Am J Psychiatry , suppl 11 , 1— The economic burden of anxiety disorders in the s. J Clin Psychiatry 60 — Roy v ix xii xv Section I. Roy and Patricia L. Bliese, Kathleen M. Wright, Amy B. Adler and Jeffrey L. Wiederhold, Alex H. Bullinger and Mark D. Juan, Beatriz S. Posttraumatic stress disorder PTSD is a severe psychiatric illness associated with disturbances in diverse neurobiological systems. The evaluation of a variety of biomarkers might facilitate a goal of modern medicine, a proper treatment for an individual patient at a given stage of disease.
This is especially important in PTSD, a disorder with a complex clinical picture, diverse symptoms, and frequent comorbidities. Biological markers platelet serotonin, platelet monoamine oxidase, plasma lipid levels, plasma dopamine beta hydroxylase, plasma cortisol and serum levels of thyroid hormones were determined, and clinical symptoms were evaluated, in 93 male war veterans with chronic combat related PTSD, using the Clinician Administrated PTSD Scale, Positive and Negative Syndrome Scale, and the Hamilton Rating scales for Depression and Anxiety.
Platelet serotonin concentration and plasma dopamine beta hydroxylase activity were similar in PTSD subjects and healthy controls. Since a great proportion of our war veterans with chronic combat related PTSD had a severe form of PTSD, complicated with the presence of psychotic or depressive symptoms, further studies are underway to elucidate the association between biological markers and particular symptoms occurring in PTSD.
Pivac et al. War trauma and combat experience result in a high prevalence of PTSD. The disorder is often chronic, frequently complicated with comorbid psychiatric diagnoses such as major depressive disorder, anxiety, mood and substance use disorders. Socio-cultural but also geographically specific comorbidities have been proposed [1,2].
In extensive studies using an ethnically homogenous population of Croatian war veterans with combatrelated PTSD , a high prevalence of comorbid diagnoses were found . The most frequent comorbidities were depression, alcohol and drug abuse, panic disorder and phobia, psychosomatic disorder, psychotic disorders, and dementia [5,6]. Recent studies identified a specific, severe, psychotic subtype of PTSD, unresponsive to antidepressant treatment . Biomarkers might be used for preclinical screening, diagnosis, disease staging, and monitoring of treatment, and their utility becomes especially important in PTSD, a disorder with a complex clinical picture, diverse symptoms, and variable course, that is complicated by various comorbidities.
Disturbances in multiple neurobiological systems e. In the studies evaluating biological markers in Croatian war veterans with combat related PTSD, we investigated platelet serotonergic markers, i. Materials and methods 1. The subjects were asked to describe their traumatic experiences and were given enough time to talk about these and other psychiatric disturbances. All patients were war veterans who had been on active duty in the Croatian armed forces range of years, most with 3 years of continuous combat experience , had similar social and cultural backgrounds, and the great majority were married.
All were screened with a comprehensive multidisciplinary evaluation conducted by 2 psychiatrists and a psychologist prior to entry into inpatient treatment. Subjects were excluded from the study if they had a positive family N. Combat-related symptoms included intrusive images of screaming soldiers, fire, bombing, rocketing, etc. Individuals taking cholesterollowering drugs were excluded.
The procedures were fully explained and written informed consent was obtained from all patients. The local Ethics committee approved this protocol. The control group consisted of healthy male volunteers, with no personal or family history of psychopathology, and receiving no medical treatment. None of the healthy subjects were receiving psychiatric or related treatment before the samples were selected.
Groups were matched on age, gender, smoking, and other socio-demographic characteristics. The control subjects agreed, and provided written informed consent, to participate in the study and to provide a blood sample. Biochemical determination A forearm vein was cannulated for blood sampling at Blood samples 8 ml were drawn in a plastic syringe with 2 ml of acid citrate dextrose anticoagulant. Platelet-rich-plasma PRP was obtained by centrifugation x g for 70 s at room temperature. Platelets were sedimented by further centrifugation of PRP at 10, x g for 5 min.
