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Stress and traumaStress and traumaNeurobehavioral Science INeurobehavioral Science I

Mgr. Michaela Viktorinová M.Sc.Mgr. Michaela Viktorinová M.Sc.

Prague Psychiatric CentrePrague Psychiatric CentreNational Institute of Mental HealthNational Institute of Mental Health

Questions:Questions: What functional and structural changes are caused by What functional and structural changes are caused by chronic stress exposure?chronic stress exposure? Who will cope better? Do personality characteristics matter? Who will cope better? Do personality characteristics matter? Does the nature of the stress matter? Does the nature of the stress matter? When can one expect the most serious consequences? When can one expect the most serious consequences?

Outline: Outline: 1. Introduction (stress theories, biology, developmental 1. Introduction (stress theories, biology, developmental trajectories)trajectories)

2. Maltreatment as a stress model. 2. Maltreatment as a stress model.

3. PTSD as a reaction to a traumatic event. 3. PTSD as a reaction to a traumatic event.

Stress and its Stress and its conceptualizationconceptualizationss

Bernard Bernard (1859): The importance of (1859): The importance of the the organismorganism’s inner ’s inner environmentenvironment. .

Cannon (1871-1945)Cannon (1871-1945) ( (Wisdom of the bodyWisdom of the body, 1932): Homeost, 1932): Homeostasisasis. . “Fight or flight” “Fight or flight” response.response. The role of the autonomic nervous The role of the autonomic nervous system. system.

Selye (1907-1982)Selye (1907-1982): : General Adaptation Syndrome ModelGeneral Adaptation Syndrome Model (GAS): (GAS): AAcute stress reactioncute stress reaction - - Resistance Resistance - - ExhaustionExhaustion. .

Lazarus (1922-2002)Lazarus (1922-2002): : The importance of appraisal in coping with The importance of appraisal in coping with stress.stress.

EpidemiologicEpidemiological researchal research,, BarkerBarker: : InsufficientInsufficient nutritionnutrition in prenatal in prenatal periodperiod leads to an increased risk of leads to an increased risk of type 2 diabetes and heart type 2 diabetes and heart disease. disease.

BehaviorBehavioral geneticsal genetics,, CaspiCaspi: MAO-A: MAO-A polymorphism polymorphism, , early early maltreatmentmaltreatment && increased stress increased stress vulnerabilitvulnerabilityy; ; 5-HT polymorphism5-HT polymorphism, , stresstresss & onset of& onset of psychiatric psychiatric diseases. diseases.

NeuroendoNeuroendocrinologicalcrinological researchresearch: : HPA HPA axisaxis ( (hypothalamic-pituitary-hypothalamic-pituitary-adrenal axis). adrenal axis).

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The role of environment and The role of environment and neuroplasticityneuroplasticity The developing brain is shaped by an The developing brain is shaped by an

early experience and is extremely early experience and is extremely sensitive to environmental stimuli. sensitive to environmental stimuli.

Birth: 100 billion neurons, 50 trillion Birth: 100 billion neurons, 50 trillion synapses.synapses.

3 yrs: 1 000 trillion synapses.3 yrs: 1 000 trillion synapses. Too many to be driven by genes only. Too many to be driven by genes only. NeuroplasticityNeuroplasticity

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Experience matters. Experience matters. Neuroplasticity determined by Neuroplasticity determined by

environment environment Hippocampus of a London taxi driver. Hippocampus of a London taxi driver. Study limitations? Study limitations?

5Maguire et al, 2006, Hipp.

Neuroplasticity: White and Neuroplasticity: White and grey matter changes induced grey matter changes induced by trainingby training

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Draganski et al, 2004, Nature; Scholz et al., 2009, Nat. Neuro

Healthy brain development Healthy brain development

Proliferation Proliferation Pruning Pruning MyelinizationMyelinization

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Healthy brain development Healthy brain development

Age 6: The brain Age 6: The brain reaches 95% of its reaches 95% of its total volume. total volume.

