1988; Hamner, 1994; Doerfler et al., 1994) or other medical illness (e.g. with a stay in hospital acting as a memory of the concentration camp sick barrack), retirement or other reasons for drop-out from work (ending workaholism as a defence mechanism), general anaesthesia (an accidental, unwanted narco-analysis procedure), trains (asso- ciation with the concentration camp transports), etc. Before the manifestation of their PTSD such patients may have had precursors of an aspecific type like surme´nage or ‘‘exhaustion’’ syndromes (adjustment disorders in DSM-IV terminology), functional syndromes (which are probably best described as undifferentiated somatoform dis- orders) or unspecified psychiatric syndromes. They also may have been given entirely different psychiatric diagnoses because the trauma criterion had not been recognised or because the flashbacks had been taken for delusions or hallucinations (Mueser and Butler, 1987; Spivak et al., 1992), a problem that is also known in dissociative identity disorder. A retrospective attempt to follow the longitudinal course of chronic PTSD showed that hyperarousal symptoms developed first, followed by avoidance symptoms, and finally by symptoms of the intrusive cluster. Symptoms plateaued within a few years after the Vietnam War, which was the stressor under study. Recording of alcohol and substance abuse revealed a course grossly parallel to PTSD symptoms (Bremner et al., 1996). Prospectively, it has been confirmed that it takes some time for the consequences of traumatic exposure to become apparent. During a two-year follow- up of veterans after Operation Desert Storm (the Gulf War), hyperarousal symptoms were more severe than symptoms of re-experiencing or avoidance. Only two years after exposure to combat, its level was significantly associated with the score on the Mississippi trauma scale (Southwick et al., 1995). Comorbidity Both in veterans (Green et al., 1989; Hovens et al., 1994) and in civilian survivors of disaster (Green et al., 1992), PTSD is often found in conjunction with other DSM diagnoses, such as major depression (Shalev et al., 1998b), dysthymia, panic, phobia, alcohol abuse, generalised anxiety disorder, obsessive compulsive disorder (OCD) and somatisation, either at a current or a lifetime base. In clinical samples, PTSD rarely develops as a single syndrome. It is questionable whether panic, phobia and dysthymia are essentially independent diagnoses with respect to PTSD or, in fact, dimensional morbidity units fitting into broader syndromes. I refer to my remarks on dimensional diagnosis in which I feel supported by Van Praag’s scepticism about traditional comorbidity conceptions (Van Praag, 1990). However, PTSD did occur as an isolated diagnosis in the above-mentioned studies, a phenomenon which existence I can confirm from personal clinical experience. Thus, the question comes back to what the essential functional elements in psychotraumatic syndromes are. To my opinion, these are, first, persistently in- creased vigilance and, second, the mnemonic elements of what caused this increased vigilance. These are intricately connected to the neurobiological processes of startle, 216 ——————————————————————————— W.S. DE LOOS defence, long-term potentiation, imprinting, kindling and memory intrusion (Post et al., 1995; Sanes and Lichtman, 1999). REFERENCES Abramson LY, Seligman MEP, Teasdale JD (1978) Learned helplessness in humans: critique and reformulation. J Abnorm Psychol 87:49–74. 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Yehuda R, McFarlane AC, Shalev AY (1998) Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol Psychiatry 44: 1305–1313. Yonkers KA, Ellison JM (1996) Anxiety disorders in women and their pharmacological treament. In Jensvold MF, Halbreich U, Hamilton JA (eds) Psychopharmacology and Women. Washington, DC: American Psychiatric Press, pp. 261–285. Zanarini MC, Frankenburg FR, Dubo ED, Sickel AE, Trikha A, Levin A, Reynolds V (1998) Axis I comorbidity of borderline personality disorder. Am J Psychiatry 155: 1733–1739. POST-TRAUMATIC SYNDROMES —————————————————— 221 ———————————————————————————————— CHAPTER 12 The Psychobiology of Post-Traumatic Stress Disorder W.S. de Loos Central Military Hospital, Utrecht, The Netherlands NEUROANATOMY AND BRAIN AREA FUNCTION Important findings on the psychobiology of post-traumatic stress disorder (PTSD) reported in the literature during the past 10 years cover a wide range of subjects. The limbic system and especially the amygdala have a critical role in the process of comparing sensory imput to stored memory and organising psychological processes and motor and physiological output (LeDoux, 1998). It has become clear that traumatic experience changes the limbic system and other parts of the brain not only functionally, but also anatomically at a submicroscopic, microscopic and even gross anatomical level. It seems that severe and overwhelming input into the system may cause loss of connections and even cell death (McEwen et al., 