The platelet pellet was washed with saline and centrifuged again. Platelet 5-HT concentration was determined by the spectrofluorimetric method, as previously described [15,16,22]. Platelet MAO activity was determined spectrofluorimetrically using kynuramine as a substrate, as previously described . Platelet protein levels were measured by the method of Lowry et al. Serum lipid levels—total cholesterol, high-density lipoprotein HDL , and triglycerides TG levels—were determined by enzymatic color test, while serum lowdensity lipoprotein LDL levels were measured using an enzymatic clearance assay.
Serum thyroid hormones: total and free triiodothyronine T3 levels were assayed using an luminoimmunochemical assay kit Johnson and Johnson Clinical Diagnostic Products, Amersham, UK. Plasma DBH activity was determined by a photometric assay, using tyramine as a substrate, by the method of Nagatsu and Udenfriend . The level of significance was p 6 N. Table 1. Plasma cortisol levels differed significantly between groups Table 2. Plasma cortisol levels were significantly higher p Table 2. Discussion In PTSD, a disorder with a complex clinical picture, diverse symptoms, and different comorbidities, the evaluation of complex biological signals might be used to improve the characterization of the baseline group characteristics, to predict a suicidal risk, to differentiate particular symptoms or syndromes, and to improve the understanding of the underlying neurobiology of PTSD.
The rationale for the use of blood platelets as a limited peripheral model for the central 5-HT synaptosomes lies in the similar pharmacodynamics of 5-HT with central 5-HT neurons [25,26]. Recent reports suggest that platelet 5-HT concentration [27,28], and platelet MAO activity [17,29,30] might serve as biological or trait markers for particular mental disturbances.
Serotonergic alterations might contribute to the cognitive disturbances and deficits in the memory systems occurring in PTSD , and platelet 5-HT has been reported to be altered in aggression  and impulsivity . In line with previous reports [15,16,32], our data indicate that platelet 5-HT concentration is not altered in war veterans with PTSD. Since biological markers have been proposed to be more closely related to basic psychopathological characteristics, i. This finding supports the hypothesis that platelet 5-HT is more related to particular trait markers, such as aggression , impulsivity , or to particular symptoms [27,28], suicidal behaviour , than to state characteristics [26,27].
Platelet MAO shares similar biochemical and pharmacological characteristics, and identical amino acid sequences, with brain MAO-B , and was proposed to represent a genetic marker for the size or functional capacity of the central monoamine systems and serotonergic system . The discrepancies between studies might be explained by the differences in the time course of PTSD i.
Our data, showing increased platelet MAO values in the large numbers of war veterans with combat related PTSD, agree with the altered platelet MAO in different personality and temperamental traits, such as sensation seeking and impulsivity [29,30], and impulse and affect dysregulation . Smoking decreases platelet MAO activity [29,30,36], but after controlling for the effect of smoking, the activity of the enzyme remained elevated data not shown in our Croatian war veterans with PTSD. Noradrenergic neurons arise from the locus ceruleus and project to diverse structures involved in learning and memory prefrontal cortex, amygdala and hippocampus , and stress response hypothalamus.
DBH is an enzyme that catalyzes the conversion of dopamine to noradrenalin. The concept of a hyperactive HPT axis, with consequent elevation of total and free T3 in PTSD patients, agrees with our data , and confirms the link between stress and clinical hyperthyroidism . Hypersecretion of corticosteroids for prolonged periods can harm cognitive processes that are disturbed in PTSD . Our data  show increased plasma cortisol levels in war veterans with combat related PTSD, adding to the contradictory findings regarding the status of basal and stimulated cortisol levels in PTSD patients.
