Self-injurious behavior (SIB) is intentional self-directed tissue injury inflicted without conscious intent to kill oneself (Simeon et al., 1992). A provisional nosology, based on the clinical phenomenology of self-injurious behavior, has been developed (Table 1) (Villalba and Harrington, 2000). However, this typology awaits etiological grounding. While a variety of neurotransmitter systems may be involved in the initiation and maintenance of repetitive self-injurious behavior (rSIB), most clinical studies to date have attended to the role of serotonin or endogenous opioids. This focus has emerged from a conceptualization of rSIB as a problem of impulse control (primarily mediated by serotonin) and/or as a maladaptive pain-related behavior (ultimately mediated by opioids) (Villalba and Harrington, 2000). Clinically significant forms of self-mutilation occur predominantly in mental retardation, pervasive developmental disorders, major psychotic disorders and cluster B personality disorders (Simeon et al., 1992). Psychodynamic formulations have suggested that self-inflicted injury may promote affect regulation, relieve anxiety, terminate dissociative experiences, discharge sexual arousal, support (dysfunctional) interpersonal relationships, generate euphoria, serve as self-punishment, establish ego/self boundaries and/or serve as a nonlethal alternative to suicide (Haines et al., 1995; Herpertz et al., 1997; Suyemoto, 1998). In this review, we address biological aspects of rSIB.
The Role of Endogenous Opioids
Repetitive self-injurious behavior (except when induced by pain) may be fruitfully viewed as a developmental syndrome--highlighting the common denominator of its prevalence among Axis II disorders (both cluster B personality disorders and mental retardation). Self-injury may be triggered by depression, anxiety, psychosis, dissociation, pain, intoxication or incarceration; however, these factors rarely lead to rSIB in patients who are not predisposed to repetition prior to adult maturation. Two important developmental features of rSIB are 1) a sensitive dependence on critical periods (and/or critical events) that determine developmental trajectories and 2) the special role of learning/conditioning during an individual's formative years.
Animal and human studies have linked early psychological trauma with subsequent rSIB. Psychological trauma (especially sexual abuse) and severe neglect may produce profoundly toxic epigenetic effects on neuropsychological development. Early social isolation of nonhuman primates frequently leads to rSIB, reduces dendritic branching in cortex and cerebellum, produces morphological changes in the striatum, alters hippocampal neuronal microstructure, and alters regional levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), substance P and leucine-enkephalin (Kraemer et al., 1997; Teicher, 2002). The hypothalamic-pituitary-adrenal (HPA) axis response to stress may also be blunted (Kraemer et al., 1997).
Neural circuits that mediate the perception of pleasure and pain serve a "pedagogical" function by reinforcing adaptive behavior and extinguishing maladaptive behavior. When these pedagogical circuits develop aberrantly (as is presumed in rSIB), maladaptive characteristics may emerge, such as impulsivity, abnormal risk-taking, learning disabilities, attentional pathology and mood dysregulation.
The experience of pain is substantially altered in rSIB patients, compromising the most basic inhibition toward self-injury. Conditions in which known pain insensitivity accompany severe SIB include schizophrenia (Dworkin, 1994) and borderline personality disorder (Kemperman et al., 1997). The cooccurrence of experimentally verified pain insensitivity (Benedetti et al., 1999) and self-mutilation (Shua-Haim and Gross, 1997; Warnock et al., 1999) has also been observed in Alzheimer's disease (AD).
Ascending neural pathways, diverging from the thalamus to discrete cortical regions, subserve different attributes of pain perception. Lateral thalamic nuclei project to somatosensory cortical loci important in localizing and assessing the intensity and duration of painful stimuli. The medial thalamic nuclei project to the anterior cingulate cortex (ACC), hypothalamus and amygdala, which mediate the perception of "pain affect" and "pain attention" (the aversive quality of pain). The pain insensitivity associated with AD may be attributed to deficits of attention mediated by the ACC, while sensory-discriminative capacity is preserved. The somatosensory cortex and thalamus are typically spared in AD, while conspicuous neuronal loss is common in the prefrontal and limbic cortices (Benedetti et al., 1999). The elevated pain tolerance of AD is associated with electroencephalographic slowing, suggesting a primary disturbance of vigilance. The pain insensitivity of AD may provide a model to explain the apparent pain insensitivity observed in other diagnoses displaying prominent attentional deficits (e.g., mental retardation, schizophrenia and dissociative disorders). Abnormal pain thresholds have been associated with hypnotizability and dissociative experience (Agargun et al., 1998).
