A converging body of scientific evidence indicates that patients with borderline personality disorder (BPD) suffer from impairments in the brain systems that regulate impulsivity, aggression, and affect. However, neuroscientists study symptoms, not diagnosis. Therefore the data presented here on the neurobiology of BPD are, more accurately, data on the neurobiology of the symptoms of BPD. These symptoms include emotional and behavioral dysregulation, identity disturbance, cognitive impairments, and interpersonal difficulties.
Most of the available evidence focuses on what are often referred to as the “core” symptoms of BPD—impulsive aggression and affect instability—and these will be discussed in some detail. Since fewer studies focus on identity disturbance and cognitive impairments, I will address these symptoms in less detail. However, there are no studies that directly investigate the biology of the interpersonal difficulties associated with BPD. Scientists conjecture that these symptoms are secondary to the more primary deficits that underlie the “core” symptoms. For example, children who are impulsive and unable to regulate emotion will be more dependent on caretakers to help them regulate their emotions, often overtaxing the abilities of these caretakers to help. People who cannot regulate their intense negative affect may be more likely to feel hurt or slighted by others and may even become mistrustful and hostile toward others. It must be emphasized, however, that, while these symptoms are part of the diagnosis of BPD, they are also found in other diagnostic categories such as sociopathy and major depression.
In general, the brain systems that inhibit aggression and impulsivity and modulate emotion appear to be less effective in BPD. The data involve studies at many levels of brain function, including genetic, neurotransmitter activity, endocrinology, neuroimaging, and pharmacology. The neurobiological impairments associated with BPD only serve as vulnerabilities or predispositions. Their presence does not cause the condition to emerge nor guarantee that it will. Most neuroscientists would argue that more than one system is generally involved and that environmental factors also contribute to whether a particular individual will develop the full blown syndrome of BPD. What has been suggested is that some environments are more likely to exacerbate or tax underlying biological vulnerabilities, whereas other environments are more likely to ameliorate the negative impact of these vulnerabilities and in some cases may even eliminate them. However, in some circumstances, genetic and innate biological factors may be so powerful that no amount of nurture will help the nature.
Understanding of the neurobiology of BPD provides a number of benefits. For instance, we can finally put to rest the nature-nurture controversy. Both genes and environment mutually influence one another. Second, the biological data will help the clinician make more sense of the polytreatment approach used in BPD, including polypharmacy, cognitive-behavioral treatment, dialectical-behavioral treatment, and psychoanalytic or psychodynamic interventions. In addition, recognizing their underlying biological vulnerabilities can create a more empathic attitude toward patients who suffer from this condition. In other words, patients with BPD are doing their best to cope with the deficits they have. 1
“NATURAL SELECTION”: AN EVOLUTIONARY CONTEXT
Considering BPD in an evolutionary context will help to make sense of the neurobiological findings. Neuroscientists agree with Darwin’s assumption that variation is healthy for a species as a whole, even if some variations may be maladaptive for a given individual. Darwin’s theory of natural selection argues that, in order for a species as a whole to survive and to adapt to changing environments, the individuals of that species need to exhibit a wide variety of physical traits and capacities. In this way, when the environment shifts (e.g., when the weather becomes colder, the food supply decreases, or a natural predator moves into the area), the animals with traits and capacities that best respond to those changes are more likely to survive and pass on their genes to their progeny. Individuals with other variations who are not able to cope with these changes are more likely to die off. Since what is maladaptive in one environment may be adaptive in another, evolutionary pressures have resulted in the retention of maladaptive variations. * It can be conceptualized that for evolutionary reasons such as these, the biological impairments of BPD have been retained in the human species. What Darwin’s theory implies is that normal is relative. Normal exists as a range. Every biological factor, whether it be height, eye color, blood type, serotonin level, cortisol level, or autonomic reactivity, exists on a continuum—a bell-shaped curve—in which some variations are more common (i.e., in the middle range of the curve) and other variations are less common (i.e., at the tails at either end of the curve). I stress Darwin’s theory of natural selection to emphasize that every symptom of BPD exists somewhere on a bell-shaped curve of the traits found in humans, albeit on the statistically less common tails of the curve. For example, one might argue that dissociation, although it leads to severe problems of memory and self-cohesion, may serve as an adaptation to traumatic environments.
