If a patient is sedated to the point that they do not respond to their surroundings, then they will also not remember what is happening in their surroundings. Implementation of “I don’t want to remember anything!” relies on this fact, and sedation is usually administered at a dose that produces unresponsiveness. Clinically this is a much easier goal to target than producing “amnesia,” where the patient is responsive, but will not subsequently remember (more on this later) [25, 26].

The heuristic of producing unresponsiveness to ablate memory formation naturally leads to the question of what is it to “experience” something? This is not a trivial question, and can certainly enter the realm of philosophy. For purposes of this chapter, conscious experience is defined in terms of brain processes [27]. Experience begins when information from the outside world registers in the brain, the initial portal being the sensory cortices via transmission through the thalamus. The thalamus is a deep-seated set of nuclei that one can consider as analogous to the key Internet hubs through which the world’s information flows [28]. But sensory “experience” is by itself not sufficient for “Experience” with a capital E [29]. Information from different parts of the brain must be integrated into what is more formally termed a “percept.” Integration occurs not only from sensory cortices, but also from memory areas that represent knowledge of the world, those being semantic memories. The integration of these memories allows the events just experienced to be deciphered as a conscious experience. After this percept forms, it has the chance to be (consciously) remembered [30, 31] (Fig. 10.2). As providers of sedation, we can interfere with any of these stages using our armamentarium of sedative potions. Our influence on these events may seem to be greater than it actually is. In fact, even when fully anesthetized, sensory experience still occurs, but as it happens that sensory input remains pretty much localized to the sensory cortices; how this happens will be explained later in this chapter [32–35]. The murky question is whether the arrival of sensory input during full anesthesia has any influence on anything afterwards—do we form unconscious memories of some sort [36, 37]? As sedation is really anesthesia using lower doses of drugs, this becomes even a more vexing issue assuming a dose–response relationship. To this point there is no literature to guide us. The state of affairs with auditory input during sedation may be analogous to the not-so-distant issue of whether neonates perceived pain, and whether this was important to prevent. When it became evident that neonates did, in fact, perceive pain, it was felt that it would be in the best interest of the patient to prevent this. Narcotics (or other methods of alleviating pain) became a requisite part of the anesthetic management of neonates during surgery. So, the philosophical question is whether children who are sedated, who no doubt receive auditory input that is registered in the sensory cortices of the brain, should also be afforded similar considerations. Fortunately for a significant percentage of pediatric patients, they have foam earplugs inserted for magnetic resonance (MR) scanning. But for others, should we not be aware of the nature of auditory input during sedation? This rhetorical question has no answer to date, but does set the groundwork for interesting research in the future. For example, at clinically relevant doses, pentobarbital is associated with auditory activation, whereas propofol does not seem to be [38].

The ability to influence information processing after sensory perception using sedative agents is much greater, as processes of information integration and subsequent memory formation are much more sensitive to drug action. Consciousness is the binding of information across different brain regions into a thought, if internally generated¹, or a percept generated from external sensory inputs. The percept incorporates sensory parameters (nature of the object/sound being experienced), previous knowledge (semantic memories; e.g., “This object is a red block”), and personal subjective memories of experiences (i.e., episodic memories; e.g., “I played with this block last time”) [39]. Another way to think of sedation is that it is administered so as to prevent information integration; i.e., when the child is “asleep,” they are not able to integrate information into a percept [2, 33, 40–45]. Sensory input may (and undoubtedly does) arrive in the brain, but it has nowhere to go. Processes connecting part A of the brain with part B are rendered largely nonfunctional by the sedative agent, so there is no chance for memory formation—at least of conscious memory (which is the form of memory we are most concerned with when we “don’t remember a thing”) [46, 47].

