Psychiatric and Biological Consequences of Stress, and their Mitigation by Psychotherapy:

developmental and clinical considerationsDRAFT COPY – NOT FOR ATTRIBUTION

PLEASE DO NOT MAKE COPIES OR DISTRIBUTE

Ed Loewenton, M.A.Morrisville, VT 0566120040227

AbstractThe substantial current knowledge of the biological correlates of psychopathology is coalescing into a coherent image of the relationship between stress, broadly defined, and the unmanageable and chronic experience of distress for which an individual seeks psychotherapy. Adverse life experiences, both subtle interpersonal events starting as early as the first few weeks of life, and discrete episodes of mortal terror, have been implicated in psychopathology since the time of Freud and Janet. Now a clear picture of the relationship is available at the neural level. This knowledge ought to be useful to help understand therapeutic techniques now in use, to re-evaluate diagnostic concepts, and to suggest eclectic models of therapy based on the individual patient profile.

The basic premise that psychopathology is caused by stress, in the broadest sense, or trauma, a more restrictive term, is really a part of folk wisdom, and seems to get discovered over and over again, as van der Kolk (2003) has complained. Janet, and Sigmund Freud, prior to his recantation, both attributed the serious psychopathology they were observing to traumatic incidents in the patients' childhoods. Currently, there is a substantial literature authored by neuroscientists who are focused on psychiatric issues that accepts as virtually axiomatic that stress, broadly defined, is the primary cause of psychopathology. A complementary literature, authored by psychodynamically and psychoanalytically oriented clinicians, recognizes the need for an understanding of psychopathology and its treatment at the neural level. This conceptual synergy has created a new discipline: Neuropsychoanalysis. Some principals of Neuropsychoanalysis include the following:1. Adverse experience causes consistent and lawful alterations in brain structure and function which are manifested as distress, symptomatology, and recognizable clinical pathology. 2. Severity of pathology and resistance to mitigation, as well as individual differential vulnerability to acquire mental illness as a consequence of stress, is determined by incidence of adverse experience in childhood, and the timing, duration, and severity of that adversity. Severe trauma and

neglect in infancy is expected to result in profound impairment throughout the life span. Details of symptom (diagnosis) are largely determined by age at which stress occurs and content of experience. 3. Adverse experiences capable of causing psychopathology are exclusively interpersonal in nature. Vulnerability to non-social trauma (e.g., earthquake) is determined by adverse early attachment experience or other childhood interpersonal trauma. 4. The nature of psychopathology consists in the patient's failure to integrate traumatic memory into a meaningful autobiographical narrative. 5. The nature of psychotherapeutic cure consists in retrieving traumatic memory and its affect, and constructing or modifying its meaning in the whole life of the patient, and in modifying the patient's attachment representations.6. These therapeutic changes in mental activity will be reflected in some lawful way in observable brain function.

Sigmund Freud would have been very comfortable with these ideas. He was originally trained as a physiologist, and always stated his intent to create a scientific discipline of mental healing. Unfortunately for Freud's efforts, the accumulation of neuroscientific knowledge and advanced technology sufficient to allow the beginnings of a high-level conceptual synthesis that might shed some light on the global processes of psychopathology and its treatment occupied most of the 20th century. At the present time, a large and exponentially expanding research literature illuminates the component processes of psychopathology: What changes occur in the brain with mental illness, and what are the mechanisms by which experience and perceptions are translated into these changes? Answers are provided that range from alterations in the molecular expression of DNA to dysregulation of neurotransmitters systems and gross deficits in morphology and function of major brain structures; from the effects of maternal prenatal psychosocial stress on the developing fetus to the effect of the mother's representation of her early attachment experiences on her interactions with her own child, with ultimate consequences for the child's mental health; and new understandings of the establishment, retrieval, modification, and extinction of memories, with possible consequences for the improvements of psychotherapeutic techniques. As will be seen in the text below, this list is too short even to be fairly representative of the accumulating new knowledge that may help us better understand psychopathology and more effectively help those afflicted with it.

There are essentially two questions that interest the neuropsychoanalyst: 1. What changes occur in the brain as a result of trauma and neglect, and how do they determine behavioral outcomes? How do these changes vary with developmental timing of the insult? How can such data be useful in designing improved therapies?2. When psychotherapy (as opposed to pharmacology) leads to remission of symptoms, especially when cure seems durable, what changes occur in the brain? Are they reversals of the insult, structurally or functionally, or do they represent an overlay of new learning that provides control over pathological

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processes, perhaps by integrating them into a new, larger functional system? How can this knowledge help to develop more effective psychotherapy?

Clinical neuroscience and attachment-oriented psychodynamic research and clinical observation have, over the past twenty years, begun to develop a robust, coherent, concordant schema to answer the first question. Some early suggestions in answer to the second question are emerging from very recent work in memory, experiential modification of genetic expression of neurotransmitter systems, and neurotransmitter system interactions. Newer therapeutic techniques, especially Eye Movement Desensitization and Reprocessing (EMDR) (Shapiro, 2003), are generating results that seem to challenge what neuroscience suggests about the nature of cure; the two data sets will obviously have to be reconciled as they mature.

Four pathways to clinically significant behavioral-affective impairment have been demonstrated or proposed:1. Persistent, more or less permanent alterations to brain structures which result in impaired function. These may occur as a result of a. Direct damage to neural structures as a result of stress consequent on persistent high levels of emotional arousal. The role of the stress-response system neuroendocrines in actual neuron loss and impaired neural development is well established by a broad literature. In this pathway, clinical diagnostic details of outcome are seen as largely determined by the timing and extent of environmental (generally psychosocial) insult. Myelination is especially sensitive to stressful levels of corticosteroids.b. Failure of "experience-expectant" (Joseph, 1999) structures to mature normally or to survive developmental pruning as a result of chaotic or absent stimulation during critical or sensitive developmental windows. Despite Barkley's doctrinaire position (personal communication), it is reasonable to suggest that the relationship between experiential deprivation and inadequate structural development obtains for all brain systems, not just the well-understood visual system. It is also reasonable to suppose that this relationship is continuous, not all-or-none. Initiation of the myelination process, necessary for full cerebral function, is dependent upon neuronal activity (Kinney, H.C., Brody, B., Kloman, A.S., and Gilles, F. , 1988).2. Conditioned aversive (fear) or conflictual (approach-avoidance) responses that may involve evolutionarily hard-wired systems (drives), may be particularly refractory to extinction, and may overgeneralize. There is some debate (van der Kolk et. al., 1997; Quirk, 2002; Ohman and Mineka, 2001; Vianna et. al., 2000) as to whether there exists a separate kind of indelible, drive- or survival-related emotional-perceptual memory. 3. Proposed failure of hemispheric integration of stressful or traumatic memories by some as yet unspecified mechanism (Siegel, 2003; van der Kolk, 2003). 4. Proposed fragmented encoding of stressful or traumatic memories due to transient impairment of hippocampal and cortical function by high levels of arousal at time of original encoding, and during efforts at retrieval. (Joseph, 1998; Arnsten & Goldman-Rakic, 1998; Murphy et. al., 1996; Diamond, Bennett, et. al., 1992; Diamond, Fleshner, et. al., 1996).

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This paper adopts the word stress rather than trauma, because stress is a broader and more inclusive term. Psychosocial and medical stress during pregnancy, particularly when prenatal maternal diets are insufficient, can result in transmission of neurohormones to the fetus which can lead to persistent dysregulation of neurotransmitters systems and impaired neural development, manifested as symptoms of behavioral and emotional pathology or as indicators that have been correlated with impaired developmental outcomes (Lou, 1994; Huizink, Robles, et. al., 2003); and with analogues or models of pathology, notably AHDH, in rodents (Brake, Noel, et. al., 1997; Brake, Sullivan, and Gratton, 2000; Brake, Sullivan, et. al., 2003).

Once the child is born, trauma as more generally understood is seen as the primary cause of psychopathology. Persistent and pervasive minor traumas, such as consistent misattunements between mother and infants, or physical and sexual abuse or severe neglect, both emotional and physical, appear to be causal or predisposing for a variety of behavioral pathologies (Schore, 2003; Hesse, et. al., 2003; Teicher et. al., 2002; Huizink, et. al. 2003).

The origins of the psychosocial stress that is associated with psychopathology can occur even before the afflicted individual's mother is pregnant (Lou, 1994). Substantial longitudinal data emerging from decades of work with the Adult Attachment Interview has shown that the characteristics of the mother's attachment to her own parents can result in behaviors, often very subtle and hard to detect, that profoundly influence her own children's psychological health (Hesse et. al., 2003; Fosha, 2003; Beebe and Lachman, 1998; Hesse, 1999).

This might suggest that manifestations of pathology, and more significantly, vulnerability to stress would be different in patients exposed to stress only as adults, and not as children, since insults are imposed on a very different and much more resilient sort of brain. This appears to be true: It is a common finding that the early life histories of patients afflicted with serious pathologies such as PTSD, schizophrenia, borderline personality disorder, bipolar disorder, and ADHD include episodes of abuse, neglect, and other adversity. In fact, these observations underlie the essential psychodynamic therapeutic axiom: psychosocial adversity in childhood determines later psychosocial behavior and susceptibility to stress, with consequential pathologic outcomes. Shapiro (2002, 2003) suggests that accelerated therapies such as EMDR in their pure form are particularly well suited for treatment of discrete episodes of trauma, in the absence of an adverse early life history. She provides examples of the enhancement of EMDR techniques with cognitive and more psychodynamically oriented interventions, as well as behavioral affect-control training, when the patients are more pervasively disordered.

EXPERIENTIAL-BIOLOGICAL PATHWAYS TO PSYCHOPATHOLOGY1. Alterations to neural structuresa. Neurotoxic effects of environmental adversity

Maternal prenatal psychosocial stress has been shown to result in behavioral and affective disturbances in the offspring, both in human studies

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and in preclinical work with rodents. Lou (1994), Huizink, et. al. (2003), and others have demonstrated the connection between maternal prenatal stress, low birth weight, neonatal cerebral volume, and measures of intelligence and psychosocial adjustment in later childhood. There is some evidence that the "difficult baby" temperament, with its potential consequences for infant-mother interactive quality, may result from high levels of prenatal maternal cortisol, some of which passes through the placental barrier (de Weerth, van Hees, Buitelaar, 2003). Maternal prenatal anxiety, number of "hassles", and cortisol levels were negatively correlated with infant cognitive-motor scores at eight months (Huizink, et. al..2003). This study did not examine the possibility that this effect was at least partly mediated by quality of attachment relationship.

Chronic high levels of cortisol are known to be neurotoxic, and to impede myelination and neurogenesis, with obvious consequences for the rapidly developing fetal brain. Similarly, prenatal and perinatal stress has been shown to produce persistent alterations in the dopaminergic neurotransmitters system, with behavioral results including hyperactivity and motivational disturbances (Brake et al., 2000). Disturbances of the monoamine neurotransmitter systems, particularly dopamine, have been observed as a consequence of exposure to unavoidable or uncontrollable stress, as well as prenatal and perinatal maternal or fetal stress. Consequences of perinatal stress-induced dopaminergic dysregulation include hyperactivity and motivational disturbances. It appears that when this occurs in very young animals this dysfunction may become permanent. Profound down-regulation of nucleus accumbens dopamine associated with unavoidable stress causes a "giving up" syndrome of learned helplessness and general reduced levels of arousal in rodents. [See Appendix B for more details on the DA system.]