GENETIC INHERITANCE AND THE ROLE OF THE ENVIRONMENT
The evidence for a genetic contribution to BPD derives from the fact that BPD tends to run in families, has a higher concordance in monozygotic than in dyzygotic twins, and has a higher frequency in biological than in adoptive relatives. 1–3 While studies do indicate a degree of genetic heritability for the diagnosis of BPD per se, there are even more data indicating an inheritance factor for the symptom components of BPD. 1,2 Genetic evidence is strongest for the symptoms of impulsive aggression and affect instability. There is also evidence for genetic inheritance of personality traits that are associated with BPD, such as novelty seeking, negativism, neuroticism, anhedonia, emptiness, low self-concept, as well as of factors associated with insecure attachment, such as difficulty with separation, clinging, and an inability to tolerate aloneness. 2,4
One particularly promising avenue of genetic research involves the serotonin system. One gene on chromosome 11, which codes for a precursor of serotonin, tryptophan hydroxylase, shows allelic polymorphism. One allele is associated with decreased serotonin activity and increased suicide attempts. 5 Another gene, involved in coding for the promoter region of the serotonin transporter has two allelic variations, one of which has reduced serotonin function and shows an association with affective symptoms such as anxiety and depression. 6 However, no single gene locus is responsible for BPD. 5 Geneticists speak of poly-gene influences and genetic-environmental interaction.
Since so much of the pathology of BPD occurs in the context of interpersonal relationships, it is assumed that interpersonal experiences play a major role in how genetic influences are expressed, with each (genes and environment) providing a 50% contribution to the overall variance. Although as yet there is no precise understanding of just how these two factors mutually influence one another, we do have some general ideas. For example, in a situation in which a child has experienced a trauma (e.g., sexual abuse by an uncle), in order for the symptom of dissociation to become a pattern of behavior, the child must possess a genetic predisposition to dissociation or hypnotizability. This predisposition then becomes activated during environmental experiences of repeated trauma and ultimately becomes patterned as a general defense mechanism to stress. However, if this traumatized child has a caretaker who is receptive to the child expressing his or her feelings about the trauma or who can serve to lessen or remove the traumatic situation, this might play a role in lessening the propensity toward dissociation. Obviously, if it is the child’s home and caretakers that are traumatic, open expression of feelings of fear and pain will not be possible, thereby strengthening the propensity toward dissociation.
The Serotonin Story
The most convincing neurobiological evidence exists for the symptom referred to as impulsive aggression. Impulsive aggression can be directed toward others (as violent acts or other inappropriate or uncontrolled expressions of anger) or toward the self (as suicide, suicidal threats or gestures, and other self-damaging acts such as cutting). It is well known that serotonin is involved in inhibiting impulsive aggression (i.e., the tendency to act on aggressive impulses). Serotonin function can be studied from a variety of vantage points, including genes (mentioned previously), cerebrospinal fluid (CSF), platelets, pharmacological challenges, and neuroimaging. An inverse relationship exists between serotonin and impulsive aggression: i.e., low levels of serotonin are associated with an increased incidence of impulsive aggression. 1,7,8
Platelet studies (measuring 5-HT) reveal that low levels of serotonin activity are associated with suicidality and aggressive self-mutilation. Platelets take up and store serotonin just like the brain, utilizing the same transporters and receptors. Therefore serotonin activity in platelets is presumed to reflect serotonin activity in the central nervous system.
Pharmacological studies using fenfluramine (FF) challenge reveal a blunted prolactin response in individuals with impulsive aggression. Administration of the serotonin agonist, FF, stimulates prolactin release. A normal prolactin response to FF depends on intact serotonin function. The more robust the prolactin response, the more robust the serotonin activity. By contrast, a blunted prolactin response to FF reflects reduced activity of the brain’s serotonin system.
PET scans measure glucose metabolism, which reflects the neuronal activity of the brain. In individuals who exhibit high degrees of aggression, neuroimaging studies using PET reveal decreased levels of glucose metabolism in pre-frontal cortex (PFC) regions, which play a role in inhibiting aggressive impulses. In normal individuals, serotonergic agents such as FF stimulate increased metabolic activity in these regions, whereas individuals with suicidal behavior and other manifestations of impulsive aggression show a blunted response (i.e., less increase in glucose metabolism) to FF.
