Neurobiology of PTSD Relevance to Memory Recall of Abuse

PTSD is associated with long-term changes in the function and structure of brain regions and neurochemical systems involved in the stress response (Bremner, 2002; Bremner, 2005b; Pitman, 2001; Vermetten & Bremner, 2002a, 2002b) (Fig. 1.1). Brain regions that are felt to play an important role in PTSD include hippocampus, amygdala, and medial prefrontal cortex. Cortisol and norepinephrine are two neurochemical systems that are critical in the stress response (Fig. 1.1). The neurobiology of PTSD is reviewed below as a background to the development of a model by which

Neuroanatomy Memory Ptsd

FIGURE 1.1. Functional neuroanatomy of traumatic stress. Lasting effects of trauma on the brain, showing long-term dysregulation of norepinephrine and cortisol systems and vulnerable areas of hippocampus, amygdala, and medial prefrontal cortex that are affected by trauma. ACTH: adrenocorticotropic hormone; CRF: corticotropin-releasing factor; NE: norepinephrine.

FIGURE 1.1. Functional neuroanatomy of traumatic stress. Lasting effects of trauma on the brain, showing long-term dysregulation of norepinephrine and cortisol systems and vulnerable areas of hippocampus, amygdala, and medial prefrontal cortex that are affected by trauma. ACTH: adrenocorticotropic hormone; CRF: corticotropin-releasing factor; NE: norepinephrine.

early abuse affects circuits and systems involved in memory, potentially leading to alterations in memory of early abuse.

The corticotropin-releasing factor (CRF)/hypothalamic-pituitary-adrenal (HPA) axis system plays an important role in the stress response. CRF is released from the hypothalamus, with stimulation of adreno-corticotropin hormone (ACTH) release from the pituitary, resulting in glucocorticoid (cortisol in humans) release from the adrenal, which in turn has a negative feedback effect on the axis at the level of the pituitary as well as central brain sites including hypothalamus and hippocampus. Cortisol has a number of effects that facilitate survival. In addition to its role in triggering the HPA axis, CRF acts centrally to mediate fear-related behaviors (Arborelius, Owens, Plotsky, & Nem-eroff, 1999) and triggers other neurochemical responses to stress such as the noradrenergic system via the brainstem locus coeruleus (Melia & Duman, 1991). Stress also results in activation of the noradrenergic system, centered in the locus coeruleus. Noradrenergic neurons release a transmitter throughout the brain that is associated with an increase in alerting and vigilance behaviors, critical for coping with acute threat (Abercrombie & Jacobs, 1987; Bremner, Krystal, Southwick, & Charney, 1996b, 1996c).

There is increasing interest in the relation between trauma and memory (Elzinga & Bremner, 2002). Patients with trauma-related disorders such as PTSD demonstrate a wide range of deficits in memory. Brain areas, including hippocampus, amygdala, and medial prefrontal cortex, may mediate these alterations in memory (Bremner, 2003a) (Fig. 1.2). The hippocampus, a brain area involved in verbal declarative memory, is very sensitive to the effects of stress. Stress in animals was associated with damage to neurons in the CA3 region of the hippocampus (which may be mediated by hypercortisolemia, decreased brain-derived neurotrophic factor, and/or elevated glutamate levels) and inhibition of neurogenesis (Gould, Tanapat, McEwen, Flugge, & Fuchs, 1998; Magarinos, McEwen, Flugge, & Fluchs, 1996; McEwen et al., 1992; Nibuya, Morinobu, & Duman, 1995; Sapolsky, 1996; Sapolsky, Uno, Rebert, & Finch, 1990). High levels of glucocorticoids seen with stress were also associated with deficits in new learning (Diamond, Fleshner, Ingersoll, & Rose, 1996; Luine, Villages, Martinex, & McEwen, 1994). However, whether physiological levels of cortisol are actually toxic to the hippocampus continues to be debated (de Kloet, Oitzl, & Joels, 1999).