Since noradrenergic and HPA systems act synergistically in response to acute or prolonged stressful stimuli, disturbances in noradrenergic and HPA axis systems would elicit a cascade of events and disrupt the regulatory mechanisms modulating response to trauma, and add to the development of PTSD symptoms. Since increased serum cholesterol is a risk factor for cardiovascular disease in PTSD patients, these findings call for dietary modification for war veterans with PTSD. The great proportion of our war veterans with chronic combat related PTSD had a severe form of PTSD, complicated with the presence of psychotic or depressive symptoms.
Therefore, further studies are underway to elucidate the association between biological markers and particular symptoms occurring in PTSD, and to facilitate the identification of the specific form or subtype of PTSD, disease staging, and monitoring of treatment. Clin Psychology Rev 18 , Spivak, Y.
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Gould, Plasma dopamine beta-hydroxylase ativity in psychotic and non-psychotic post-traumatic stress disorder, Psychiatry Res 77 , Kagan, G. Leskin, B. Haas, J. Wilkins, D. Foy, Elevated lipid levels in Vietnam veterans with chronic posttraumatic stress disorder, Biol Psychiatry 45 , This circuitry is involved in memory retrieval, survival behaviour, navigation including virtual reality tracking, wellbeing, and the integration of emotion and cognition. These processes are all implicated in the cognitive neuroscience of PTSD.
Two modalities of treatment are outlined that have been found effective in contributing to the treatment of PTSD - hypnosis and EEG-neurofeedback. The Theta Rhythm 1. Survival Behaviour and the Hippocampus Theta activity is a brain rhythm that oscillates between 4 and 8 cycles per second and is positioned in the EEG spectrum between the slower delta rhythm and the faster alpha rhythm. Now through intracerebral EEG recording, place cells in epileptic patients have been shown to resonate at theta frequencies in virtual reality studies , with theta augmented by active navigation when compared with passive navigation .
Entrainment of Circuitry for Integrating Cognition and Emotion The hippocampus is involved in circuitry synchronised by the theta rhythm. Non-rhythmic neuronal impulses of brain stem origin, once they have been relayed to the septum, are converted into rhythmic theta bursts and are transmitted to the hippocampus and then to the cortex and so are detectable by scalp electrodes.
These are maintained via feedback loops . Recent research extends the domain to other limbic structures. This includes a recurrent network involving the hippocampus, medial mammilliary bodies, anterior thalamus, post cingulated entorhinal cortex and subiculum, and then back to the hippocampus.
There is in addition an ascending modulatory circuit from the supramammillary nucleus of the hypothalamus which contains cells determining the frequency of the theta rhythm. This circuit can act independently of the hippocampus, and via reciprocal connections can modulate the hippocampus, infralimbic cortex and prefrontal cortex .
Therefore circuitry is available for the integration of cognition and emotion. This occurs through topographically specific connections from neocortex and ascending connections from the brainstem. It has a fundamental role in all long distance regional connectivity in the brain. Long range connectivity is essential to navigation, the historical signature of theta in animals.
Furthermore Bland and Oddie  have proposed that theta oscillations coordinate activity in brain regions involved in updating motor plans on the basis of sensory input. In other words theta is the conduit for sensory-motor integration, where afferent sensory input is organised and directed to regions orchestrating a motor plan and allowing for a motivated navigational response. Similarly, during a virtual movement, taxi driver navigational task, theta oscillations were recorded from intra cranial electrodes in epileptic patients ; with searching distinguished from goal seeking behaviour by the frequency and distribution of theta.
Here theta entrainment is seen to strengthen the connection weights of hippocampal-cortical loops phase-locked to the theta rhythm. These loops are widely dispersed to distal parts of the brain. In a landmark study Von Stein et al  on the basis of empirical studies proposed an inverse relation between the frequency of the EEG oscillation and the scale and range of functional synchrony. Theta oscillations were associated with the fMRI blood oxygenation signals representing both activation and deactivation.