Perhaps the most fascinating neuroimaging evidence in support of the serotonin story comes from the fMRI studies of Pietrini et al., 9 which involved normal subjects. Subjects are directed to imagine themselves being aggressive, both in a restrained and an unrestrained way. Even normal subjects, when they imagine themselves being aggressive, show decreased activity in a PFC region called the ventro-medial PFC. An even greater decrease is associated with the unrestrained versus the restrained aggression fantasy.
While the evidence associating low serotonin with increased aggression and impulsivity is quite conclusive, the evidence for other neurotransmitters is less certain. With respect to dopamine, it is known that dopamine activity in mesolimbic circuits is involved in modulating affective responses to the environment. Studies suggest that increased dopamine activity in these pathways is associated with increased irritability and aggression. 7
Results concerning the norepinephrine system (NE) are contradictory. Most studies indicate that increased NE is associated with increased aggressive behavior, whereas other studies suggest that decreased NE activity is associated with increased aggression. Since increases in norepinephrine appear to be involved in coping with external danger, it is theorized that perhaps high levels of NE are associated with outwardly directed aggression, whereas low levels may be associated with inwardly directed aggression.
Lastly, GABA activity inhibits aggression. Low levels of GABA activity appears to be associated with increased aggression.
Individuals with BPD suffer from affect instability, including symptoms of anxiety, depression, irritability, lability of affect, and emotional hypersensitivity. For example these individuals become distraught even at slight criticism, react with rage to disappointments and minor slights, and feel terror and/or abandonment in response to separations. It is fairly well agreed that the symptoms of affect instability have neurobiological underpinnings, but these are less well understood than those for impulsive-aggression. 1
The NE system modulates arousal and attention to external stimuli. For example, a surge of activity in the locus ceruleus (LC), a midbrain structure where the majority of NE projections originate, is responsible for waking us from the sleep state. In general, increased arousal, alertness, and engagement with the environment appear to be associated with increased activity of the NE system, whereas decreased arousal and withdrawal from the environment are associated with decreased NE activity. When we fall asleep, the NE system turns off.
It is assumed that dysregulation of the NE system is associated with many of the symptoms of affect instability. Novel or threatening stimuli result in increased activity within the locus ceruleus, which is associated with irritable aggression. In humans, increased engagement with the environment in the form of risk taking and outwardly directed aggression, irritability, and heightened emotional reactivity is associated with increased NE activity. It is therefore postulated that increased NE may contribute to the symptoms of affect instability found in patients with BPD. Studies using d-amphetamine (which increases norepinephrine activity) support this proposal. In patients with BPD, a dysphoric response to the administration of d-amphetamine is associated with symptoms of affect instability.
GABA plays a role in tranquilizing or damping down strong surges in emotion. An imbalance of the GABA system is implicated in affect instability. There are high levels of GABA receptors in the emotional processing regions of the brain, particularly the amygdala. Agents such as lithium, valproate, and carbamazepine all serve to increase GABA activity and this is the most likely mechanism for their mood stabilizing effect.
The acetylcholine system (ACh) is implicated in emotional reactivity, as evidenced by the results of studies in which substances that enhance ACh activity were administered. 1,4 When cholinergic agents, such as physostigmine and procaine, are given to depressed patients, they increase the depression; when these agents are given to euphoric bipolar patients, the patients become depressed. Studies have found that, when patients with BPD are given physostigmine, their mood swings toward depression, and that those with the greatest degree of affect instability react most strongly. In studies in which BPD patients were given procaine, they showed marked and variable emotional reactions, particularly depression and other unpleasant feelings.
INTERACTIONS BETWEEN NEUROTRANSMITTER SYSTEMS
The neurotransmitters discussed here operate as neuromodulators, meaning that they influence not only synaptic transmission, but also gene expression, protein synthesis, and synaptic growth. The symptoms of BPD are presumed to be the result of interactions between neuromodulatory systems. For example, serotonin interacts with NE. Both decreased serotonin and increased NE may predispose to impulsive aggression toward the outside world, whereas decreased serotonin and decreased NE may predispose to self-directed aggression. GABA also interacts with NE. An imbalance between the NE and GABA systems is presumed to predispose to affect instability. Neuromodulatory circuits link the midbrain and ventral striatum with limbic and cortical structures, which is why impairments in neuromodulator systems can have such wide ranging effects on emotion, behavior, and cognitive abilities.