Thalamus

Cingulate gyrus

Hypothalamus

Cerebrum

Medial prefrontal cortex

Corpus callosum

Pituitary gland

Orbitofrontal cortex

Thalamus

Cingulate gyrus

Hypothalamus

Cerebrum

Corpus callosum

Medial prefrontal cortex

Pituitary gland

Orbitofrontal cortex

Hypothalamus

Amygdala

Hippocampus

Brain stem

FIGURE 1.2. Brain areas involved in memory and the stress response. Brain areas that mediate memory, including the hippocampus, amygdala, and anterior cingulate, have been shown in brain imaging studies to be altered in patients with early-abuse-related PTSD. Source: Bremner, J. D. Does Stress Damage the Brain? Fig. 2.2, p. 44.

Amygdala

Hippocampus

Brain stem

FIGURE 1.2. Brain areas involved in memory and the stress response. Brain areas that mediate memory, including the hippocampus, amygdala, and anterior cingulate, have been shown in brain imaging studies to be altered in patients with early-abuse-related PTSD. Source: Bremner, J. D. Does Stress Damage the Brain? Fig. 2.2, p. 44.

Antidepressant treatments were shown to block the effects of stress and/or promote neurogenesis (Czeh et al., 2001; Lucassen, Fuchs, & Czeh, 2004; Malberg, Eisch, Nestler, & Duman, 2000; Nibuya et al., 1995; Santarelli et al., 2003a). It has also been found that phenytoin blocks the effects of stress on the hippocampus, probably through modulation of excitatory amino acid-induced neurotoxicity (Watanabe, Gould, Cameron, Daniels, & McEwen, 1992). Other agents, including tianeptine, dihydroepiandosterone (DHEA), and fluoxetine, have similar effects (Czeh et al., 2001; D'Sa & Duman, 2002; Duman, 2004; Duman, Heninger, & Nestler, 1997; Duman, Malberg, & Nakagawa, 2001; Garcia, 2002; Lucassen et al., 2004; Malberg et al., 2000; McEwen & Chat-tarji, 2004). There is new evidence that neurogenesis is necessary for the behavioral effects of antidepressants (Santarelli et al., 2003b; Watanabe, Gould, Daniels, Cameron, & McEwen, 1992), although this continues to be a source of debate (Duman, 2004; Henn & Vollmayr, 2004).

The hippocampus demonstrates an unusual capacity for neuronal plasticity and regeneration. In addition to findings noted above related to the negative effects of stress on neurogenesis, it has recently been demonstrated that changes in the environment—for example, social enrichment or learning—can modulate neurogenesis in the dentate gyrus of the hippocampus and slow the normal age-related decline in neurogenesis (Gould, Beylin, Tanapat, Reeves, & Shors, 1999; Kempermann, Kuhn, & Gage, 1998). Rat pups that were handled frequently within the first few weeks of life (i.e., were picked up and then returned to their mother) had increased Type II glucocorticoid receptor binding that persisted throughout life, with increased feedback sensitivity to gluco-corticoids and reduced glucocorticoid-mediated hippocampal damage in later life (Meaney, Aitken, van Berkel, Bhatnager, & Sapolsky, 1988). These effects appear to be due to a type of "stress inoculation" from the mothers' repeated licking of the handled pups (Liu, Diorio, Day, Francis, & Meaney, 2000). Considered together, these findings suggest that early in the postnatal period there is a naturally occurring brain plasticity in key neural systems that may "program" an organism's biological response to stressful stimuli. These findings may have implications for victims of childhood abuse.

