by the use of modern science and technology.Brain imaging has demonstrated that certain central nervous system (CNS) areas that are activated or inactivated during consciousness or during reappearance of consciousness.Animal studies using optogenetic and selective brain stimulation revealed that certain brain areas are critical for re-starting consciousness from unconsciousness statues.It is believed that cortex and related subcortical nuclei that form neuronal connections and feedback controls with cortical neurons play important roles in consciousness (Koch et al., 2016).It is no doubt that sensory sent through the spinal cord, and motorrelated neuronal activity contribute to consciousness.
For our sensory experience, the more we learn, and more complex it becomes.For many years, we treat all pain as one type of pain, or we called it acute pain.Identification of capsaicin receptors and opioid receptors has greatly helped us to understand pain.Recent progress in synaptic plasticity leads to our understanding of chronic pain is completely different from acute pain.How about consciousness?Are there different forms of consciousness that are mediated by different chemical proteins and receptors?Are there different types of consciousness, for one, obedient consciousness that required minimal effort to brain activity, and highly self-aware, and sustained consciousness?In this review, I will first briefly review recent advances in the thalamus-cortex investigation of consciousness, and discuss the possible roles of the anterior cingulate cortex (ACC) in consciousness.Then, from a pharmacological point of view, I will discuss several proteins, receptors, and chemicals that interfere with consciousness, and their possible synaptic functions that take place in the thalamus-cortex network.

| RECENT NEW APPROACHES FOR STUDYING CONSCIOUSNESS
Brain functional imaging provides a powerful tool to investigate possible neuronal mechanisms for consciousness in healthy humans.By designing different visual/ sensory/auditory sensory stimulation cues, one can compare brain imaging to detect which brain regions are specially related to consciousness or self-recognition (Gu et al., 2013;Mashour, 2022;Scheinin et al., 2021).In addition, it is also possible to perform the same study in patients with disorders of consciousness (DOC), and such studies with a comparison with human subjects certainly reveal brain areas or brain connectivity that contribute to consciousness (Qin et al., 2010).
Animal research using anesthesia combined with brain stimulation, recent studies have revealed several key pathways that are able to wake animals from anesthesia, an indirect way to approach consciousness (Afrasiabi et al., 2021;Redinbaugh et al., 2020Redinbaugh et al., , 2022)).For example, in primates, Tasserie et al. (2022) reported that deep brain stimulation of the thalamus restored consciousness during anesthesia (Tasserie et al., 2022).Interestingly, Redinbaugh et al. (2022) found that thalamic deep brain stimulation using multi-microelectrode could reduce the level of consciousness during anesthesia, indicating that thalamus-related activity may be able to produce biphasic modulation of the consciousness.These works provide clear evidence that animal experiments during anesthesia may help us to understand the basic mechanism of brain circuits to consciousness.
Cellular and synaptic studies in cortical and related circuits have found that glutamate is the major transmitter in the circuits.Optogenetic, whole-cell patch, and molecular approaches can provide detailed synaptic mechanisms (Bliss et al., 2016;Zhuo, 2016b).Thus, these projection systems are not grey boxes anymore.By using optogenetic and virus approaches, one can investigate the neuronal mechanism for transmission and modulation of consciousness.