IDENTITY DISTURBANCE IN BPD: “THE MIND-BODY CONNECTION”
Neurobiological investigations into the underlying neural substrate of identity are sparse. Nevertheless, they are extremely interesting, since they underscore the “mind-body connection” in how the brain deals with stress and emotion.
Depersonalization is characterized by an altered subjective experience regarding the familiarity of self and surroundings, but with intact reality testing. Patients often report feelings such as being unreal, strange, remote, and having sensations of not being present and other perceptual illusions. Neuroimaging studies using PET 10 reveal that, compared with normal subjects, patients with depersonalization show altered metabolic activity in posterior cortical regions—decreased activity in temporal cortex and increased activity in parietal and occipital cortex. These regions are critical in processing external unimodal sensations (visual, auditory, and tactile stimuli) and integrating them with one another (i.e., multimodal sensation) as well as with somatosensory signals from the body. Somatosensory signals from the body, processed particularly in the parietal cortex, are a critical component of our body schema, our sense of location in space, and our overall sense of self. Deficits in unimodal and multimodal perceptual areas may explain some of the odd perceptual illusions and distortions that patients report, such as a “flattened, two dimensional perspective.” The “as if” quality of detachment from the world and even one’s own body may be explained by the metabolic alterations in the parietal areas that integrate externally with internally derived sensations. It is known that even in normal subjects, during threatening situations, there is a shift of metabolic activity away from frontal regions to the posterior cortex, since this is where external sensory inputs are processed. Detecting danger signals takes priority over higher reasoning skills during a threatening situation. This helps to explain why patients with depersonalization often become worse when under stress, since they already have increased parietal lobe activity.
Further evidence that the parietal lobe is critical for an integrated sense of self comes from a group of neurological patients who suffered actual tissue damage to the parietal cortex from stroke, trauma, or tumor. These patients frequently exhibit symptoms of outright denial or neglect of body parts and areas of the perceptual world. 11 Patients with depersonalization only have decreased metabolism in the parietal cortex and therefore their symptoms are less severe than patients in whom there has been an assault to cortical tissue.
Sierra and Berrios 12 focus on the symptoms of depersonalization that involve feelings of “mind emptiness” and indifference to pain. Their studies address the alterations in activity in the anterior brain regions: the right prefrontal cortex and the anterior cingulate. The prefrontal cortex processes the emotional significance of events and the cingulate is essential to regulating what we pay attention to. They hypothesize that depersonalization symptoms result when disconnections occur between these frontal regions.
Many patients with BPD self-mutilate and report that they do not feel pain during such acts as cutting or burning. Experimental evidence suggests that patients with BPD appear to have an increased pain threshold, independent of other confounding variables such as dissociation and psychotropic medication. 13,14 This threshold goes even higher during periods of emotional distress. This increase in pain threshold during stress may explain the reports of analgesia during self-mutilation. Since the cingulate is involved in pain perception, it is possible that alterations of cingulate activation may contribute to alterations of pain threshold.
In summary, it appears that patients with depersonalization have functional disconnections in the brain circuits that integrate the perception of external events with the emotional significance of those events and with the state of the individual’s body, circuits that enable the individual to determine what is adaptive to pay attention to. Indeed, such functional disconnections, as opposed to the outright tissue damage found in neurological patients, may turn out to be a common etiology of many psychiatric disturbances. For example, the delusions and hallucinations of schizophrenia can be explained by impaired integration of brain regions. 15,16
Another manifestation of the identity disturbance found in BPD can be the presence of conversion symptoms. One neuroimaging study examined a patient with conversion hysteria, in whom a left sided paralysis developed following a psychological trauma. 17 The patient was instructed to prepare to move and then actually move, first her good right leg, followed by her “paralyzed” left leg. It is known that under normal circumstances a series of steps is involved in motor action. The PFC is involved in the willed or voluntary control of motor action. The PFC then signals pre-motor areas, which in turn signal primary motor cortex, which in turn, activates motor neurons to perform the action. In this patient, as expected, metabolic activity on PET scan reveals normal activity in pre-motor and primary motor areas in the left hemisphere associated with the normal right leg. However, when trying to move the “paralyzed” left leg, the PET scan showed normal activity in the pre-motor region (preparation for movement) but failed to show activation in the right hemisphere primary motor cortex, thus explaining the “paralysis.” Instead the PET scan revealed increased activity in the right orbito-frontal and right cingulate cortex. The authors suggested that these structures inhibited prefrontal, voluntary (willed) effects on the right primary motor cortex when the patient tried to move her leg. In other words, the brain regions involved in processing emotional significance and directing conscious attention served to inhibit actual brain activity in the regions responsible for triggering body movement. This same group of researchers 18 found that PET scans of normal subjects with hypnotically induced paralysis were similar to the PET scans of the patient with conversion paralysis. This suggests that hypnosis and hysteria may share a common neurophysiological mechanism.