The few studies of the effects of early stress on neurobiology conducted in clinical populations of traumatized children have generally been consistent with findings from animal studies (Cicchetti & Rogosch, 2001; Cicchetti & Walker, 2001; Gunnar & Vazquez, 2006; Hart, Gunnar, & Cicchetti, 1996). Research in traumatized children has been complicated by issues related to psychiatric diagnosis and assessment of trauma (Cicchetti & Walker, 2001). Some studies have not specifically examined psychiatric diagnosis, while others have focused on children with trauma and depression, and others on children with trauma and PTSD. Sexually abused girls (in which effects of specific psychiatric diagnoses was not examined) had normal baseline cortisol and blunted ACTH response to CRF (De Bellis et al., 1994), while women with childhood abuse-related PTSD had hypercortisolemia (Lemieux & Coe, 1995). Another study of traumatized children in which the diagnosis of PTSD was established showed increased levels of cortisol measured in 24-hour urine samples (De Bellis et al., 1999a). Emotionally neglected children from a Romanian orphanage had elevated cortisol levels over a diurnal period compared to controls (Gunnar, Morison, Chisolm, & Schuder, 2001). Maltreated school-aged children with clinical-level internalizing problems had elevated cortisol compared to controls (Cicchetti & Rogosch, 2001). Depressed preschool children showed increased cortisol response to separation stress (Luby et al., 2003). Adult women with a history of childhood abuse showed increased suppression of cortisol with low-dose (0.5 mg) dexamethasone (Stein, Yehuda, Koverola, & Hanna, 1997). Women with PTSD related to early childhood sexual abuse showed decreased baseline cortisol based on 24-hour diurnal assessments of plasma cortisol, increased cortisol pulsatility (Bremner, Vermetten, & Kelley, in press), and exaggerated cortisol response to stressors (traumatic stressors [Elzinga, Schmahl, Vermetten, van Dyck, & Bremner, in press] more than neutral cognitive stressors) (Bremner et al., 2002). We also found that patients with PTSD had less of an inhibition of memory function with synthetic cortisol (dexamethasone) than normal subjects (Bremner, Vythilingam, Vermetten, Newcomer, & Charney, 2005b). In a study of ACTH response to CRF challenge in children with depression with and without a history of childhood abuse, children with depression and abuse had an increased ACTH response to CRF challenge compared to children with depression without abuse. These children were in a chaotic environment at the time of the study, indicating that the ongoing stressors may have played a role in the potentiation of the ACTH response to CRF (Kaufman et al., 1997). Adult women with depression and a history of early childhood abuse had an increased cortisol response to a stressful cognitive challenge relative to controls (Heim et al., 2000) and a blunted ACTH response to CRF challenge (Heim, Newport, Bonsall, Miller, & Nemeroff, 2001). These studies suggest that early abuse is associated with long-term changes in the HPA axis.

Studies have also shown changes in the brain in patients with a history of early stress and PTSD as well as other mental disorders. A 12% reduction in left hippocampal volume in 17 patients with childhood abuse-related PTSD compared to 17 case-matched controls was found that was significant after controlling for confounding factors (Bremner et al., 1997) (Fig. 1.3) (also see color insert). In a recent meta-analysis, we pooled data from all of the relevant published studies and found smaller hippocampal volume for both the left and the right sides, equally in adult men and women with chronic PTSD (Kitayama, Vaccarino, Kutner, Weiss, & Bremner, 2005).

Hippocampal Volume Abandoned Children

FIGURE 1.3. Hippocampal volume reduction in PTSD on magnetic resonance imaging (MRI). There is smaller hippocampal volume in this patient with PTSD (right) compared to a control (left). Source: Bremner, J. D. Brain Imaging Handbook. Fig. 6.3, p. 101.

NORMAL PTSD

FIGURE 1.3. Hippocampal volume reduction in PTSD on magnetic resonance imaging (MRI). There is smaller hippocampal volume in this patient with PTSD (right) compared to a control (left). Source: Bremner, J. D. Brain Imaging Handbook. Fig. 6.3, p. 101.

We hypothesize that stress-induced hippocampal dysfunction may mediate many of the symptoms of abuse-related PTSD that are related to memory dysregulation, including both explicit memory deficits as well as fragmentation of memory in abuse survivors.

We have also found smaller hippocampal volume in patients with other abuse-related mental disorders. Both women with early abuse and dissociative identity disorder (DID) (Vermetten, Schmahl, Lindner, Loew-enstein, & Bremner, 2006) and women with early abuse and borderline personality disorder (BPD) (Schmahl, Vermetten, Elzinga, & Bremner, 2003b) had smaller hippocampal volume than controls.