| KEY THALAMUS-CORTICAL NETWORK
The thalamus-cortex network is well known for transferring peripheral sensory information to the cortex, including gentle touch, pain itching, and visual and auditory signals.Cumulative evidence suggests that this sensory information including nociceptive information is not diffusely distributed in the cortex.For example, for painful information or unpleasant information, it has been demonstrated that ACC and the insular cortex (IC) play vital roles in the coding of unpleasantness or pain (Bliss et al., 2016;Zhuo, 2008Zhuo, , 2014Zhuo, , 2016aZhuo, , 2016b)).It has been proposed that the thalamus-cortex networks play critical roles in consciousness (Llinas et al., 1998;Roy & Llinas, 2008).Interestingly, in a key milestone article of neural science by Albright et al. (2000), both cortical regions have been suggested to contribute to consciousness.It has to be pointed out that there are different aspects of consciousness including awareness of the environment by sensory stimuli, and volition, the voluntary control of thoughts and feelings (Albright et al., 2000).To understand synaptic and molecular mechanisms of consciousness, it is highly possible that the very first component of consciousness can be tackled at the present time and consciousness of different forms of pain is a key indicator for consciousness (Ambron, 2023).
By using human brain imaging and non-human primate studies, it becomes clear that the thalamus and its related cortical areas play important roles in consciousness (Afrasiabi et al., 2021;Mashour, 2022;Redinbaugh et al., 2020;Scheinin et al., 2021).It is generally accepted that the thalamus-cortex projections play key roles in consciousness, and inhibition or disruption of such projections will lead to loss of consciousness, and activation of this system can facilitate the recovery from unconsciousness.Based on these observations, I would like to propose a possible network for consciousness, especially for the awareness component of consciousness.As shown in Figure 1, the projection from the thalamus to the prefrontal cortex including ACC serves as a core network circuit for consciousness.Callosal projections link two sides of the cortical network together to add the flexibility and complexity of these consciousness circuits.The other indirect links with subcortical regions and cortical areas serve as possible loops to maintain the excitability of these core circuits.Thus, a lesion of one side of the brain or regions will only affect or reduce the level of consciousness, and will not completely block the consciousness (Figure 1).

| PAIN AND CONSCIOUSNESS
Acute pain, which is a short-lasting stimulus, is known to increase the level of consciousness.It has been proposed that sensory pain-related consciousness may provide an excellent model for studying consciousness itself (Ambron, 2023;Gu et al., 2013;Tiengo, 2003).In patients with DOC, it has been reported that there is a strong correlation between the responsiveness to nociceptive stimuli and the level of consciousness (Thibaut et al., 2018).These findings suggest that there is a certain overlap in neuronal circuits for pain perception and consciousness such as ACC and IC.More interestingly, it has been reported that repetitive transcranial magnetic stimulation (rTMS) over ACC was able to increase pain perception in patients with DOC (Naro et al., 2015).Consciousness can be a result of a network within the brain that is capable of storing and retrieving key self-information.A synaptic mechanism such as plasticity may play an important role in maintaining the status of consciousness by activating certain engram synapses that are previously learned.Disruption of such network or general reduction of network activity will lead to minimal consciousness statues or loss of consciousness.Two key components that are likely important for consciousness are the storage of key The direct projection from the thalamus to ACC serves as a key (if not the only one) core circuits for consciousness.The projection to PFC directly or indirectly may also contribute to this core.In addition, different subnuclei of thalamus project to somatosensory, visual and auditory cortices to convey sensory information from the outside world.Pyramidal cells in these cortical areas form connections with ACC/PFC neurons directly and indirectly.Through callosal projections, each side of ACC may also affect other side of ACC by excitatory connections, these positive feedback circuits provide a dual circuits for maintain consciousness.Furthermore, in case of one side of brain injury, the other side of circuits may take over to maintain minimal level of consciousness.In addition, the pyramidal cells of ACC may also project to subcortical and spinal cord neurons.These long distance positive feedback circuits may also contribute to the consciousness.information about self; and sensory signalling that recalls the consciousness.Some of this sensory information can serve as a background activity that contributes to the maintenance of consciousness; and loss of such background activity, which can be caused by visual, auditory, somatosensory, motor position, etc., may lead to subconsciousness statues such as sleep.Therefore, it is very easy to use such sensory information to recall consciousness back from sleep.Loss of one of such sensory background activities may lead to plasticity, and one may use other sensory information such as auditory to compensate for the loss of visual information (such as deaf man).A good dancer may use body position and muscle tones to gain a better level of consciousness, and a musician may be more use auditory signalling to do so.A thinker may use logical thinking to gain more consciousness.It is thus possible to propose that for those people who neither use a lot of sensory information nor inner brain activity, their consciousness level may be lower than those they use them.