The process of mental calculation disclosed theta synchronisation of a network distributed through frontal, temporal and parietal cortices. Consciousness Theta activity has long been associated with altered states of consciousness, including dreaming, meditation, hypnosis, and hypnogogia - the border between waking and sleeping. Relations between theta and normal consciousness have now been affirmed through studies of working memory, becoming popularised through considerations of theta as the electrical signature of the hippocampus in animals and the role of the hippocampus in encoding and retrieval of episodic memory in man.
To mention three studies, Burgess and Gruzelier  found that theta power increased with the conscious recognition of words, while Klimesch et al  showed that aside from theta accompanying the recognition process itself, during encoding only the words that were later to be recognised were accompanied by increases in theta power. A recent meditation study comparing long versus short term meditators practising Sahaja Yoga underscores the fundamental roles of theta not only in meditation, but also in wellbeing, and in top down and long range connectivity .
When instructed through internalised attention to meditate to achieve a state of bliss, long term meditators were best distinguished from novices by theta activity in anterior and midline regions. Subjective ratings of bliss also correlated positively with theta activity. The synchronisation of theta disclosed a locus in the left prefrontal region, and from this locus synchronisation was widely distributed, extending to posterior association cortices bilaterally. It is noteworthy that the left prefrontal locus has before been associated with both the expression of positive affect and with internalised attention.
Theta is augmented in conscious memory judgements. Theta is involved in top-down internalised processing exemplified by visual imagery, working memory and meditation. Theta is associated with positive emotion.
Theta synchronises hippocampal circuits which organise sensory input and orchestrate a motor plan, and which coordinate cognition and emotion. Theta is involved in long range circuitry in the brain and facilitates connectivity. The Hippocampus Considering first the hippocampus, this has been implicated in PTSD through its role in episodic memory retrieval, as well its susceptibility to stress . A reduction in hippocampal volume has been reported in a majority of studies of PTSD . This may be reversible, for following antidepressant treatment evidence was found of hippocampal neurogenesis and an increase in volume in PTSD, along with alleviation of stress .
Putatively abnormal functional connectivity has been reported in a standard working memory task in a mixed group of PTSD patients . Whereas bilateral parietal areas and the left precentral gyrus were more activated in PTSD than in controls, other areas were less activated and these included the inferior medial frontal lobe, bilateral middle frontal gyri and right inferior temporal gyrus. Lannis et al  took this hypothesis further by examining the memory circuits involved in the recall of traumatic events which were provoked by scripts and compared with the recall of neutral events.
In support of dependency on nonverbal episodic memory with PTSD there was a striking laterality effect. Whereas in patient controls a left hemispheric circuit underpinned autobiographical memory retrieval, in both PTSD groups the right hemisphere was activated in line with image-based retrieval. Furthermore in patients with PTSD without flashbacks, interpreted as exhibiting a dissociative response to trauma, circuitry was consistent with the evocation of heightened awareness of bodily sensations . Considering first the EEG spectrum, Begic and colleagues [24, 25] have conducted two studies with Croatian war veterans, replicating an elevation in fast wave beta activity which was found to be widely distributed.
Elevated beta activity is consistent with raised levels of anxiety. Similarly in a study which examined EEG asymmetry in PTSD, right parietal activation was found associated with an anxious arousal syndrome.
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The right lateralised effect supported the right hemispheric involvement reported in functional imaging studies . Regarding EEG connectivity, Chae et al  examined an EEG measure called nonlinear dynamical complexity which has been interpreted as indexing connectivity of neuronal cell assemblies and the integration of sensory input with ongoing neuronal activity .
The higher the complexity, the higher the connectivity. Lower complexity, an index of reduced connectivity, was disclosed in patients in over half of the 16 derivations recorded, and while these included the 4 temporal lobe electrodes the effects were more widely distributed. Similarly, in a conference abstract Leiberg et al  report EEG coherence patterns of motor accident survivors recorded while viewing trauma relevant pictures. Reduced coherence connectivity was disclosed between temporal, centroparietal and frontal areas.
