Which of the following concepts refers to the diminished sensitivity to a stimulus that occurs due to constant exposure to that stimuli?

Abstract

Habituation is defined as a decrement in response as a result of repeated stimulation not due to peripheral processes like receptor adaptation or muscular fatigue. It is a process occurring within the nervous system (in animals with nervous systems). Habituation is definedin more detail by a number of parametric properties, involving such factors as stimulus frequency and intensity, pontaneous recovery of the habituated response, etc. Sensitization is defined as an increase in response as a result of (usually strong) stimulation.

Habituation primarily refers to stimulus-response systems that are ‘hard-wired,’ i.e., the stimulus elicits the response in the absence of any training, as in reflexes, fixed action patterns, arousal, etc. In neural systems where analysis has been possible, habituation is due to synaptic depression; a decrease in probability of transmitter release at appropriate synapses within the habituating circuit, and sensitization is an increase in the probability of transmitter release, due either to intrinsic or extrinsic processes. In vertebrates, at least, dishabituation, the disruption of habituation due to a strong extra stimulus, appears to be an independent superimposed process of sensitization. Habituation (and sensitization) appear to be ubiquitous in the animal kingdom and are extremely adaptive processes.

3.2.1 Habituation

Habituation is a gradual decrease of strength of risk sensitivity due to:

Repeated exposure to stimuli, which creates a sense of familiarity. The more familiar we become with stimuli, the more we start to like them, the more previous hostile or anxious emotions will be compensated and fade away.

Increased expectancy around stimuli, which creates a sense of control. The brain knows what is going to happen and does not need to anticipate so strongly anymore. The need for awareness gradually decreases. In this way, we can become complacent to risks that were previously being perceived as hazardous.

The result of habituation is that the impact of the anxiety response weakens. All processes that usually follow, like safety alertness, will also be activated with reduced strength. Although the dangerous stimulus stays the same, we stay more relaxed. Habituation occurs while perceiving all sorts of stimuli. The more we are exposed to stimuli, the stronger the process of habituation will be. Because habituation depends on the amount of stimuli, it is also related to the spectrum of situations in which stimuli occur. Stimuli that are both present at work and in private life have a higher tendency of becoming habituated because they have more exposure.

All sensory processes are liable to habituation. We constantly lose the freshness of newly learned experiences.

Habituation is one of the main reasons why the risk sensitivity at home generally is so low. A lot of accidents happen in the domestic environment because we are too complacent. The fact that 50 percent of serious accidents occur in the domestic environment is a direct result of habituation. An example is boiling water that we use daily while cooking food or making tea. Boiling water can be very dangerous and can even kill children. Due to daily habituation, boiling water gradually loses its ability to evoke risk sensitivity. At work, a fair amount of accidents occur when boiling water is involved. We can recognize the same with tools that are used both at home and at work. We all know examples of a sawyer in a sawmill who has lost some fingers. This usually happens to those who have many years of experience and in the meantime have lost their risk sensitivity. One small distraction can be enough to saw not only the wood but also the fingers. Usually such an accident precludes the end of that profession, so one would expect that every sawyer is very alert to this potential mistake. The fact that it still happens shows the strength of habituation.

Habituation constantly challenges alertness and eventually tends to win

The habituation model

As the use of systematic desensitization declined, the habituation model emerged as the predominant approach to exposure therapy (Mathews, 1971). Habituation in the context of exposure therapy refers to response decrement, namely, a decrease in fear or anxiety. Exposure therapy using the habituation model begins with the creation of a fear hierarchy, similar to stage two of Wolpe’s systematic desensitization procedure. Throughout construction of the hierarchy, clinicians elicit subjective units of distress (SUDs; Wolpe, 1973) ratings for each trigger. SUDs ratings can be on any scale, although a smaller range of values (e.g., 0–10) may be useful when working with children and adolescents (Kendall et al., 2005). Similar to systematic desensitization, exposure therapy under the habituation model is conducted in a graduated fashion, in which the initial exposures are associated with a low SUDs rating. Treatment protocols based in part on the habituation model suggest that exposures should be terminated when at least a 50% reduction in SUDs is achieved (Foa, Hembree, & Rothbaum, 2007). Clinicians also use SUDs ratings as indicators to move on to the next item on the patient’s fear hierarchy. Therefore the patient’s level of fear or anxiety guides each individual exposure as well as the overall course of therapy under the habituation model.