ENVIRONMENTAL CONTRIBUTIONS TO BPD
The Synergy of Nature and Nurture
Nature and nurture have a complex mutual influence on one another. The picture now emerging indicates that, in individuals born with an innate, genetic predisposition to the biological impairments described above, the kind of environment they grow up in (such as the kind of parental care they receive) can influence their ultimate outcome. Some environments seem to exacerbate or “bring out” these impairments, whereas others may lessen or ameliorate them. Therefore, it should not be surprising that patients with BPD often have a prior history of physical abuse, sexual abuse, or neglect. A growing body of research on the neurobiologic effects of trauma helps to explain how early trauma experiences may contribute to the emergence of symptoms of BPD.
The Neurobiological Effects of Trauma
It is now well established that childhood neglect and abuse can lead to life-long impairments in neurobiological systems, including the autonomic nervous system and the hypothalamic pituitary adrenal axis (HPA). Patients with BPD often respond abnormally to stress. This may be a direct result of their innate impairments (as mentioned earlier) or may be secondary to the neurobiological changes that are associated with abuse and neglect.
During acute stress, initial brain responses normally involve increased catecholamine activity (leading to sympathetic nervous system arousal) and increased production of cortisol (via the HPA), with increases generally in proportion to the degree of stress. These neuroendocrine systems, which help the individual cope with stress, are normally well-balanced responses that shut down after the stress is dealt with. Catecholamines and cortisol are synergistic. 19 Catecholamines (the “stress hormone”) provide the increased metabolic energy and blood flow to the muscles necessary for “fight or flight.” Increased activity of the HPA leads to the production of cortisol, which should perhaps be considered the “anti-stress hormone,” because it then acts to inhibit the production of catecholamines and results in the shutting down of these defensive stress responses. As these physiologic responses to stress shut down, activity within the HPA is suppressed, due to the negative feedback inhibition of cortisol. Glucocorticoid receptors in the hippocampus, amygdala, and hypothalamus are all important in detecting cortisol levels and providing negative feedback inhibition to the HPA and the restoration of baseline levels of cortisol.
However chronic, unrelenting stress can lead to permanent negative effects on the brain. 5,19 Although first studied in Vietnam veterans, we now know even early maltreatment of children can produce enduring biological changes. These changes include damage to brain tissue as well as dysregulation of neuroendocrine systems. With respect to the stress response, the resultant clinical picture appears to differ among individuals. Some remain hypersensitive to stress, with increased corticotropin-releasing factor (CRF) and increased cortisol (a picture often found in chronic depression). Others have a normal stress response, with normal levels of cortisol. Still others may become hyposensitive to stress, with decreased CRF and decreased cortisol. It is as if the HPA axis has become “exhausted.” While there is a great deal of controversy and conflicting studies in the field of neurobiological correlates of trauma, a number of interesting neurobiological patterns appear to emerge.