1992). Several studies have reported decreased hippocampal volume on the right side (Bremner et al., 1995) and functional studies have shown increased activity in the amygdala of the right hemisphere and decreased activation of Broca’s area, suggesting a decreased capacity to put experiences into communicable language (Van der Kolk et al., 1995). This seems to support the more or less obligatory observation of alexithymia in PTSD patients, their inability to express emotions effectively (Sifneos, 1973; Krystal, 1988). Decreased hippocampal volume is also associated with functional deficits in verbal (declarative) memory (Yehuda et al., 1995a). Left hippocampal volume reduction has been found after childhood abuse without the reported correlation with short-term verbal memory deficits (Bremner et al., 1997a; Stein et al., 1997). The explanation offered for this discrepancy is that neuronal plasticity in the very young has the effect that short-term memory functions normally mediated by the hippocampus are partially taken over by other brain structures. A decrease in hippocampal volume has not been found in all studies of this kind but other gross anatomical differences were then found in a study of traumatised children, e.g. smaller intracranial and cerebral volumes negatively correlating with abuse duration. More specifically, a gender by diagnosis effect revealed greater corpus callosum area (middle and posterior regions) Anxiety Disorders: An Introduction to Clinical Management and Research. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and J. Zohar. © 2001 John Wiley & Sons, Ltd. Anxiety Disorders. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and D. Zohar. Copyright © 2001 John Wiley & Sons Ltd Print ISBN 0-471-97893-6 Electronic ISBN 0-470-84643-7 reduction in males (De Bellis et al., 1999b) which also suggests a link with the problem of lateralisation in PTSD for which evidence has been found at a neurophysiological level (Brende, 1992; Schiffer et al., 1995; Spivak et al., 1998). The results of functional anatomical studies using positron or single photon emission are not very conclusive either. They point to involvement of the ventral anterior cingulate gyrus and the right amygdala (increased regional blood flow during exposure to combat-related stimuli) and suppression of Broca’s area function (also reported by others (Van der Kolk et al., 1995) in one study (Shin et al., 1997), activation of the left amygdala and nucleus accumbens during trauma-related stimu- lation in another (Liberzon et al., 1999a), while a third found a decrease in blood flow in the medial prefrontal cortex (area 25), which is relevant for inhibiting amygdala function and extinction of fear conditioning (see LeDoux, 1998), and a less than normal activation of the anterior cingulate (area 24) contrasting with the finding mentioned before (Bremner et al., 1999). NEUROPHYSIOLOGY Kindling A basic neurophysiological concept for the understanding of the phenomena of intrusive memory, traumatic nightmares, acoustic startle, etc. is long-term potenta- tion (Teyler and DiScenna, 1987; Lynch et al., 1988) or the kindling model of epilepsia (Racine, 1978; Adamec, 1990; Wolf et al., 1990; Post et al., 1995). In fact, traumatic dissociative or intrusive memory phenomena have many features in common with complex behavioural attacks or temporal epilepsy. Although speculat- ive, it is conceivable that under certain conditions very strong sensory input may develop into limbic seizures. In panic disorder with agoraphobia some support has been found to link this condition to complex partial epilepsy under the hypothesis that there may be a common neurophysiological substrate (Toni et al., 1996). Event-related Potentials Scalp-recorded event-related potentials (ERPs) are the reflections of patterned neural activity associated with information processing in the brain. Subjects are told to detect infrequent, target (task-relevant) stimuli and ignore other, non-target stimuli. The P3 or P300 component is recorded as a positive deflection typically occurring between 300 and 900 msec. and reflects the selective perceptual process used in identifying stimulus relevance. The P300 is affected by the personal meaningfulness of the stimulus to the subject. In a study comparing veterans with and without PTSD, combat-related pictures as non-target stimuli enhanced P300 deflections in PTSD subjects while P300 latencies and reaction times to target stimuli were prolonged. It points to an altered state of early and late cognitive selective attention and confirms 224 ——————————————————————————— W.S. DE LOOS the vulnerability to traumatic reminiscences (Attias et al., 1996a). It even proved possible to discriminate PTSD patients and controls, classifying 90% of the patients and 85% of the controls correctly (Attias et al., 1996b). In addition, in survivors of road traffic accident with mild head injury, accident-related words produced a P300 that was very significantly higher in PTSD patients and that correlated