More obvious is the connection between outright physical or sexual abuse of the infant or very young child, or exposure to other experience which is painful or intensely frightening, such as repeated surgery or familial violence. High levels of corticosteroids associated with high arousal are known to destabilize the normal Hypothalamic-Pituitary-Adrenal (HPA) system, and ultimately may lead to permanent structural dysregulation. Normally, high levels of cortisol are self-regulating; cortisol receptors throughout the brain are activated, resulting in a down-regulation of the hormonal cascade which results in increased cortisol levels. In conditions of chronic high emotional arousal, activity in the Locus Coeruleus-Sympathetic-Noradrenaline axis helps to maintain high levels of corticotropin releasing factor (CRF) from the hypothalamus, resulting in continued high levels of cortisol. Some of the structures on which cortisol receptors are located are especially vulnerable to these chronic high levels; among them are the hippocampus and the cerebellar vermis. Neurons on which cortisol receptors are located are rendered hypersensitive to stimulation by glutamate neurotransmitter. Resultant excessive calcium influx in such a scenario ends up in the cellular mitochondria, which produce the energy on which the cell runs. The mitochondria essentially run out of energy trying to expel this calcium, and the cell dies. High chronic levels of cortisol also appear to impede hippocampal neurogenesis (Sapolsky), which is required for the hippocampal encoding of new associations (memories, learning).

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Approximately half of patients with major depressive disorder are hypercortisolemic.

The hippocampus is, in the most general sense, responsible for allowing the organism to make sense out of the environment by creating spatial maps, temporal histories, and overall representations (memories) assembled from ongoing and stored (remembered) data in all modalities, including the peripheral senses, internal somatic senses including autonomic nervous system responses, stimulus value (good or bad) signals from the amygdala, and motor response sensory and outcome feedback. It is not hard to see how either damage to the structure or its failure to develop adequately might impact behavioral development in the growing infant. Although it would seem to be a bad design of nature to concentrate cortisol receptors on such an important structure where they might be capable of doing such damage, in fact the cortisol receptors provide important signals of arousal to the hippocampus.

The well-known U-shaped curves describing the relationship between arousal and learning, and more recently corticosteroid levels and hippocampal function (Diamond, Bennett, et. al., 1992), are understandable at the common-sense, functional face-value level, which is to say they make sense from a behaviorally adaptive and evolutionary point of view. At very low levels of arousal, measured anecdotally or electrophysiologically, tasks, skills, or rote materials are less effectively learned and retained than at higher levels; at levels of arousal high enough to correspond to stress, there is a progressive breakdown in the establishment of long-term memory. At the neural level, this relationship is seen in the hippocampal responses which mediate long term memory storage, which are maximally enhanced at intermediate corticosteroid levels, and break down at either high or low extreme values. Since cortisol responses are determined in large part by the biological saliency of events, i.e., their reward value, either negative or positive, this relationship would serve to limit what is learned and remembered to those events most important to the organism. Events that do not cause an increase in arousal are not likely to be remembered. Likewise, failure to remember events that cause traumatic levels of arousal might be seen as having a protective value.

In any case, reduced hippocampal size is a known correlate of chronic high levels of stress and is seen in Post-traumatic Stress Disorder (PTSD), depression, and other pathologies (Teicher, 2002; Sapolsky, lots). Since it has been generally impractical or impossible to measure hippocampal size in individuals who have not yet developed psychopathologies, it has been suggested that anomalies in structure, in this case the hippocampus, are genetically determined and precede or enhance the risk for mental illness. Until very recently Sapolsky (2001), has maintained that there was no evidence for such an assertion.

Recently, however, points have been scored on the side of genetically-based susceptibility, when it was shown that reduction in hippocampal volume, long known as a correlate of pathological stress reactions, notably in Post Traumatic Stress Disorder (PTSD), could be observed in the non-traumatized identical twins of Vietnam veterans who were being treated for PTSD (Gilbertson, Shenton, Ciszewski, Kasai, et al ., 2002). Even Robert Sapolsky, whose work of over a decade has established him as a significant

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expert and major proponent of the contribution of stress to limbic system damage, especially in the hippocampus, responded to the article reporting this revelation with what seemed to be capitulation (Sapolsky, 2002).

But Robert Sapolsky is not a psychoanalyst; and so he does not immediately move to the argument that both the Vietnam vet and his twin must have had difficult childhoods, difficult in particularly similar ways because they are identical twins. Thus, the twin who served in Vietnam was predisposed to a pathological reaction to his experiences because he had a smaller hippocampus as a result of childhood adversity. As far as I know, there has not been any longitudinal research demonstrating that infants who start out with hippocampi of equal size will end up with variously sized organs depending on their experiences. Some evidence now argues against that position. Evidence that survivors of childhood abuse and neglect have smaller hippocampi in early adulthood proves to be equivocal (Teicher, Andersen, Polcari, et. al., 2002). The authors advance the argument that trauma-induced loss of hippocampal cells is masked by the rapid development of this organ during childhood and early adulthood. Stress also suppresses production of new granule cells, and early stress prevents the normal prepubertal overproduction of synapses in CA1 and CA3, but does not prevent pruning, which leads to an enduring deficit in synaptic numbers (Teicher, Andersen, Polcari, et. al., 2002).

In adults, hippocampal neuronal death as a consequence of major depressive disorder is well-established. Approximately half of all depressives have chronically elevated levels of cortisol, both resulting in and resulting from loss of hippocampal cells, with resulting loss of negative HPA feedback, and disturbances of memory, cognition, and attention.

In addition to its well understood contribution to motor coordination and balance, the cerebellum is now known to be involved in cognition and emotion. The cerebellar vermis provides modulation of the limbic system, particularly the amygdala, and is most likely involved in self-soothing behaviors such as rocking. The cerebellar vermis is known to be reduced in size in borderline personality disorder, ADHD, schizophrenia, and in survivors of childhood sexual and physical abuse and neglect. Limbic kindling, a precursor to seizure activity, may result from a combination of high chronic levels of emotional arousal and loss of vermal regulation. This phenomenon is correlated with dissociative symptoms, disturbances of body image, aberrant somatic experiences, experiences of déjà vu, synesthesia, and other significant behavioral disturbances including episodes of rage. Since the cerebellar vermis is well supplied with cortisol receptors, it is apparent how a destructive positive feedback circuit could be established between uncontrolled emotional arousal and continued vermal loss. Similarly, the hippocampus could be involved in such an auto-destructive circuit, since it supplies a down-regulating signal to the hypothalamus.

In the discussions below concerning therapeutic interventions and mechanisms of recovery, it will be seen that the very faculties needed for recovery, including those involved in meaning-making and affect control, are structurally impaired by psychopathological stress, which increases cortisol level and further damages hippocampus and other structures, including cerebellar vermis, which leads to limbic kindling, and prefrontal cortical

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monoamine overstimulation, with cognitive and attentional consequences. A vicious circle (Roozendaal, B., Phillips, R.G., Power, A.E., Brooke, S.M., Sapolsky, R.M., McGaugh, J.L. 2001) is thus defined:

In addition to the destructive effects of high negative arousal on self-regulation of the HPA circuit, maternal separation and inattentive nursing in rats impair the development of inhibitory benzodiazapine and GABA receptors in the amygdala, resulting in increased amygdala stimulation of hypothalamic CRF output, again raising corticosteroid levels. "In short, early stress programs and primes the mammalian brain to be more fearful, and to have an enhanced noradrenergic, corticosteroid and vasopressin response to stress." (Teicher, Andersen, Polcari, et. al., 2002, P. 6)

b. Neurodevelopmental Failure Resulting from Insufficient or Chaotic Neural Stimulation

Joseph (1999) discusses the "experience-expectant" property of developing neural structures. Teicher refers to the mammalian brain "designed to be sculpted into its final configuration by the effects of early experience" (Teicher, Andersen, Polcari, et. al., 2002, P. 2). Prior to birth, the developing brain contains two to three times the full adult complement of immature neurons, which migrate to their final positions and arborize in an attempt to establish appropriate connections . More than 50% of these neurons are eliminated prior to birth by apoptosis (programmed cell death). Fluctuations in corticosteroid levels play a critical role in the initiation and termination of this process.

Neurogenesis ceases in most brain regions at birth, although stem cells continue to generate neurons within the hippocampal dentate gyrus

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throughout life. From birth to 5 years of age, the brain triples in mass, lagely due to myelination of fiber tracts. Myelination markedly increases the speed and accuracy of information exchange. Myelination rate varies markedly between brain regions. Critical motor and primary sensory systems myelinate at an early age whereas the process is quite protracted in the prefrontal cortex, associational cortices, cerebellum, basal ganglia (motor skills), and hippocampus. Gender also effects myelination rate in some regions such as the corpus callosum and hippocampus. Neuronal activity is required for the initiation of myelination for the axon of any given neuron, since the process involves a signal from the neuron to the adjacent oligodendrocyte. (Kinney, Brody, et. al., 1988). It has also been suggested that developmental deficits in specific segments of the corpus callosum reflect developmental failures in the specific cortical structures for which they provide inter-hemispheric communication (De Bellis, et. al., 1999; Teicher, 2002).

The corpus callosum is strongly implicated in the etiology of trauma-induced psychopathology by its putative function in healthy integrative encoding of stressful experience in both hemispheres, and replicable observations of its grossly reduced size in most major psychopathologies (Teicher et. al., 2002; De Bellis et. al., 1999; Loewenton, 2002). The Corpus Callosum consists entirely of axons, and so any interference with normal myelination is likely to impair communication between the cerebral hemispheres. It will be seen [in the second edition] that hemispheric integration is an important construct in both theories and therapies of trauma and its therapy (Davidson, 2000).

During childhood there is a marked expansion of axonal and dendritic arborizations and a rapid increase in synaptic contacts. This process mirrors the earlier overproduction and elimination of neurons. There is a substantial overproduction of synapses, receptors, dendrites, and axons that are pruned back during the transition into adulthood without cell death. This has been observed in humans, primates, and rodents. Overproduction and elimination specifically affects excitatory synapses and the density of glutamate, dopamine, and neurotensin receptors. Dopamine receptors prune immediately after the onset of puberty in the nigrostriatal system of rats, prune in early adulthood in the prefrontal cortex, but do not prune in the limbic connections to the nucleus accumbens. Normal pruning may remove redundancy and unmask an earlier developmental defect leading to the emergence of symptoms in late adolescence or early adulthood (Teicher, 2002; De Bellis, 1999).

