Structural and functional plasticity of the human brain in posttraumatic stress disorder

Structural and functional plasticity of the human brain inposttraumatic stress disorder

J. Douglas Bremner1,*, Bernet Elzinga2, Christian Schmahl3, and Eric Vermetten4

1Departments of Psychiatry and Behavioral Sciences and Radiology, Emory University School ofMedicine, Atlanta, GA, USA and the Atlanta VAMC, Atlanta, GA, USA 2University of Leiden,Section of Clinical and Health Psychology, Leiden, The Netherlands 3Department ofPsychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Mannheim,Germany 4Dutch Military Hospital and University of Utrecht, Utrecht, The Netherlands

AbstractPosttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brainareas involved in the stress response include the medial prefrontal cortex, hippocampus, andamygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms andmemory include glucocorticoids and norepinephrine. Dysfunction of these brain areas isresponsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients haveincreased amygdala reactivity during fear acquisition. Other studies show smaller hippocampalvolume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of thetrauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD.The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressanttreatments and changes in environment can reverse the effects of stress on hippocampalneurogenesis, and humans with PTSD showed increased hippocampal volume with bothparoxetine and phenytoin.

KeywordsPET; depression; cortisol; glucocorticoids; stress; PTSD

IntroductionChildhood abuse is a pervasive problem that is often associated with lastingpsychopathology. For instance, 16% of women have a history of childhood sexual abuse(rape or fondling) based on nationwide surveys (McCauley et al., 1997). Ten percent ofwomen (13 million) suffer from posttraumatic stress disorder (PTSD) at some time in theirlives (Kessler et al., 1995), and PTSD is twice as common in women as in men. Childhoodsexual abuse is the most common cause of PTSD in women (Kessler et al., 1995). Thispaper reviews the long-term effects of childhood abuse on brain and neurobiology, as wellas the functional plasticity of the brain in the aftermath of trauma. Findings are reviewed inPTSD and other mental disorders related to early abuse, including borderline personalitydisorder (BPD) and dissociative identity disorder (DID).

Copyright © 2008 Elsevier B.V. All rights reserved*Corresponding author. Tel.: +1 (404) 712 9569; Fax: +1 (404) 712-8442; [email protected] .

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Published in final edited form as:Prog Brain Res. 2008 ; 167: 171–186. doi:10.1016/S0079-6123(07)67012-5.

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Psychological effects of traumaTrauma results in a range of mental symptoms, including PTSD, BPD, DID, substanceabuse, anxiety, and depression. Most of the research has been done in PTSD patients,however these patients frequently have co-morbid symptoms with these other disorders,which led to the use of the term “trauma-spectrum disorders” (Bremner, 2002). Risk factorsfor PTSD include prior history of stress, low years of education, prior psychiatric history,young age, and lack of social support (Bremner et al., 1995c). In one study Vietnam combatveterans with a history of childhood abuse had fourfold increased relative risk of PTSD(Bremner et al., 1993b). Childhood abuse was the factor most strongly associated with riskfor PTSD, even after controlling for level of combat exposure, months in Vietnam, andparticipation in atrocities. Twin studies also show that there is a genetic contribution toPTSD risk (Goldberg et al., 1990).

Effects of stress on memory and the hippocampusStudies in animals show that stress impacts adversely on the brain, especially on thehippocampus. Stress, acting through increased excitatory amino acids, decreased brain-derived neurotrophic factor (BDNF), and/or increased glucocorticoids, is associated with aloss of branching of neurons in the hippocampus and an inhibition of hippocampalneurogenesis (Uno et al., 1989; Sapolsky et al., 1990; Nibuya et al., 1995; Smith et al.,1995;Sapolsky, 1996; Duman et al., 1997). These effects are reversed by a variety ofantidepressant treatments (Malberg et al., 2000; Duman et al., 2001; Santarelli et al., 2003;Duman, 2004). In addition, an enriched environment has been shown to promotehippocampal neurogenesis (Kempermann et al., 1997, 1998).

