Brain Substratum Of Pathogenic Neurotic Belief In Panic Disorder: A Single Case Study

The aim of the study was to demonstrate how recent research achievements in the neuroscience of emotions can influence practical management of anxiety disorders. Using the data obtained from analysis of psychophysiological mechanisms in one case of panic disorder, the type of threat, key threat stimuli, and the structure of the pathogenic neurotic belief were ascertained and, on this basis, an individually tailored therapeutic procedure was designed. Its application resulted in almost complete dissipation of the neurotic belief, which represented the key p athogenic mechanism in the case studied. The study called attention especially to the importance of detailed diagnostics of memory mechanisms underlying the formation of neurotic belief in the psychotherapy of anxiety disorders.


IN TROD UCTION
The d etection of a threatening event and the control of d efense against it are brain capabilities of basic survival value. Recent ad vances in anim al and hum an resear ch elu cid ated the organization principles of system s und erlying these processes, their neuronal circuitry and molecular mechanisms that provid e new insights into normal as w ell as pathological executive processes related to these important behavioral functions. Key neural circuits of the system present limbic structures includ ing amygd ala and insula, as well as other interconnected stru ctu res su ch as the p eriaqu ed u ctal gray and hyp othalam u s (LeDou x, Cicchetti, Xagoraris & Rom anski, 1990; LeDou x, 1995; Arm on y & LeDou x, 2000; Phan, Wager, Taylor & Liberzon, 2002;Kober, Barret, Joseph, Bliss-Morreau, Linquist & Wager, 2008). All these stru ctu res interact w ith a nu m ber of cortical areas involved in cognitive functions but the system m ay act relatively ind epend ently, w ithout consciou s recognition of a threatening stimulu s (Öhman, Flykt & Lund qvist, 2000;Öhman, 2005).
A basic step of ad ap tive behavior and norm al functioning represents recognition of threat stim u li based on both innate and learned exp eriences. While innate stim u li are lim ited in number, the acquired ones result from remembering of various cues associated w ith d anger experiences in the previou s life. When a d anger is recognized , the system triggers a d efense response w hich is p artly innate, "pre-program med " and p artly ind ivid u ally specific. The response includ es autonomic and end ocrine changes, more or less specific behaviors and accomp anying feelings of fear or anxiety. Whereas fear is a resp onse to an actu al d anger and is typ ically triggered by sp ecific stim u li, anxiety is m ostly consid ered as a state of p rep aration for a pred icted threat, w hich can be real or im aginary.
Cu rrent fu nctional neu roim aging stu d ies focu sed on clinically significant anxiety accu mulated great am ount d ata for a qu antitative m eta-analysis. Etkin and Wager (2007) have recently published such analysis for emotional processing in p osttrau matic stress d isord er (PTSD), social anxiety d isord er (SAD), and specific p hobia. Accord ing to these find ings comm on cond itions related to these d isord ers w ere greater activation of the am ygd ala and insula in p atients, comp ared to matched controls. Besid es this characteristic shared across d isord ers, there w ere also imp ortant d ifferences betw een them. Most striking w as the marked hyp oactivation in portions of the cingulate and prefrontal cortices in PTSD patients, w hich w as not observed in SAD and specific phobia (Etkin & Wager, 2007).
Although anxiety d isord ers com monly involve an innate mechanism that u nfold s d uring life, such as a tend ency for extreme shyness, various other mechanism s and functions contribute significantly to anxiety p athologies (Barlow , 2000). In the pathogenesis of panic d isord er there are at least tw o such contributing mechanisms: the Pavlovian fear cond itioning, w hich increases a number of threat stimuli, and formation of neurotic belief, w hich could explain amp lification of the perceived threat and the self-perpetuating character of the d isord er.
In this context, the present clinical practice stresses the importance of t w o aspects of brain functioning in anxiety d isord er: (i) frequent occurrence of malad aptive patterns of thinking and (ii) formation of beliefs that und erlie such thinking. The rem arkable efficiency of cognitive-behavioral treatment of these d isord ers that focu ses on thoughts and beliefs ju stifies this recognition of the p athogenic role of the factors m entioned (Barski & Ahern, 2004;Barlow , Gorm an, Shear & Wood s, 2004). Based on these find ings an intention of the current stud y is to d emonstrate one selected case of panic d isord er as an exam ple how the present und erstand ing of d efense mechanisms m ay be useful in practice of psychotherap y.
The main aim of the stud y w as to d em onstrate that the recurrent perception of threat to life w as in this p atient the result of misinterpretation of one or tw o key symp tom s by his neurotic belief. Using clinical d ata and d ata from testing the emotiogenity of the selected stim uli, the d isord er w as analyzed in terms of the threatening stimu li, of the character of the experienced threat, of the mechanism s w hich transformed nu merous insignificant or benign stim uli into threatening ones, and of the mechanisms that contribu ted to the long -lasting d uration of this transform ation. The creation and application of an ind ivid u ally shaped psychotherapeutic proced ure, w hich w as d esigned to m od ify his neurotic belief, w as the second aim of the stud y.