Teicher, Andersen, Polcari, et. al., (2002) suggest that overproduction of synapses is genetically programmed, and that the final configuration of the circuitry occurs by elimination of synapses based on cell interactions. The effect of these interactions is to reduce the degree of initial programmed redundancy, and to selectively promote the development of neuronal innervation patterns that can coexist because they are mutually compatible or interdependent. This process results in increased matching of the functions of the nervous system with the conditions of the outside world. In Teicher's view, the developing mammalian brain is a rich neural network whose primary task is to acquire new information and develop skills. This rich network performs slowly, at great metabolic expense, and requires long

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periods of deep sleep. At a certain stage of development, excess and redundant connections are sculpted to speed performance of acquired skills, reduce metabolic demands and sleep requirements while sacrificing a certain degree of plasticity. Because the brain is designed to develop in this fashion, it is intrinsically shaped by the effects of early experience, and the consequence of inadequate or deleterious experience may be enduring and irreversible.

According to Joseph (1999), synaptic and dendritic circuits that remain unstimulated are not only subject to pruning, but the neurons comprising them may be "rewired" or "taken over" by more heavily used, related functions. A notable recent discovery is the re-wiring of the primary cortical visual circuits to accept input from the primary somatosensory areas for the fingers in individuals who have lost their eyesight. Alternately, he suggests, circuits, especially limbic, exposed to chaotic, inadequate, or inconsistently contingent stimulation may become unstable or hyperactive, with consequences for attachment behavior and emotional responsiveness. Circuits (i.e., amygdala, hippocampus, cingulate cortex, orbitofrontal cortex) responsible for emotions and socialization, in a neglectful, inconsistent, or abusive environment, may fail to develop or develop inadequately. I suggest that, given the involvement of the cerebellum in proprioception, balance, and kinesthetic sense, an infant who is not rocked or handled may acquire an inadequately developed cerebellar vermis, and thus an impairment in the limbic regulation provided by that structure. Limbic kindling, or sub-seizure electrical recruitment in the temporal lobe, as seen in EEG measures, is a common feature of PTSD, ADHD, borderline personality Disorder, schizophrenia, and non-diagnosed (asymptomatic) early childhood abuse survivors (Teicher, 2002). Associated with episodes of limbic kindling or actual temporal lobe epilepsy are dissociative symptoms, alterations in body image, hallucinations, transient synesthetic experiences, among other things.

Maternal separation in rats, which could be considered both a negative contribution to pathology (failure or absence of stimulation) and a neurotoxic event has been shown to cause a permanent increase at the mRNA gene-expression level in the sensitivity of the HPA axis, and is seen to be causal in the well-known finding that maternal separation in infancy in rats and primates causes fearful or inhibitory behavioral temperament in these animals. This finding represents yet a third mode of environmental alteration of brain and behavioral response (Francis, et. al., 2002).

On the more phenomenological level of attachment development, aside from neural impairments, chaotic, inconsistent, aversive, or absent interactions with the primary caregiver would encode enduring maladaptive representations of interpersonal schemas (Stern, 2000). This would result in pathological "Internal Working Models" (Bowlby, 1988). Fonagy, et. al., suggest that this is less important than the development of a durable capacity for forming attachments, the "Interpersonal Interpretive Mechanism", the quality of which would seem more to correspond to a basic neurologic capacity dependent on experience-initiated and experience-molded neural development.

In summary, the foregoing two sections suggest a pathological synergy of stress and inadequate early experience, acting in critical or

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sensitive developmental periods, resulting in impaired cognitive, interpersonal, and affective capacity and control. The combination of these factors can result in autodestructive positive feedback loops, establishing lifelong vulnerability to stress-induced psychopathology.

Developmental Considerations: The role of Cerebral Laterality and neural maturation in Psychopathology

Prominent theorists, researchers, and therapists specializing in the investigation and treatment of the consequences of traumatic experiences and traumatic early-attachment histories have made much of the functional differences between the left and right cerebral hemispheres, and the role of the failure of integration of the hemispheres in the symptoms of Post Traumatic Stress Disorder (Schore, 2003; Shapiro, 2003; van der Kolk, 2003). A search through the literature of cerebral laterality would suggest a less extensive role for left-right differences. Chiron et. al. (1997) reports imaging studies showing slightly greater cerebral function in the right hemisphere from birth to about 2 1/2 years, primarily in the right posterior visual-spatial association areas. Starting at about 2 1/2 years and continuing through adulthood, resting cerebral blood flow is greater in the left hemisphere. This is interpreted to reflect the later development of language abilities in the left hemisphere.

There is some evidence that neural development is more rapid during the first year of life in the right hemisphere, corresponding to the establishment of basic autonomic regulatory functions, which are mediated exclusively by the right hemispheric limbic system (Spence, Shapiro, Zaidel, 1996), and some functions important to social interactions, for example, right hemisphere visual areas specializing in the recognition of faces, and perception of speech prosody (Schore, 2003; Trevarthen, 1996). In mature mammals, the left hippocampus mediates the encoding of verbal narratives, while the right hippocampus is involved in the creation of visuospatial maps.

Between the ages of four and 14, Paus et al. (1999) observed that cortico-spinal tracts mature symmetrically, but the greatest changes in cortico-cortical myelination occurred in the left hemisphere, presumably reflecting the development of language capabilities. Kinney et. al. (1988) found a wide range of values not only for onset and achievement of mature myelination, from the earliest weeks of life to adulthood, but also duration, from less than a year to over three years respectively. The authors defined a period of maximum vulnerability to interferences with myelination from the seventh month of gestation through the eighth month of life, by which time myelination has started at almost all parts of the brain. The period between initiation of myelination and maturation are regarded as the interval in which structures are most vulnerable to insult (e.g., stress), or possibly poverty or absence of environmental stimulation. During the first year, myelin maturation is achieved in parts of the visual and motor systems, central and posterior parts of the corpus callosum (again corresponding to motor and primary visual sensory areas). Critical periods extend from 7 to 15 months of life for parietal cortex, anterior corpus callosum, and some cerebellar and limbic sites. Window of vulnerability extends beyond the first two years in prefrontal cortex, subcortical association areas, basal ganglia, and limbic system. Although some hemispheric asymmetry is involved in the

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timing of maturation, the most important differences have to do with bilateral timing of maturation of brain systems, proceeding from structures mediating primary capabilities to those involved in more integrative processes.

Although the verbalized (spoken) aspects of expressive language are not significantly in evidence until the second year of life, Trevarthen (1996) shows evidence for left hemisphere dominance in expressive gestures with the right hand during what he calls "Proto-conversational play" with the mother in infants as young as four weeks. Interestingly, mild distress seemed to result in increased self-touching, in most infants predominantly with the left hand, as well as more symmetrical use of right and left hands in expression of distress. In mature mammals, the right amygdala, and not the left, mediate the retrieval of learned avoidance responses, while the left amygdala may be more important in signaling the positive reward value of stimuli. There is considerable evidence that right hemisphere structures mediate negative emotional states, while the left hemisphere structures are more involved in the processing of positive emotions (Davidson, 2000; Trevarthen, 1996). Interestingly, successful cognitive training that reduces negative affective response to emotional stimuli is accompanied by enhanced prefrontal cortical function in the left hemisphere (Davidson, 2000).

The right hemisphere is predominant in controlling autonomic nervous system (ANS) responses. Right-hemisphere damaged patients demonstrate hypoarousal in heart rate and skin conductance response; ADHD children show reduced or absent R>L differences in the size of cortex and basal ganglia, concomitant with reduced ANS and heart rate responses to performance demands (Loewenton, 2002-b). Subjects showed evoked potential response and ANS responses, including skin conductance and heart rate, predominantly in right hemisphere when exposed to emotionally negative stimuli. However, sensory recognition of the stimuli appeared to be mediated equally by both hemispheres (Spence, Shapiro, Zaidel, 1996).

Evolutionary Considerations and the Nature of Associative LearningIt has been proposed that the nature of the experiences required for

healthy early development of emotional regulatory and cognitive systems is to a great extent evolutionarily determined (Bowlby, 1988; Hesse et. al., 2003). Invocation of evolutionary concepts, specifically reproductive fitness, risks reification of hypothetical relationships because they have face value, and the circularity of the argument that something must be so because we can ascribe adaptive advantages to the observed results of organism-environment interactions. A good example is the suggestion by Teicher et. al. (2002) that individuals who have acquired a pathologically reactive limbic system as result of early traumatic or neglectful caregiving have been physiologically programmed by experience to cope with a hazardous enviroment, and that this outcome is evolutionarily determined. This is not very different from the invocation of "Creative Design" to explain the present characteristics of living organisms. Nonetheless, there appears to be a relationship between the availability of certain kinds of experience and healthy development, and it appears that other kinds of stimulation cannot be substituted. The task of Neuropsychoanalysis is at least to try to keep these explanations anchored to behavioral and biological observations.

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Infants develop attachments to a primary figure, or caregiver, usually the mother, beginning right at birth. The identity of this figure is determined not by feeding, but by quantity, regularity, and consistent predictability of physical contact and behavioral interaction. Behaviorally, a primary attachment figure (usually the mother) must be keenly sensitive and responsive to the infant's emotional state, and able to help the infant maintain states of emotional arousal within adaptive limits. Separation from the attachment figure results in high levels of arousal; prolonged separation may result in more or less permanent, pathological neurological changes. It is well established that certain lapses in maternal behavior cause pathological behavior in children that may persist in some form throughout life, and that may be associated with predictable vulnerabilities to stress through life. Episodes during which the caregiver loses her exclusive characteristic as a locus of safety, however briefly and subtly, if frequent, result in dissociative-like infant responses (Hesse, 1999; Hesse, Main, et. al., 2003; Beebe & Lachmann, 1988).

Although the relationship between high levels of fear and anger and unresponsive caregivers or frequent uncontrollable pain from physical abuse has obvious face value, it is less clear how more subtle aspects of the interaction between child and caregiver could give rise to high chronic levels of emotional arousal, with consequent neural damage as proposed above. This relationship is discussed in detail by Loewenton (2002), with particular reference to Bowlby's (1988) security-exploration equilibrium. In short, it requires the evocation of the notion of evolutionarily determined, biological drive; the frustration of such a drive leads to fear or anger (Bowlby, 1988). Persistent severe frustration of such a drive may thus induce neurotoxic levels of adrenaline, noradrenaline, and glucocorticoids. I have suggested (Loewenton, 2002) that the paramount drive of Homo Sapiens is the need to make sense of experience.