Consistent with the effects of stress on brain structures that mediate memory, including thehippocampus, prefrontal cortex, and amygdala, PTSD is associated with a wide range ofmemory deficits (Bremner, 2003). Memory can be categorized as declarative (memory forfacts or lists, mediated in part by the hippocampus) or non-declarative (memory for thingslike riding a bike, or conditioned responses) (Schacter, 1996). PTSD patients show deficitsin declarative memory, enhanced responses to conditioning, and perseverative errors(possibly related to frontal lobe dysfunction) (Elzinga and Bremner, 2002).

Studies in PTSD showed deficits in hippocampal function as measured withneuropsychological tests of declarative memory function (Bremner et al., 1993a, 1995a,2004b; Uddo et al., 1993; Yehuda et al., 1995; Vasterling et al., 2002, 2006; Vasterling andBremner, 2006). One recent study showed a decline in verbal declarative memory functionfrom before to after Iraq deployment, showing that combat exposure resulted in changes incognitive function (Vasterling et al., 2006). Several studies have also shown smallerhippocampal volume and/or N-acetyl aspartate (NAA, a marker of neuronal integrity)measured with magnetic resonance imaging (MRI) in PTSD (Bremner et al., 1995b, 1997b,2003c; Stein et al., 1997; Freeman et al., 1998; Schuff et al., 2001; Villarreal et al., 2002;Lindauer et al., 2004; Shin et al., 2004; Kitayama et al., 2005; Vythilingam et al., 2005;Jatzko et al., 2006). Two recent meta-analyses showed that this effect was seen for both leftand right hippocampus, and was seen equally in men and women (Kitayama et al., 2005;Smith, 2005; Jatzko et al., 2006). However effects were only seen in adults (including thosewith early life stress) and not in children (De Bellis et al., 1999, 2001; Carrion et al., 2001).Findings from animal studies in fact show that early life stress may not have an immediateeffect on the hippocampus, but may only manifest during the adult phase of development(Brunson et al., 2001).

Bremner has outlined a model of trauma-spectrum disorders (Bremner, 2002). Thesepsychiatric disorders, ranging from depression to BPD, DID and PTSD, are all linked to

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stress and share (at least in part) common bases in the brain. Studies in these disorders infact show that exposure to early childhood abuse is associated with smaller hippocampalvolume, including depression (Vythilingam et al., 2002), PTSD (Bremner et al., 1997b,2003c), BPD (Driessen et al., 2000; Schmahl et al., 2003), and DID (Vermetten et al.,2006a). In addition, these disorders are associated with increased cortisol response tosymptom provoking stressors for PTSD (Bremner et al., 2003a; Elzinga et al., 2003) andBPD (Elzinga et al., unpublished data, 12/12/06). BPD (Driessen et al., 2000; Schmahl et al.,2003) and DID (Vermetten et al., 2006a) (but not PTSD) are also associated with smalleramygdala volume.

Stress and neurohormonal systemsAlterations in the hypothalamic-pituitary-adrenal (HPA) axis have also been associated withstress-related psychiatric disorders. Corticotropin releasing factor (CRF) plays an importantrole in the stress response. Chronic stress exposure is associated with increases in CRF inanimal studies (Arborelius et al., 1999). Central CRF administration is associated with fear-related behaviors (decreased exploration, increased startle, decreased grooming). Stress-induced lesions of the hippocampus result in a removal of inhibition of CRF release from thehypothalamus. Other findings from animal studies include a blunted adrenocorticotropinhormone (ACTH) response to CRF challenge, increased cortisol in the periphery, andresistance to negative feedback of dexamethasone (Arborelius et al., 1999). Two studieshave shown increased concentrations of CRF in PTSD (Bremner et al., 1997a; Baker et al.,1999). Some studies (Yehuda et al., 1991b, 1994, 1996), but not others (Young and Breslau,2004a, b) found decreased cortisol in 24 h urines or in diurnal salivary samples. Two studiesusing comprehensive measurement of plasma cortisol at multiple time points found lowercortisol concentrations in the afternoon (Yehuda et al., 1996; Bremner et al., 2007). Womenwith early childhood sexual abuse and PTSD were found to have lower afternoon cortisoland an increase in cortisol pulsatility compared to controls (Bremner et al., 2007). Otherstudies found increased lymphocyte glucocorticoid receptors (Yehuda et al., 1991a), super-suppression of cortisol with low-dose (0.5 mg) dexamethasone (Yehuda et al., 1993),blunted ACTH response to CRF, increased cortisol response to stressors (Bremner et al.,2003a) and to traumatic reminders of early trauma (Elzinga et al., 2003). Women withdepression and early trauma also had increased cortisol response to public speaking (Heim etal., 2000).