In addition to the hippocampus, other brain structures, including the amygdala and prefrontal cortex, have been implicated in a neural circuitry of stress. The amygdala is involved in memory for the emotional valence of events and plays a critical role in the acquisition of fear responses. The medial prefrontal cortex includes the anterior cingulate gyrus (Brodmann's area 32) and subcallosal gyrus (area 25), as well as orbitofrontal cortex. Lesion studies demonstrated that the medial prefrontal cortex modulates emotional responsiveness through inhibition of amygdala function (Morgan & LeDoux, 1995). Conditioned fear responses are extinguished following repeated exposure to the conditioned stimulus in the absence of the unconditioned (aversive, e.g., electric shock) stimulus. This inhibition appears to be mediated by medial prefrontal cortical inhibition of amygdala responsiveness (Quirk, Garcia, & Gonzalez-Lima, 2006).

Animal studies also show that early stress is associated with a decrease in the branching of neurons in the medial prefrontal cortex (Radley et al.,

2004). Women with PTSD related to childhood sexual abuse had smaller anterior cingulate volumes based on MRI measurements (Kitayama et al.,

Based on findings related to the effects of antidepressants on neurogen-esis, we assessed the effects of the selective serotonin reuptake inhibitor (SSRI) paroxetine on outcomes related to function of the hippocampus. We studied 28 patients with PTSD and treated them for up to a year with variable doses of paroxetine. Twenty-three patients completed the course of treatment, and MRI post-treatment was obtained in 20 patients. Neuropsychological testing was used to assess hippocampal-based declarative memory function and MRI was used to assess hippocampal volume before and after treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. These findings suggested that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD (Vermetten, Vythilingam, Southwick, Charney, & Bremner, 2003).

Functional neuroimaging studies have been performed to map out the neural circuitry of PTSD related to early abuse (Bremner, 2003b; Bremner, 2005b; Bremner & Vermetten, 2001). These studies are consistent with dysfunction in a network of related brain areas including amygdala, medial prefrontal cortex, and hippocampus. We measured brain blood flow with positron emission tomography (PET) and [15O]H2O during exposure to personalized scripts of childhood sexual abuse. Twenty-two women with a history of childhood sexual abuse underwent injection of H2[15O] followed by PET imaging of the brain while listening to neutral and traumatic (personalized childhood sexual abuse events) scripts. Brain blood flow during exposure to traumatic versus neutral scripts was compared between sexually abused women with and without PTSD. Memories of childhood sexual abuse were associated with greater increases in blood flow in portions of anterior prefrontal cortex (superior and middle frontal gyri-Areas 6 and 9), posterior cingulate (Area 31), and motor cortex in sexually abused women with PTSD compared to sexually abused women without PTSD. Abuse memories were associated with alterations in blood flow in medial prefrontal cortex, with decreased blood flow in subcallosal gyrus-Area 25, and a failure of activation in anterior cingulate-Area 32. There was also decreased blood flow in right hippocampus, fusiform/inferior temporal gyrus, supramarginal gyrus, and visual association cortex in PTSD relative to non-PTSD women (Bremner et al., 1999a). This study replicated findings of decreased function in medial prefrontal cortex and increased function in posterior cingulate in subjects with combat-related PTSD during exposure to combat-related slides and sounds (Bremner et al., 1999b).

In another study by Shin et al. (1999), 8 women with childhood sexual abuse and PTSD were compared to 8 women with abuse without PTSD using PET during exposure to script-driven imagery of childhood abuse. The authors found increases in orbitofrontal cortex and anterior temporal pole in both groups of subjects, with greater increases in these areas in the PTSD group. PTSD patients showed a relative failure of anterior cingu-late/medial prefrontal cortex activation compared to controls. The PTSD patients (but not controls) showed decreased blood flow in anteromedial portions of prefrontal cortex and left inferior frontal gyrus.