METHOD S
The p atient (a married m an, aged 48 years, emp loyed as a car d river) started ind ivid u al cognitive behavioral (CB) intervention in the course of his hospitalization in a psychiatric clinic w here he w as ad mitted w ith a severe form of p anic d isord er (F 41.0 accord ing to DSM -IV). H is first contact w ith psychiatry shortly preced ed the hospitalization. H is neurotic troubles w ere for many years d isregard ed and interp reted by specialists as an u nimp ortant corollary of cervicobrachial pathology and d ysphagia of unknow n origin. At the time of hosp italization his inability to w ork lasted for alm ost one year.
The gathering of relevant d ata and therapeutic intervention w ere d one in sessions of varying d uration (more than 60 min at the beginning, approxim ately 30 min at the end of intervention), w hich took place at varying intervals (tw o sessions d uring a w eek at the beginning, one session per tw o w eeks at the end ). The sessions w ere structured accord ing to the d iagnostic and therap eutic progress. The m ajor tasks of the CB intervention could be listed as follow s: (1) ascertaining the key anxiogenic symp tom; (2) ascertaining the level of conviction that this symptom w as the sign of a m ajor threat to life; (3) looking for a proced ure for intentional ind uction of this symptom, and , by this w ay, of threat states; (4) d etailed explanation of anatomic and physiologic know led ge relevant to the d isord er (bre athing; function of the brain d efense system); (5) exploration of the p atient's neurotic experiences w ith the aim to find ou t confirmation of expert explanations of w hat is behind his anxiety d isord er; (6) d emonstration that the key symp tom and , consequent ly, the anxiety state can be intentionally evoked and removed ; (7) formulation of rational arguments against w rong interpretation of the significance of the key symptom; (8) elaboration of an efficient nonpharmacological proced ure which the patient could use for mastering his anxiety states issued from everyd ay situ ations.
In the therapeutic w ork d irected interview s w ere used as a basic tool for gathering relevant d ata, as for instance history of anxiety troubles, hypochond riac attitud es and beliefs, role im p airm ent, changes in fu nctional statu s, m ed ical co -m orbid ity, etc. The assessm ent of the anxiety states that occurred d uring therapeutic sessions w as based on the patient's d etailed d escription of evoked feelings and on observation of visible behavioral changes. The intensity of the states w as expressed by the p atient as a comp arison w ith the strongest analogous state experienced in the past. The measure of conviction, w ith w hich the patient held his w rong belief w as based on its evaluation on a graphical scale. The present state of neurotic psychopathology w as assessed by Knobloch's Inventory of neurotic symptoms N 5, w hich gathers d ata about the prevalence and intensity of 33 frequent neurotic symptoms. The anxiety states ind uced d uring the sessions w er e removed by a proced ure based on a progressive muscle relaxation technique. The attempt to correct neurotic belief started from the first session and the proced ure used in it evolved in the course of the intervention accord ing to the information obtained in a parallel d iagnostic investigation. Its basic id ea w as to offer the patient sufficient factual and experiential material for an attitud e change. In the latter case it comprised m aterial from hierarchically d ifferent brain mechanisms supposed ly engaged in the form ation and m aintenance of the belief.

Type of threat
From basic threat cond itioning situations (threat to som atic or mental integrity, threat to social status, and threat of major loss) the threat to life by constriction of a irw ays w as d etermined as a d ominant recurring su bjectively perceived menace. The perception of the threat w as not the chief complaint; nevertheless, w hen d irectly asked , the patient realized this aspect of his health p roblem s w ithout great hesitation. The level of threat fluctuated betw een high d uring anxiety states and low in period s betw een attacks.

Key threat stimuli
The d ysp nea linked with a feeling of pressure on the upper sternu m w as established as the key symptom. The p atient believed that th e d yspnea that w as associated w ith the sym ptom could cause suffocation and d eath. Every anxiety state that evolved d uring therapeutic sessions w as preced ed by this sym ptom. Moreover, the w hole set of subjective feelings and specific behaviors of anxiety states comprised tachypnea, impaired sw allow ing, feeling of tension, d izziness, inner trembling, sw eating, palpitations, imp aired seeing, restlessness, visible attempts to sw allow, and rapid eyelid movements. The anxiety states occurring d uring the sessions (35 states) evolved either spontaneou sly in the context of the patient's reports about past significant life situ ations or issued from the therapist's attemp ts to ind uce them intentionally.