An intrinsic pain inhibitory system can be activated in the presence or anticipation of pain. Stress may trigger the hypothalamus to release proopiomelanocortin (POMC), a prohormone that is subsequently cleaved to yield adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH) and ß-endorphin. The ACTH facilitates vigilance and stimulates the release of energy substrates to support the fight/flight response, while ß-endorphin provides relief from pain that may be encountered in fight or flight. In addition, b-endorphin may allow an animal to escape or fight despite injuries that would typically hamper mobility. This so-called "stress-induced analgesia" may account for the apparent analgesia experienced by wounded soldiers and athletes (Hilgard, 1976). Interestingly, superficial damage to skin produces both analgesia and an invigoration that facilitates fight/flight (Brodal, 1998).
Stress-induced analgesia may play a role in the apparent pain insensitivity of rSIB. Certain commonly observed aspects of rSIB support an endorphin hypothesis. These include: 1) psychic numbing associated with SIB episodes (opioid anesthesia), 2) escalation of the repetition and severity of rSIB (addiction) and 3) post-cessation dysphoria (withdrawal). Habitual SIB is associated with elevated mean plasma metenkephalin (Coid et al., 1983) as well as marked secretion of ß-endorphin immediately following SIB episodes (Sandman, 1990/1991). Sandman (1990/1991) discovered an uncoupling of ß-endorphin and ACTH secretion in some patients with chronic SIB. Since ACTH protects against opiate tolerance (Crofford and Casey, 1999), isolated ß-endorphin secretion predisposes tolerance and the drive to repeat an SIB. Moreover, without the vigilance-enhancing effect of ACTH, unopposed ß-endorphin binding in the ACC (Davis et al., 1997) may lead to hypovigilance and increased pain insensitivity. A similar uncoupling of ACTH and ß-endorphin has been reported in heroin addiction (Sandman, 1990/1991). A study of SIB in mentally retarded subjects found that a post-SIB dissociation of POMC peptides predicted a therapeutic response to naltrexone (ReVia) (Sandman, 1990/1991). Individuals that had the greatest post-SIB elevation of ß-endorphin showed the greatest improvement in SIB with naltrexone (Sandman, 1990/1991).
In some regards, cutaneous SIB resembles acupuncture, and substantial evidence supports an opioid mediation underlying the potent analgesia of acupuncture (Ulett et al., 1998; Wu et al., 1999). Acupuncture is typically administered to produce analgesia by penetrating the skin with sharp needles or by superficially burning it with lighted punks of Artemis vulgaris ("moxibustion"). Likewise, cutting and light burning are the most common types of cutaneous SIB. The distal forearm is a very effective site for inducing acupuncture analgesia (Wu et al., 1999) and tends to be a preferred site for cutaneous SIB. Brain imaging during the induction of acupuncture analgesia has demonstrated activation of the hypothalamus and its descending projections to the raphe nucleus and periaqueductal gray matter, and deactivation of rostral ACC, amygdala and hippocampus (Wu et al., 1999).
A final observation regarding the potential opioid involvement in SIB comes from the evidence pointing to a special role for opiates in mediating maternal-infant interaction. Mother's milk contains caseins that are digested into opioids. Moreover, nonnutritive suckling in humans and animals is extremely antinociceptive (Blass, 1997), which may account for the reinforcing feature of oral autostimulation (e.g., digit sucking). Human obstetric data suggest that a neonate's opiate responsivity is not fixed and may be "imprinted" (up- or downregulated) by environmental influence during a critical period (Jacobson et al., 1990). The opioid system's capacity to permanently imprint early influences may be important in accounting for the toxic epigenetic effects of child abuse and neglect that are found so prevalently among rSIB patients. A permanent deficit may induce perpetual opioid "craving" and consequential autostimulatory tendency. Rhesus monkeys reared in social isolation engage in a wide variety of self-injurious behavior, including head banging, self-biting, self-slapping and eye gouging. Some investigators have noted the parallel between the SIB observed in these monkeys deprived of maternal contact and the SIB observed in patients with severe cluster B personality disorders (many of whom have been abused or neglected during childhood) (Kraemer et al., 1997).
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