In their discussion of etiology of psychopathology, Hesse et. al.(2003) discussed the empirically well-demonstrated link between frightening, non-physically abusive behavior by the parent and disorganized attachment status of the infant. The mother, evolutionarily determined as that which the infant must approach in states of fearful arousal also becomes an object of avoidance, eliciting a conflictual, approach-avoidance situation, resulting in behavioral disorganization and dissociation. According to the authors of this chapter, their central argument is that "lapses in the monitoring of reasoning or discourse during discussions of loss or trauma may be subtle indicators of sporadic representational/mental disturbances, which mediate proportionally subtle and anomalous parental behaviors, that can in turn have adverse effects upon the offspring, even in the presence of otherwise sensitive parenting." (P. 59). "Our central position is that, as long as the infant is not directly frightened by the parent, insensitive parenting in itself will not lead to disorganization, but rather to the formation of `organized' (avoidant or resistant/ambivalent) insecure attachments. Fear of the parent, in contrast, is anticipated to lead to disorganized attachment." (P. 66). Although other theories of early development would suggest that frightening parental behaviors are likely to have negative results in the offspring, it is specifically attachment theory that posits that the biological function of the child's tie to its primary caregiver is protection, and that among the ground-

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living primates, the attachment figure is the infant’s primary solution to situations of fear. In this framework, parental behavior which frightens the infant will not only drive the infant away from but also toward the parent. This unsolvable experience may lead to disorganization and disorientation for the infant. In turn, acording to the authors, this may cause a dysregulation of attention and emotion, and restrict or alter the child's capacity for normal conscious processing.

As noted above, precisely that paradigm may result in dopaminergic dysfunction, and the appearance of emotionally dissociative or helpless behavior. [See Appendix A for details of my drive concept.] Thus, a repertoire of situations involving child-caregiver interaction would be capable of eliciting high chronic arousal states which might be neurotoxic.

Although there is good evidence for the foregoing arguments, I find them inadequate. In reading the literature, one must get the sense that beyond the established causal relationships discussed, certain forms of stimulation have persistent neurological and behavioral outcomes that do not have face value, but seemed to be prewired, and depend on the purely biological identity of the mother, based on recognition of voice and odor which appears to be established at birth. An example (cited above) is the alteration to the stress response at the DNA level in neonatal rats subject to maternal separation. It has also been found that handling of rat pups by humans during brief separations enhances adult rats' stress tolerance. It turns out that it is not the handling, but the resultant increase in maternal licking on reunion, that produces the effect (Levine & Mody, 2003). Thus, a biologically determined source of the stimulation is required.

But attachment figures are not selected only for their properties as sources of physical safety. The nature of playful mother-infant communication is also a factor, as well as the mother's ability to express emotional empathy and to communicate her understanding of the infant's mental state; the infant has the sensation of "existing in the heart and mind of the other" (Fosha, 2003, p. 228). An objective characterization of this process is more difficult. I suggest that such interactions also satisfy biological drives that are subsets of the security-exploration equilibrium. A sensitively attuned mother is able to provide just the right amount of novelty in play, satisfying exploratory drives (Beebe and Lachman, 1988); and her ability to vary her behavior with the arousal states of the infant and to respond sensitively to his changing emotions ratifies both his sense of continuity as a self and his sense of the continuity and lawfulness of his environment, particularly his social environment, satisfying security needs. Something about such an interchange clearly reduces arousal level. I suggest that the same process is involved after acquisition of spoken language, when being listened to without judgement is reliably seen to reduce negative affect and arousal, as is the opportunity to associate with others who share a perspective, with whom one has something in common. I have experienced this both personally (on both sides of the interchange) and as a therapist. There is no face-value phenomenological explanation for this that I can think of, although, in the reductionist spirit of this paper, I could propose a neural mechanism. Briefly, these interactions provide ratification of a a belief and confirmation of an expectation, that is, an associative

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mental map. Sometimes this belief may simply be "I exist". This process of confirmation is inherently rewarding, resulting in an increase in dopaminergic function in the Nucleus Accumbens and a reduction in physiological arousal, in just the way winning a bet or finding a peanut under a cup based on a stored mental map is rewarding. Speculatively, the process of matching mental state with environmental confirmation results in hippocampal activity which reduces HPA arousal through projections to the hypothalamus. In any case, this concept unfortunately requires an ad hoc proposition: Empathetic social interaction reduces negative arousal because it signals that the individual is part of a group (or dyad) that will offer support and protection, thus enhancing reproductive fitness. That this is seldom experienced as a conscious thought during the mundane experience of social interaction is beside the point; it is part of our evolutionary, biological inheritance.

Even more problematic is the notion of exploration - subsuming mastery, self-direction and play - as an evolutionarily determined, biological drive, which also includes constructs such as ideal arousal level and preferred balance of novelty and predictability. That the need for play and novel experience exists is unarguable. Why its satisfaction is so rewarding, in fact, required for proper development and part of the determination of attachment choices, is not at all clear. An even stronger motive appears to be the need for perceptions that reflect a consistent environment that changes predictably with the organism's responses. The general consensus has been that there is an obvious adaptive value to a motive that causes the organism to learn about its environment and to be able to maintain a predictively accurate mapping of it and succesfully interact with it. Even more mystically, Piaget suggested* that the ability carries with it its own motivation. How such a mechanism might operate is not obvious.

And yet, frustrations of any of these needs - secure social proximity, validation/confirmation/empathic reflection, exploration, mastery - have been seen to result in negative arousal states, disturbances of behavior, and if severe and persistent, to alter brain systems in such a way as to render the individual pathologically vulnerable to stressful events.

In summary, three conclusions may be drawn from the foregoing material. First, a coincidence of timing of environmental insult and the sequence and peak activity of the development and maturation (i.e., peak vulnerability) of various brain structures must influence the nature of the observed pathological symptoms. Second, appropriate early experiences are required for the robust development of the various brain structures. These experiences must provide the sort of stimulation encoded and demand the sort of response mediated by the structures that are in peak periods of myelination and development of dendrites and synapses. Third, the timing and topology of experiences required by the brain in its earliest months are to some extent evolutionarily determined by needs for security, exploration, and a consistent, lawful environment. Failure of the environment to provide plentiful, consistent, lawfully contiguous stimuli impairs the developing * No, I don’t know the reference! But I know this was discussed in some class or other at Penn 30+ years ago. I didn’t dream it. At least, I don’t think so. I am not going to read Piaget’s dense verbiage just to find it!

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neural structures mechanically, functionally, and in the earliest months, often indelibly. Injury to these structures impairs the perception and encoding of these necessary stimuli, as well as the ability of the infant to respond in an orderly way to them, reducing, nullifying, or rendering destructive their developmental value.

The phenomonological aspects of this relationship are especially well formulated by Daniel Stern (2000), in suggesting how a concept of self in newborns emerges from the constant and predictable association of basic perceptions: simple visual, autonomic, somatic, tactile, and auditory sensations, just those that would be mediated by the earliest-maturing structures. The healthy development of these early self-structures and their associated brain mechanisms involve a circular interpendence of both. As social and emotional responses emerge from the early development of relevant neural structures and their interaction with the primary caregiver, a concept of self-with-other is built around the core of primary self. This layered construction of the self progresses through the maturation of language-supporting structures and the development of spoken language skills, which requires intensive and orderly interaction with caregivers. Stern's concept of Representations of Interactions which are Generalized - RIG's - is more or less equivalent to Bowlby's (1988) concept of the Internal Working Model (IWM), in which representations of social interactions are central to personality formation and the lifelong interpersonal response tendencies. Fonagy et. al. (2002) propose an alternative mechanism, the Interpersonal Interpretative Mechanism, which they suggest operates independently of the content of specific interpersonal experiences, and is more a structural-functional attribute of the individual acquired in childhood. This notion would be more compatible, I think, with the sort of blended, interdependent psychodynamic-neurological model advanced in this paper.

One of the most difficult things to grasp about Stern's model is the absence of a homuncular center. He is really proposing that a set of associations are simultaneously active, in the Hebbian sense, so that the the experience of conscious self in interaction with the environment reliably includes a reasonably constant set of current and stored sensations, perceptions, events, spatial maps, sequential narratives, and so on. In a healthy individual, there is substantial continuity to the overall image which comprises these elements, and thus a continuity of the self-representation. It is not hard to see how this image develops through alert waking awareness of the flow of one's own sensations and consistent social interactions. It is also not hard to see how this image might be degraded through episodes of arousal, physiologically intense enough to interrupt hippocampally mediated narrative assembly of sensations which are thus individually encoded as fragments: sensory (both external and internal, somatic and ANS), affective (amygdala-signaled, positive/negative), and motor-habit.

It is known that although the hippocampus mediates not only the storage of visuo-spatial maps and sequential event episodes or narratives, but also traces as simple as clasically conditioned avoidance learning, memories are generally stored in the relevant cortical association areas, and can also be stored without hippocampal involvement. So there is some

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evidence for the assertion (van der Kolk, 2003; Van Der Kolk, Burbridge, Suzuki, 1997) that they can be stored as dissociated fragments. A variety of structures, including the amygdala and the sensory association areas, are capable of storing experiences without the mediation of the hippocampus (although recent evidence casts some doubt on the amygdala as a locus of long-term storage). Although the hippocampus can be involved in simple aversive or avoidance conditioning, under conditions of higher arousal, as during a traumatic episode, it has been shown that hippocampal function can be substantially impaired. Carlson (2001) suggests that the primary function of the hippocampus is to create declarative or episodic maps combining stored information from distributed systems encoding basic auditory, visual, affective, and response information. Since similar biochemical pathways appear to be operating in the creation of a long-term memory in these components systems, it is not clear that there is some sort of memory that is particularly resistant to extinction. However, the fundamental concept in trauma therapy of fragmented memories that are stored in the absence of the usual biographical narrative would seem to have a well-supported neurological referent.

There is also evidence that psychological stress can impair both working memory and long-term encoding of associative memory that is mediated in the hippocampus (Arnsten, Goldman-Rakic, 1998; Diamond, Fleshner, Ingersoll, Rose, 1996; Mesches, Fleshner, et.al., 1999). However, high acute stress hormone level can cause retrieval of a shock avoidance response that had apparently long since been extinquished (Izquierdo, Barros, Medina, Izquierdo, 2000). Administration of yohimbe (increased adrenaline-ANS arousal) elicited traumatic flashbacks in combat veterans with PTSD.

I have found no evidence, on the other hand, to support van der Kolk's suggestion that there is a class of memory uniquely resistant to extinction. Vianna, Izquierdo, et. al., (2000) suggest that there is no grounds for dividing either long-term or short-term memory into sub-classes based on neural mechanisms of storage or retrieval. Nonetheless, alternative or non-associative models of fear learning that may be resistant to unlearning have been suggested. Ohman and Mineka (2001) suggest that there may be a specially evolved kind of fear response and encoding, which (a) is preferentially activated in aversive contexts by stimuli that are fear relevant in an evolutionary perspective; (b) is automatically activated by such stimuli; (c) is relatively refractory to cognitive control. (d) originates in a dedicated neural circuitry, centered on the amygdala.

Recent findings have shed some light on the properties of memory storage and retrieval that may have relevance to a discussion of traumatic memory and psychopathology and its treatment. It appears that memories are not extinguished, but rather are replaced or altered with a conflicting trace, by the same process that encoded the original fear memory. The process of deconditioning of aversive learning, for example, actually involves learning that the conditioned stimulus no longer is associated with the aversive or fear-producing stimulus.