Emotional processing theory (EPT; Foa & Kozak, 1986; Foa & McNally, 1996; Rachman, 1980) proposes that habituation is one mechanism underlying exposure therapy. In EPT, it is posited that fear is represented in memory as a set of propositions about the feared stimulus, the associated response, and the meaning of the stimulus and response (together referred to as a fear structure; Foa & Kozak, 1986). Exposure therapy activates fear structures and integrates information that is incompatible with them as a form of corrective learning. This incompatible information may take the form of habituation of physiological arousal to the feared stimulus or a change in the meaning of the feared stimulus or the response, such as a reduction in the perceived likelihood of harm (Foa & Kozak, 1986). Within-session physiological habituation to the feared stimulus may enable the integration of corrective information about the meaning of the stimulus or response, leading to between-session habituation.

According to EPT, three of the most important predictors of exposure therapy outcome are initial fear activation, between-session habituation, and within-session habituation (Foa & Kozak, 1986). Initial fear activation refers to the patient’s level of fear to the object or situation during the first exposure trial. Greater initial fear of the given exposure target is thought to be predictive of treatment success because activation of the fear structure is a necessary element of emotional processing (Foa & Kozak, 1986). Fear reduction over both the course of individual therapy sessions (within-session habituation) and treatment (between-session habituation) are proposed as two additional predictors of favorable treatment outcome. Both forms of habituation are thought to indicate successful integration of new information toward the formation of a new nonfear structure. In the laboratory, habituation may be indexed via decreased psychophysiological responding or lower SUDs ratings over time (Foa & Kozak, 1986). In the therapy setting, habituation is measured via SUDs ratings, given that tools for measuring physiological responding are not always available for use in treatment.

Evidence for the role of initial fear activation, between-session habituation and within-session habituation as predictors of treatment outcome is mixed. Foa and Kozak (1986) review a number of studies that lend support to the utility of these indices as predictors of successful exposure therapy in clinical samples, including specific phobia, agoraphobia, and obsessive–compulsive disorder. More recently, however, reviews have questioned the existing evidence for these indicators as useful predictors (Craske et al., 2008; Craske, Treanor, Conway, Zbozinek, & Vervliet, 2014). According to a review by Craske et al., positive evidence for the relation between initial fear activation and treatment outcomes is limited to heart rate, and other studies have demonstrated either no relation with other treatment outcome variables or did not directly test the relation (2008). Further, while research suggests that within-session habituation of self-reported fear and physiological indices typically occurs, there is limited evidence that this index relates to long-term outcomes (Craske et al., 2008). Finally, although there is some evidence in support of between-session habituation as a valid predictor of treatment outcome, other studies have not demonstrated this association. In some studies, the relation between between-session habituation and treatment outcome is not directly tested. Improvement has also been shown to occur in the absence of significant between-session habituation of physiological measures (Craske et al., 2008), suggesting that this index may not be critical to successful exposure treatment.

Of note, some studies in clinical samples have directly tested the habituation model of exposure therapy by measuring these three predictors. In a study of adults with panic disorder and agoraphobia completing an abbreviated course of exposure therapy, neither physiological activation nor within-session or between-session reduction of physiological or experiential measures of anxiety was predictive of the treatment outcome, measured as panic disorder symptom severity (Meuret, Seidel, Rosenfield, Hofmann, & Rosenfield, 2012). Similarly, a study of anxious youth found that on the whole, initial fear activation, within-session habituation, and between-session habituation did not predict anxiety-related outcomes at post-treatment or 1-year follow-up, although initial fear activation predicted less anxiety at follow-up among participants without generalized anxiety disorder (Peterman, Carper, & Kendall, 2019). The limited empirical evidence in support of elements of the habituation model, including the roles of initial fear activation, within-session habituation, and between-session habituation, led to the development of a second model of modern-day exposure therapy: the inhibitory learning model.

Habituation and Dishabituation

Repetition of the acoustic stimulus results in rapid habituation of the response pattern, the second acceleration/deceleration almost disappearing after the first stimulus presentation. Although habituation is a fundamental issue in the scientific literature on cardiac reflexes (Graham, 1979), the rapid habituation of this response has been inadequately investigated. According to Graham's classical model, cardiac defense should be resistant to habituation. However, the rapid habituation of the response, especially the second acceleration/deceleration, is a consistent finding in studies where the intense noise is repeated several times with intertrial intervals (ITI) between 100 and 120 s. The first acceleration/deceleration also shows habituation, but the habituation trend is less pronounced (Ramírez et al., 2005). Two recent studies have examined the habituation and dishabituation of cardiac defense within a single session manipulating (1) the time interval between stimulus repetition (Mata et al., 2009) and (2) the acoustic quality and meaning of the stimulus (Vila et al., 2007).