Max.: 11,5 yrs in girls, Max.: 11,5 yrs in girls, 14,5 yrs in boys. 14,5 yrs in boys.

On average, boys tend On average, boys tend to have greater total to have greater total cerebral volume than cerebral volume than girls. girls.

(Lenroot & Giedd, 2006)(Lenroot & Giedd, 2006)

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Healthy brain developmentHealthy brain development

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(Lenroot & Giedd, 2006, Neurosc and Biobeh Rev)

Healthy brain developmentHealthy brain development

Grey matter volume Grey matter volume undergoes a rapid growth undergoes a rapid growth in childhood and slows in childhood and slows down during the down during the adolescence. adolescence.

Peaks: 11 yrs in girls, 13 Peaks: 11 yrs in girls, 13 yrs in boys. yrs in boys.

The grey matter volume The grey matter volume then tends to gradually then tends to gradually decrease. decrease.

10(Lenroot & Giedd, 2006, Neurosc and Biobeh Rev)

Healthy brain developmentHealthy brain development

White matter White matter (myelinization)(myelinization)

White matter develops White matter develops from birth onwards from birth onwards following a rapid path following a rapid path of growth during of growth during puberty. puberty.

It peaks right after It peaks right after the grey matter the grey matter volume growth (11 yrs volume growth (11 yrs in girls, 13 yrs in in girls, 13 yrs in boys). boys).

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(Lenroot & Giedd, 2006, Neurosc and Biobeh Rev)

White and grey matter White and grey matter volume growth trajectories volume growth trajectories

White matter volume White matter volume follows a linear line of follows a linear line of development with an development with an equal amount of equal amount of growth in all areas of growth in all areas of the brain. the brain.

The growth of the The growth of the grey matter volume is grey matter volume is an inverted U-shape. an inverted U-shape. Increases in volume Increases in volume are different in are different in different brain different brain regions. regions.

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HPA axisHPA axis

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Lupien et al., 2009, Nature

Prenatal stress Prenatal stress Animal models: Animal models: Stress in pregnancy leads to an increased maternal production of glucocorticoids → Stress in pregnancy leads to an increased maternal production of glucocorticoids → placenta → foetus → increase in its HPA axis activity → secondary changes found inplacenta → foetus → increase in its HPA axis activity → secondary changes found in hippocampus, amygdala, OFC etc. (Koehl et al., 1999).hippocampus, amygdala, OFC etc. (Koehl et al., 1999). Behavioral consequences Behavioral consequences in offspring: anxious and depressive symptoms, learning in offspring: anxious and depressive symptoms, learning difficulties, drug seeking behavior. difficulties, drug seeking behavior.

Human studies: Human studies: In line with animal findings. In line with animal findings. Prenatal stress is linked with a lower birth weightPrenatal stress is linked with a lower birth weight, , increased HPA axis activityincreased HPA axis activity at at 6 6

months, months, 5 5 and evenand even 10 10 yrsyrs (Lyons-Ruth et al., 2000; Gutteling et al., 2005; Glover, (Lyons-Ruth et al., 2000; Gutteling et al., 2005; Glover, 1997). 1997).

BehaviorBehavioral consequencesal consequences in offspringin offspring: ADHD, antisoc: ADHD, antisocial behaviorial behavior, psychiat, psychiatric ric diseasesdiseases ( (mood disordersmood disorders) ) etcetc. .

Maternal care is an important intervening factorMaternal care is an important intervening factor.. Its quality can intensify or alleviate Its quality can intensify or alleviate consequences of prenatal stress. consequences of prenatal stress.

Examples: Lower cortisol levelsExamples: Lower cortisol levels a and different gene expression were found in children nd different gene expression were found in children born to women traumatized byborn to women traumatized by 9/119/11 (Yehuda et al., 2005(Yehuda et al., 2005; Yehuda et al., 2009; Yehuda et al., 2009))..