well with state of anxiety (Granovsky et al., 1998). Non-target traumatic pictorial stimuli initially produced earlier and approximately five times greater P300 amplitudes but showed amplitude reduction and latency prolongation on repetition. This effect was not observed for target stimuli. It points to the activation of an inhibitory mechanism related to the cognitive processing of traumatic stimuli (Bleich et al., 1996). In an attempt to resolve the conflicting results, with respect to whether the abnormal physiologic responses in PTSD reflect a general abnormality or are restrictively linked to trauma-related stimuli, a differential analysis was made in survivors of a ship fire with and without PTSD and other manifest or subclinical psychiatric diagnoses for word and non-word (complex) stimuli with respect to intrusion, arousal and avoidance. The complex (non-word) stimuli were thought to be causing attenuated amplitudes at an early stage after stimulus onset (100–150 msec.), a higher positive amplitude in the 200–300 msec. time period and to be related to intrusion. Arousal and avoidance were related to emotionally meaningful words and correlated independently to P300 amplitude, suggesting that avoidance and arousal have another neurobiological basis than intrusion (Blomhoff et al., 1998). The findings of this study in ERP abnormalities preceding the P300 seem to correspond with findings in sexually assaulted women with PTSD in whom the ERP phase at 50–300 msec., described as mismatch negativity, in response to auditory non-word (tone) stimuli was found to be increased. It was concluded that there should be abnormalities in preconscious auditory sensory memory in PTSD (Morgan and Grillon, 1999) in addition to the abnormalities in conscious processing reported in earlier studies. It thus seems as if this is a general abnormality not linked to trauma-related stimuli. STARTLE Acoustic startle is an oligo-synaptic response mediated through the cochlear root neurons to the nucleus reticularis pontis caudalis in the brain stem, where pre-pulse inhibition by higher structures via the pedunculopontine tegmental nucleus can occur, to spinal and facial motor neurons resulting in eye-blink and body movements. It occurs at about 300 msec., well within conscious reaction time. Pre-pulse inhibition and habituation of the startle response are stable neurobiological properties of the normal population (Ornitz and Guthrie, 1989; Cadenhead et al., 1999), even in periods of war stress (Shalev et al., 1996). Deficiency of pre-pulse inhibition has been reported for numerous psychiatric disorders (Ornitz et al., 1999). Both clinically and in the laboratory, acoustic startle is a striking phenomenon in post-traumatic syn- dromes (Butler et al., 1990; Paige et al., 1990; Shalev et al., 1992; Shalev and THE PSYCHOBIOLOGY OF POST-TRAUMATIC STRESS DISORDER ———— 225 Rogel-Fuchs, 1992; Orr et al., 1995; Morgan et al., 1996; Orr et al., 1997). Also in children with PTSD, acoustic startle shows little tendency to habituation and shows decreased pre-pulse inhibition (Ornitz and Pynoos, 1989). Conflicting results in the demonstration of increased startle in PTSD patients may be a consequence of different baseline conditions at experimentation. Increased startle is perhaps not a chronic condition in PTSD but the consequence of a greater conditioned emotional response triggered by anticipation of the test situation. Hence, emotionally charged test procedures can be especially informative in distinguishing PTSD patients from other diagnostic groups (Morgan et al., 1995; Grillon et al., 1998a). However, some test circumstances may result in specific aversively conditioned reactions that are independent from PTSD, such as darkness increasing startle responses in all combat veterans independently (Grillon et al., 1998b). An interesting result was obtained when the increased startle response was replicated in right-handed women with sexual assault trauma one to 27 years previously. In addition to the expected result, asymmetry was found with greater responses for the left orbicularis oculi EMG confirming a laterality effect that has been found with different methods as well (Brende, 1992; Schiffer et al., 1995; Spivak et al., 1998). The adrenergic  2 -receptor is thought to play a role in the generation of the startle response, especially its  2C - subtype as has been found in transgenic mice (Sallinen et al., 1998). The increase of PTSD symptomatology by yohimbine, an  2 -receptor antagonist (Southwick et al., 1993a; Southwick et al., 1999), and the decrease of startle responses in a child by clonidine, an  2 -receptor agonist (Ornitz and Pynoos, 1989), are concordant with this finding. OLFACTORY STIMULI Another interesting limbic phenomenon is the EEG response to odours significantly associated with traumatic experience (McCaffrey et al., 1993). As is the case in acoustic startle, the alarm centre of the central nervous system cannot be shut off from olfactory input. Mammals do have eyelids but no ear lids or nose lids. Also clinically, odours prove to be very strong triggers for conditioned emotional responses. CIRCULATORY, SYMPATHETIC AND MOTOR RESPONSES Base-line Blood Pressure and Heart Rate The development of physical disease after and caused by emotional experience or traumatic life events has always been intriguing, to the public even more so than to clinical medicine. It is a domain of complex interactions and the much needed prospective follow-up studies have rarely been possible to carry out. Raised blood 226 ——————————————————————————— W.S. DE LOOS [...]