In the first study, an intense white noise was presented three times by maintaining the time interval constant between the first and third presentation (30 min) and manipulating the moment of the second stimulus presentation, closer to the first one or closer to the third one. This was done in such a way as to increase and decrease symmetrically, in six-group conditions, the ITI between the three stimulus presentations. For the ITI between the first and second presentation, the time intervals were 2.5, 7.5, 12.5, 17.5, 22.5, and 27.5 min. The corresponding ITI between the second and third presentation for the same six conditions were 27.5, 22.5, 17.5, 12.5, 7.5, and 2.5 min Figure 2 presents the results for the two most extreme conditions: condition 1 (2.5 min between trial 1 and 2; and 27.5 min between trial 2 and 3) and condition 6 (27.5 min between trial 1 and 2; and 2.5 min between trial 2 and 3). It can be seen in Figure 2 that the expected pattern of the response, with its two accelerative/decelerative components, is observed for both conditions in the first stimulus presentation (trial 1). The expected habituation of the response – faster for the second acceleration/deceleration – is also observed in the second stimulus presentation (trial 2) when the ITI was the shortest (2.5 min). However, reduced habituation in trial 2 and increased dishabituation in trial 3 (recovery) is also observed when the ITI was the longest (27.5 min).

In the second study, a white noise and a human scream, matched in intensity and duration (95 dB and 2 s duration), were presented three times in the following sequence: 10-min rest period followed by three presentations of either the white noise or the human scream with an ITI of 120 s. Immediately after the last presentation, the same sequence was repeated with the other stimulus. As expected, the response showed rapid habituation within each sequence. However, the response pattern with its two accelerative/decelerative components was fully dishabituated (recovered) when the human scream was presented in the first sequence and the white noise in the second sequence (see Figure 3 left panel). In the opposite order, the dishabituation effect was not evident (Figure 3 right panel).

Exposure in vivo

Marks (1978) has argued that exposure therapy works through emotional habituation. Habituation is defined as a decrease in fear reactions in response to repeated exposure to the feared stimulus. In panic disorder and agoraphobia, exposure targets fear of bodily sensations (interoceptive exposure) and agoraphobic situations (Emmelkamp and Powers, 2010; Meuret et al., 2012).

Meta-analyses and reviews of exposure for panic disorder and agoraphobia (Mitte, 2005; Sanchez-Meca et al., 2010) show that exposure in vivo has a substantial effect size for reducing agoraphobic symptoms. Additionally, exposure-based interventions (including virtual reality exposure, Meyerbröker, 2014) show strong effect sizes in reducing agoraphobic avoidance behavior (Meyerbroeker et al., 2013; Moscovitch, 2009). Interestingly, therapist guidance during exposures appears important (Gloster et al., 2011). This large Randomized Control Trial showed that guided exposure in vivo was more effective than exposure without therapist guidance in reducing the number of panic attacks, avoidance behavior, and improvement in global functioning.

Introduction to exposure

There are a few exercises that can be useful to illustrate the psychoeducation concepts that are key to exposure readiness. The therapist can first approximate the arc of habituation with the youth using something that is neutral or less anxiety provoking. For example, the therapist and the youth can put sticky jelly on their hands or put a rock in their shoes, and see how the experience of these sensations of stickiness or discomfort change over time. Often, the sensation is diminished with time, and using distraction via a conversation about a topic of interest, or watching a brief video clip, can aid in the illustration of how we can gain control over the intensity of a sensation. To illustrate the power of negative reinforcement, the therapist can engage the youth in the mindful preparation for exposure. In the LEAP program, in the first session of the group-based exposure phase of treatment, members are told that they are going to give an impromptu talk in front of the group. This is a high-anxiety experience for many young adults, particularly those with social phobia. The therapist leads the members through a mindful examination of the thoughts, feelings, sensations, and urges they are experiencing as the speech/exposure moment approaches, and then tells the group that they will not engage in the exposure today and focusing each member’s attention on the relief that is experienced at hearing this. This is a salient way to explain the process of negative reinforcement that is associated with escape and avoidance behavior, the antithesis of exposure.