There are abnormalities of circuitry in PTSD widely distributed in the brain and with a limbic locus, in keeping with both abnormal integration and with evidence of reduced complexity connectivity. In PTSD there is atypical right hemispheric circuitry, in keeping with image-based retrieval which is dissociated from left hemispheric narrative processes, and associated with anxious arousal. In PTSD there is EEG evidence of elevated fast frequency activity and right parietal activity in keeping with an anxious arousal syndrome.
Neurophysiology of Hypnosis EEG studies have consistently associated theta activity with hypnosis , perhaps assisted by the mentally relaxing effects of hypnosis . Functional imaging studies show that hypnotizable subjects following hypnosis may alter their perceptual abilities in line with instructions, as would follow from increased cognitive and physiological flexibility and mental efficiency [29, 31].
Neural circuitry is altered and there is evidence of an uncoupling of lateral left frontal functions , hypothesized to facilitate the orchestration of behaviour by the therapist . Theoretically hypnosis has obvious affinities with the symptoms of PTSD.
In fact trauma may be viewed as an hypnotizing agent, for trauma can trigger responses with hypnotic features such as amnesia, identity distortion, dissociation, numbing, verbal stupor and stupor . Spiegel  has articulated three clusters of symptoms of PTSD in parallel with hypnosis as follows: intrusive flashbacks and nightmares with hypnotic absorption; dissociation with hypnotic dissociation; exaggerated response to disturbing stimuli with hypnotic automaticity.
Hypnosis can enable the access of these symptoms and facilitate their reprocessing. High hypnotisability has often been found to be a characteristic of patients who suffer from PTSD . Hypnotherapy and PTSD Hypnosis has been widely used as a treatment for PTSD for over a century , but there are few controlled studies or systematic case studies . In a meta analysis of Flammer and Bongartz  only one controlled study  was cited and this involved a successful brief intervention 18 J.
Since then Bryant et al  reported a controlled study with civilian trauma survivors randomly assigned to six sessions of either cognitive-behavioural therapy CBT consisting of exposure, cognitive restructuring and anxiety management, to the same CBT package coupled with hypnosis, or to counseling. At 6 month follow-up counseling was less successful than the other approaches, with CBT when combined with hypnosis the more successful in reducing the reexperiencing of symptoms. In a single case study Degun-Mather  effectively treated a Korean war veteran who 40 years later presented with depression and was unable to further contain PTSD with dissociative fugues.
This will be presented in some detail to provide a flavour of the hypnotic approach. Hers was a multimodal treatment approach designed in three phases. The first stage involved stabilization through education and CBT with hypnosis.
The second was grounded in hypnotic reprocessing of traumatic memories through a safe-remembering method and hypnotic dreams, along with cognitive reevaluation of traumatic events to resolve negative affect. The third involved further memory integration aided by dream elaboration with and without hypnosis, and rehabilitation. It was originally developed to produce an hypnogogic state for the purposes of enhancing creativity when benefits were found in enhanced wellbeing and psychic integration .
Subsequently it was effective as one part of a multimodality approach along with temperature biofeedback, visualization, systematic desensitization, rhythmic breathing and autogenic training in the treatment of veterans with alcoholism and alcoholism with depression , and importantly war veterans with PTSD . The protocol aims to facilitate a rise in levels of theta Hz over alpha Hz in a state of eyes-closed relaxation. Normally on closure of the eyes and onset of relaxation the EEG displays high amplitude rhythmic alpha activity. With further deactivation alpha activity slowly subsides and slower theta activity gradually becomes predominant.
Until our studies, though widely practiced by EEG-neurofeedback practitioners, this apparently promising approach lacked validation, though an accumulation of results with other EEG protocols in the field of ADHD through small scale controlled studies  suggested that therapeutic claims may well be of promise. We first provided evidence of operant control of the J. We went on to demonstrate mood enhancement in socially anxious medical students when compared with a mock feedback control , and to extend the music results to ballroom dance performance .
