**2.1. Coma—definition and theories**

Coma is defined as a state of unconsciousness and lack of response to noxious stimuli. The physiopathology of consciousness and coma state is not entirely understood. It is not clear if a "coma center" exists or if the diverse pathological states that induce coma do so through different mechanisms. From this perspective, coma is similar to the anesthetic state, which is caused by several pharmacological agents, with different chemical structures. It is also unclear if a common center, on which all anesthetics act, exists. Based on histology and physiology, Sir Francis Crick postulated that the claustrum has a central role in maintaining consciousness (as it is connected with nearly all cerebral structures), like the conductor of an orchestra [1]. Recent studies have shown that during isoflurane anesthesia on the rat, functional connectivity of the claustrum with medial prefrontal cortex and mediodorsal thalamus decreased [2]. As for coma state, there are no definitive studies proving the role of the claustrum in its physiopathology.

Regarding EEG activity, comas are different. The same coma state, defined by a lack of consciousness and of response to external pain stimuli may exhibit different EEG aspects. Thus, there are comas with prevalent alpha waves (alpha comas), beta waves (beta comas), theta waves (theta comas) or delta waves (delta comas). A common characteristic of these coma states is that if they are secondary to intoxication or metabolic encephalopathies, they have a positive prognosis, regardless of the EEG pattern, with response to external pain stimuli. If there are secondary to brain stem lesions or hypoxic ischemic encephalopathies and lacking response to external pain stimuli, comas bring a negative prognosis [3].

Comas secondary to TBI are caused by diffuse axonal injury (DAI) and by hemorrhages that compress the brain stem. Diffuse axonal injury occurs due to rapid (rotational) acceleration, which causes lacerations in the neuronal cytoskeleton and therefore block neuronal transport [4]. Hameroff and Penrose support the hypothesis that conscious processes are based in the microtubules of the neuronal cytoskeleton [5, 6]. Furthermore, it is known that volatile anesthetics interfere with the function of these microtubules. Nevertheless, if this theory proves true—that consciousness is based on and influenced by neuronal cytoskeleton microtubules that might explain loss of consciousness secondary to diffuse axon injury.

Another etiology of coma is nonconvulsive status, defined as prolonged seizures there are not clinically manifested and associate altered mental status [7], secondary to TBI (8–16%), to stroke—HAS (3–31%) and craniotomy [8]. The mechanism of loss of consciousness during epilepsy is not entirely understood. Blumenfeld Hal et al. affirm that a common mechanism exists—a cortico-subcortical network dysfunction. Therefore, a decrease in cerebral blood flow (CBF) was noticed in frontoparietal association areas and the anterior and posterior interhemispheric regions with (CBF) increases in bilateral midline subcortical structures [9].

Besides, a loss of connectivity between medial and lateral frontoparietal association areas and upper brainstem/medial diencephalon was observed [10]. They state that these corticosubcortical connectivity malfunctions (occurring in generalized tonic-clonic seizures, complex partial seizures and temporal lobe seizures) are caused either by indirect inhibition or by convulsions initiated in these structures.