Stimulus fading

Stimulus fading is a behavioral procedure that entails the gradual approach of the feared stimuli (e.g., an unfamiliar person) closer to the child, allowing time for habituation (or adjustment) to the stimulus prior to each move closer. Stimulus fading is commonly used in treatment for anxiety and SM specifically (Viana et al., 2009). “Fade-in” strategies can be used in any feared situation and encourages the child to approach, rather than avoid these situations. For children with SM, exposure practice fade-in refers to gradually introducing a new individual (i.e., a person the child has not verbalized to or in front of before) into the child’s speaking circle. Typically, the new individual gradually gets closer in proximity to the child, as the child continues to speak to someone already in their speaking circle. Eventually, the new individual becomes engaged in the activity and additional strategies are used to promote the child’s ability to speak to the new individual.

An initial fade-in session in PCIT-SM typically begins with the child and parent together in a room alone. To help the child warm up and feel more comfortable, the parent is coached to engage their child in CDI. Once the child is engaging with the parent, the parent is coached (via an unobtrusive bug-in-the-ear approach) through VDI sequences, in order to promote child speech and verbalization while it is just the parent and child in the room. Once the child is responding consistently to the parent, the fade-in of a new person begins. It is often beneficial to have two therapists present for this initial session—one to coach the parent and one to fade-in with the child, while using CDI and VDI skills. Alternatively, it is recommended that the therapist have the ability to coach both parties (i.e., the parent, and the new person who may not have any formal training) through use of two walkie-talkie sets or other bug-in-the-ear technologies. The unfamiliar person (e.g., the second therapist) may begin by sitting outside of the therapy room with the door slightly open until the child maintains or resumes verbal communication with his or her parent. The unfamiliar person might slowly open and/or move slowly into the entrance of the room, careful to move closer only as the child remains consistently responsive to the parent. For example, if the child reduces his or her speaking behavior, the unfamiliar person must wait to move closer until the child again continues to speak with the parent. The unfamiliar person is coached to begin using CDI skills once they are in the clinic room with the child (e.g., reflection: “You told your mom you wanted to play with the dolls”; labeled praise: “You are being so brave and talking to mom loud enough for me to hear” or “You’re playing so nicely in here”; behavior description: “You are driving the car along the track”). Once the child is speaking comfortably in front of the unfamiliar person, that person can begin prompting the child using VDI skills.

The quickness with which successful fade-ins occur will vary across children. At first, the child may only answer the unfamiliar person’s questions to their parent(s) or in a barely audible volume. Shaping techniques (discussed subsequently) may be necessary in order to support the child in speaking directly to the unfamiliar person. Once the child is speaking to the unfamiliar person, the parent is coached to slowly move out (i.e., “fade out”) of the room while the child engages with the unfamiliar person, typically at a rate similar to the speed with which the fade-in process took. One goal of the first fade-in session is for the child to speak with the unfamiliar person with the parent outside of the room. However, this first step may take more than one fade-in session. Importantly, throughout the session, the child is continuously rewarded through checks (i.e., immediate reinforcement) for speaking. Fade-ins can be used in clinic settings, as well as in home and community (e.g., school) settings, to introduce new people into the child’s speaking circle.

Exposure to the US or the CS: Habituation and Extinction

The process by which a fear response can be learned was described above. This same response can also be inhibited. One or both of the following processes can be used clinically to reduce fear responding. The first process is called habituation and it occurs through the repeated presentation of the US without the CS. The CS comes to have no predictive value for the occurrence of the US such that later presentations of the CS do not elicit a CR. The other process that can lead to inhibition of the CR is called extinction. Extinction is when the CS is presented without an accompanying US. A tone may be presented to a dog but food no longer follows. Eventually, the predictive value of the CS is diminished such that the CS no longer produces a CR.

