Anxiolytic Effects of Transcranial Magnetic Stimulation—An Alternative Treatment Option in Anxiety Disorders?

J Neural Transm (2009) 116:767–775 DOI 10.1007/s00702-008-0162-0

BIOLOGICAL PSYCHIATRY - REVIEW ARTICLE

Anxiolytic effects of transcranial magnetic stimulation—an alternative treatment option in anxiety disorders?

Peter Zwanzger Æ A. J. Fallgatter Æ M. Zavorotnyy Æ F. Padberg

Received: 15 April 2008 / Accepted: 18 November 2008 / Published online: 10 January 2009 Ó Springer-Verlag 2008

Abstract In contrast to major depression, only few Keywords Anxiety disorders Á Panic Á PTSD Á studies are available so far on the effects of repetitive Treatment Á Transcranial magnetic stimulation Á transcranial magnetic stimulation (rTMS) in anxiety dis- rTMS orders. In order to summarise available data concerning the putative anxiolytic action of repetitive rTMS, a systematic literature review was carried out. Although interpretation Introduction of the results is difficult because of a large variety of used treatment protocols and the lack of a placebo-controlled Originally introduced in 1985 as a method for non-invasive design in the majority of studies, there is evidence for focal brain stimulation (Barker et al. 1985) transcranial anxiolytic action of rTMS both from preclinical trials and magnetic stimulation (TMS) has been studied both as a studies in humans. Based on the idea of interhemispheric diagnostic and therapeutic tool in neuropsychiatry for more imbalance and/or deficits in cortico-limbic control as a than 20 years. In its repetitive form (rTMS) the technique model for human anxiety, inhibitory rTMS of the prefrontal has been investigated extensively as a therapeutic option in cortex has been shown to exert beneficial effects in a major depression. Several controlled studies and meta- number of studies in healthy subjects, patients with PTSD analyses have demonstrated antidepressant effects of rTMS and panic disorder. However, to further elucidate the of the dorsolateral prefrontal cortex (DLPFC) (e.g. Burt putative anxiolytic action of rTMS in patients with anxiety et al. 2002; Martin et al. 2003; Couturier 2005; Gross et al. disorders future studies have to be conducted addressing in 2007). However, from two recent, large, randomized and particular the limitations of the studies mentioned above. placebo-controlled multicenter studies, only one supported an antidepressive effect of rTMS (O’Reardon et al. 2007), the other one not (Herwig et al. 2007). Besides major depression, anxiety disorders represent one of the most frequent groups of psychiatric disorders (Kessler et al. 2005). Amongst available treatment strategies psychotherapy and pharmacotherapy or their P. Zwanzger (&) Á M. Zavorotnyy combination are recommended as first line treatment Department of Psychiatry, University of Munster, according to current treatment guidelines (Bandelow et al. Albert-Schweitzer-Strasse 11, 49149 Mu¨nster, Germany 2002; Zwanzger and Deckert 2007). Although available e-mail: [email protected] treatment is safe and effective in many patients, about F. Padberg 25% of patients do not respond to treatment and show a Department of Psychiatry and Psychotherapy, high risk of chronicity (Ballenger 1998; Barlow 2002). Ludwig-Maximilian University Munich, Munich, Germany In contrast to major depression, in anxiety disorders non-pharmacological, biological treatment strategies are A. J. Fallgatter Department of Psychiatry, Psychosomatics and Psychotherapy, currently not available as an additional treatment option in University of Wu¨rzburg, Wu¨rzburg, Germany therapy refractory cases. 123 768 P. Zwanzger et al.

Amongst brain stimulation techniques, solely rTMS has in turn be associated with the increased experience of fear been investigated so far with regard to putative anxiolytic in these patients and with their inability to suppress emo- properties. However, only very few studies are available so tional or disorder-relevant information. far on the impact of rTMS on anxiety disorders. In this Another theory, which has been formerly proposed for paper, an overview over reports on the effects of rTMS in human anxiety is the so-called ‘‘Valence-hypothesis’’. anxiety both in animals and humans will be provided. According to this model, withdrawal-related emotions such Moreover, potential mechanisms by which putative anx- as anxiety are located to the right hemisphere, whereas iolytic effects of rTMS might be mediated will be approach related emotions such as joy or happiness are discussed with regard to future research strategies in the biased to the left hemisphere (Davidson et al. 1999). Along ﬁeld of panic and anxiety. with this hypothesis, there is some evidence that anxiety disorders might be associated with increased right-hemispheric activity (Heller and Nitschke 1998; Van Honk et al. Neuroanatomical basis of fear and anxiety in humans 1998, 1999).