Memory is not a unitary process, but rather a complex set of interrelated physiologic processes, and as such is continually malleable over time. At its simplest level, there are two distinct forms of memory—conscious and unconscious—and this chapter will focus on the former [48]. Conscious memory requires the formation of a percept, which is the sine qua non of consciousness. In other words, one has to be conscious to form a conscious memory. Thus, when someone is unconscious, for the purposes of this chapter specifically as a result of sedation, conscious memories will not be formed. As an illustrative side point, questions of whether patients in persistent vegetative states (PVSs) are “conscious” revolve around the question of information integration, the ability to form a percept from external or internal experience [49]. As someone in a PVS cannot respond, electrophysiologic evidence of information integration is sought in these patients. Various approaches have been used to identify electrophysiologic signatures of information integration to use as a surrogate of “consciousness.” However, even very sophisticated methods suffer from statistical artifacts, and one still cannot be sure whether consciousness is or is not present. On a much larger scale, this also is the case during sedation/anesthesia. To date, there is no reliable EEG-type monitor (or for that matter, any other type of monitor) that can tell us whether a patient is sufficiently sedated, sufficiently anesthetized, or sufficiently amnesic for a particular situation [50–53]. Thus, it is not surprising that even when we think a patient is well sedated, they can be “playing possum” and suddenly wake up; i.e., they have the ability to integrate information despite our best efforts. This fear of sudden arousal leads to even higher dosing of sedative agents, wandering dangerously close or actually into the state of anesthesia (by definition preventing arousal in 50 % of patients when a surgical incision is made). Thus, it would be desirable to utilize sedative agents that not only sedate but can also affect the last stage of memory formation, that of incorporation of the conscious percept into a lasting conscious memory. This last process is the most sensitive to drug effect, occurring at concentrations lower than those producing sedation, as long as the drug has specific amnesic properties [54–56]. These are much fewer in number than those producing sedation, but they are widely used, consisting of the benzodiazepines, propofol, and ketamine. These drugs have the ability to impair formation of long-lasting memories (defined as longer than 30–60 min) for conscious percepts formed during periods of arousal sufficient for information integration, a state often termed “awareness.”

To be aware is to experience your surroundings and can be proven by responding appropriately to verbal commands (e.g., “Squeeze my hands twice.” Parenthetically it is very difficult to prove or disprove awareness without any behavioral measures, and that is why it is difficult to know if patients in a PVS are conscious) [57, 58]. In fact, a significant proportion of patients who are “fully” anesthetized can be aware, but virtually none of them consciously remember this experience of awareness afterwards [59].

This is the key section in which “amnesia” will be defined. To be clear, amnesia in this chapter is being used in the context of administration of sedative drugs [25, 60]. Amnesia generally refers to any pathologic state in which memory is affected (e.g., Alzheimer’s dementia, transient ischemic amnesia, traumatic amnesia, etc.). These amnesias can be classified as either anterograde or retrograde, depending on which memories are affected. If the insult affects only memory after the insult, this is termed anterograde amnesia and is the type of amnesia produced by drugs (more on this later). A much more intriguing type of memory loss is retrograde amnesia, subject of many movies. This refers to loss of memories before the insult, usually some type of traumatic event (e.g., head injury, electroconvulsive therapy), where the time frame of loss of memory ranges from minutes (not remembering how the accident occurred, for instance) to months, possibly years. Retrograde memory loss has never been convincingly demonstrated for any drug to date. “Amnesia” as used in this chapter (and generally any investigation of acute drug administration) refers to the drug-induced inability to remember a conscious percept and in many studies is demonstrated by the lack of memory for pictures or words seen or heard while drug was being given [56]. The presence of conscious percepts allows one to be aware, in other words able to integrate information either from external or internal sources. We can only observe external awareness, as illustrated by the question of whether patients in a PVS are internally aware. Awareness is evidenced by appropriate behaviors to the environment (e.g., ability to follow commands in the presence of sedative drugs). Awareness occurs in the “here and now,” but to remember being aware at some past point requires further processing of information into a memory. In order for this to occur, the conscious percept has to be consolidated into a lasting memory [55] (Fig. 10.3).

Consolidation is a fundamental area of neuroscience investigation, finding its roots in the works of Donald O. Hebb in the middle of the last century. Hebb was a psychologist keenly interested in the basis of memory and proposed that the brain was plastic; in other words, neurons changed their connections (synapses) with each other based on how they were activated [61]. In essence, a memory resides in the altered synaptic connections in the brain [62]. Thus, consolidation produces a brain different from what it was before and that difference is a memory. These specific changes, referred to as Hebbian learning, are the result of many dozens of physiologic and molecular processes, each having its own particular time frame [63, 64]. The sum total of these processes are termed consolidation and become active once a conscious percept is learned, defined as acquiring information from the outside world. Consolidative processes are present to varying degrees for the life of the memory. A corollary of the fact that consolidative processes are continuously active is that memories are continuously malleable [65–68]. The whole question of the reliability of eyewitness testimony revolves around this physiologic fact. Other times, malleable memories can get out of hand, resulting in “flashbacks” of increasing intensity producing posttraumatic distress syndrome where memories are closely linked to flight or fight fear responses [69–71]. But the most common fate of memories is that they decay over time [72].