One group of individuals who develop symptoms of PTSD present with the somewhat paradoxical situation of increased CRF and decreased cortisol. In chronic depression, with increased cortisol and increased CRF, glucocorticoid receptors are down-regulated in number and sensitivity. Therefore, there is decreased negative feedback of HPA and a resultant higher level of cortisol. By contrast, in PTSD, several studies reveal an increase in the number and sensitivity of glucocorticoid receptors. This increase in glucocorticoid receptor activity leads to increased negative feedback of HPA and tonically attenuated levels of cortisol. The salient neuroendocrine feature of PTSD is not low cortisol. Low cortisol is simply a “downstream” result of the increase in glucocorticoid receptor function and enhanced negative feedback. Although for many years it was assumed that trauma can cause the system to try and adapt by decreasing the responsiveness of the HPA system, there is evidence for the fact that individuals who go on to have PTSD (since some do not) as a result of trauma appear to have low levels of cortisol from the outset. Although more studies are needed to confirm this hypothesis, it may be that the decreased production of cortisol in response to trauma is what makes these individuals more likely to develop PTSD in the first place. Some of the symptoms of PTSD that appear to reflect catecholamine hyperarousal (insomnia, hypervigilance, exaggerated startle) may occur because there is insufficient cortisol to shut down the catecholamine response.
When trauma results in high levels of circulating cortisol, this can lead to atrophy and even cell death in the hippocampus. 19,20 Evidence for small hippocampal volume is seen in Vietnam veterans with PTSD and women with a history of childhood sexual abuse. 21 While this to some extent contradicts other findings concerning PTSD, it appears that high levels of cortisol can damage the hippocampus, which in turn further exacerbates the impaired down-regulation of cortisol and leads to a run-away situation that can further compromise hippocampal function. Some symptoms of impaired memory function may also be explained by hippocampal dysfunction.
In patients with a history of childhood abuse, decreased cortical development and integration have often been observed. 22 A higher incidence of abnormalities on EEG is found, predominantly left-sided, which may reflect decreased development of the left hemisphere. These is also evidence for deficits in right-left hemisphere integration and a smaller corpus callosum, which may predispose to right-left integration deficiencies.
Clinical symptoms result from biological consequences of trauma.
A number of the clinical manifestations of BPD may be explained by these biological consequences of trauma. For example, difficulties in reflecting on emotional experiences and putting feelings into words, as well as a tendency toward black and white thinking and difficulties integrating negative and positive attributions, may result from decreased left hemisphere (verbal) development and from impairments in right hemisphere (emotional)-left hemisphere integration. Impairments in memory for traumatic events may be related to damage to hippocampal tissue. The “somatization” reactions often seen in BPD may result from chronic overactivity of the autonomic nervous system, both parasympathetic and sympathetic.
Maternal Care Can Alter Gene Expression
Genes are not destiny.
Over the course of one’s life, certain genes are turned on (expressed) while others are turned off (suppressed), with the environment serving to modulate the expression of genes. The fact that the environment contributes to control over gene expression may help to explain why some children, although born with emotionally dysregulated temperaments, do fairly well despite their vulnerability. 23
Studies using animal models strongly suggest that the type of maternal care can produce lifelong differences in offspring, at a behavioral and physiological level, and that this effect is mediated through the regulation of gene expression. 24–26 Since the brain systems that regulate behavior, affect, and body physiology are preserved throughout the animal kingdom, animal studies can serve as good models for human functioning.
Effects of separation.
The amount of care a mother rat provides can be altered by artificially separating the pup from the mother. 24 When rat pups are taken out of their nest briefly (for about 15 minutes) and handled by humans, rat mothers show increased maternal care (in the form of licking and nursing) toward these “handled” pups. The pups who receive the increased care are less fearful for the rest of their lives than the non-handled pups, who did not receive increased maternal care. However, when pups are removed from the nest for long periods of time, their mothers show them decreased attention, which results in a number of lifelong injurious effects, including increased fearfulness, decreased thyroid production, decreased serotonin and glucocorticoid receptors in the hippocampus, and increased reactivity of the HPA axis. 24,27
“High and low lickers”: Some mothers are naturally better than others.
A spectrum of differences exist with respect to maternal care in rats (as measured by amount of licking/grooming and style of nursing). 24 Some mothers are naturally HIGH in maternal care (HIMC), while others are LOW in maternal care (LOMC). These differences are transmitted across generations, meaning the offspring of HIMC mothers are less fearful than the offspring of LOMC mothers. In addition, the female offspring of HIMC mothers are more likely to grow up and be HIMC mothers, whereas the female offspring of LOMC mothers are more likely to grow up to be LOMC. In other words, pups reared with good maternal care are less fearful and better mothers than those reared with poor maternal care.