Theories of the processing of fear, anxiety, and related behaviour in humans have been derived from preclinical rTMS protocols for therapeutic interventions models and suggest a network of interconnected neuroanatomical regions including the amygdala, hippocampus, There are two common protocols of rTMS stimulation: thalamus, and the prefrontal cortex (PFC) (LeDoux et al. high frequency rTMS ([5 Hz) and low frequency rTMS 1990; Davis 1992). Within this network, the amygdala has (B1 Hz). High frequency rTMS has been shown to exert been considered as the key structure, responsible for pro- facilitating effects on neuronal excitability. In contrast, low cessing of fear-relevant information and activation of the frequency rTMS (B1 Hz) shows different effects on neu- fear-response both in animals and in humans (Gorman et al. ronal excitability, which is in line with the findings from 2000). electrical stimulation (Post et al. 1997). Preferred processing of disorder-relevant information Post et al. (1997) proposed that rTMS stimulation and focussing selective attention on it is conceived as an parallels animal studies of neuronal plasticity using evoking and sustaining factor for anxiety disorders (e.g. electrical stimulation. High frequency electrical stimula- MacLeod et al. 1986). The ability to suppress this auto- tion is known to induce long-term potentiation (LTP), matic processing is severely impaired in patients with whereas low frequency stimulation induces long-term anxiety disorders. In his functional neuroanatomical stud- depression. Post et al. (1997) proposed that when applied ies, LeDoux et al. (1990) showed that particularly the in the same stimulation frequency identical effects would amygdala plays a major role in these rapidly proceeding be obtained with rTMS. In humans, Chen et al. (1997) pre-attentive processes. The lateral PFC on the other hand studied for the first time the effects of low frequency is thought to be crucially involved in mechanisms under- rTMS on motor cortex excitability. In this study, the lying the regulation of emotion, such as inhibition and group investigated motor evoked potentials (MEPs) after extinction (Ochsner and Gross 2005; Kalisch et al. 2006). a 15 min series of rTMS in a frequency of 0.9 Hz. They Numerous studies have successfully demonstrated an demonstrated that low frequency rTMS of the motor inhibitory top-down control of the PFC on the amygdala, cortex reduced MEPs by 19.5% (Chen et al. 1997). thus providing evidence for a cognitive modulation of Moreover, the effect lasted for at least 15 min after emotional processes by frontal cortical structures (Hariri discontinuation of rTMS treatment. et al. 2000, 2003; Taylor et al. 2003). Interestingly, in Based on these findings, several groups started to subjects with increased state anxiety, a reduced involve- investigate the specific effects of low frequency rTMS in ment of these prefrontal control structures was found psychiatric disorders. It has been hypothesised that low (Bishop et al. 2004). Moreover, patients with panic disor- frequency rTMS might be in particular effective in neu- der showed diminished activation in the inferior frontal ropsychiatric disorders, which are associated with brain gyrus during anticipated fear (Boshuisen et al. 2002). hyperexcitability and related episodic behavioural or cog- Likewise a reduced cerebral blood flow in the right nitive activation (for review see Hoffman and Cavus 2002). orbitofrontal cortex was observed during an unexpected Amongst these disorders, focal dystonia, epilepsy, myoc- panic attack (Fischer et al. 1998). These converging lines lonus, obsessive compulsive disorder Tourette’s syndrome, of evidence suggest an endophenotype for anxiety disor- hallucinations and posttraumatic stress disorder (PTSD) ders that primarily consists of an insufficient activation of have been investigated. Although many of these publica- the PFC, which goes along with reduced inhibitory control tions only report case series or single cases the majority of of the amygdala; reduced inhibition of the amygdala would observations suggested that low frequency rTMS might 123 Anxiolytic effects of transcranial magnetic stimulation 769 exert beneficial effects in this group of disorders (Hoffman For evaluation of anxiety-related behaviour an elevated and Cavus 2002). plus-maze test was performed. Although pronounced Recently, a new rTMS stimulation protocol was effects have been found in active coping strategies during developed (Huang et al. 2005) using a so-called theta- a forced swim test after rTMS in the HAB group and not burst pattern. In its intermittent form, theta-burst stimu- in the LAB group, no significant changes were obtained lation exerts a facilitating effect mimicking LTP in animal when results of the elevated plus-maze test were analysed studies (e.g. Hess and Donoghue 1999), while continuous (Keck et al. 2001). Moreover, two studies have described TBS protocols induce inhibitory effects on neuronal anxiety inducing properties of rTMS treatment in animals. activity. In humans, intermittent TBS, applied to human