Also, retrieval (by exposure to a fear- or avoidance-eliciting stimulus, or by exercise of a learned complex motor habit, for example) of a memory trace renders that trace labile and subject to alteration or replacement. In

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the case of conflicting learned responses, it is the current dominant trace (the one governing behavior) that is most vulnerable to change or extinction unless it is further reinforced, i.e., retrained (Walker, Brakefield, et. al., 2003; Eisenberg, Kobilo, et. al., 2003).

The foregoing material presents, in total, a rather gloomy picture. Adverse events in childhood, from before birth through puberty, can shape the brain in such a way as to render the individual pathologically vulnerable to stress throughout the lifespan. These events can be persistent, subtle failures in mother-infant relationship; prenatal environment; discrete episodes of trauma, in the usual sense, e. g., physical or sexual abuse, injury, or exposure to violence; neglect, that is, absence of stimulation. These brain alterations may involve structural deficits that are unlikely to be reversed, or significant alterations in function that may likewise be permanent. It cannot be presumed that all biological systems in a healthy mammal are "properly designed", or self healing, requiring only re-exposure to benign and accomodative environment (the essential Rogerian notion). The accumulating evidence is that in pathological states, along with alterations and disturbances of other systems, the HPA system is thrown out of adjustment at the high end of its response range, and thereafter behaves in an autodestructive manner, apparently losing the ability to self-regulate. A similar phenomenon occurs in cartilage, which, when damaged, secretes an inflammatory substance that results in further cartilage deterioration. The development of psychopathology appears to involve the disturbance of stress-control systems outside of their normal range of homeostasis, in which a pathological positive feedback mechanism is established that may, through damage to neural structures, become persistent or permanent.

So what can be done? What does effective psychotherapy comprise? When it works, what is going on? Can we suggest anything that might be happening at the neural level that helps to explain successful psychotherapy; and what is the evidence for such curative processes? I will review the current approaches to the treatment of PTSD, look for the common elements in psychodynamic psychotherapy, and suggest what I think is happens when things get better, and a few speculative notions as to how further improvements might be made.

Begging the reader's indulgence, I would first like to add a little more to the foundation of my arguments by reporting a few more recent results from the work of neuroscientists. 1. In a study by Francis et. al. (2002), neonatal rats subjected to daily prolonged maternal separation demonstrated significant HPA hyperreactivity, behavioral inhibition and fearfulness, with corresponding structural changes at the molecular level. After weaning, these rats were housed in cognitively and socially enhanced environments. Behavioral and HPA functional changes were robustly reversed, but these changes were not seen at the molecular level of DNA expression. Interestingly, rats subjected to handling but not maternal separation showed no changes when exposed to enriched environment. Authors cite studies demonstrating that postnatal handling reverses the effects of prenatal stress on the development of the HPA axis as well as on behavioral reactivity to stress; and post-weaning housing conditions can reverse the effects of stressful treatment imposed

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during the first week of life. The two manipulations employed in this study are probably too far separated in time to be considered any sort of analog of misattunement and repair; more important, the dysregulation induced by the first manipulation and corrected by the second appears to be dependent on a sensitive or critical developmental period.

What is it that changes in the brain as a result of the "therapeutic" enriched environment described in this study? The authors propose that enriched environment permitted development of some compensatory mechanism, since they saw no evidence of structural changes; although they speculate that under other circumstances structural reversal of adverse consequences at the cellular level might also occur. Alterations in gene expression associated with maternal separation are thus rather resistant to subsequent environmental influences. The authors suggest the hippocampus and prefrontal cortex as potential sites for the sort of compensatory effect seen in their study. Environmental enrichment alters frontal cortical function, and medial prefrontal cortex provides inhibitory regulation over HPA responses to stress. Environmental enrichment also increases serotonin production and receptor binding in the hippocampus, in a manner similar to that provided by antidepressant medications. The authors had previously found that "...neither postnatal handling or maternal separation had any effect on serotenergic function, suggesting that plasticity within this system may emerge at a later date and thus served as a substrate for the effects of [beneficial] post-weaning environments." (p.7843). The authors suggest that individual differences in responses to environmental inputs can be influenced by events occurring at multiple stages in development. Effects of environmental inputs at a later stage of development appear to depend on previous experience.

2. Several studies (Davidson, 2000; others) have shown that cognitive stress training enhances left PFC function. Positive affect seems to be mediated by the left hemisphere, negative by the right. Enhanced control of negative emotion, increased activity in left prefrontal cortical regions and reduced activity in the amygdala are seen in neuroimaging studies.2-a. Patients successfully treated with EMDR demonstrated increased activity in the anterior cingulate gyrus and left frontal lobe, although did not show a reduction in limbic activity (Levin, Lazrove, van der Kolk, 1999). 3. Intermittent separation during infancy followed by reunion with the mother were shown to lead to a significant reduction in both the cortisol response and the response of the noradrenergic system following social isolation in juvenile squirrel monkeys at 2 and 3 years of age (Levine and Mody, 2003). 4. Increased shock avoidance or escape training may reduce the involvement of the amygdala in memory retrieval (cited in Coleman-Mesches and McGaugh,1995). 5. As noted above, extinction of a memory trace requires new learning of a competing response. When a memory is retrieved, it must be reconsolidated and re-encoded, or will more easily be replaced by a competing (extinction) response. During extinction, the dominant trace (of the two competing traces) is most labile and subject to disruption.

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6. A new learned habit (memory) may be strengthened by a night's sleep. If a second new habit is learned immediately after the first, the second memory will be the one strengthened by a night's sleep, and will replace the first one, even though it does not interfere with the first habit at the time of initial training. If a second habit is learned six hours later, it does not replace the first new habit. If the first habit is learned without interference, it will continue to strengthen over several days. If the first habit is practiced on the second day, it will show enhancement as a result of the night's sleep. If a second habit is learned immediately after the first habit is rehearsed, the first habit will show considerable degradation on the third day, while the second habit will demonstrate sleep-related strengthening.7. Fear memories may be particularly durable, and reappear after apparent extinction. Acquisition of fear memory and its extinction appear to be mediated by two separate systems. Extinction of fear appears actually to be the overlay of new learning that the formerly fear-eliciting stimulus is no longer dangerous (Quirk, 2002). This new learning appears to involve increased cortical inhibition of activity in the amygdala (Davidson, 2000).8. Hippocampal activity may encode information about the context of a fear-producing contingency, rather than the stimulus-response contingency itself. Hippocampal impairment, as in states of high arousal, would allow encoding of fear responses without accompanying adaptive contextual memory.9. Hippocampal neurogenesis is enhanced by novelty, environmental enrichment, and exercise, with potential consequences for improved contextual and narrative encoding and new learning (Rhodes, van Praag, et. al., 2003; Lu, Bao, Chen, Xia, et. al., 2003; Cotman CW, Berchtold, 2002).10. Antidepressants such as Prozac produce therapeutic effect by increasing hippocampal neurogenesis, which is why, although they reach therapeutic concentrations in the brain within a few hours, treatment effects are not seen for two or three weeks (Sapolsky, others).

THERAPYThere are some general principles that appear universal to

psychodynamic treatments. They are implemented in a variety of ways, varying in their degrees of directiveness or willingness of the therapist to actively intervene in the process, and in the emphasis on present behavior or past conflict, among other variables.

All psychodynamic therapies provide an environment of rapport and empathy. This satisfies the biological need of the patient to be recognized and understood. To be understood may also satisfy the drive to have perception of reality confirmed, or to be acknowledged as existing. This sort of relationship with a therapist may begin the process of restructuring the patient's Internal Working Model, or generalized representation, of interpersonal experiences. One of the most important effects of this process is the reduction of traumatic levels of arousal, allowing more relevant emotions and narratives to be retrieved, recognized, and verbalized.

All psychodynamic therapies offer a safe environment for retrieval and expression of strongly negative emotions and cognitions. If the retrieval of a

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highly aversive representation - associate of a network of perceptions, cognitions, and somatically-felt affect - occurs in a safe and non-aversive setting, it may be re-encoded with less of the negative affect. In other words, strongly aversive responses to an event, recent or in the past, may be extinguished. This process has been referred to as deconditioning or desensitization.

Many therapies are structured to enhance the retrieval of older memories, which are assumed to be traumatic and to be causal in the patient's current complaint or symptoms. Retrieval in the safe setting may reduce associated affect, as in the previous paragraph. Retrieval of memories may also be aversive; I suggest that avoidance of retrieval of traumatic memories (“repression”?) may be essentially similar to any other aversive avoidance habit, and may thus be similarly extinguished by the new learned response of retrieval and verbal report, that occurs without negative consequence.

The ultimate goal of most psychodynamic therapies is to interpret, reinterpret, or help the patient construct the meaning of the retrieved negative representations -episodic, somatic, affective, or sensory - of the presumed original traumatic experiences. These representations are thus incorporated into a larger context. If this is successful, the extreme limbic response to the associative network or any of its fragments is substantially reduced, as these elements become part of a coherent context. Current difficulties are shown to be related to events of the past, memories of which the patient may not have had complete current access to. Expression of affect in regard to recent symptomatic episodes may, by their common inclusion in older memories of conflict, enhance retrieval of these original traumatic experiences. Non-directive psychodynamic therapies generally allow representations and narratives to emerge spontaneously.

In the treatment of disorders of chronic arousal, such as PTSD, more directive or interventionist protocols have been formulated that seemed to be able to accelerate this process with some patients. Fosha (2003), in the process of what she calls Accelerated Experiential-Dynamic Psychotherapy (AEDP), uses her own emotional responses and the related prosody and body language to accelerate and amplify the patient's expression of the genuine emotion that is associated with her current difficulties. This mirroring and amplification of the patient's emotional energy is analogous to attunement of the mother with infant, in which mother can influence the infant's arousal level. The use of mirroring also enhances the patient's sense of being understood, and may accelerate the formation of a deep therapeutic alliance. In circumstances where the patient avoids (represses) the affect associated with reported cognition, the therapist's emotion may serve as a model. This role of therapist as emotional surrogate is acknowledged by the patient in Fosha's case study (2003). In fact, jump-starting the patient's emotional response may not always be so easy. In this case report, it is clear that the patient was subjected as a child to unavoidable and uncontrollable traumatic stress caused by her mother's rage episodes, presumably over a long period of time. This is known to cause an apparent dissociation of affect from experience, and a persistent and refractory blunting of arousal, along with a syndrome of conditioned helplessness and withdrawal from effort.