Transgenerational transmission has traditionally been interpreted as genomic inheritance. Cross-fostering studies, however, suggest that non-genomic environmental factors play a large role. In cross-fostering, rat pups are removed from the nest of their biological mother and placed in the nest of a foster mother. If this is done soon after birth, the foster mother rears her foster-pups just as she would her own biological pups. When the biological offspring of HIMC mothers are reared by LOMC mothers, they grow up to be identical to the biological offspring of LOMC mothers with respect to fearfulness and maternal care—i.e., they are more fearful and the females are more likely to exhibit LOMC behavior as adults. Conversely, when the biological offspring of LOMC mothers are reared by HIMC mothers, they are less fearful and the females are more likely to exhibit HIMC behavior as adults. Studies suggest that maternal care alters the behavior of offspring by influencing the functioning of a variety of neuroendocrine and neurotransmitter systems involved in affect, hormonal, and behavioral regulation, including the HPA axis (production of CRF, and glucocorticoid receptors [GR]), and neurotransmitter activity in the amygdala. As mentioned previously, production of CRF is responsible for the release of cortisol during stress and GRs in the hippocampus are important in downregulating cortisol levels. Benzodiazepine (BNZ) receptors (subunits on GABA receptors) in the amygdala are involved in downregulating the fear response. These biological systems are the result of the expression of genes.
The rat pups who receive increased maternal care as a result of brief separation, the biological offspring of HIMC mothers, and the cross-fostered pups of LOMC mothers reared by HIMC mothers all appear to resemble one another physiologically as well as behaviorally! They all exhibit decreased CRF mRNA in the hypothalamus, increased GRs in the hippocampus, and increased BNZ receptors in the amygdala. This is reflected in their being less fearful to threat and novel situations. Conversely, rat pups who are neglected by their mothers following long-separation, the biological offspring of LOMC mothers, and the cross-fostered pups of HIMC mothers reared by LOMC mothers also all resemble one another, exhibiting increased CRF mRNA in the hypothalamus, decreased GRs in the hippocampus, and decreased BNZ receptors in the amygdala, resulting in behavioral signs of increased fearfulness to threat and novelty.
Distinguishing between genomic and behavioral transmission.
Another set of experiments further supports the cross-fostering results of behavioral (i.e., non-genomic/environmental) transmission of bio-behavioral traits. If differences in maternal care are transmitted only through genetic inheritance, then the offspring of LOMC mothers should be LOMC mothers whether or not they are “handled.” (Remember pups handled briefly by humans receive increased maternal care when they are returned to the nest.) If differences are transmitted behaviorally, then handling will affect the outcome. The results were conclusive. When the biological offspring of LOMC mothers are briefly handled by humans, they resemble the biological offspring of HIMC mothers on measures of fearfulness and cortisol metabolism. Even more significant, perhaps, is that, when the female offspring become mothers, they exhibit HIMC behavior. What this highlights is that environmental factors can influence the trajectory of development not only in the immediate next generation but even in subsequent generations, through the influence of maternal care on female offspring.
It is interesting to note that handling stimulates better mothering in mothers who are poor to begin with, but has no effect on mothers that are already good mothers. In the same set of experiments, when the offspring of HIMC mothers are briefly handled, this does not cause the mothers to increase their maternal care. You might say they were already “good enough.”
Effects of maternal care on brain development.
Differences in maternal care in rats are also associated with differences in cognitive development, as a result of enhanced development in the hippocampus, a structure involved in memory and spatial learning (as well as in cortisol regulation). 28 HIMC is associated with increased synaptogenesis, increased cholinergic release, and increased NMDR receptors (which are involved in long-term memory).
Research on monkeys confirms rat research.
The work of Suomi using rhesus monkeys 25 supports all of the findings in rats. These studies are even more relevant to humans, since rhesus monkeys display an array of characteristic emotions remarkably similar to human infants and young children. In the natural setting, a number of infant monkeys show increased fearfulness and anxiety-type behavior to threat and novelty and are less likely to be dominant in the troop hierarchy. Another group show unusually high levels of impulsiveness and aggression. These monkeys often exhibit low levels of CSF 5-HIAA (as found in human studies). These are features which are similar to the traits found in BPD. Since cooperation and dominance hierarchy play a strong role in troop functioning, these behaviors often result in a poorer outcome for many of these poorly adapted animals. However a negative outcome is not inevitable. Complex interactions with the environment seem to mediate each animal’s socio-emotional functioning.