Project Ice StormProject Ice Storm: : The extent of prenatal stress corresponds to subsequent The extent of prenatal stress corresponds to subsequent cognitive and behavioral development in children cognitive and behavioral development in children (King & Laplante, 2005)(King & Laplante, 2005). .

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Postnatal stressPostnatal stress Animal models:Animal models: Separation from the mother ( Separation from the mother (HPA), poor maternal HPA), poor maternal

care (care (GR in hippocampus). Exposure to stress in adolescence GR in hippocampus). Exposure to stress in adolescence leads to greater GR levels than the same kind of stress in adulthood. leads to greater GR levels than the same kind of stress in adulthood.

Human studies: Human studies: Children in day care have heightened GR levels. No Children in day care have heightened GR levels. No

consequences for further development. consequences for further development. Maternal care matters. Depressed mothers have children with a Maternal care matters. Depressed mothers have children with a

HPA axis reactivity (Lupien et al., 2000). HPA axis reactivity (Lupien et al., 2000). Adolescence as a period with a Adolescence as a period with a HPA axis reactivity (precursor HPA axis reactivity (precursor

of a later onset of psychiatric diseases?)of a later onset of psychiatric diseases?) Adolescence as a period where the stress consequences become Adolescence as a period where the stress consequences become

visible for the first time. Adolescents with a low SES have visible for the first time. Adolescents with a low SES have GR GR levels. Changes in hippocampus observed in animal models have levels. Changes in hippocampus observed in animal models have not been detected. not been detected.

Limitations of comparisons with animal models. Limitations of comparisons with animal models.

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Meaney’s experiments: Stress Meaney’s experiments: Stress and epigeneticsand epigenetics

16Liu et al, 1997, Science; Hackan et al., 2010, Nature Rev Neuro

Stress in adulthoodStress in adulthood Animal models:Animal models:

Acute stress (Acute stress (GR → amygdala activation → better emotional GR → amygdala activation → better emotional memory consolidation)memory consolidation)

CChronic stress (chronic hronic stress (chronic GR alters hippocampus function →GR alters hippocampus function → atroatrophyphy). ).

Changes, including those of chronic stress, are reversible at Changes, including those of chronic stress, are reversible at this point. this point.

Human studies: Human studies: In line with results from animal studies.In line with results from animal studies. Acute Acute GR in adultsGR in adults improves retrieval of emotionally salient improves retrieval of emotionally salient

information but worsens retrieval of neutral information. information but worsens retrieval of neutral information. baseline GR in adults with depression and adults suffering baseline GR in adults with depression and adults suffering

from PTSD. Decreased function and hippocampus size in from PTSD. Decreased function and hippocampus size in PTSD and depression. PTSD and depression.

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Summary: Impact of stress on Summary: Impact of stress on brain structure and function in brain structure and function in

different stages of different stages of development development

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Lupien et al, 2009, Nature Reviews

Critical periods?

Sensitive periods? Sensitive periods?

The period of max. The period of max. impact: impact: Frontal cortex: 14-16 Frontal cortex: 14-16

letlet Corpus callosum: 9-10 Corpus callosum: 9-10

letlet Hippocampus: 3-5 let. Hippocampus: 3-5 let.

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Evidence for the existence of Evidence for the existence of critical periods: Age matters!critical periods: Age matters!

1) Maercker et al., 2004: Women traumatized 1) Maercker et al., 2004: Women traumatized before the age 12 tend to develop more often before the age 12 tend to develop more often depression, while women traumatized in between depression, while women traumatized in between 12 and 18 yrs have a greater probability of 12 and 18 yrs have a greater probability of developing PTSD. developing PTSD.

2) Hall et al., 1998: Repeated sexual abuse is 2) Hall et al., 1998: Repeated sexual abuse is associated with a lower hippocampus/PFC associated with a lower hippocampus/PFC volume if it occurred in early volume if it occurred in early childhood/adolescence. childhood/adolescence.