Intentional evocation of threat states
At first d iagnostic and soon afterw ard s therapeutic reasons led us to intentional evocation of anxiety states. The states w ere ind uced by im agining past situ ations in w hich anxiety states evolved (4 cases) or by various maneuvers, such as mild physical load , Rhom berg postur e, orthostatic response, apnea, hyperventilation, and increase of intrap ulm onary pressure (27 cases). The latter proced ure w as finally selected for therapeutic app lication of evoked anxiety (20 cases). The increase of intrap ulm onary pressure reliably ind uced the key sym ptom until the last session in w hich intentionally evoked anxiety w as u sed (session N o. 13). The intensity of ind u ced anxiety rem ained ap p roxim ately at 50 % of its m axim al p ossible valu e all over this period .

Structure of the pathogenic belief
The brain substratu m of the pathogenic belief could be im agined as a nonspecific evalu ation system enabling transfer of information and its comp arison w ith mem ory and several d istinct mem ory record s related to the neurosis. At the beginning of C B intervention the patient used the following chain of arguments for explaining the perceived menace to life: pressure on upper chest signals constriction of the upper airways lead ing to insufficient lung ventilation w hich could cau se suffocation (conclusion further sup ported by the accomp anying d ysp nea). After accepting factual correction of this mistaken cognitive evalu ation (in the 5th session), the patient explained his p ersisting high conviction about the life -threatening character of his attacks by stating that he ju st feels it so. These tw o rep orts su ggest imp lication of at least tw o mem ory systems in the structure of the patient's neurotic beliefmemory for facts and associative mem ory. As revealed by the analysis of the p atient's med ical history, the association betw een pressu re on chest or d ysp nea, and the state of threat to life could take place in the p ast d uring an episod e of his first intense anxiety state, w hich w as consid ered as a heart attack. This association w as strengthened m any times after this event d uring the subsequent neurotic d evelopment and represented a m ore important comp onent of the belief becau se of its biological d eep roots. It is conceivable that a cognitive exp lanation of the symp tom significance appeared second arily.

Procedure for correcting the pathogenic belief
The main d em onstrations and argu ments offered to the patient for correcting his interpretation of the key symptom were as follow s: (1) the upper airw ays rem ain open even in the anxiety state; (2) the control of breathing is basically an au tomatic process; (3) respiratory muscles are und er volu ntary control even in anxiety; (4) the key symptom and consecutive anxiety can be intentionally ind uced and removed ; (5) reorientation of attention can m od ify the intensity of anxiety; (6) new anxiogenic stimuli and situ ations can be created by fear cond itioning; (7) none of the hund red s of anxiety states experienced in the p ast compromised the p atient's life; (8) the therapist w hose basic professional imperative is not to harm his p atient ind uced intentionally these "highly d angerous states"; (9) d em onstration of the d efense system role in a misinterpretation of the key symptom and in other aspects of the anxiety d isord er. Develop ment of the p atient's conviction w ith w hich he held the belief that d yspnea w as a life-threatening state is d ocu mented in Table 1. Further d ata presented in Table 1 d em onstrate a consid erable relief from neurotic symp toms at the end of intervention and an increased ability to m aster everyd ay anxiety states by non-pharmacological proced ure. Until the last session the patient rep orted frequent occurrence of such states; how ever, contrary to the period before correction of his neurotic belief these states w ere of short d uration, and though qu alified as d isagreeable, they w ere not consid ered as life-threatening. The p atient w as able to stop their d evelop ment w ithin a period of tens of second s by a special behavioral proced ure w hich issued from CB intervention. In fact he used his ow n proced ures for mastering anxiety states even in the p ast, prior to the intervention, but their efficacy w as incomp arably low er. Another noticeable change w hich evolved after correction of the p atient's neu rotic belief w as his increased ability to follow detailed genesis of anxiety states. He repeatedly reported on new, so far unid entified anxiogenic stimuli and situ ations.