These two studies have investigated the effects of rTMS motor cortex, led to significantly increased facilitation treatment for 10 days (150% motor threshold, 15 Hz) on (Huang et al. 2005). The facilitating effect of a single anxiety-related behaviour and have found that rTMS TBS session lasts far more than 30 min, i.e. longer than under these circumstances leads to a pronounced increase effects observed after conventional high frequency rTMS in anxiety-related behaviour (Isogawa et al. 2003, 2005). (cf. Arai et al. 2007); even more impressive, Nyffeler Taken together, the majority of preclinical studies do not et al. (2006) described TBS effects on the excitability of confirm a putative anxiolytic action of rTMS in animals. the visual cortex lasting for up to 24 h (Nyffeler et al. However, compared with the Kanno study the later reports 2006). It seems that using TBS, effects comparable to show important differences with regard to stimulation those of high frequency rTMS can be evoked, but with the parameters and study design. First, stimulation intensity advantage of having putative treatment effects maintained was markedly higher in the later studies when compared longer by using a less aversive, shorter stimulation to the study by Kanno et al. (2003). Second, studies by protocol. Isogawa used a 10-day stimulation treatment protocol, when anxiogenic effects were observed (Isogawa et al. 2003, 2005). Finally, all of these studies used high fre- Evidence for anxiolytic effects from preclinical studies quency rTMS. This form of magnetic stimulation has largely failed to show anxiolytic effects in humans. A large number of preclinical studies have been conducted Unfortunately, no studies are available so far on anxio- investigating effects of TMS in animal models. Most lytic effects of rTMS in animals using a low frequency studies have focused on putative antidepressant-like effects treatment protocol. of TMS employing, i.e. the forced swim test (FST; Fle- ischmann et al. 1995; Keck et al. 2001; Tsutsumi et al. 2002; Zyss et al. 1997). Moreover, also investigations Studies in healthy volunteers of neurochemical aspects confirmed antidepressant-like properties of TMS (e.g. Ben-Shachar et al. 1997 or Ben- First evidence for a putative anxiolytic action of rTMS in Shachar et al. 1999). humans was derived from studies in healthy volunteers. In view of these findings, it was discussed whether These first studies were based on the assumption of TMS would exert also anxiolytic effects along with anti- increased right-hemispheric activity in anxiety disorders depressant properties. So far, only few preclinical studies according to the ‘‘Valence-hypothesis’’ (Heller and Nit- have focused on anxiolytic properties of TMS using schke 1998; Van Honk et al. 1998, 1999). Based on this anxiety specific tasks in animals. Kanno et al. (2003) theory, van Honk and Schutter conducted a series of investigated the effects of TMS in Wistar rats using the experiments in healthy subjects and showed that supra- elevated plus-maze test. After a 3-day series of rTMS a threshold low frequency rTMS of the right DLPFC results significant improvement in anxiety-related behaviour was in decreased anxiety-related behaviour. In particular, they observed. rTMS treated animals spent significantly more demonstrated that active low frequency rTMS in healthy time on the open arms of the elevated plus-maze and subjects compared to sham rTMS is associated with a showed an increased number of open-arm-entries (Kanno decrease in self-rated anxiety along with a contralateral et al. 2003). Moreover, this effect was accompanied by a increase in theta-EEG activity (Schutter et al. 2001). reduction of elevated plus-maze challenge associated 5- Moreover, low frequency rTMS of the right DLPFC is HT release as revealed by in vivo micro-dialysis measures followed by selective attention to angry faces, which was (Kanno et al. 2003). Keck et al. (2001) investigated interpreted as an anxiolytic effect through right-hemi- putative anxiolytic effects of rTMS in Wistar rats strati- spheric inhibition (d’Alfonso et al. 2000). In contrast, low fied for high (HAB) and low (LAB) anxiety-related frequency rTMS of the left DLPFC resulted in the opposite behaviour. Rats were treated with high frequency rTMS effect (d’Alfonso et al. 2000). The same effect was (20 Hz, 1,000 stimuli per day) in two 3-days series. observed when healthy subjects underwent an emotional 123 770 P. Zwanzger et al. stroop task indexing selective attention to masked and low frequency group did not improve (Cohen et al. 2004). unmasked fearful faces. It was hypothesised that rTMS Only minimal effects on PTSD symptoms were obtained would modulate only selective attention in the unmasked after a 1 Hz rTMS over the left DLPFC, although a task, the latter being under inhibitory cortical control. In decrease in anxiety measures was observed (Rosenberg fact, the authors found that rTMS significantly reduced et al. 2002). vigilant attention for fearful faces in an unmasked task (Van Honk et al. 2002). Panic disorder Taken together, these studies suggest