| CONTRIBUTION OF ACC TO CONSCIOUSNESS
It has been proposed that ACC may play a key role in consciousness (Albright et al., 2000), and such conclusions are mainly generated from human imaging studies.It is believed that neurons in the ACC may contribute to the conscious self.Dehaene et al. (2003) reported that conscious but not subliminal conflict affected ACC in normal human subjects (Dehaene et al., 2003).Interestingly, in patients suffering from schizophrenia, the activity in the ACC was reduced.In patients with DOC, Qin et al. (2010) reported that the degree of consciousness in patients with DOC was correlated with neural activity in the ACC triggered by auditory self-related stimuli, further confirming possible roles of ACC in consciousness (Qin et al., 2010).More interestingly, in healthy subjects, Stottinger et al. (2015) reported that ACC along with the anterior insula was activated at the moment when conscious representations are updated (Stottinger et al., 2015), indicating that ACC activity can contribute to conscious self-recognition.

| GLUTAMATERGIC SYNAPSES IN THE CONSCIOUSNESS NETWORK AND ACC
Using different experimental approaches, excitatory transmission in the ACC has been well documented (Bliss et al., 2016).Glutamate serves as a principal excitatory transmitter for fast transmission since inhibition of glutamate AMPA and kainate (KA) receptors will abolish all basic excitatory transmission.Excitatory synapses onto cortical pyramidal cells are likely to be heterogeneous.In some synapses, postsynaptic currents are purely mediated by AMPA receptors, while in other synapses, both AMPA and KA receptors contribute to postsynaptic responses.KA receptor-mediated currents are usually small, however, in the case of the repetitive firing of action potentials, KA currents may summate generate big responses in part due to their slow kinetics (Wu et al., 2005).Recent studies reported that silent synapses or pure NMDA receptor synapses exist in the adult cortex, including ACC (Zhuo, 2023).These silent synapses may contribute to a postsynaptic form of long-term potentiation (LTP) (post-LTP) (Figure 2).
In addition to its postsynaptic expression, presynaptic KA and NMDA receptors have also been reported in cortical synapses (Chen et al., 2021;Koga et al., 2015;Wu et al., 2005).Activation of these receptors may contribute to the regulation of excitatory and inhibitory transmission.Furthermore, activation of KA receptors in the ACC has been reported to contribute to a presynaptic form of LTP (pre-LTP) (Koga et al., 2015).

| NMDA RECEPTOR AND ITS DEPENDENT SYNAPTIC PLASTICITY
NMDA receptors are known to contribute to synaptic LTP (Bliss & Collingridge, 1993).In the ACC, there are two key forms of LTP: pre-LTP and post-LTP.For post-LTP, NMDA receptors, including GluN1 and GluN2 (GluN2A-D) isoforms, have been reported to contribute to the induction of LTP (Bliss et al., 2016;Li et al., 2019).LTP induction protocols such as theta burst stimulation (TBS), pairing training and spike-EPSPs can induce NMDA receptor-dependent LTP.The expression of NMDA receptor-dependent LTP requires postsynaptic modification or insertion of GluA1-containing AMPA receptors.AC1-dependent, protein kinase A (PKA) phosphorylation of AMPA receptors GluA1 contributes to LTP (Liauw et al., 2005;Miao et al., 2019;Yamanaka et al., 2017).A recent study using selective knock-in mice demonstrates that phosphorylation of AMPA receptor GluA1 plays an important role in synaptic potentiation.However, the same LTP did not require CaMKII/PKC phosphorylation site serine 831 (Ser831).These results demonstrate that ACC LTP employs a different mechanism than hippocampal LTP (Song et al., 2017).
In addition to post-LTP, an NMDA receptorindependent form of LTP can also be readily induced in the ACC by paired-pulse low-frequency stimulation.This form of LTP is resistant to NMDA receptor blockade and was inhibited in mice lacking the KA receptor GluK1 subunit (Koga et al., 2015).Pharmacological experiments using a potent GluK1-selective KA receptor antagonist, UBP310, further confirmed that this form of LTP is KA receptor-dependent.Both genetic and pharmacological evidence consistently indicates that this form of LTP is pre-LTP.Pre-LTP in the ACC is sensitive to a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, ZD7288 (Koga et al., 2015).In addition, p42/p44 mitogen-activated protein kinase inhibitors PD98059 and U0126 suppressed the induction of pre-LTP and did not affect the maintenance of pre-LTP.The activation of presynaptic extracellular signal-regulated kinase was required for the induction of pre-LTP (Yamanaka et al., 2016).