D ISCUSSION
Much of our present und erstand ing of the brain mechanism s involved in the hu man anxie ty comes from stud ies of fear cond itioning in animals. The stud y of neurobiologic basis of fear and anxiety started at the beginning of the 20th century and its course can be marked by several m ajor d evelop m ents (Cannon, 1929;Pap ez, 1937;Klü ver & Bu cy, 1939;MacLean, 1952). This research accu mulated d ata w hich finally m ad e it possible to d raw the brain system med iating the d efense against threat (Aggleton & Mishkin, 1986;LeDou x, 1987). The application of this animal mod el for the explanation of hu man emo tions in the field of neurotic anxiety have brou ght better und erstand ing of the pathogenic mechanisms of these d isturbances and very efficient therapeutic proced urethe cognitive behavioral therapy.
In the context of d efense system fu nctioning the curr ent stud y concerns the d urability of the fearful experience. Its main resu lt w as the d emonstration of an alm ost comp lete d issip ation of neurotic belief, w hich represented the key pathogenic mechanism in the case of panic d isord er stud ied . This result w as obtained in sp ite of the fact that the em otiogenity of key threat stimuli rem ained intact. The find ing is consistent w ith observations about the frequent return of anxiety after successful treatment in hu man (Rachman, 1989) and about the reinstatement of fear responses follow ing successful extinction after placing the anim al into a d ifferent context (Bouton & Sw artzentruber, 1991;Jacobs & N ad el, 1985) and suggests that overcoming fear involves acquiring completely new memories. Thu s, in our case the patient learned in some new context that the key stim uli no longer signal threat to live.
The m ore general contribu tion of the stud y w as the d emonstration how recent research achievements in the neuroscience of d efense behavior could influence practical m anagem ent of anxiety d isord ers. The opinion that neurotic anxiety is in the m ajority of cases an ad equ ate response to a threat cou ld even have a breakthrough character in this clinical d omain. In the d iagnostics of these d isord ers attention shou ld be focused on the stim uli or situ ations w hich the patient evaluates as threatening, on circum stances of their form ation and long -lasting persistence, on the character and d uration of ind uced threat states, and on mechanism s w hich are able to m ake other efficient threat stim u li from p reviou sly neu tral or benign ones. In psychotherap y this new und erstand ing w ould enable to formulate goals d irected to key pathogenic mechanisms, su ch as misinterpretation of the significance of d efinite stimu li, etc.
In the light of present know led ge about the fu nction of the d efense system, the story of our patient could be retold in the follow ing w ay. H is neurotic troubles started in the past by an event w hose mem ories w ere very vivid and reports on it surprisingly d etailed in spite of the fact that it happened 14 years ago. At that time, in the context of a long -lasting w orking overload , the p atient experienced an intense state of threat, w hich comprised severe d yspnea, feeling of suffocation, feeling of airw ays constriction, signs of hypocap nea, and intense fear of life because he consid ered the state as a m anifestation of myocard ial infarction or some other life-compromising event. Thou gh any d etailed analysis of the resulting memory record was not possible d ue to the time elapsed , some id ea about its structure could be formulated . Sim ilarly as the m em ory from fear learning in anim al exp erim ents (Ku kleta , 1972), w hich w as show n to consist of separate comp onents, the record of the event had to have mu ltiple brain representation. The particip ation of a d eclarative memory system for the events w as certain as w as the p articipation of a system for learned facts. The former created a temporarily categorized record of the w hole event, the latter enabled evalu ation of the health risk of the situ ation. Another mem ory comp onent w as created by the mechanism of emotional associative learning, w hich linked variou s sensory aspects of the event w ith threat to life. Thorough clinical examination w hich follow ed the event exclud ed any serious pathology and this conclu sion influenced the mem ory comp onents, but not in the same w ay. N ew , m ore recent inform ation abou t med ical examinations w as ad d ed to the register for events and factu al memory w as upd ated by new d ata abou t his health state. Contrary to these favora ble mod ifications of cognitive mem ory comp onents the malignant significance of bod ily stimuli, w hich w as obtained by associative learning, rem ained untouched . These associations evid ently became the core of future neurotic belief in w hich the symptoms inte rpreted as signs of p ossible suffocation (pressure on upper chest, d ysp nea) played a lead ing role. Sporad ic anxiety states happening in the follow ing years prevented extinction of these associations and contribu ted to further neurotic d evelopment. Five yea rs before the intervention, short-lasting, transitory constrictions of the upper esophagus enlarged the set of anxiety symptoms. This fu nctional d isturbance of esophageal peristalsis transformed eating into a life-threatening activity w ith perceived threat d epend ent on the w ater content of the sw allow ed m orsel.
The formulation of the chain of causes and consequences in the neurotic d evelopment of our p atient w as based on verifiable d ata from the p atient's med ical history, on testing the emotiogenity of the stim uli selected , and on the know led ge of brain memory mechanisms. In conclusion, the stud y attem pted to point ou t some reserves in the d iagnostics of mechanism s implicated in ind ivid ual neurotic d evelopment and to show how focusing on these mechanism s can serve in the d esigning of efficient cognitive behavioral therapeutic proced ures.