There has been considerable interest in the relationship between stress, aging, anddehydroepiandosterone (DHEA). DHEA declines with aging (Orentreich et al., 1992;Barrett-Connor and Edelstein, 1994; Flynn, 1999; Johnson et al., 2002) and there has beenconsiderable interest in the ability of DHEA supplements to block the normal effects ofaging, although there is no convincing data that DHEA has such effects. DHEA also isimportant in the stress response. Chronic stress increases DHEA and DHEA-S (Fuller et al.,1984). DHEA also has antistress effects, blocking the effects of glucocorticoids onperipheral tissues as well as the hippocampus (Kimonides et al., 1998; Kaminska et al.,2000) and decreasing anxiety (Prasad et al., 1997). Studies of DHEA in patients with stress-related psychiatric disorders are contradictory, while studies in adult depressed patientsshowed both increases (Heuser et al., 1998) and decreases (Goodyer et al., 1996; Herbert etal., 1996) as well as no change (Michael et al., 2000; Young et al., 2002) in levels. Studiesof DHEA in PTSD have been equally contradictory, with one study citing lowerconcentrations relative to controls (Kanter et al., 2001) while the other showed elevations(Spivak et al., 2000). We recently measured DHEA and DHEA-S at multiple time pointsover a 24 h period in women with early abuse and PTSD, and found elevations in bothDHEA and DHEA-S (Bremner et al., 2007).

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We performed a comprehensive assessment of memory, cortisol, DHEA, and thehippocampus in women with sexual abuse before 13, with and without PTSD, and healthynonabused women. All subjects underwent assessment of hippocampal structure with MRI,assessment of hippocampal function with PET in conjunction with a paragraph encodingdeclarative memory task, assessment of HPA axis function at baseline and with a stressfulchallenge, and neuropsychological testing of declarative memory function. Early childhoodsexual abuse before the age of 13 was defined as rape or molestation as assessed with theEarly Trauma Inventory (Bremner et al., 2000). All subjects were free of psychotropicmedication for 4 weeks before study.

Women with a history of early childhood sexual abuse and the diagnosis of PTSD (N = 10)were compared to abused non-PTSD women (N = 12) for hippocampal function using PET.All subjects were scanned during encoding of a paragraph and control task in conjunctionwith injection of 0–15 water and PET imaging of the brain. MR images were obtained formeasurement of hippocampal volume, with an additional group of nonabused normalwomen (total N = 33). Subjects (N = 56) were also admitted to the GCRC for a 24 h period,for measurement of plasma cortisol, DHEA, and estradiol measured at 15 min intervals for24 h. Salivary cortisol was measured after reading of a traumatic script related topersonalized childhood abuse experiences.

In addition, salivary cortisol was measured before and after a 20 min cognitive challenge(arithmetic, color-word naming, problem solving under time pressure, and negativefeedback). Women with abuse and PTSD had smaller hippocampal volume (Bremner et al.,2003b), a failure of hippocampal activation with declarative memory tasks (Bremner et al.,2003b), lower plasma cortisol concentrations in the afternoon (Bremner et al., 2007),increased cortisol pulsatility (Bremner et al., 2007), increased plasma DHEA concentrations(Bremner et al., 2007), increased cortisol response to stress (Bremner et al., 2003a),increased cortisol response to traumatic reminders (Elzinga et al., 2003), and impaireddeclarative memory measured with neuropsychological testing (Bremner et al., 2004b).