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MaltreatmentMaltreatment Maltreatment and neglectMaltreatment and neglect encompass all forms of encompass all forms of

emotional and physical violence including sexualemotional and physical violence including sexual, , that pose that pose a possible or actual threat on child’s development, its well-a possible or actual threat on child’s development, its well-being and dignity. being and dignity.

20% 20% of womenof women a andnd 5-10% 5-10% of menof men report the experience of report the experience of being maltreated in childhood. being maltreated in childhood.

23% 23% of all reportof all report physical maltreatmentphysical maltreatment (WHO, 2014). (WHO, 2014). The most endangeredThe most endangered: : children less than 4 yrschildren less than 4 yrs, adol, adolescents escents

and handicapped childrenand handicapped children. . ConsequencesConsequences: : psychiatric disorderspsychiatric disorders ( (the average time the average time

that passes between the onset of maltreatment and that passes between the onset of maltreatment and development of depression isdevelopment of depression is 11,5 let (Widom et al., 2007), 11,5 let (Widom et al., 2007), drug abusedrug abuse,, risky sexual behavior, delinquency.. risky sexual behavior, delinquency..

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Amygdala reactivity in Amygdala reactivity in maltreated children maltreated children

Institutionalized Institutionalized childrenchildren

Longitudinal studyLongitudinal study Increased Increased

amygdala volumeamygdala volume Implications? Implications?

22Mehta et al, 2009, JCPP

Hippocampus and abuseHippocampus and abuse Children:Children: So far, research has not demonstrated any causal So far, research has not demonstrated any causal

relationship between hippocampus changes and maltreatment. relationship between hippocampus changes and maltreatment. Adults: Adults: Studies found smaller hippocampus in adults who were Studies found smaller hippocampus in adults who were

maltreated as children. maltreated as children. 2 hypotheses: 2 hypotheses:

““Neurotoxicity hypothesisNeurotoxicity hypothesis””: Long-term exposure to GR as a result of : Long-term exposure to GR as a result of extreme stress leads to cell death [ Stress -> Smaller hippocampus ]. extreme stress leads to cell death [ Stress -> Smaller hippocampus ]. However, why do PTSD patients present lower levels of GR? However, why do PTSD patients present lower levels of GR?

““Vulnerability hypothesisVulnerability hypothesis”: Smaller hippocampus volume is not a ”: Smaller hippocampus volume is not a consequence of exposure to stress but rather a pre-existing factor for consequence of exposure to stress but rather a pre-existing factor for consequent development of PTSD [Smaller hippocampus volume + consequent development of PTSD [Smaller hippocampus volume + Stress -> PTSD ]. Stress -> PTSD ].

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Changes in Arcuate fasciculus as a Changes in Arcuate fasciculus as a consequence of verbal abuse in consequence of verbal abuse in

children children DTI studyDTI study 16 children with a history of 16 children with a history of

verbal abuse verbal abuse Lower FA in arc. fasciculus, Lower FA in arc. fasciculus,

cingulus and fornix. cingulus and fornix. Correlations: FA and VIQ, Correlations: FA and VIQ,

inversed FA w/ depression, inversed FA w/ depression,

somatization and anxiety. somatization and anxiety.

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Choi et al., 2009, Biol Psych

Changes in the visual cortex of Changes in the visual cortex of young women sexually abused young women sexually abused

in childhoodin childhood Cut-offCut-off for significant for significant

effects of abuseeffects of abuse: : < 12 < 12 yrs.yrs.

ExplanationExplanation? ?

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Tomoda et al., 2009, Biol Psych

SummarySummary Exposure to early, chronic stress alters Exposure to early, chronic stress alters

consequent brain development. consequent brain development. AgeAge is a critical factor. is a critical factor. Consequences of stress are often visible Consequences of stress are often visible much much

later. later. Consistent findings: Consistent findings: Hypoactivity in neuronal Hypoactivity in neuronal

networks linked with emotional regulation incl. networks linked with emotional regulation incl. PFC (Carrion et al., 2008; Chugani et al., 2001); PFC (Carrion et al., 2008; Chugani et al., 2001); amygdala hyperactivity triggered by fearful and amygdala hyperactivity triggered by fearful and angry stimuli (Dannlowski et al., 2011: “limbic angry stimuli (Dannlowski et al., 2011: “limbic scars”).scars”).