Implicit Memory

One major paradigm to assess implicit memory abilities in infancy is the visual paired comparison paradigm that involves exposing the infant to pairs of a stimulus and then showing this familiarized stimulus simultaneously with a novel one. Similarly, in the visual habituation paradigm, a stimulus is presented sequentially and either after fixation time decreased to a pre-set criterion (infant-controlled) or after a particular number of presentation trials (fixed), a novel stimulus is presented. In both paradigms, infants' looking time is assessed and a difference in fixation times to familiar compared to novel stimuli is taken as a measure of recognition memory. The most influential model, the comparator model, assumes that during the task, a memory trace of the visual stimulus is gradually constructed, information about the stimulus is retrieved from memory, and this memory traced is compared with the current visual input. Theoretically, it is still debated whether infants' preferences measure adult-like explicit memory capacities or implicit memory. Notwithstanding this debate, the assessment of infants' visual preferences yielded evidence for immediate as well as delayed recognition capacities showing an age-related increase in recognition memory during infancy. For example, Bushnell (2001) found that newborns prefer their mother's face to the face of an unfamiliar woman even if they had not seen their mother's face for 15 min. In addition, using the habituation method, Pascalis et al. (1998) demonstrated that 4-month-old infants are already capable of recognizing a previously unfamiliar face after a delay of 24 h. Furthermore, the influence of stimulus complexity and meaning was demonstrated because 5-month-olds retain abstract patterns for 48 h and recognize faces after a 2-week retention interval (Fagan, 1990).

Studies applying visual preference paradigms within different cultural environments found no differences regarding rate of habituation, exhibition of novelty preference, or different measures of visual attention, such as fixation time, in infants, toddlers, and young children (e.g., Kennedy et al., 2008).

Classical and operant conditioning methods are also frequently applied to study learning and memory in infancy. In a classical conditioning study by Little et al. (1984), 10- to 30-day-old infants' eyelid response was conditioned by pairing an air puff (unconditioned stimulus) with a tone (neutral stimulus). After repeated presentations of these coupled stimuli, infants showed an eyelid response (conditioned response) when only the tone (conditioned stimulus) was presented, and 20-day-old infants exhibited savings even 10 days after the conditioning session in terms of requiring shorter presentations of the paired stimuli to evoke the conditioned response. Because neuropsychological studies confirm that classical conditioning is based on cerebellar processes, it can be concluded that it taps implicit memory.

Rovee-Collier and collaborators developed the mobile conjugate reinforcement procedure, an operant conditioning method to study learning and retention in 2- to 6-month-old infants. Within the mobile task, one leg of the infant is connected to an overhead mobile. In a first baseline phase, leg kicks do not generate movement of the mobile, whereas in the following reinforcement phase, leg kicks produce mobile movement. Learning of the contingency between own motor activity and movement of the mobile is indicated by an increased kick rate during reinforcement compared with baseline activity. The train task was developed as an age-adapted variant to assess whether infants older than 6 months of age learn to press a lever to move a miniature train. Studies applying the mobile and the train task have found that the duration of long-term memory increases linearly within the first two years of life: While 2-month-old infants show retention up to 2 days after training, those aged 6 months remember the mobile for 2 weeks, and 18-month-old infants retain the contingency over an interval of 13 weeks (for an overview, see Hartshorn et al., 1998). By implementing a reminder, the retention of 3-month-old infants was increased up to 4 weeks (Rovee-Collier, 1995). However, memory assessed by this task is quite specific because retention of the contingency is disrupted if training and test situation differ in any detail (e.g., Rovee and Fagen, 1976). Since learning of the contingency between motor activity and a visual event is attended by cerebellar activation, it is assumed to represent implicit memory (Nelson, 2002). However, Rovee-Collier (1997) argues that recognizing the mobile after the delay is expressed by a motor response and thus reflects an early form of explicit memory.

In a study by Graf et al. (2012), the mobile task was applied to assess contingency learning and associative memory in 3-month-old Cameroonian Nso farmer and German middle-class infants. Infants participated in two sessions at intervals of 24 h and when they reached a pre-set learning criterion during reinforcement they were tested for immediate and long-term retention. Results showed that 3-month-old infants in both cultural contexts are able to learn and to retain the relation between own leg kicks and the visual event indicated by an increased kick rate after reinforcement as well as after the 24 h delay compared with the baseline level of response. Nevertheless, culture-specific experiences influenced performance in this task: Although a higher proportion of Cameroonian Nso infants reached the critical increase during reinforcement and were thus classified as learners, this difference was not attributable to the advanced gross motor abilities of Nso infants but instead based on the level of baseline response. Depending on culture-typical experiences in motor handling (lying on the back with arms and legs free to move in Germany vs being carried in a sitting position in close body contact restricting movement of the limbs in Cameroon), German middle-class infants showed a higher level of baseline activity compared with Cameroonian Nso farmer infants impeding the achievement of the learning criterion. To conclude, this study demonstrated that cultural differences concerning infants' everyday experiences influence the level of motor response and hence affect learning performance in this task which is why characteristics of the context ought to be considered before applying this task across different cultural environments. With respect to the likely influence of culture on particular aspects of memory, this study confirms the assumption that implicit memory processes, here indicated by learning of the contingency and recognition of the mobile after the delay, do not display cultural memory differences.