Neurohormonal modulation of memoryGlucocorticoids affect learning and memory. Elevations of glucocorticoids within thephysiological range result in reversible deficits in memory function in animals (Oitzl and deKloet, 1992; Bodnoff et al., 1995) as well as human subjects (Newcomer et al., 1994, 1999;Kirschbaum et al., 1996; Lupien et al., 1997, 1999, 2002; de Quervain et al., 2000; Wolf etal., 2001). Glucocorticoids released during stress, possibly acting through the hippocampus,may explain in part the acutely reversible as well as chronic effects that stress has ondeclarative memory (Kirschbaum et al., 1996; Porter and Landfield, 1998; de Kloet et al.,1999; Wolf, 2003). Greater deficits are seen in younger subjects in comparison to oldersubjects, hypothesized to be secondary to age-related decreases in glucocorticoid receptordensity (Newcomer et al., 1995). Impairment of working memory by glucocorticoids mayrequire noradrenergic stimulation to have its effect (Elzinga and Roelofs, 2005). We used aprotocol of 1 mg of dexamethasone, followed by 2 mg one day later, and found animpairment in declarative memory function (percent retention of a paragraph after a delay)in healthy subjects, but not patients with depression (Bremner et al., 2004d) or PTSD(Bremner et al., 2005c). We hypothesized that this might be due to disease-related decreasesin glucocorticoid receptor function. This is consistent with the idea of PTSD as an“accelerated aging” (Bremner and Narayan, 1998) related to common theories ofprogressive hippocampal atrophy and dysfunction in both processes. We have also shownthat endogenous cortisol release stimulated by a cognitive stress challenge in healthysubjects impaired delayed recall of words and a spatial memory task at 24 h (Elzinga et al.,2005).

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In women (with and without PTSD), with a history of early abuse, memory functioning wasalso affected after exposure to personalized scripts (Elzinga et al., 2003). For neutralparagraphs encoded after exposure to the trauma scripts there was an impairment in delayedrecall relative to paragraphs encoded in a no-stress condition (Fig. 1). Recall 24 h later of anemotional paragraph presented immediately after the trauma scripts was positivelycorrelated with cortisol response to the stressful challenge, meaning that cortisol enhancedconsolidation of emotional memories. Another study in male healthy subjects has shown thatendogenous cortisol levels in healthy subjects who became upset during a social speech taskwere positively correlated with enhanced delayed memory recall of pictures, which wasespecially prominent for recall of unpleasant pictures (Abercrombie et al., 2005). Takentogether, these findings are consistent with animal models suggesting that glucocorticoideffects on learning require emotional arousal (Roozendaal, 2000).

Catecholamines released during stress also modulate the encoding and retrieval of memory(McGaugh, 2000). Administration of epinephrine (which is released from the adrenal)affects memory consolidation with an inverted U-shaped curve. Memory improves up to apoint and decreases with high doses (Gold and van Buskirk, 1975; Liang et al., 1986).Lower doses of norepinephrine injected into the amygdala promote memory for aninhibitory avoidance task while higher doses inhibit memory (Liang et al., 1990). In humans,noradrenergic beta-blocker medications blocked the formation of emotional memories(Cahill et al., 1994), while enhanced norepinephrine release was associated with enhancedencoding of emotional memories (Southwick et al., 2002). Vasopressin and oxytocin havebeen shown to modulate memory formation in both animals (McGaugh, 2000) and humansubjects (including those with PTSD) (Pitman et al., 1993).

Fear conditioning and extinctionOne of the most classic laboratory paradigms that has been used as a model for PTSD isconditioned fear. In animal models, the pairing of light and shock leads to fear responses tothe light alone. With exposure to light alone there is a gradual decrease in fear responding(called “extinction to fear”) (Davis, 1992). Re-exposure to the light-shock at a later timepoint results in a rapid return of fear responding (Quirk, 2002). Medial prefrontal corticalinhibition of the amygdala (which plays a critical role in fear responses) is felt to representthe neural mechanism of extinction to fear responding (Quirk et al., 2006). This brain area isknown to mediate emotion, as represented by the famous case of Phineas Gage (Damasio etal., 1994). Phineas Gage was a 19th century railroad worker who was injured by a spike thatentered through his eye socket and lesioned his medial prefrontal cortex (mPFC). Areasinvolved included the orbitofrontal, anterior cingulate (25/24/32), and mesofrontal cortex(9). Speech and cognition remained intact. He had marked deficits in his ability to judgesocial contexts, behave appropriately in social contexts, and assess emotional nonverbalsignals from others. Based on these findings and others, the mPFC has been judged to play acritical role in the emotion and social function.