Just as the thalamus is a key hub for sensory experience and integration that allows consciousness to exist, a seahorse-shaped structure in the medial temporal lobes (almost adjacent to the thalamus, as it turns out) called the hippocampus is a similarly important mediator of conscious memory [73–75]. The hippocampus connects incoming information with diverse locations in the brain, where previous memories reside, to allow new memories to be created (Fig. 10.4). Without the hippocampus, no conscious memories can be formed, and this was first appreciated in the famous neurologic case involving a patient with the pseudonym HM. HM had bilateral temporal lobectomies for the treatment of intractable epilepsy in 1956 [75]. This operation was a well-accepted form of treatment in the era where the brain was considered to operate under the principle of equivalency. This principle rests on the thought that if one part of the brain was damaged or removed, another part would take over that function, thus minimizing the impact of pathology or surgical intervention. Indeed, it was thought that surgical intervention could remove the diseased focus in the brain, thus ameliorating symptoms of the disease, in particular epilepsy [76]. To a large extent this was true for epileptic foci in many cortical regions. However, epileptic foci commonly reside in the temporal lobes, and it soon became apparent that significant removal of the medial temporal lobes bilaterally (which happened to contain the hippocampi) resulted in severe impairments of conscious memories. This was described most famously by Scolville and Milner [75]. For those interested, a quite accurate depiction of what life would be like without the ability to form conscious memories is made in the film Memento [77]. The hippocampus is also important in “readout” of newly formed memories, and in a sense this readout is “practiced” during certain stages of sleep [78–81]. Sleep will improve conscious memories, and the adage “get a good night’s sleep” is not without merit [82]. Not surprisingly, detailed investigations of how hippocampal mechanisms interact with memory are ongoing topics of research.

The fate of virtually all memories is that they are forgotten over time. This is a fortunate event, as otherwise our brains would be filled with useless information. Some rare cases of the inability to lose old memories have been described [83]. Ebbinghaus, a psychologist, first described the decay of memories over time over 150 years ago [84]. Most memories are forgotten soon after learning, but this process continues at a slower pace as long as we measure it [72]. They key to understanding the nature of drug-induced amnesia is to understand the forgetting of memories over time. For, in fact, memories can be and are formed in the presence of amnesic drugs [85]. The fact that at low concentrations of, for example, benzodiazepines, virtually all processes required to form a conscious memory are operational—namely, sensory perception, information integration, learning, and initial conscious memory formation—explains why behavior is visibly normal, other than possibly being affected by some sedation (e.g., being “drunk”). If we measure what happens to memories formed in the presence of an amnesic drug over time, we find that they disappear very rapidly [54]. In fact, in the case of midazolam or propofol, no discernible memory is present after 30–60 min (Fig. 10.5). Thus, drug-induced amnesia is typified by the inability of memories to be remembered over time. The mechanism(s) underlying this effect is (are) still unknown, but could be summarized as the inability of consolidation to function normally, so that the memory cannot be retained at its usual strength over time. These qualities set the stage for an event such as date rape, where a small amount of a substance active at GABAergic receptors is secretly administered, usually with alcohol to mask any sedative effect. No suspicion is aroused; observers note no particularly abnormal behavior [86]. However, the victim experiences a complete lack of even the most traumatic memories of events transpiring in the presence of the drug. Fortunately these same qualities are much more commonly used for beneficial uses, where propofol or midazolam (and likely ketamine) can produce amnesia for events transpiring in the presence of drug even when the patient is awake (or using more accurate terminology: aware).