| KETAMINE AND CONSCIOUSNESS
NMDA receptors play multiple roles in cortical synapses.Its main role is its contribution to synaptic plasticity, including LTP and long-term depression (LTD) (Bliss et al., 2016).Depending on the stimulation pattern and postsynaptic depolarisation, activation of the NMDA receptor may lead to LTP and LTD in the cingulate cortex.Postsynaptic AMPA receptors, including different subtypes of receptors-mediate synaptic potentiation and depression (Bliss et al., 2016).In addition, there are reports of silent or pure NMDA receptors in the adult cortex (Zhuo, 2023).In physiological awake conditions, these NMDA receptors may contribute to synaptic transmission.Ketamine is an old anesthetic agent that acts as a non-competitive NMDA receptor antagonist.It is reported that ketamine-induced anesthesia is accompanied by the development of slow oscillation across the cortex (Ballesteros et al., 2020).
In healthy human subjects, low-dose of ketamine can produce altered states of consciousness (Vlisides et al., 2018), suggesting that NMDA receptor functions play important roles in controlling consciousness under physiological conditions.Considering that most of NMDA receptors are inhibited at resting membrane potentials, these results suggest that the ketamine effect may be mediated by non-activity-dependent synaptic plasticity mechanisms, such as functional NMDA receptors and/or presynaptic NMDA receptors.

| GENETIC AUTOANTIBODIES AND CONSCIOUSNESS
Additional evidence for the contribution of glutamatergic NMDA receptors to consciousness comes from patients with anti-NMDA encephalitis (Lynch et al., 2018;Panzer et al., 2014).In these cases, patients' antibodies bind to F I G U R E 2 Different forms of long-term potentiations (LTPs) in cortical excitatory synapses.Two major forms of LTPs have been reported in the anterior cingulate cortex (ACC) excitatory synapses: presynaptic form of LTP (pre-LTP) and postsynaptic form of LTP (post-LTP).In pre-LTP, the induction requires activation of glutamate KA receptors at presynaptic side.Postsynaptic activation of NMDA receptor is not required.The expression of pre-LTP is due to more release of glutamate from presynaptic terminals.For post-LTP, activation of NMDA receptors is required.The expression is mainly mediated by the phosphorylation of AMPA receptors by cAMP PKA signalling pathways.In addition, some synapses may be silent before the LTP induction, the expression of functional AMPA receptors in these synapses may also contribute to post-LTP.For long-lasting form of LTP, gene regulation and protein synthesis are required.
the NMDA receptors and cause loss or reduction of NMDA receptor functions (Panzer et al., 2014).Consequently, these patients suffer from impaired consciousness, movement disorders, other psychiatric symptoms, and even death.The positive allosteric modulators of NMDA receptors may be used in the future for the treatment of such patients (Mannara et al., 2020;Warikoo et al., 2018).It has been reported that positive allosteric modulation of NMDA receptors can enhance synaptic LTP (France et al., 2022).It may be possible that these new chemicals may be used to modulate the level of consciousness in the future.