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In Fosha's (2003) report of quickly successful, two-session (?) therapy, I suggest the following processes are operative.1. Rapid establishment of rapport through the emotional expression of the therapist and the use of non-verbal cues. This reduces arousal and enables verbal report. 2. Expression of emotion related to current conflict is accelerated and enhanced by therapist’s calculated attunement to and modification of dyadic vitality affects.3. The retrieval of the original traumatic memory about the mother is accelerated and enhanced by the full experience of the associated fear and sadness. If this felt emotion of traumatic fear, the incidence of which is initially attributed to the interactions with the husband, involves a high enough arousal level, it is presumed, based on the foregoing biological findings and theoretical considerations in this paper, that retrieval of the original traumatic memory would be impaired. Thus it is commonly expected that such memories are not accessed until there has been some stabilization of affect.4. The patient engages in a spontaneous cognitive reframing between sessions. Experience with husband is brought into a larger context, in which he is no longer experienced as terrifying as the mother was to the child. An examination of outcomes reduces the perceived risk, and patient assumes some responsibility for her feelings and actions. Locus of control moves toward the patient. This satisfies the competence drive, and is associated with the re-energizing the dopaminergic nucleus accumbens function, which is experienced as rewarding, and reverses the patient's dissociation of affect and arousal from event representation. She is now able to feel appropriately and may be able to act adaptively on these feelings. Fortunately, her initial use of this recovered faculty is rewarded and thus strengthened. 5. Adaptive action tendencies - the appropriate use of emotion as signal and motive - enables more adaptive function in patient's environment. The meaning of emotional signals is re-learned in this new context. Exercise of this new ability is rewarded, consolidating new learning. 6. What has not occurred in this brief report is what is assumed to be the ultimate goal: the thorough retrieval of the traumatic-fear-inducing events in childhood, and the creation of a meaning of these events within the patient's adult context.

In any case, lower brain structure control of response to current conflict (amygdala, autonomic nervous system, etc.) may be assumed to have been transferred to cortical structures, and motivational-emotional processes made more nearly normal.

Fosha's (2003) AEDP uses techniques from the general attachment literature, but is not really an attachment based therapy, not focusing on issues of security. It does acknowledge the importance of what I regard as a related drive concepts, that of the need to be recognized and understood, which is a subset of the security constellation.

Neborsky's model of treatment of trauma actively elicits the expression of affect, directly encourages the narrative with which it is associated, and, more directly than most therapies, re-interprets and re-constructs that narrative, in the process allowing the emotion to be

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expressed adaptively. The protocol is not much different from Fosha's, except that Neborsky does not participate emotionally, and is much more cognitively directive. The question arises: How much of this patient's cognitive reframing is compliance, especially in this case of a dependent and over-controlled, intraputative patient? And then - does it matter, if the goal is to place affect and traumatic memory into an adaptively useful narrative, to allow higher-structure control of limbic processes (in my system - and Davidson's - the real goal)? Any therapeutic belief that is not subject to experiential refutation and undoing, and that will motivate adaptive, mature behaviors subsequently, will do. Stern (2000) discusses this possibility as undesirable. However, if the therapist guides the narrative construction and cognitive reframing based on the available empirical data that has reliably evolved from developmental and attachment research, the validity of such a strategy is apparent.

Neborsky's model is that of the classical psychoanalytic triangle of conflict - the relationship of symptoms, current conflict and origin in past trauma. He works with these elements in whatever order they come up, in contrast to most psychoanalytic technique (Malan, 2001). His brief treatment does not allow much time for development of therapeutic relationship. If the patient were more heavily defended, if the traumatic memories were more thoroughly fragmented, if current arousal responses were more pathologically intense, such quick results would not be possible. One assumes the patient's regular therapist has already done most of this groundwork.

Neborsky accelerates the process by specifically (explicitly) teaching the patient to recognize emerging affect, and to observe in real-time her defenses against it. In this process, he leads the patient into full experience of emotion. He replaces Fosha's emotional contribution with psychoeducation, which he lists as one of his key techniques. Eliciting full emotions in this cognitive-oriented framework has the effect of allowing the patient to experience it more reflectively, i.e., to put the emotion itself into a meaningful context, without the necessity of first having to retrieve and then reframe the representations of the traumatic events from which it originated. This detoxifies the emotion sufficiently to allow the associated memories to be retrieved, a process which probably requires that there be less than traumatic levels of arousal. Finally, the cognitive elements of the patient's emotionally abusive (invalidating) intergenerational history are arranged into a coherent context. The therapist succeeded in such activist intervention because he knew, based on attachment theory, where he was going. Neborsky suggests a positive outcome in general terms, but I must say, in this case, where refractory obesity is the presenting complaint, I would like to see behavioral measures of weight loss and the claimed improvements in mood and marital relationship.

Neborsky's claimed that the emotional expression is the cure, and is more important than interpretation, is refuted by Yalom’s very large survey of group therapy patients, and by Neborsky's own recount of his therapy, which is largely composed of cognitive reframing techniques, and fairly aggressive ones, at that.

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These models of therapy, in fact, the models exemplified by any case-report I've read so far, comprise one or more of the following elements.

The development of a therapeutic alliance - "holding environment" - provides for the safe expression and modulation of affect when it is elicited. It also allows the building of a more adaptive Internal Working Model (Bowlby, 1988; Stern, 2000) of interpersonal relationship, by means of, among other factors, dyadic disruption and repair. (It has occurred to me that the innoculative effect of brief maternal separation against later isolation stress in the infant monkey may be due in part to the development of a primate version of an internal working model, that includes a representation of separation and reunion, not unlike the establishment of a durable representation of interpersonal conflict as an opportunity for understanding and the strengthening of relationship, rather than an aversive end in itself.) The initial development of rapport may also reduces dysfunctional levels of presenting anxiety by satisfying the patient's frustrated security-cluster drive to be acknowledged and understood. (A client of mine, expressing genuine emotion for the first time, explained his tears of relief: "Someone is listening to me".)

Reframing of the emotional response guides the patient to the proper identification and accurate experience of affect. Defensive current emotions may be more accurately identified, which offers the possibility of restoration of their proper, adaptive function. Identification and contextualization of the underlying traumatic affect is likely to await the retrieval of the associated memories. Ideally, this experience of genuine or "core affect" (Fosha, 2003) elicits the original memories with which it is associated. Initially, or perhaps exclusively, these may be fragmentary, depending on the arousal level (and thus hippocampal function) at the time of the traumatic events. I would suggest that the science and art of the psychotherapist is most challenged at this juncture.

The reframing or re-interpretation of the meaning of the events, sensations, and emotions constituting the traumatic events is perhaps the most nearly universal element in psychodynamic therapy. In some cases, a context, a narrative, a meaning must be constructed de novo. Infrahuman evidence (cited above) suggests that the underlying mechanism is the greater participation by frontal cortical structures in a complete narrative associative context, and reduced participation by subcortical structures that provide an aversive signal to the experience of the memories in the here and now. Typically, a part of the new context or narrative includes an understanding of the appropriate and adaptive nature of the original traumatic emotions at the time of trauma, and the understanding that they are not appropriate or relevant to the patient's current life. Learning that these emotions are normal, and may be used adaptively and appropriately in present and future interpersonal relations, is generally also a part of this reconstruction. Interestingly, Davidson (2000) reviews considerable evidence that this sort of therapeutic intervention may lead to a reduction in right hemispheric activity, generally associated with the experience of negative affect, and an increase in left hemisphere activity, associated with greater narrative competence and the experience of positive affect.

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Encouraging new behaviors on the basis of this new understanding begins the establishment of new associative structures that may bring about enduring changes in personality. Stern's (2000) model of personality as the accumulation of representations of self and self-with-other, and the evidence for replacement of learned habit rather than its extinction, suggests to us that the active learning and rehearsal of new behaviors is necessary for the personality changes hoped for in cases of severely dysfunctional patients. It appears that a key element in this process may be movement of the locus of control from outside the patient to within the patient (exploratory and mastery drives). Henry (1997) than an important corollary of this process that is also therapeutically important is that the patient achieve an understanding of the practical extent of the domain of his responsibility. The homily (reference?) comes to mind: "grant me the equanimity to let go of what I cannot control, the strength to act on what I can control, and wisdom to know the difference" (or something to that effect).

I suggest that a relatively activist therapeutic strategy is indicated, addressing all aspects of this dysregulation, including provision of new learning that will allow stress-response systems to return to and be kept within an adaptive, self-regulating homeostatic range. If strongly learned fear habits are not subject to extinction, but are overlaid by newly learned cortical inhibitory control, which is dominant-trace labile, than that would suggest that the therapist ought either to continue maintenance therapy at some reduced schedule along with a behavioral follow-up, or help the patient to establish self-reinforcing behavioral protocols along with environmental changes to assure maintenance of gains.

Differences in the amygdalar involvement and durability of extinction in condition shock avoidance in rats seem to be dependent on whether or not the training involved active escape learning. This suggests that locus of control may be a critical element in successful therapy of trauma. Fosha's term "adaptive action tendency" (2003, p. 239) refers to the reconnection of pathologically intense affect to the circumstances in which such affect would be adaptive and appropriate. Emotion is both a signal of the value of an event and a stimulus to action to cope with that event. According to Davidson (2000), "what may be particularly abnormal in disorders such as PTSD and depression is not the display of abnormal emotion, but rather the display of perfectly normal emotion in inappropriate contexts. For example, in the case of PTSD, the extreme fear and anxiety were most likely very adaptive in the original traumatic context."

An understanding of the biological aspects of psychopathology suggests, perhaps somewhat speculatively, some additional techniques. In fact, some of them may be recognizable as alternative interventions already in use.

Severe chronic arousal present during the session may impair retrieval or new learning of narrative or context structure. Techniques to reduce arousal during the session are also available to the patient out of session, especially if there is a danger of suicide. Such techniques may include progressive muscle relaxation, and breathing or other meditative techniques. Strenuous physical exercise may also serve this purpose (personal observation).

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Effort should be made to restore the HPA-axis function to a homeostatic range, and so that self-regulation may be restored. If this cannot be done, than the newly learned narrative patch, the work around, reducing amygdalar involvement in reactivation of condition traces, will be the sole leg on which the therapy stands. I propose the use of those manipulations known to enhance hippocampal neurogenesis and dopaminergic-meso-accumbens function: exercise, novelty and enriched environment, assignment of simple tasks of mastery out of session (especially but not necessarily interpersonal). With enhance hippocampal function comes restoration of the hippocampal role in the regulatory feedback arousal, as well as enhanced inability to in code the new narrative that will form the core of the therapy. And yes, I would prescribe Prozac or a functional equivalent to assist in this if regular strenuous exercise were impractical, or the patient not compliant.

Severe chronic dysregulation of arousal, although psychogenic in origin, may profitably be viewed as a structural, physical illness. Its treatment exclusively by psychodynamic means is bound to be slow and uncertain. Such dysregulation occurs entirely outside the control of frontal cognitive mechanisms; in fact, the frontal cortex is impaired or even "shut down" (Arnsten AF, Goldman-Rakic PS., 1998) during episodes of pathological arousal.

Additional behavioral or somatic techniques are suggested by an understanding of biological processes. The valence of traumatic terror is a function of the involvement of the amygdala in a resonant arousal circuit. Speculatively, rhythmic body techniques, providing gross kinesthetic input, may stimulate the cerebellar vermis, which, although traumatically impaired, may assist in reduction of limbic kindling. Teicher (2002) has suggested that this may be the contribution of rocking to the healthy development of the infant brain; that is, it helps to develop circuits useful for self-soothing throughout life. In experiments with isolated infant monkeys and cloth mothers, research following that of Harlow reported that infant monkeys raised with swinging cloth mothers were less violent, self abusive, and socially impaired. Reduction of amygdalar involvement in arousal may reduce negative association to inappropriate contemporaneous events and objects.