This medial prefrontal area also plays an important role in the modulation of theneurohormonal response to stress. This area mediates peripheral cortisol and sympatheticresponses to stress (Diorio et al., 1993). Dysfunction of this area could explain alteredneurohormonal responses to stress in PTSD patients.

Studies in PTSD have shown dysfunction in the medial prefrontal cortical response to stressand traumatic reminders. We previously found decreased medial prefrontal function incombat veterans with PTSD exposed to combat-related PTSD (Bremner et al., 1999b). In asecond study we showed that women with PTSD related to early childhood sexual abuse hada decrease in medial prefrontal function in response to scripts of early childhood sexual

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abuse (Bremner et al., 1999a). A second study of exposure to emotional word pairs (e.g.,rape-mutilate) showed decreased medial prefrontal and hippocampal function in abusedwomen with PTSD (Bremner et al., 2003d). Another study used “Stroop” words (say thecolor of a color word, e.g., green, which leads to slowing of response time, due to inhibitionof response) with an emotional Stroop component (name the color of a word like “rape”).The Stroop paradigm is associated with activation of anterior cingulate. Studies of theemotional Stroop (e.g., say the color of the word rape) has been associated with a slowerresponse time in abuse-related (Foa et al., 1991) or combat-related PTSD (McNally et al.,1990). We studied neural correlates of the emotional Stroop in women with a history ofearly abuse with and without PTSD. We found that performance of the emotional Stroopwas associated with decreased function in the mPFC in the PTSD patients (Bremner et al.,2004c).

We also have assessed neural correlates of conditioned fear in PTSD. Pairing of light andshock leads to increased fear responding and increased startle to light alone (conditionedfear). Conditioned fear and startle response are mediated by the central nucleus of theamygdala. Failure of extinction occurs with lesions of the mPFC (which inhibits theamygdala).

We studied fear conditioning with PET in women with a history of early abuse and PTSDand healthy nonabused women (Bremner et al., 2005b). Subjects were exposed to repeatedand intermittent exposure to a blue square on a screen in the absence of shock (habituation),exposure to a blue square with a shock (fear acquisition), and then exposure to the bluesquare in the absence of shock (extinction). On a separate control day, they received randomshocks instead of paired exposures; otherwise the protocol was the same. PTSD subjectsexperienced increased anxiety with fear acquisition and extinction. PTSD subjects also hadincreased amygdala blood flow during fear acquisition and decreased medial prefrontalblood flow during extinction. Increased amygdala blood flow during fear acquisition in thePTSD patients was correlated with increased PTSD symptoms, anxiety, and dissociationduring fear acquisition. Increased amygdala blood flow during fear acquisition wascorrelated with decreased medial prefrontal blood flow during fear extinction in all of thesubjects. There was a highly significant negative correlation between increased anxiety anddecreased medial prefrontal blood flow during extinction in the PTSD patients (r = 0.90; p =0.006).

Effects of treatment on the brain in PTSDWe have also assessed the effects of the selective serotonin reuptake inhibitor paroxetine onbrain and cognition in PTSD. Previous multisite randomized placebo-controlled trials haveshown efficacy for paroxetine over placebo in PTSD (Marshall et al., 2001; Tucker et al.,2001). Antidepressants have also been shown to promote neurogenesis in the hippocampus,a brain area involved in learning and memory (Duman et al., 1997). In an open-label studywe showed a 5% increase in hippocampal volume after 9 months of treatment withparoxetine, as well as a 30% improvement in verbal declarative memory function measuredwith neuropsychological testing (Vermetten et al., 2003). Paroxetine treatment was alsoassociated with a decreased cortisol and heart rate response to a stressful task (Vermetten etal., 2006b).