The advantages of theta training for the performing arts went beyond anxiety reduction and relaxation training [43, 50, 51]. The order of magnitude of the benefits for theta training were of professional significance, were replicable, and by their nature - the enhancing of artistic aspects of music performance - were consistent with associations between the hypnogogic state and creativity .
These effects can best be understood through both the cognitive and affective effects of theta. Trauma may trigger responses with hypnotic features and shared processes such as absorption, dissociation and automaticity. PTSD patients are characterized by hypnotic susceptibility. Hypnotherapy assists in memory revivification and the integration of fragmented episodic memories, against a background of anxiety reduction, empowerment and psychic integration. Theta training has been found effective in treating PTSD as part of a multimodal programme. Theta training has elevated mood and empowerment.
From the evolving neuroscience of PTSD, abnormalities of circuitry have been inferred. Therefore, techniques such as theta training and hypnosis, which through the elevation of theta facilitate the synchrony of long distance connectivity in the brain, are likely to provide a valuable adjunct to CBT approaches. Finally, the advent of wireless bluetooth EEG recording has potential 20 J. References  J.
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- Radiotherapy and Brachytherapy.
Bremner, Functional brain imaging and the induction of traumatic recall: A cross-correlational review between neuroimaging and hypnosis, International Journal of Clinical and Experimental Hypnosis 52 3 , Hypnosis in the treatment of post-traumatic stress disorder. Casebook of Clinical Hypnosis. American psychological Association, Washington , Hollander, S. Cardena, Hypnosis in the treatment of trauma: a promising, but not fully supported, efficacious intervention, International Journal of Clinical and Experimental Hypnosis 48 2 , Flammer and W.
Bongartz, On the efficacy of hypnosis: a meta-analytic study, Contemporary Hypnosis 20 , Brom, R. Kleber, P. Defares, Brief psychotherapy for post-traumatic stress disorders, Journal of Consulting and Clinical Psychology 57 5 , Bryant, M. Moulds, R. Guthrie, R. Nixon, The additive benefit of hypnosis and cognitive-behavioral therapy in treating acute stress disorder, Journal of Consulting and Clinical Psychology 73 2 , Brende, The use of Hypnosis in Post-traumatic conditions.
Gruzelier, T. Egner, Critical validation studies of neurofeedback. Budzynski, J. Biofeedback techniques in behavior therapy. Shapiro, T. Barber, L. DiCara, J. Kamiya, N. Peniston, P. Kulkosky, Alpha-theta brainwave training and beta endorphin levels in alcoholics, Alcoholism: Clinical and Experimental Results 13 , Kulkosky, Alcoholic personality and alpha-theta brainwave training, Medical Psychotherapy 3 , Saxby, E.
Peniston, Alpha-theta brainwave neurofeedback training: An effective treatment for male and female alcoholics with depressive symptoms, Journal of Clinical Psychology 51 , Kulkosky, Alpha-theta brainwave neurofeedback for Vietnam veterans with combat-related posttraumatic stress disorder, Medical Psychotherapy 4 , Vernon, T. Egner, N. Cooper, T Compton, C. Neilands, A. Sheri, J. Gruzelier, The effect of training distinct neurofeedback protocols on aspects of cognitive performance, International Journal of Psychophysiology 47 , Egner, E.
Strawson, J. Egner, J. Gruzelier, Ecological validity of neurofeedback: Modulation of slow wave EEG enhances musical performance, NeuroReport 14 , Raymond, C. Varney, J. Raymond, I. Sajid, L. Parkinson, J. Gruzelier, Biofeedback and dance performance: A preliminary investigation, Applied Psychophysiology and Biofeedback 30 , Edge, L.