These studies have relied on specific traumatic cues to activate personalized traumatic memories and PTSD symptoms in patients with PTSD. Another method to probe neural circuits in PTSD is to assess neural correlates of retrieval of emotionally valenced declarative memory. In this type of paradigm, instead of using a traditional declarative memory task, such as retrieval of word pairs like "gold-west," which has been the standard of memory research for several decades, words with emotional valence, such as "stench-fear," are utilized (Bremner et al., 2001). We used PET in the examination of neural correlates of retrieval of emotionally valenced declarative memory in 10 women with a history of childhood sexual abuse and the diagnosis of PTSD and 11 women without abuse or PTSD. We hypothesized that retrieval of emotionally valenced words would result in an altered pattern of brain activation in patients with PTSD similar to that seen in prior studies of exposure to cues of personalized traumatic memories. PTSD patients during retrieval of emotionally valenced word pairs showed greater decreases in blood flow in an extensive area that included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (Brodmann's Areas 25, 32, 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex (Fig. 1.4) (also see color insert). There were no differences in patterns of brain activation during retrieval of neutral word pairs between patients and controls.

Another study examined neural correlates of the Stroop task in sexually abused women with PTSD. The Stroop task involves color-naming semantically incongruent words (e.g., the word "green" is printed in the color red, and subjects are asked to name the color of the word). The Stroop task has consistently been found to be associated with activation of the anterior cingulate in normal subjects, an effect attributed to the divided attention or inhibition of responses involved in the task. Emotional Stroop tasks (e.g., where a trauma-specific word like "rape" is printed in a certain color, and the subject is asked to name the color) in abused women with PTSD have also been shown to be associated with a delay in color naming(Foa, Feske, Murdock, Kozak, & McCarthy, 1991). Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent PET measurement of

Left hippocampus

Trauma Abuse Figure

FIGURE 1.4. Decreased medial prefrontal function with exposure to emotionally valenced words like "rape-mutilate." There was a decrease in medial prefrontal and hippocampal blood flow with exposure to trauma-related words in women with a history of early-childhood-abuse-related PTSD compared to controls. Source: Bremner et al., 2004.

Fusiform, inferior temporal gyrus

Medial prefrontal & orbitofrontal cortex

FIGURE 1.4. Decreased medial prefrontal function with exposure to emotionally valenced words like "rape-mutilate." There was a decrease in medial prefrontal and hippocampal blood flow with exposure to trauma-related words in women with a history of early-childhood-abuse-related PTSD compared to controls. Source: Bremner et al., 2004.

cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. These findings were consistent with dysfunction of the anterior cingulate/medial prefrontal cortex in women with early abuse—related PTSD (Bremner et al., 2003a).

We compared hippocampal function and structure in 33 women with and without early childhood sexual abuse and PTSD. Women with abuse with and without PTSD were studied during encoding of a verbal memory paragraph compared to a control task in conjunction with measurement of brain blood flow with PET. There were significantly greater increases in blood flow during verbal memory encoding in the hippocampus in non-PTSD abused women relative to PTSD women. PTSD women also had smaller left hippocampal volume on MRI volumetrics compared to abused women without PTSD and non-abused, non-PTSD women. Differences in hippocampal activation were statistically significant after covarying for left hippocampal volume, suggesting that failure of activation was not secondary to smaller hippocampal volume in patients with PTSD (Bremner et al., 2003b).

We have extended functional imaging studies to patients with abuse-related mental disorders other than PTSD. In a study of women with early trauma and BPD, exposure to scripts of an abandonment situation were associated with decreased medial prefrontal and hippocampal blood flow (Schmahl et al., 2003a). Decreased medial prefrontal/anterior cingulate was seen in BPD women with early abuse during exposure to a script of their early trauma (Schmahl, Vermetten, Elzinga, & Bremner, 2004).

Although some studies have demonstrated increased amygdala function in PTSD, the experience to date suggests that increased amygdala involvement is not necessarily seen in all of the study paradigms applied to PTSD. It is more likely that specific tasks are required to show increased amygdala function in PTSD. For instance, we found increased amygdala activation during acquisition of fear in a classical fear conditioning paradigm in women with early childhood sexual abuse-related PTSD (Bremner et al., 2005a) (Fig. 1.5) (also see color insert).

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