Long-term memory is the final stage of processing of information acquired from the outside world, a process termed “learning.” Learned information has thus experienced sensory and cognitive manipulations located in diverse regions of the brain. Thus, a sine qua non of memory function is that different parts of the brain must be able to communicate amongst themselves. These processes of communication have become the mechanisms of most interest in terms of understanding anesthetic and sedative drug actions on cognition and consciousness [44–47, 87]. Using quite sophisticated measurement and analytic techniques, connectivity between different brain regions can be quantitated [88]. Measures of the complexity of information (information content) flowing between these regions can be obtained as well [89]. It is no surprise that such complex processes are inhibited at low doses of anesthetic sedatives. Memory impairment from sedation is based on these inhibitory mechanisms [90]. At higher drug doses, key brain regions participating in the maintenance of consciousness, namely, the thalamus, are disconnected from the rest of the brain (or, alternatively, the cortical brain becomes disconnected from itself (clustered) preventing information flow), and the person falls asleep, or more correctly is anesthetized [88, 91, 92].

Similar inhibitory mechanisms of information processing could be at play to produce amnesia when sedation is minimal. As explained previously, amnesia is best characterized as the inability to retain a memory over time, which means that a memory was formed in the first place—in other words, learning has occurred. Learning can only occur if all the processes important in the formation memory function well. Behaviorally, the person experiencing an amnesic concentration of drug will appear to be relatively normal, as most of their brain functions are working well. Specifically, information is transmitted through the thalamus to sensory cortices of the brain, and this information is forwarded to other brain regions for processing. The first way station after sensory perception is working memory, which can be considered a scratchpad containing information from different parts of the brain, which are then collated into a percept [93, 94]. These working memory processes are located in the front part of the brain (prefrontal cortex) and involve communications with the thalamus and hippocampus to process a memory [95]. Working memory processes are transient and are most sensitive to sedation [96, 97]. As sedation increases, these processes become increasingly impaired, and information cannot be then further processed and thus cannot be learned as a memory. We all experience this when we are too sleepy to remember some bit of information given to us (prototypically a telephone number, thus the popularity of napkins as external scratchpads in bars). Ergo, for the amnesic effect of a drug to be expressed, working memory must be intact. Newly acquired information must be transferred from working memory into long-term memory stores located in diffuse regions of the brain, with the hippocampus anchoring learning and retrieval of these memories [55]. The long-term memory that was just learned in the presence of amnesic drugs is then quickly forgotten. Both long-term and working memory processes can be indexed by electrophysiologic measurements. Indeed, amnesic drugs affect electrophysiologic measures of long term, but not working memory processes [85].

This chapter will focus on conscious memory processes, as described so far. This is primarily related to the fact that it is much easier to study the effects of drugs on conscious memory, as behavioral changes (i.e., recognition of previously experienced stimuli, “Did you see this picture before?”) are robustly measureable. Unconscious memories are hard to detect, as changes in behavior based on these memories can be quite subtle. It is especially difficult to determine if a change in a memory-related behavior is as a result of effects on conscious or unconscious processes. Thus, controversy usually surrounds the interpretation of these studies in terms of drug effects on unconscious versus conscious memories [37].

In clinical practice, it is unusual, particularly in pediatric patients, to produce a state where some quantity of drug is given, but at a dose where little sedation is apparent. Such a situation would amplify the differences between amnesic (e.g., propofol, midazolam, ketamine) and non-amnesic (pentobarbital, probably dexmedetomidine) drugs. Typically, in practice a deep state of sedation is produced, where little responsiveness is present. As detailed previously, if stimuli are not perceived, then they will not be remembered (at least as conscious memories). When propofol is administered in a similar fashion to dexmedetomidine, namely, giving a loading dose over a 10-min period, the effects on memory between these drugs are virtually indistinguishable, despite the fact that propofol has stronger and more specific amnesic properties. However, what is clinically relevant is if drug concentrations become low enough that patients wake up and become responsive while they still have some drug in their system. At these low concentrations, amnesic drugs such as propofol will prevent retention of any memories learned in this state, whereas dexmedetomidine will probably not.

The adjective “brief” is used to represent the fact that very few studies have been conducted to examine the interaction of drugs with sedation versus their amnesic effects. As discussed so far, both effects are closely related and are difficult to dissect out. The vast majority of studies examining the interaction of sedative drugs with memory have been conducted in healthy adult volunteers, in order to control the many factors that can affect memory other than the presence of drug. Remarkably fewer studies have been conducted in children, and to a large extent, as far as memory effects of drugs are concerned, children are considered as “small adults,” which undoubtedly is not true. However, at this time, this is all we have to guide us.