Inter-individual differences. Inter-individual differences. Resilience? Resilience?

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Posttraumatic stress disorder Posttraumatic stress disorder (PTSD)(PTSD)

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PTSDPTSD The onset of PTSD is determined by a variety of The onset of PTSD is determined by a variety of

neurophysiological and psychological factors. neurophysiological and psychological factors. PTSD is one of many reactions that the organism PTSD is one of many reactions that the organism

can present when faced with trauma. Other can present when faced with trauma. Other include: include:

Depression, psychosis, anxiety disorders, somatic Depression, psychosis, anxiety disorders, somatic diseasesdiseases

Spontaneous recovery from PTSD is definitely Spontaneous recovery from PTSD is definitely possible. possible.

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Criteria forCriteria for PTSDPTSD Intense, stress reaction to a traumatic event. Intense, stress reaction to a traumatic event. Persistent, re-experiencing of the event in a form of: Persistent, re-experiencing of the event in a form of:

Intrusive memories Intrusive memories Recurring dreams Recurring dreams Recurring feelings and sensations linked to the traumatic event Recurring feelings and sensations linked to the traumatic event Experiencing significant distress when reminded of the event Experiencing significant distress when reminded of the event

Avoiding thoughts, feelings or conversations linked to a trauma. Avoiding thoughts, feelings or conversations linked to a trauma. Avoiding activities, places or people reminiscent of the trauma. Avoiding activities, places or people reminiscent of the trauma. Inability to fully access the traumatic memories. Inability to fully access the traumatic memories. Feelings of disconnection from others, emotional blunting. Feelings of disconnection from others, emotional blunting.

Increased arousal: Increased arousal: Sleep disturbances Sleep disturbances Irritability/anger outburstsIrritability/anger outbursts Difficulties with concentration of attention Difficulties with concentration of attention Hypervigilance Hypervigilance Increased fight/flight response Increased fight/flight response

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PTSD: Cognitive modelsPTSD: Cognitive models Dunmore et al., 2001: Dunmore et al., 2001: Exaggerated negative Exaggerated negative

appraisal of traumatic event appraisal of traumatic event and of its and of its consequences (including the capacity to cope). consequences (including the capacity to cope).

How can we identify a traumatic memory: How can we identify a traumatic memory: Intentional remembering only leads to a poor Intentional remembering only leads to a poor

reconstruction of a traumatic event. reconstruction of a traumatic event. Conscious access to trauma is limitedConscious access to trauma is limited.. IIntegration with other autobiographical memories is ntegration with other autobiographical memories is

limited. limited. Even subtle stimuli lead to its traumatic re-experiencing Even subtle stimuli lead to its traumatic re-experiencing

in the form of vivid flashbacks. in the form of vivid flashbacks.

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Normal, autobiographical Normal, autobiographical memoriesmemories

Traumatic memoriesTraumatic memories

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Stories, wordsCan be added, altered

Related to other memories and to some context

“There and then”Organized into a coherent, concrete

story

Stories, wordsCan be added, altered

Related to other memories and to some context

“There and then”Organized into a coherent, concrete

story

Almost real-life sensationsStatic, “frozen”

Isolated, standing independently of other memories

“Here and now”Disorganized, fragmented, incoherent

Almost real-life sensationsStatic, “frozen”

Isolated, standing independently of other memories

“Here and now”Disorganized, fragmented, incoherent

The avoidance cycleThe avoidance cycle

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The memory is not processed, worked through

Intrusive contents (memories, dreams, thoughts)

Re-experience of massive fear, feelings of helplessness…

Suppressed thought or memory which is attempted to be avoided

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Intrusive thoughts and the emotional Intrusive thoughts and the emotional versionversion of of Stroop test: Stroop test: War veteransWar veterans andand PTSDPTSD