Keeping formal score of the therapeutic process encourages perseverance and builds confidence. Shapiro (2003), in discussing EMDR, suggests regular periodic measure of affect to trace progress. A client who engages in journaling also assumes considerable control of his own healing process, adding to a sense of mastery and competence.

If strongly learned fear habits are not subject to extinction, but are overlaid by newly learned cortical inhibitory control, which is dominant-trace labile, than that would suggest that the therapist ought either to continue maintenance therapy at some reduced schedule along with a behavioral follow-up, or help the patient to establish self-reinforcing behavioral protocols along with environmental changes to assure maintenance of gains.

Summary

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An understanding of the biological correlates of severe psychopathology, along with a new understanding of memory processes and biologically and evolutionarily determined drives, suggests the value of a pragmatic, eclectic model of therapy. Results from the investigation of learning and memory, both older and more recent, along with the developing and recently much more coherent clinical neuroscience, helps to explain and ratify the value of a wide variety of techniques, some of which have been in use for many decades. Continued research into the effectiveness of these techniques and circumstances which call for their use in a variety of combinations is warranted; enough is now known to provide intelligent and productive speculations regarding combinations that might enhance therapeutic effectiveness. Likewise productive would be the continuation of research into the biological correlates of effective, non-pharmacological psychotherapy.

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APPENDIX AA return to the concept of Biological Drives as fundamental to psychodynamics

Stern's (2002) system of development of the senses of self and domains of relatedness yields a conceptually elegant and parsimonious explanation of why intersubjective therapy works, and why a "transference" relationship is in fact the key to improvement in the patient's life. But it is not complete.

We understand that the genuine sharing of experience, at verbal or non-verbal levels of self-integration, is healing. We understand that the newborn's first task is to construct the layered and always (throughout the lifespan) forming senses of self, in order to engage in that critical adventure of life, the genuine sharing of experience; and that that sharing starts in rudimentary form during the earliest months of life. We see that failures in the emergent, subjective, and core senses of self, essentially always failures of caregiving in infancy, and have lasting destructive consequences directly related to empathic and reality-testing functions.

Environmental impingements on continuity, coherence, and agency are largely disruptions to the person's experience of the center of the real world, that is, the self. Failures in the sharing of intersubjective experience are also pathogenic. It becomes difficult to resist the conclusion that at least part of the pathogenic nature of these failures is the considerable distress they engender. Stern's formulation begs the question of why this is so.

For a credible explanation, we return to Bowlby's hypotheses about the homeostatic equilibrium between security and exploration. Bowlby's fundamental justification for regarding security needs as real biological drives rests on the evolutionary explanation of their value. If the infant were not motivated to seek proximity to a primary attachment object that could guarantee its safety, it would be unlikely to survive to reproductive age. I suggest that the same is true of the need to be able to experience, interpret, and represent the environment in a consistent manner (emergent self); maintain a stable sense of coherent, continuous, and effect-producing self separate from others who are also comprehended as having the same defining characteristics (core sense of self and other); and obtain ratification and confirmation of perceptions, cognitions, and emotions in the self and in others (intersubjective relatedness); and finally, engage in symbolic behavior to enhance and solidify intersubjective relatedness and obtain social validations of the perceptions of the environment (sense of verbal self). These senses of self represent abilities which can determine the viability and survivability of the individual, whether by means of direct reality-testing of the immediate environment or participation in social relationships that provide meaningful enhancements of security.

I am suggesting that the development, maintenance, and exercise of these abilities are as motivating as hunger and the avoidance of physical harm. I think it would be an interesting exercise to explain the tendency of victims of abuse to attribute good qualities to the abuser and bad qualities to the self within this framework, rather than making use of the complex and convoluted constructions necessary for the development of such concepts as "splitting". In fact, the field of cognitive dissonance, of which we have not

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heard much lately, tacitly and implicitly rested on such assumptions as I am making explicit, and would have had an explanation for the cognitions of abuse victims also. Stern (2000, Page 136) points out that this view, insofar as it pertains to intersubjective relatedness, is in accord with the formulations of Self psychologists. He goes on to make the same points as I do regarding the relationship of intersubjective relatedness to security and attachment goals, and discusses the ways in which extreme disturbances of this one dimension of psychic experience define different psychotic states. At one pole is the sense of cosmic psychic isolation, and at the other is the feeling of total psychic transparency. Stern also argues for the survival value and evolutionary origins of the phenomenon of intersubjective relatedness.

Psychodynamic factors that result in pathology are in the final analysis predominantly the results of maladaptive adjustments to the frustrations of biological drives.

The drives whose frustrations are most often at the root of pathology in our culture are a.) the need for attachment and security, which includes proximity to attachment object and acknowledgment of the existence of the individual by an attachment object, two of the subcomponents that are most relevant to our interest in early origins of pathology;b.) the need to achieve and express self-agency. This construct subsumes exploratory behavior, as well as (more obviously) mastery and competence.c.) the need to make sense of the environment, to have sets of object-representations that are compatible with each other and with perceptions. My study of the broad field of psychology to date suggests to me that in fact this may be the transcendent human drive, the prime imperative. Many of the classic psychodynamic defense mechanisms are rooted in this drive.d.) the need to reproduce, and to produce offspring. The manifestations of this are both culturally and biologically determined, and include motivations to engage in sex and to ensure the availability and fidelity of a mate.e.) the need to destroy (by means of aggression) or escape from (flee) objects or events that threaten injury or death.

Consistent frustrations in an interpersonal context, predominantly with caregiver(s), and most importantly the mother, are encoded as generalized representations which include the arousal and affect associated with the pattern of interaction. Frustration of these drives causes high levels of arousal which is experienced as anger and/or anxiety (fear), which are manifested respectively by aggression or withdrawal (flight). (Arousal is neutral in regard to categorical affect, and may be experienced as anger, fear, or in some cases, joy or other positive categorical affect. The sign of the affect - good/nurturing/survival vs. bad/dangerous/aversive is determined by input from the amygdala.) The experience of the arousal and affect may be directly expressed as aggression or flight, or may be repressed or dissociated. The manifestation is determined temperamentally and situationally, and also largely by association with representations of characteristic experiences with others during states of high arousal, for example, if the frustrating attachment object also punishes the child for expressions of anger.

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Reactions to threat, fear, abuse, may result in behaviors that elicit very different diagnoses. I'm referring specifically to aggression (anger) turned inward vs. anger turned outward. The former might contribute to (apparent) syndromes such as hysteria, depression, dependent, avoidant, obsessive-compulsive; the latter might contribute to personality types such as paranoid, narcissistic, borderline. The ethological concept of displacement behavior is at the root of this phenomenon. Anger is not expressed as agression in situations where it is unsafe to do so. It is either expressed as self-injury (and in humans, that can be very complex) or is displaced onto safe targets.

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APPENDIX B: Experientially Determined Disturbances of the Meso-Accumbens Dopaminergic Response

Relevant to our discussion of the abusive or neglectful early childhood environment, and profound disturbances of attachment in general, is the paradigm of expected reward associated with negative experience. This is the common protocol for eliciting conflict-dependent anxiety. This paradigm has been shown in the laboratory to result in profound and persistent inhibition of DA response in the nucleus accumbens. The other, related, paradigm relevant to discussions of etiology of developmental psychopathology is the experience of insoluble stress; protocols to explore this in the laboratory include restraint shock and other non-contingent aversive events. This, also, is known to result in profound inhibition accumbens dopaminergic activity, after an initial increase in DA activity related to initial attempts to cope with the aversive event. This down regulation is concurrent with significant sustained high-level of dopamine release in the cortex, a consistent reaction to high stress level that has been associated with cognitive impairment. Behavioral correlates of these neural events include "conditioned helplessness" and loss of previously acquired competitive responses (anhedonia). Thus, both approach-avoidance conflict and an inescapable aversive environment result in neural events that can produce behaviors very familiar to observers of a variety of severe psychopathologies. The reduction in nucleus accumbens dopamine activity appears dependent on stress-induced high levels of the neurotransmitter in the cortex. Antidepressants have been shown to reverse some of these effects (Cabib, S. & Puglisi-Allegra, S., 2002).

At least in the case of approach-avoidance conflict, it appears that activity of the amygdala is necessary for inhibition of accumbens dopamine. It appears that the prefrontal cortex and amygdala work in concert to inhibit accumbens dopamine release, producing the behaviors described above. Cabib, S. & Puglisi-Allegra, S. (2002) suggest that this process is adaptive under normal situations by reducing the reward value of environmental stimuli that are no longer behaviorally meaningful. Increased dopamine signal in the nucleus accumbens is associated both with with appetitive goal-directed behavior and was the flight-flight response, that is, the reaction to aversive stimuli. Cabib, S. & Puglisi-Allegra, S. (2002) suggest that profound down-regulation upon failure of coping behaviors in unavoidable and uncontrollable situations may be adaptive since these responses may be, at best, a useless waste of energy. This phenomenon at the neural level is reflected in dissociative behavior, with concomitant observation of profound inhibition of emotional display and parasympathetic activation even with an internal environment of high chronic cortisol levels. (Henry). Clinically, I suggest that this might be seen in the negative symptoms of schizophrenia.

Dysregulation of monoamine transmitters, viewed as central in psychopathology, has consequences for vulnerability to high cortisol levels (SE), and rigidity and impulsivity in behavioral responses and motivational failures (DA). At least the DA system is known to be vulnerable to prenatal maternal stress, including psychosocial stress. (Lou) It may be difficult to separate the contributions to pathological infant-child development of prenatal maternal stress with its consequences for purely physical brain development, likely mediated body cortisol crossing the placental barrier, and the less-than-ideal attachment behaviors of the sort of mother that would experience high prenatal stress. Prenatal maternal stress is known to affect DA function in offspring, resulting in inhibitory PFC-mediated dysregulation. Some of the pathology seen in attachment-disordered dyads may in fact have started during gestation, since it is fair to

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assume that the mother's disordered attachment representations predate the birth of the offspring.

Self-regulation of affective states at the neural level involves increase in nucleus accumbens dopaminergic activity in many instances. Any specific act that makes us "feel better", that is, that results in attainment of an appetitive goal, will result in a dopaminergic signal in that structure. This also includes any cognitive confirmation of expectations. The ingestion of any addictive substance, wherever else its locus of action in the brain, must also stimulate accumbens dopamine.

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Ochsner KN, Bunge SA, Gross JJ, Gabrieli JD. Rethinking feelings: an FMRI study of the cognitive regulation of emotion. J Cogn Neurosci. 2002 Nov 15;14(8):1215-29. The ability to cognitively regulate emotional responses to aversive events is important for mental and physical health. Little is known, however, about neural bases of the cognitive control of emotion. The present study employed functional magnetic resonance imaging to examine the neural systems used to reappraise highly negative scenes in unemotional terms. Reappraisal of highly negative scenes reduced subjective experience of negative affect. Neural correlates of reappraisal were increased activation of the lateral and medial prefrontal regions and decreased activation of the amygdala and medial orbito-frontal cortex. These findings support the hypothesis that prefrontal cortex is involved in constructing reappraisal strategies that can modulate activity in multiple emotion-processing systems.