Glutamate, dissociation, and PTSDAlterations in glutamatergic function has also been implicated in PTSD as well asdissociation (Krystal et al., 1996; Chambers et al., 1999). Symptoms of dissociation are animportant part of the psychopathological response to stress. Symptoms of dissociation

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measured with the Clinician Administered Dissociative States Scale (CADSS) (Bremner etal., 1998) are:

Do things seem to be moving in slow motion?

Do things seem to be unreal to you, as if you are in a dream?

Do you feel as if you are watching the situation as an observer or spectator?

Do you feel disconnected from your own body?

Do you see things as if you were in a tunnel, or looking through a wide-anglephotographic lens?

Does this experience seem to take much longer than you would have expected?

Increased dissociative symptoms at the time of trauma predict long-term PTSD (Bremner etal., 1992; Marmar et al., 1994). Although symptoms of dissociation are not part of the DSMcriteria for PTSD, they are part of the criteria for acute stress disorder, and symptoms ofdissociation are frequently seen in PTSD patients. PTSD patients are observed clinically tohave an increased dissociative response to the original trauma, and then have chronicincreased susceptibility to dissociative responses to minor stressors and traumatic reminders.

Although the neurobiology of dissociation has been studied less than PTSD, alterations instress hormones likely play a role in these symptoms. One particular neurotransmittersystem that has been hypothesized to play a role in dissociative symptoms is the excitatoryamino acid glutamate (Krystal et al., 1994, 1996; Chambers et al., 1999). Glutamate isreleased during stress (Moghaddam et al., 1997), and high levels of glutamate are associatedwith toxicity to the hippocampus. Glutamate acts at the N-methyl-D-aspartic acid (NMDA)receptor, and is highly concentrated in the hippocampus. Glutamate is involved in memoryat the molecular level. Excessive levels of glutamate can cause cytotoxicity as seen inpatients with epilepsy. Stress inhibits glucose utilization, and thereby impairs reuptake ofglutamate in glia with associated cytotoxicity.

Several lines of evidence support alterations of glutamatergic function in dissociation. TheNMDA antagonist, Ketamine, when administered to normal subjects, results in an increaseddissociative symptoms as measured with the CADSS (Krystal et al., 1994). In addition,increased dissociative states correlate with smaller volume of the hippocampus (which asnoted above has a high concentration of NMDA receptors) in women with early abuse andPTSD (Stein et al., 1997; Bremner et al., 2003b). A correlation between dissociative statesas measured with the CADSS and smaller hippocampal volume was seen in women withearly abuse and DID (Fig. 2). Phenytoin (dilantin) is an antiepileptic drug that is efficaciousin the treatment of epilepsy. Phenytoin modulates glutamatergic function and blocks theeffects of stress on the hippocampus in animal studies (Watanabe et al., 1992). Weconducted a pilot project in nine PTSD subjects of the effect of phenytoin on symptoms ofPTSD and the brain. Phenytoin resulted in a decrease in PTSD symptoms (Bremner et al.,2004a) as well as a 5% increase in right hippocampal and right cerebral volume (Bremner etal., 2005a).

ConclusionsWe have presented evidence for long-term alterations in brain and neurobiology in PTSD.Brain areas involved in the stress response include the mPFC, hippocampus, and amygdala.Neurohormonal systems that act on the brain areas to modulate PTSD symptoms andmemory include glucocorticoids and norepinephrine. Dysfunction of these brain areas isresponsible for symptoms of PTSD.

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The related symptom area of dissociation is felt to be related to alterations in glutamatergicfunction; however, more research is needed in this area.

Brain imaging studies show that PTSD patients have increased amygdala reactivity duringfear acquisition. Other studies show smaller hippocampal volume. A failure of medialprefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized torepresent a neural correlate of the failure of extinction seen in PTSD.

The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressanttreatments and changes in environment can reverse the effects of stress on hippocampalneurogenesis. In humans with PTSD, paroxetine increases hippocampal volume andimproves memory function in conjunction with improving PTSD symptoms. Phenytoin,which blocks the effects of stress on the hippocampus in animal studies, also increaseshippocampal volume in PTSD patients.