Stroop test: Stroop test:

EmEmotionalotional Stroop test Stroop test forfor PTSD: PTSD:

REDRED BLUEBLUE GREENGREEN REDRED BLUEBLUE GREENGREEN GREEN GREEN RED BLUE GREEN

MILLIONAIREMILLIONAIRE FRIENDSHIPFRIENDSHIP FINGERPRINTSFINGERPRINTS FIGHTFIGHT TREETREE CONCRETECONCRETE CHARLIECHARLIE L LOVEOVE

McNally et al., 1990

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Neuronal correlates of PTSD Neuronal correlates of PTSD Shin et al., 2005:Shin et al., 2005:

Comparing Comparing 13 m13 menen withwith PTSD a PTSD andnd 13 m 13 menen with traumatic experience with traumatic experience withoutwithout developing PTSD.developing PTSD.

PTSD PTSD groupgroup showedshowed abnormalit abnormalitiesies inin amygdalamygdala reactivitya reactivity, , cingulcingulaar r ccortexortex ( (increasedincreased) a) andnd mPFCmPFC ( (decreaseddecreased). ).

Gilbertson et al., 2002:Gilbertson et al., 2002: Twin study focusing on hippocampus volumeTwin study focusing on hippocampus volume, , comparing comparing 2 2 groupsgroups: :

11stst group group: : War veteransWar veterans withwith PTSD vs. PTSD vs. non-exposed twins. non-exposed twins. 22ndnd group group: : War veterans withoutWar veterans without PTSD vs. PTSD vs. non-exposed twins. non-exposed twins.

ResultsResults: : War veterans withWar veterans with PTSD PTSD had smallerhad smaller hippocampu hippocampus volumess volumes than war veterans without PTSDthan war veterans without PTSD. .

BUT: Healthy non-exposed twins did not differ in their hippocampus BUT: Healthy non-exposed twins did not differ in their hippocampus volumes when compared to their twins, war veterans wih PTSD.volumes when compared to their twins, war veterans wih PTSD.

Gilbertson et al., 2002

War experience does not cause hippocampus atrophy BUT smaller hippocampus volume could be a vulnerability marker for the onset of PTSD.

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Risk factors forRisk factors for PTSD PTSD

Low IQLow IQ.. HigherHigher IQ seems to be a protective IQ seems to be a protective factor factor (Breslau et al., 2006). (Breslau et al., 2006).

Smaller hippocampus volumeSmaller hippocampus volume as a result of e.g. as a result of e.g. early maltreatment early maltreatment (Bremner et al., 2006). (Bremner et al., 2006).

GeneticGenetic factors factors (True et al., 1993). (True et al., 1993).

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Cognitive-behavioral therapy Cognitive-behavioral therapy ofof PTSD PTSD

AimAim 1 1: : Reduction of re-experiencing the traumatic event by Reduction of re-experiencing the traumatic event by the elaboration of trauma and identificationthe elaboration of trauma and identification of its triggers. of its triggers. Methods: guided imaginationMethods: guided imagination, , reproductions..reproductions..

AimAim 2: 2: Mod Modification of itsification of its extremely negative connotationsextremely negative connotations by assigning them new meaningsby assigning them new meanings, identifi, identification of a core cation of a core feature of trauma and its altered emotional processing. feature of trauma and its altered emotional processing.

AimAim 3: 3: Reducing the avoidance of people, places.. Reducing the avoidance of people, places..

EMOTIONSFear

PHYSIOLOGYHypervigilance

BEHAVIOREscape from others,

monitoring possible dangers.

BELIEFSIf I approach,

I can be in danger. CORE BELIEF: The world is dangerous. Others are evil. I am vulnerable.

My relationships with others

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Thank you. Thank you.

viktorinovaviktorinova@pcp.lf3.cuni.cz@pcp.lf3.cuni.cz