Priming is also applied to assess implicit memory in verbal children and adults. In a prototypical priming task, the picture completion task, pictures are presented and after a delay ranging from seconds to months, the pictures are presented again but in a fragmented mode (i.e., only a fraction of information is presented). Priming is indicated when prior exposure to the pictures facilitates their subsequent recognition which can be measured by the reaction time or by the level of information required to name (i.e., to recognize) the picture. Regarding priming in early childhood, Gollin (1960), for example, demonstrated that 30- to 41-month-old children show a priming effect after a delay of 1 week. Several studies comparing priming in children at different ages and adults found no age-related effects (e.g., Parkin and Streete, 1988). Although priming as an implicit memory task is not assumed to be influenced by cultural factors, studies demonstrating its universality across cultures are largely missing.

An exception is the study by Vöhringer et al. (in preparation) who used a picture completion task to assess implicit memory in 3;4-year-old German middle-class and Cameroonian Nso children. Results showed that children from both cultural contexts exhibited a priming effect indicated by faster recognition of a prime (a picture they saw during a priming phase) compared to a nonprime. German middle-class children showed a higher recognition speed than Cameroonian Nso farmer children, potentially relying on extended experiences with two-dimensional pictures. Calculating a difference score between recognition speed of primes versus no-primes, however, revealed no differences between children from the two cultural contexts. To sum up, this study showed that although recognition speed differs across cultural contexts, priming (implicit memory) is not affected by cultural context.

Taken together, results from cross-cultural studies show that visual paired comparison, habituation, mobile, and priming paradigms are only slightly or not influenced by culture-specific factors. These findings strengthen the theoretical idea that these tasks tap implicit memory processes.

Developmental Changes in the HPA Axis

Newborns have the capacity to mount physiologically significant cortisol and ACTH responses to environmental stressors. Specifically, stressors that elicit pain, such as heel lances, promote sensitization to the response while handling stressors, such as physical examinations, show habituation over time. Although newborns show robust cortisol responses to even mild stressors, across the first year of life it becomes increasingly difficult to elicit cortisol responses to the same types of stressors. This period of hyporesponsiveness mimics the stress hyporesponsive period that researchers have studied in rat pups between 4 and 14 days of age, and it is uncertain whether infants enter the functional equivalent of this period during the first year of life. By 1 year of age, infants typically show no increases in cortisol to stressors such as separations or stranger approach, even while exhibiting significant behavioral distress (Hostinar and Gunnar, 2012). Research suggests that physiological changes including improved negative feedback regulation of the HPA axis and decreased adrenocortical sensitivity to ACTH, may at least partially explain hyporesponsiveness of the system during this period. Relationships with caregivers also act as an important moderator of the HPA response. Children who experience supportive adult care are better able to buffer cortisol responses, while children who have been separated from their caregiver exhibit elevations in cortisol to the same stressors. Over time, children develop the ability to regulate HPA responses in the absence of caregivers. Although able to mount a significant cortisol response, newborns lack the typical diurnal cortisol rhythm seen in adults and instead show two peaks that are 12 h apart and do not depend on the time of day. By 3 months of age, infants usually develop a more adult-like rhythm that includes high morning and low evening cortisol levels. Watamura et al. (2004), reviewed in Hostinar and Gunnar (2012), report that napping in toddlers seems to facilitate decreases in cortisol across the day, possibly involving development of the circadian HPA axis rhythm through age 3.

Levels of corticosteroid-binding globulin (CBG), a factor that binds circulating cortisol and renders it biologically inactive, may explain differences in cortisol levels across early childhood. In adults, about 80% of cortisol is bound to CBG, but CBG levels are low in newborns, and adult levels are not reached until approximately 6 months of age. Thus, although total plasma cortisol is low in newborns, levels of free cortisol in infants under 6 months often surpass older infants and children because of increasing cortisol levels and low levels of CBG. Young infants also show marked increases in free cortisol to very minor stressors such as undressing. Remarkably, the HPA axis is relatively mature by 6 months of age (Hostinar and Gunnar, 2012).