| MODULATORS OF CONSCIOUSNESS: CAFFEINE AND ALCOHOL
It is known that the modulation of synaptic transmission may affect the level of consciousness.Effects produced by caffeine, a common ingredient of tea and coffee are a good example.Using animal anesthesia as a model, Fox et al. (2020) reported that caffeine is able to reverse the unconsciousness induced by light anesthesia in adult rats (Fox et al., 2020).Subsequently, Fong et al. (2018) showed that caffeine injected intravenously accelerate human emergence from isoflurane anesthesia (Fong et al., 2018).These results provide strong evidence that brain excitatory indeed play an important role in the loss of consciousness during anesthesia, and it is possible to explore the basic mechanisms of consciousness using pharmacological approaches in both human and animals.Interestingly, they also found that alteration of anesthesia and consciousness levels are correlated well with brain electroencephalogram (EEG) activity, a common parameter obtained in humans.At the cellular level, it is believed that caffeine produced this effect by increasing intracellular cAMP level, triggering immediate early genes, and regulation of the dopamine-and cAMPregulated phosphoprotein, M(r) 32 kDa (Fisone et al., 2004;Lindskog et al., 2002) and inhibit neuronal adenosine A receptors in the brain.
Alcohol is well known to cause unconsciousness or death when it is consumed at higher dosages.At a low dose range, alcohol can cause disinhibition and anxiolytic effects (Harrison et al., 2017).Cumulative evidence indicates that alcohol affects both excitatory and inhibitory transmission in the brain (Zorumski et al., 2014).One of the key actions is that alcohol enhances the actions of γ-aminobutyric acid (GABA) at certain GABA A receptors and inhibits the function of NMDA receptors.Effects of alcohol on AMPA as well as KA receptors have also been reported.It is thus predictable that alcohol also affects central synaptic plasticity such as LTP.These actions provide a basic mechanism of CNS dysfunction caused by alcohol such as memory impairment, blackouts and loss of consciousness.

| INHIBITORY TRANSMISSION AND ANESTHETIC AGENTS
GABA is the major inhibitory transmitter throughout the CNS (Figure 3).Most of inhibitory effects are mediated by postsynaptic GABA A subtype receptors, including its role in anesthesia and inhibition of consciousness.With the key cortical and subcortical regions that contribute to consciousness, GABA A receptor-mediated major inhibitory action.Inhibition of excitatory transmission by activating GABA A receptors likely led to widespread inhibition of neural transmission.Most commonly used anesthetic agents such as propofol, etomidate, thiopental, and isoflurane act through GABA A receptors (Brohan & Goudra, 2017;Hemmings et al., 2019).The proposed targets include endogenous sleep circuits, and ascending arousal pathways (Hemmings, 2017).With the ACC, it has been reported that ACC pyramidal neurons receive local inhibitory modulation (Bliss et al., 2016;Cao et al., 2010).

| THE SYNAPTIC HYPOTHESIS OF CONSCIOUSNESS
Based on brain imaging and network studies, I would like to propose that the thalamus-cortex serves as a key component in consciousness.Among cortical areas, ACC may be one of the key harbors for it, although alternative cortical areas may be able to compensate for the loss of such function when ACC activity is lost.Recent network studies reveal that ACC forms multiple connections with other cortical areas, and ACC-ACC connections may well serve as an alternative centre to maintain consciousness.For example, in case of loss of one side of the ACC function, the other ACC may take over.It is also likely that this network is complex, and has multiple feedback systems.Thus, a lesion of any component will not lead to a loss of consciousness completely.Figure 1 proposes some initial models for such loops.
Based on this hypothesis, it is well predicted that external stimulation can recall consciousness from unconsciousness.Furthermore, due to the rich expression of plastic excitatory synapses among these circuits, it is like that consciousness can be trained and enriched.I would suggest that consciousness can be categorized into three basic levels, basic, normal, and high level.Learning will lead to a high consciousness level, at least to the related environment or sensory inputs.Humans and animals are highly sensitive to contextual information and novel subjects.This environment information will process through the hippocampus and hippocampus-related structures.
For consciousness, it maybe it is the status of electrical flow to keep the circuits to be active.It is thus not precisely located in several nuclei or neurons.It is consistent with networks that have multiple layers in order to be constantly or not easily affected by lesions or interruption.However, it is sensitive enough to synaptic activity with circuits that can have a range of levels to be operated.Inhibition or overexcitation can lead to loss of consciousness, if appropriate information cannot be recalled, such as names, visual identification sensory, etc.Since ACC neurons are likely activated and contribute to many key brain functions, it is likely that consciousness cannot be stored or carried out by the soma of pyramidal cells; instead, I propose that consciousness is processed by certain synapses that form specific connections with other cortical and subcortical areas.In order to effectively recall updated consciousness information, these synapses are likely to be trained and learned.Thus, the same groups of neurons may carry out different tasks through these highly diversified synapses.Consciousness is a result of neuronal activities of a subset of the brain network.It is unlikely processed by selective regions or nuclei.Selectivity is not coded by action potentials but by the firing of certain groups of neuronal networks.