Lancaster, Phenomenological analysis of superior musical performance facilitated by neurofeedback: Enhancing musical performance through neurofeedback: playing the tune of life, Transpersonal Psychology Review 82 in press. Gruzelier, Learned self-regulation of EEG frequency components affects attention and event-related brain potentials in humans, NeuroReport 12 , Gruzelier, EEG Biofeedback of low beta band components: Frequency-specific effects on variables of attention and event-related brain potentials, Clinical Neurophysiolog, a , Cooper, T.
Compton, C. The amygdala is the central neuronal structure for expression of fear memory and fear conditioning emotional function. Due to the prominent connections with the cingulate and prefrontal cortex and hypothalamus, the amygdala can be considered as a part of the limbic circuitry. For regulation of contextual stimulus cognitive function , the amygdala interacts with the memory circuit of the hippocampal cortex.
Limbic circuitry, which incorporates structures of the great limbic lobe, prefrontal cortex and cingulate cortex, conveys impulses to the hypothalamus, which is the main executive structure for the interaction with endocrine pituitary and brainstem tegmental autonomic and transmitter neuromodulatory functions. Human stressrelated changes of emotional functions show specificities related to phylogenetic specialization of the human cortex and developmental differences related to the prolonged developmental vulnerability throughout childhood and adolescence.
Keywords: amygdala, limbic system, stress, emotional brain 1. For contemporary neuroscience it is a challenging task to disclose the psychobiological mechanisms of PTSD. The crucial question is to determine abnormalities of neuronal circuitry which underlie the cascade of biological and psychological responses following the activation of fear-related neuronal systems. Although many researchers suggest the rather poorly defined term and concept of limbic circuitry should be abandoned from use , the concept of the limbic system is still 1 Corresponding Author: Ivica Kostovic.
The following arguments can be used in support of this approach: The limbic structures form the great limbic lobe of Broca, in a topographically specific manner limbus means margin closely associated with two subcortical structures — the amygdala and the septum. The limbic cortices such as the hippocampus and anterior cingulate cortex, together with subcortical structures such as the amygdala, are frequently altered in individuals with PTSD.
The amygdala, which is responsible for fear reactions [4,5,2,3], is closely associated with two regions, namely the frontal cortex and hypothalamus, which were included in the limbic system according to the concept presented by Nauta . The hypothalamus, extensively connected to the limbic cortical and subcortical structures, can be considered as the executive part of the limbic circuitry, receiving input from the hippocampus, amygdala and frontal lobe, and conveying impulses to the periaqueductal gray part of the limbic midbrain area and the pituitary gland.
Through the hypothalamus, limbic structures can regulate autonomic and endocrine responses following stress. For a long time, limbic emotional functions were considered to be separate from cognitive-memory functions. Today we know that contextual stimulus cognitive function and fear conditioning emotional function form the so-called contextual fear conditioning, and require both the amygdala and hippocampus .
Thus, through fear conditioning, emotional and cognitive function of limbic structures in the primate brain work together and their function seems to be disturbed in PTSD. The significant changes observed in PTSD patients in the anterior cingulate cortex and hippocampus with neuroimaging techniques does not necessarily mean causal relationship.
Thus, it is not known whether these are just consequences of abnormal brain function at the level of different chemical-transmitter pathways throughout the prolonged period. The chemically identified transmitter pathways which innervate the limbic cortex Figure 1 and subcortical structures frontal cortex, anterior cingulate cortex, amygdala are affected in different mental disorders and are not specific for PTSD.
Dopaminergic, serotonergic, noradrenergic and cholinergic pathways which modulate emotional behavior and cognitive functions were reported to be affected in PTSD  but also in other mental disorders. Therefore, it is better to analyze transmitter dysregulation. Figure 1. The midbrain limbic area is the source of noradrenergic shown and dopaminergic-serotonergiccholinergic not shown pathways which innervate the limbic cortex and the amygdala.