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Ohman A, Mineka S. 2001 Fears, phobias, and preparedness: toward an evolved module of fear and fear learning. Psychol Rev. Jul;108(3):483-522.An evolved module for fear elicitation and fear learning with 4 characteristics is proposed. (a) The fear module is preferentially activated in aversive contexts by stimuli that are fear relevant in an evolutionary perspective. (b) Its activation to such stimuli is automatic. (c) It is relatively impenetrable to cognitive control. (d) It originates in a dedicated neural circuitry, centered on the amygdala. Evidence supporting these propositions is reviewed from conditioning studies, both in humans and in monkeys; illusory correlation studies; studies using unreportable stimuli; and studies from animal neuroscience. The fear module is assumed to mediate an emotional level of fear learning that is relatively independent and dissociable from cognitive learning of stimulus relationships.

Paus, T., Zijdenbos, A., Worsley, K., Collins, D. L., Blumenthal, J., Giedd, J.N., Rapoport, J.L., Evans, A.C. (1999). Structural maturation of neural pathways in children and adolescents: in vivo study. Science. 283(5409):1908-11

Peeters, F., Nicholson, N.A., Berkhof, J. (2003). Cortisol responses to daily events in major depressive disorder. Psychosomatic Medicine 65(5):836-841.Depressed patients showed reduced cortisol response to emotionally negative events. Approximately half of depressed patients show higher chronic levels of cortisol (Sapolsky, others); baseline not reported in this study, also did not report medication status. Results may have been a ceiling effect.

Poulton R, Menzies RG. Non-associative fear acquisition: a review of the evidence from retrospective and longitudinal research. Behav Res Ther. 2002 Feb;40(2):127-49.It is axiomatic that the capacity to experience fear is adaptive, enabling rapid and energetic response to imminent threat or danger. Despite the generally accepted utility of functional fear, the nature of maladaptive fear remains controversial. There is still no consensus about how specific fears and phobias are acquired and modulated. Two major schools of thought are apparent: those suggesting dysfunctional fear arises largely as the result of associative-conditioning processes versus those who favour more biologically based etiological explanations. In this regard, the non-associative model of fear acquisition postulates the existence of a limited number of innate, evolutionary-relevant fears, while emphasising conditioning modes of onset for evolutionary-neutral fears. Recent retrospective and longitudinal studies have tested predictions from the non-associative model. In general, findings support non-associative hypotheses and are difficult to reconcile with neo-conditioning explanations of fear acquisition. These data suggest that four pathways to fear may provide the most parsimonious theory of fear etiology. The theoretical and practical implications of adding a fourth, non-associative path to Rachman's (Behav. Res. Ther. (1977) 15, 375-387) three 'associative' pathways are discussed. Unresolved issues requiring further investigation are considered.

Quirk, G.C. (2002). Memory for Extinction of Conditioned Fear Is Long-lasting and Persists Following Spontaneous Recovery. Learning and Memory 9:402-407.Quirk, G.J., Likhtik, E, Pelletier, J.G., Pare', G. (2003). Stimulation of Medial Prefrontal Cortex Decreases the Responsiveness of Central Amygdala Output Neurons. Journal of Neuroscience. 23(25):8800-8807.In extinction of auditory fear conditioning, rats learn that a tone no longer predicts the occurrence of a footshock. Recent lesion and unit recording studies suggest that the medial prefrontal cortex (mPFC) plays an essential role in the inhibition of conditioned fear following extinction. mPFC has robust projections to the amygdala, a structure that is known to mediate the acquisition and expression of conditioned fear. Fear conditioning potentiates the tone responses of neurons in the basolateral amygdala (BLA), which excite neurons in the central nucleus (Ce) of the amygdala. In turn, the Ce projects to the brainstem and hypothalamic areas that mediate fear responses. The present study was undertaken to test the hypothesis that the mPFC inhibits conditioned fear via feedforward inhibition of Ce output neurons. Recording extracellularly from physiologically identified brainstem-projecting Ce neurons, we tested the effect of mPFC prestimulation on Ce responsiveness to synaptic input. In support of our hypothesis, mPFC prestimulation dramatically reduced the responsiveness of Ce output neurons to inputs from the

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insular cortex and BLA. Thus, our findings support the idea that mPFC gates impulse transmission from the BLA to Ce, perhaps through GABAergic intercalated cells, thereby gating the expression of conditioned fear.

Rhodes JS, van Praag H, Jeffrey S, Girard I, Mitchell GS, Garland T Jr, Gage FH. (2003). Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behav Neurosci.117(5):1006-16.

Roozendaal, B., Phllips, R.G., Power, A.E., Brooke, S.M., Sapolsky, R.M., McGaugh, J.L. (2001). Memory retrieval impairment induced by hippocampal CH3 lesions is blocked by adrenocortical suppression. Nature Neuroscience 4(12):1169-1171.

Sapolsky, R.M. (2001). Depression, antidepressants, and the shrinking hippocampus. Proceedings of the National Academy of Sciences 98(22), 12320-12322.Sapolsky, Robert M. (2002) Chickens, eggs, and hippocampal atrophy. Nature Neuroscience 5(11): 1111-1112.

Schommer, N.C., Hellhammer, D.H., Kirschbaum, C. (2003). Dissociation between reactivity of the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system to repeated psychosocial stress. Psychosomatic Medicine 65(3): 450-60.

Schore, A.N. (2003). Early Relational Trauma, Disorganized Attachment, and the Development of a Predisposition to Violence. In Solomon, Marion F., and Siegel, Daniel J. (Eds.) Healing Trauma: attachment, mind, body, and brain. New York: W. W. Norton & Co.

Seedat, S., Stein, M.B., Kennedy, C.M., Hauger, R.L. (2003). Plasma cortisol and neuropeptide Y in female victims of intimate partner violence. Psychoneuroendocrinology 28(6):796-808.Morning plasma cortisol was lower in victims of partner violence with or without current or lifetime PTSD history.

Siegel, D.J. (2003). An Interpersonal Neurobiology of Psychotherapy: The Developing Mind and the Resolution of Trauma. In Solomon, Marion F., and Siegel, Daniel J. (Eds.) Healing Trauma: attachment, mind, body, and brain. New York: W. W. Norton & Co.

Shapiro, F. (Ed.) (2002). EMDR as an Integrated Psychotherapy Approach: Experts of Diverse Orientations Explore the Paradigm Prism. Washington, D.C.: American Psychological Association.

Shapiro, F., and Maxfield, L. (2003). EMDR and Information Processing in Psychotherapy Treatment: Personal Development and Global Implications. In Solomon, Marion F., and Siegel, Daniel J. (Eds.) Healing Trauma: attachment, mind, body, and brain. New York: W. W. Norton & Co.Shors TJ, Seib TB, Levine S, Thompson RF. (1989). Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus. Science. 14;244(4901):224-6. Exposure to uncontrollable shock massively impaired LTP relative to exposure to the same amount and regime of controllable shock. These results provide evidence that controllability modulates plasticity at the cellular-neuronal level.

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Solomon, M.F. (2003). Connection, Disruption, Repair: Treating the Effects of Attachment Trauma on Intimate Relationships. In Solomon, Marion F., and Siegel, Daniel J. (Eds.) Healing Trauma: attachment, mind, body, and brain. New York: W. W. Norton & Co.

Spence, S., Shapiro, D., & Zaidel, E. (1996). The role of the right hemisphere in the physiological and cognitive components of emotional processing. Psychophysiology 33:112-122.Stout, Amy K., Raphael, Heather M., Kanterewicz, Beatriz I., Klann, Eric, & Reynolds, Ian J. (1998). Glutamate-induced neuron death requires mitochondrial calcium uptake. Nature Neuroscience 1 (5):366 - 373We have investigated the role of mitochondrial calcium buffering in excitotoxic cell death. Glutamate acts at NMDA receptors in cultured rat forebrain neurons to increase the intracellular free calcium concentration. Although concurrent inhibition of mitochondrial calcium uptake substantially enhanced this cytoplasmic calcium increase, it significantly reduced glutamate-stimulated neuronal cell death. Mitochondrial inhibition did not affect nitric oxide production or MAP kinase phosphorylation, which have been proposed to mediate excitotoxicity. These results indicate that very high levels of cytoplasmic calcium are not necessarily toxic to forebrain neurons, and that potential-driven uptake of calcium into mitochondria is required to trigger NMDA-receptor-stimulated neuronal death. Calcium ultimately may ruin mitochondria through a number of mechanisms. Normally, mitochondria can absorb excess calcium from cells. But constantly cycling calcium out of the cytoplasm may sap mitochondria of energy they normally produce to charge cells.

Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP. (2002) Developmental neurobiology of childhood stress and trauma. Psychiatr Clin North Am. 25(2):397-426, vii-viii.

Teicher, H.M., Feldman, R., Polcari, A., Anderson, C.M., Andersen, S.L., Webster, D.M., Navalta, C.P. (2002). Early Adverse Experience and the Neurobiology of Borderline Personality Disorder: Gender Differences and Implications for Treatment. In Pearson, K.H., Sonswalla, S.B., & Rosenbaum, J.F. (Eds.) Women's Health and Psychiatry. Lipincott, Williams, and Wilkins.

Trevarthen, Colwyn (1996). Lateral Asymmetries in Infancy: Implications for the Development of the Hemispheres. Neuroscience and Biobehavioral Reviews. 20(4):571-586.

van der Kolk, B.A. (2003). Post-traumatic Stress Disorder and the Nature of Trauma. In Solomon, Marion F., and Siegel, Daniel J. (Eds.) Healing Trauma: attachment, mind, body, and brain. New York: W. W. Norton & Co.

Van der Kolk, B. A., Burbridge, J. A. and Suzuki, J. (1997). The psychobiology of traumatic memory. Clinical implications of neuroimaging studies. Ann NY Acad Sci 821: 99-113.

Van Praag, H.M. (2002). Crossroads of corticotropin releasing hormone, corticosteroids, and monoamines. Biological interface between stress and depression. Neurotoxicology Research 4(5-6):531-555.CRH and cortisol overproduction may lead directly to depressive symptoms, or indirectly by inducing or increasing monoamine system hyperactivity. Compare this with findings of reduced cortisol/monoamine ratio in depression or PTSD (Henry).

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Vianna, M.C.M., Izquierdo, L.A., Barros, D.M., Walz, R., Medina, J.H., Izquierdo, I. (2000). Short- and Long-term Memory: Differential involvement of neurotransmitters systems and signal transduction cascades. An. Acad. Bras. Ci. 72(3):353-364.

Walker, M.P., Brakefield, T., Hobson, J.A., Stickgold, R. (2003). Dissociable stages of human memory consolidation and reconsolidation. Nature 425:616-620.

© Edward Loewenton 2004

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