... SSRIs, MAO inhibitors, the anti-kindling drugs carbamazepine and valproate, other serotonergic substances, clonidine, propranolol, anti-opioids and lithium REFERENCES Adamec RE (1990) Does kindling model anything clinically relevant? 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Geracioti TD (1999) Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder Am J Psychiatry 156: 585–588 Bhatnagar S and Meaney MJ (1995) Hypothalamic-pituitary-adrenal function in chronic intermittently cold-stressed neonatally handled and non-handled rats J Neuroendocrinol 7: 97 108 Blanchard EB (1990) Elevated basal levels of... stress disorder and major depression: a chronobiological analysis Biol Psychiatry 40: 79 –88 ———————————————————————————————— PART III Research Methods ———————————————————————————————— SECTION A Methods of Experimental Psychology Anxiety Disorders Edited by E J L Griez, C Faravelli, D Nutt and D Zohar Copyright © 2001 John Wiley & Sons Ltd Print ISBN 0-4 7 1-9 78 9 3-6 Electronic ISBN 0-4 7 0-8 464 3 -7 ————————————————————————————————... Serotonin Indirect evidence points to an important role of the serotonin system in the brain in patients with PTSD Selective serotonin re-uptake inhibitors (SSRIs) are probably the most effective drugs to control a number of very disturbing symptoms in PTSD, especially impulsiveness and anger, and, to a substantial degree, also post-traumatic nightmares They may be the first choice to be tried (Van der... specify The following is the most commonly accepted definition: Anxiety Disorders: An Introduction to Clinical Management and Research Edited by E J L Griez, C Faravelli, D Nutt and J Zohar © 2001 John Wiley & Sons, Ltd 250 ——————————————— P EELEN, D HERMANS AND F BAEYENS Learning refers to the change in a subject’s behavior or behavior potential to a given situation brought about by the subject’s repeated... responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers Biol Psychiatry 45: 14 47 1454 Seeman TE and Robbins RJ (1994) Ageing and hypothalamic-pituitary-adrenal response to challenge in humans Endocr Rev 15: 233–260 Shalev AY, Bonne OB, Peri T (1996) Auditory startle response during exposure to war stress Compr Psychiatry 37: 134–138 Shalev AY, Freedman... produce receptor down-regulation and a sharp and almost complete decline of end-organ activity This is applied in the treatment of prostate cancer by the use of a long-acting LHRH agonist that down-regulates testosterone production to almost zero, but in physiological circumstances it is not known to occur and the neuroendocrinology of major depression with its increased activity of the HPA-axis does... feedforward autoreceptor, and serotonin which may also potentate the NMDA receptor (McEwen and Magarinos, 19 97) Neuroprotection by GABA-ergic inhibi˜ tion or by neurotrophins (NT) such as brain-derived neurotrophic factor (BDNF) and NT-3 may decrease under certain stressful circumstances A postulated consequence of hippocampal atrophy with respect to the striking down-tuning of the HPA-axis, is the... Pitman RK (1989) Endogenous opioids and stress induced analgesia in post-traumatic stress disorder Psychopharmacol Bull 25: 108–112 Van der Kolk BA, Hostetler A, Herron N, Fisler RE (1994a) Trauma and the development of borderline personality disorder Psychiatr Clin North Am 17: 71 5 72 9 Van der Kolk BA, Saporta S (1991) The biological response to psychic trauma: mechanisms and treatment of intrusion and. .. and treatment of intrusion and numbing Anxiety Res 4: 199–212 Wan R, Diamant M, De Jong W, De Wied D (1992) Differential effects of ACTH4–10, DG-AVP, and DG-OXT on heart rate and passive avoidance behaviour in rats Physiol Behav 51: 5 07 513 Webster RA (1989) The catecholamines (noradrenaline and dopamine) In Webster RA, Jordan CC (eds) Neurotransmitters, Drugs and Disease Oxford: Blackwell Scientific . and to be related to intrusion. Arousal and avoidance were related to emotionally meaningful words and correlated independently to P300 amplitude, suggesting that avoidance and arousal have another. regions) Anxiety Disorders: An Introduction to Clinical Management and Research. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and J. Zohar. © 2001 John Wiley & Sons, Ltd. Anxiety Disorders. . are excitatory amino acid neurotransmitters, especially glutamate, via its N-methyl-D-aspartate (NMDA) receptor and possibly also its kanainate type feedforward autoreceptor, and serotonin which