Another problem in the interpretation of transmitter changes in the neuronal circuitry are interindividual probably at least partly genome-based differences in response to stress. Sex and gender differences in organization of emotional circuitry are probably an additional confounding factor influencing abnormalities of transmitters in PTSD.
For example, it was recently reported  that the activity of the amygdala on the left side of the brain relates to memory for emotional material in women. In men, however, memory for the same emotional material relates to the activity of the amygdala on the right side of the brain. Furthermore, women activate a smaller network involving the left amygdala, but demonstrate greater overlap between brain areas involved in ongoing emotional processing and memory, which might explain why women tend to have stronger emotional memories than men.
Papez's circuit connects the limbic cortex of the hippocampus and the cingulate gyrus with the hypothalamus and thalamus. Limbic Circuitry One of the most famous limbic circuits is Papez's circuit, initially described in as a hypothetical circuit for emotional functions. At the time, it was unclear where emotional reactions were integrated, but Papez selected the great limbic lobe of Broca as the most likely candidate structure for those functions.
Subsequent intensive studies of visceral and emotional brain regions  in fact confirmed that some components of Papez' circuit are involved in different aspects of emotional behavior, namely autonomic, motor and hormonal responses. One portion of that circuit, which connects the hippocampus, is today known as the memory circuit. Topographical position and connections of amygdala. Note the afferent connections from the auditory cortex and efferent connections to the hypothalamus stria terminalis and cortex. Subsequent findings on the connectivity of the limbic cortex and associated subcortical nuclei amygdala, septum have enlarged the extent of limbic circuitry.
Thanks to modern tracing techniques, it was shown that most of the pathways streaming to the limbic cortex and out of the limbic cortex pass through the lateral hypothalamus i. In addition, it has been shown that the prefrontal cortex also projects to the hypothalamus and receives various limbic projections. The projections of the orbitofrontal cortex to the amygdala and hypothalamus represent an additional reason why the orbitofrontal cortex was considered to be important for different aspects of emotional behavior.
Altogether, limbic circuitry involves classical limbic structures, the hypothalamus, and prefrontal and cingulate cortices. Through the hypothalamus, all endocrine functions of the hypophysis can be controlled; the projection to periaqueductal gray matter provides control of autonomic functions, while the presence of steroid receptors provides feedback mechanisms for the effects of adrenal and steroid hormones.
Schematic representation of connections between the cortex, amygdala and hypothalamus. Note the central position of the amygdala and key executive position of the hypothalamus. The Amygdala The amygdala is definitively a central structure in the regulation of expression of fear memory Figure 3. In order to provide this function, especially fear conditioning, the amygdala receives massive projections from sensory cortices Figure 4.
The afferent projections required for auditory provoked conditioning originate from primary and I. For the processing of visually conditioned stimuli and the well-known function of the amygdala in negative emotions related to the recognition of faces [4,5], more complex cortical processing is needed between primary and associative visual areas of the occipitotemporal lobe.
These sensory driven inputs terminate in the lateral nucleus of the amygdala. From the lateral nucleus, there are extremely elaborate intra-amygdaloid connections [9,3,10,11] to the central nucleus of the amygdala Figure 4. In order to convey amygdala output, several crucial pathways exist which can explain different functions of amygdala. Brainstem projections to the periaqueductal gray matter are involved in autonomic expression of fear responses, with participation from the lateral hypothalamus. For neuroendocrine control, there are well defined projections through the bundle known as stria terminalis, which terminates in the hypothalamic nucleus, the socalled bed nucleus of the stria terminalis.
The stria terminalis is also known as the neuroendocrine pathway of the amygdala. These projections are also crucial for control of pituitary functions. However, the most massive projection is the amygdalofugal pathway to orbitofrontal and medial frontal cortex, essential for interactions of fear memory and working memory. Phylogenetic Specializations of The Limbic Circuitry in The Human Brain In considering experimental data on stress-related changes of brain function, one must consider that human limbic circuitry is composed of a number of phylogenetically specialized areas.
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