Future studies should use brain imaging and neurobiology to assess plasticity in PTSD.These can include both functional neuroimaging and neuroreceptor imaging to track thecourse of change during treatment, or to predict which traumatized individuals will developchronic PTSD. The information from such studies will provide valuable information thatwill guide the development of new treatments.

Discussion: Chapter 12OITZL: Did I miss something about the temporal aspect of PTSD? That is, are theredifferences between individuals who may have had PTSD for a limited duration like 6months and those with chronic PTSD who have had PTSD for many years?

BREMNER: We’re starting to study this in people that are coming from Iraq. The argumentthat we make is that people coming from Iraq in the first 6 months to a year after their returnhave a different type of PTSD than some of the older PTSD veterans from Vietnam. Untilnow the subjects we have studied have chronic forms of PTSD, such as the PTSD related toabuse in early childhood or Vietnam combat veterans with PTSD. We are looking atadolescents with abuse-related PTSD in which the PTSD is more acute, but that study is notcompleted. And then we do have a current study that is looking at returning Iraqi veteranstrying to get people in the first 6 months after they were discharged from service. We aredoing a brain imaging and intervention that involves mindfulness-based stress reduction.

JOËLS: The number of newborn cells in adult brain is extremely low. It is not well knownhow many newborn cells there are in children, but from the little that is known it is not a lot.Even if these numbers are doubled and you look over a couple of weeks, the increase inhippocampal volume or 5% you see in your studies after paroxetine treatment cannot easilybe explained by these newborn cells. So where do you think this increase of volume comesfrom? Is it maybe a change in blood flow or something else?

BREMNER: It could be that in addition to new neurons developing with paroxetinetreatment, there are other contributions to increased volume such as an increase in dendriticbranching. It could also be that treatment results in an increase in water content. However,we have preliminary data showing an increase in N-acetyl aspartate (NAA) measured withmagnetic resonance spectroscopy (MRS) in the hippocampus of PTSD patients. NAA is amarker of neuronal integrity, so this suggests that paroxetine has effects on neuronalstructure.

SECKL: I would like to ask a slightly different type of question and also about your findingswith DHEA, which among us as endocrinologists has been a graveyard for many people’s

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careers. But it is a pretty unique association: Do you think there is a fundamental underlyingdiathesis in this condition with this altered 17 hydroxylase? What is your thinking about thisfinding?

BREMNER: Our study showed that DHEA is elevated in women with abuse-related PTSD,and also that there was an elevation in DHEA to cortisol ratio where there was even more ofa difference between the patients and the controls. From the standpoint of PTSD pathology,you can argue that it is a paradoxical finding since DHEA supposedly should haveantiglucocorticoid-protective effect on the hippocampus. Here we are getting elevatedlevels, and smaller hippocampal volume and lower cortisol in the same subjects. In terms ofthe pathophysiology of why it is elevated, I do not know if I have a good explanation. If youlook at the depression literature it is a mixed literature. In PTSD there are two studies thathave a single sample, one significantly decreased and one significantly increased. Do youwant to comment? I am not an endocrinologist.

YEHUDA: You have a lot of data and it is really impressive that you can get so manymeasures on the same subjects, and that is really what helps you make progress in the fieldbecause we tend to make these observations usually in different subjects; to me that isterrific. However, I am wondering I think there is a point in your presentation where youpresent like this is the theory and here are the data, the data don’t fit the theory, and then wecome back then about the theory, e.g., you have one slide about traumatic stress spectrumand all that, and depression and PTSD should be alike and elevated cortisol and cortisoldamages the brain. Ok all that’s fine and we know that is in the literature out there. But nowyou have collected your data, you are one of the few people on the planet that have multiplemeasures in the same cohort. So you can say, “Hey wait a minute, I have low cortisol atbaseline and small hippocampuses, ha!” So what does that do to those slides in thebeginning of the talk that summarize the literature and form the basis of your model? Howdo you feel about extending that?