In deprived environments—for example, when monkeys are separated from their mothers—a poorer outcome can result. Monkeys who are separated from their mothers and reared with peers exhibit low levels of CSF 5-HIAA. By contrast, monkeys reared by their mothers are less aggressive and fearful, are more likely to be dominant, and exhibit higher serotonin activity.
There is allelic variation in the gene that is responsible for serotonin production, the serotonin transporter gene. One allele (LS) shows reduced serotonin function. When monkeys with this allele are deprived of maternal care and reared by peers, they show decreased CSF levels of 5-HIAA. However, when monkeys with the LS allele are reared by their mothers, they do not show decreased CSF levels. This indicates that maternal care can protect against the deleterious effects of having the LS allele for serotonin metabolism.
A similar example of this relates to differences in monkeys’ tendency to consume alcohol. Thus, monkeys with the LS allele who are raised by peers show an increase in alcohol consumption, whereas monkeys with the LS allele who are reared by their mothers do not show this increase in alcohol consumption. The fact that mother-rearing versus peer-rearing can affect serotonin metabolism and alcohol consumption supports the hypothesis that environmental influences can ameliorate the effects of genetic vulnerabilities.
Enhanced attachment relationships are associated with an improved outcome for biologically vulnerable offspring. Foster studies were carried out during the first 6 months of life using mothers with high degrees versus low degrees of nurturant attachment behavior. Infants of normal temperament reared by foster mothers exhibited normal levels of bio-behavioral development, independent of the degree of maternal attachment behavior. However, surprisingly, when temperamentally fearful and anxious infant monkeys (high-reactive) were raised by foster-mothers with high levels of nurturant attachment behaviors, they not only did as well as their normal-temperament peers, they seemed to be precocious in their development! As infants they showed better levels of attachment to their foster mothers, left their mothers sooner, explored their environment more, and weaned more easily than their normal peers. These individuals, who (remember!) began life showing signs of increased fearfulness and anxiety, as older youngsters appeared to be even more adept than their normal peers at recruiting and retaining other group members during antagonistic encounters. As a consequence, most rose to and maintained top positions in the dominance hierarchy. By contrast high-reactive infants raised by regular mothers (i.e., mothers who did not posses the extra high levels of nurturance) tended to drop to and remain at the lower levels of the hierarchy. The females in these studies who began life fearful and anxious but were raised by highly nurturant foster mothers appeared to be more likely to adopt the maternal style of the foster mother than of their own biological mother.
CONCLUSIONS: IMPLICATIONS FOR BPD
A variety of animal studies reveal that early attachment relationships have a major and lifelong influence on innate biological and behavioral propensities. Trauma and neglect appear to exacerbate these tendencies, whereas adequate maternal care can buffer these effects. In the case of rhesus “super-moms,” biological vulnerabilities not only disappeared but individuals often did better than those with normal temperaments. Attachment studies in humans reveal that attachment styles, both secure and insecure types, show transgenerational effects—i.e., mothers exhibit with their baby the same kind of attachment they had with their own mother. While this effect may be related to psychological factors such as “internalized object relations” or “internal working models,” it may also be due to biological effects, such as environmental influences on gene expression.
What this large body of neuroscience research suggests with respect to BPD is that, while patients with BPD may be born with innate genetic tendencies for impaired brain systems for regulating impulses and affect, the environment they find themselves born into may be critical in determining whether or not they develop the full blown syndrome of BPD.
As to what the future holds, research is needed along a number of avenues. It would be of interest to find out if any of the psychological interventions with BPD (e.g., psychodynamic treatment, cognitive-behavioral therapy, dialectical behavior therapy) result in alterations of biological systems, such as the reactivity of the HPA axis. Research is needed to identify the exact nature of caretaking behaviors in human parents that can ameliorate the negative effects of innate fearfulness, aggression, and impulsiveness in children. In addition, the research suggests that treatment for BPD ought to start early. Infants with temperamental vulnerabilities may be more at risk for developing BPD. Their caretakers may need extra help to develop the skills and capacities for helping these vulnerable children.