| DISORDER OF CONSCIOUSNESS AND BRAIN INJURY
The research of consciousness can benefit from the investigation of disorder of consciousness, or impaired consciousness.Loss of consciousness occurs when there is damage to the brain.There are three major forms of DOC, including coma, vegetative state, and minimally conscious states.In these situations, loss of consciousness is prolonged or even permanent.Several clinical studies indicate that the impairment of the thalamus-cortex and thalamus/basal ganglia contribute to the DOC (Lutkenhoff et al., 2015;Yu et al., 2021), providing F I G U R E 3 Excitatory and inhibitory synapses in the cortex.Cortical pyramidal neurons receive excitatory and inhibitory innervation from projection and local neurons.In most cases, long-distance projections are excitatory, and local innervation is inhibitory.Cortical neurons also form excitatory connections within the same regions.Glutamate is the principle excitatory transmitter for excitation, and GABA is the key inhibitory transmitter.At postsynaptic sites, both AMPA and KA receptors may contribute to excitatory transmission, although these excitatory synapses are not homogenous.Some synapses only express functional AMPA receptors, and some synapses contain both of them.At presynaptic sites, there are KA receptors as well.For inhibitory transmission, GABA A receptor mediate most of inhibitory transmission.GABA B subtype receptor may distribute presynaptically to modulate the transmission.
clinical human evidence for the important roles of the thalamus-cortex network in consciousness.No doubt, the prolonged loss of consciousness may trigger subsequent plastic changes within the brain.As compared with the DOC, the use of anesthesia has also facilitated the search for a mechanism for acute loss of consciousness.Future studies of these mechanisms using animal models will help us to better understand the mechanism for reversible loss and permanent loss of consciousness.

| AGEING AND NATURAL DEATH: LOSS OF CONSCIOUSNESS?
It is well known that old animals and humans tend to be less aware or conscious (Cheng et al., 2020).The ability to learn, and form new memory are significantly reduced.At the synaptic level, it has been reported that hippocampal late-phase LTP is impaired in old animals that performed poorly in memory tests.In those animals that show normal memory performance, late-phase LTP is normal (Bach et al., 1999).This finding suggests the importance of synaptic LTP in age-related memory loss.Recently, it has also been reported that synaptic tagging in the ACC is reduced in middle-aged animals (Zhou et al., 2023).Similarly, synaptic plasticity is less robust in the aged animals' cortex.It is quite possible that these reduced synaptic LTP and tagging will contribute to altered consciousness levels in orders.It will be very important to investigate the last moments of natural death by ageing if the loss of consciousness is due to the failure of synaptic transmission and plasticity in the brain.Natural death due to ageing may be related to changes in consciousness or shutdown of the consciousness network.It remains to be explored if deep brain stimulation and/or novel chemicals that increase synaptic activity/plasticity may prolong life before natural death.

| CONCLUSION AND FUTURE DIRECTIONS
Recent studies from human brain imaging and animal experiments have provided new insights into consciousness.Among several possible mechanisms, the thalamus projection to the brain is thought to be the core mechanism.Excitatory transmission and plasticity may play important roles in consciousness.Inhibitory transmission contributes to excitatory/inhibitory balance, thus, also controls consciousness.Studies using different experimental approaches reveal possible selective circuits (by optogenetic) and proteins (by gene manipulation and chemicals).From a basic research point of view, the future needs to reveal molecular and cellular mechanisms for the neuronal mechanism of consciousness.Animal experiments during anesthesia at least provide a good animal model for such studies.For clinical application, deep brain stimulation will only help to understand consciousness in humans, but also help patients with DOC.More importantly, how learning may affect the level of consciousness of human beings will be a vital question for neurons as well as society.Maybe that is an evolutionary force for human beings as well.High levels of consciousness due to constant brain learning may lead to prolonged life of the brain.Many brains decide to give up hope for life, at least in part, due to poor levels of consciousness during ageing.