BREMNER: There’s some pattern that you know, e.g., that we can see correlations betweenmemory performance measured at the time of the 24 h cortisol measure. In normal subjectsthere is an inverse correlation, so the higher the cortisol the lower the memory functionwhich makes sense in terms of what is known about how administration of cortisol impairsdeclarative memory function in normal subjects. Because of time I did not show the trial inwhich we have given dexamethasone to healthy subjects in a 3-day protocol. After 3 daysmemory function becomes impaired in healthy subjects but not in the PTSD patients. Wecan see low cortisol and small hippocampal volume in the same subjects. And then we putthem through a trauma-specific task that gives them anxiety and cortisol release is increased.So there could be some pattern cortisol release that causes hippocampal damage andmemory impairment. But…

YEHUDA: How can it do that when it is low? How does low basal cortisol causehippocampal damage?

BREMNER: Well low basal cortisol does not cause hippocampal damage. And we do notfind correlations between hippocampal volume and cortisol in our patients with PTSD fromtraumas 20 years ago.

YEHUDA: You did not show cortisol and hippocampal volume correlation?

BREMNER: No we don’t have this correlation; there is not a correlation in PTSD. So youknow whether cortisol at one point in time resulted at the time of trauma in a kind of damagethat would be a speculation. I do not know if we could ever really look at that. But what itlooks like more is that there is a pattern of findings in subjects at baseline that, maybe,

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points at some central pathological process that leads to lower cortisol and smallerhippocampal volume that may not even be related in terms of the pathogenesis.

YEHUDA: It is at the heart of the matter of when we decide that maybe cortisol does notdamage the hippocampus. I mean how much data do you need to look at the literature andsay “Ha, this does not apply here.” But it does not sound that there ever is going to beevidence of such a correlation for some of us.

DE KLOET: There is a literature out there, in which it is stated explicitly that high cortisolconcentrations are damaging to the hippocampus, but in my opinion that cannot begeneralized because there many situations like exercise that also produce high cortisol, butthat are paradoxical not damaging at all. Only if levels of cortisol are chronically elevatedfor prolonged periods of time under conditions of distress one may see deterioration of theimmune system, metabolic changes, and impairment of brain function. The question then is:What is special in the pattern of cortisol secretion that it damages the brain?

YEHUDA: The point is that at some time the data that we get should force us to have newmodels and abandon models that don’t fit the data. Because then we are just trying to makethat data fit models that are no good and you can have low cortisol and small hippocampalvolume and somehow it still becomes important to say at some time there was no highcortisol, why, maybe, maybe not, maybe that does not fit, I am just wondering at what pointwe do that.

DE KLOET: I think the jury is out. There is a need for good controlled studies to measurethe pulsatile patterns of cortisol to demonstrate what the actual significance of cortisol is,whether it is a predisposing factor or a consequence of the PTSD condition.

Abbreviations

ACTH adrenocorticotropin

BDNF brain-derived neurotrophic factor

BPD borderline personality disorder

CRF corticotropin releasing factor

DHEA dehydroepiandosterone

DID dissociative identity disorder

mPFC medial prefrontal cortex

MRI magnetic resonance imaging

NAA N-acetyl aspartic acid

NMDA N-methyl-D-aspartic acid

PET positron emission tomography

PTSD posttraumatic stress disorder

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Fig. 1.Effects of a traumatic script on memory recall. There was a significant difference in delayedparagraph recall for paragraphs encoded after exposure to traumatic scripts compared toparagraphs encoded at a pre-stress baseline (t(22) = −3.39, p<0.01). This showed that stressimpaired the ability to consolidate declarative memory.

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Fig. 2.Relationship between hippocampal volume measured with MRI and dissociative statesmeasured with the CADSS in women with early abuse and the diagnosis of dissociativeidentity disorder. There was a significant negative correlation between hippocampal volumeand dissociative states (r = −0.54; df = 14; p<0.05), suggesting that increased levels ofdissociation were related to smaller hippocampal volume. This correlation was not shownfor amygdala volume. In addition there was not an association between level of PTSDsymptoms and hippocampal volume in these patients.

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