that the putative anxiolytic action of low frequency rTMS of the right In panic disorder, no controlled studies have been con- DLPFC may be related to a reduction of right prefrontal ducted so far. Garcia-Toro et al. (2002) reported on three activity which may normalise interhemispheric dysbalance patients suffering from panic disorder who mildly in anxiety disorders according to the ‘‘Valence-hypothe- improved after low frequency rTMS of the right DLPFC, sis’’. An overview over the studies in healthy volunteers is whereas high frequency stimulation could not exert bene- given in Table 1. ficial effects to these patients. Mantovani et al. (2007) investigated six panic disorder patients using 1 Hz rTMS over a 2-week treatment period and found a marked Studies in patients with anxiety disorders improvement of panic and anxiety (Mantovani et al. 2007). Interestingly, in this study anxiolytic effects were apparent There are only few studies on anxiety disorders available as early as in week 1. Another report showed a marked so far. These reports have mainly investigated patients improvement of both anxiety and occurrence of panic suffering from PTSD or panic disorder. Stimulation pro- attacks after low frequency rTMS of the right DLPFC as tocols have largely followed protocols employed in studies well as a reduction of panic symptoms experimentally with healthy volunteers. No studies have been carried out induced by cholecystokinin-tetrapeptide (CCK-4) and the in patients with social anxiety disorder or generalised CCK-4-induced ACTH and cortisol release after a 2-week anxiety disorder so far. treatment period (Zwanzger et al. 2002). Based on these results, Zwanzger et al. (2007) investi- PTSD gated whether inhibitory effects mediated by low frequency rTMS would influence panic and anxiety after a The majority of studies have been conducted in patients single session of rTMS treatment (Zwanzger et al. 2007). with PTSD. In an open study, Grisaru et al. (1998) inves- This study was designed as a sham-controlled proof-of- tigated the impact of rTMS in 10 patients with PTSD after concept study and employed the CCK-4 panic-model low frequency rTMS over the motor cortex (Grisaru et al. (Bradwejn et al. 1990; Eser et al. 2007) in healthy volun- 1998). In this study, patients reported a decrease of PTSD teers. Eleven subjects underwent a CCK-4 panic challenge symptoms such as avoidance, anxiety and somatization after treatment with active or sham rTMS in a cross-over following one session of rTMS (Grisaru et al. 1998). design. When compared with sham treatment, active rTMS McCann et al. (1998) described beneficial effects in did however not influence panicogenic effects of CCK-4. patients with PTSD after rTMS treatment. This group Moreover, no changes were observed in CCK-4-associated reported on two patients suffering from treatment resistant stimulation of the hypothalamic-pituitary-adrenal system depression and PTSD. They showed that, in contrast to (Zwanzger et al. 2007). It was concluded, that a single 20 Hz rTMS, application of low frequency rTMS over the session of rTMS might be not sufficient enough to overrule right DLPFC with a frequency of 1 Hz led to a marked strong anxiogenic effects after intravenous neuropeptide improvement of PTSD core symptoms along with sub- administration. stantial reductions in PFC metabolism measured by means Prasko et al. (2007) compared active and sham rTMS of proton emission tomography. as an add-on strategy to standard pharmacological treat- In a more recent study, patients with PTSD were ment with a serotonin-reuptake inhibitor (SSRI). Although investigated using a double-blind sham-controlled design clinical symptoms improved in both groups under anti- (Cohen et al. 2004). Twenty-four patients were randomly depressant treatment, groups did not differ with regard to assigned to 10 sessions of either a 1 or 10 Hz or sham active or sham rTMS treatment (Prasko et al. 2007). rTMS. It has been shown that in contrast to prior reports Taken together, data on the effects of rTMS in anxiety high frequency rTMS of the right DLPFC with 10 Hz disorders is still inconsistent so far. In fact, several reports improved both core symptoms of PTSD (re-experiencing showed beneficial effects in patients with anxiety disor- and avoidance) and overall anxiety levels, whereas the ders. However, conflicting results were reported in PTSD

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Table 1 Overview of rTMS studies in patients with anxiety disorders

Diagnosis McCann et al. Grisaru et al. Garcı´a-Toro et al. Rosenberg et al. (1998) (1998) (2002) (2002) PTSD PTSD PD PTSD

Design Case report Open label Open label in 2 phases Open label Randomized – – – ? Sham –––– Challenge –––– N 2103;212 Sex ratio (M:F) 0:2 7:3 na 12:0 Age (years) 29 and 42 21–53 na 54 ± 9.1 Handedness Both na na na Site of stimulation Right frontal Left motor cortex Right PFC; left PFC Left PFC Right motor cortex No. of sessions 17; 30 1 10 10 Stimulated sites per 1211 session Shape of the coil Figure 8 Angular-shaped na Figure 8 Intensity 80% MT 100% MC 110% MT 90% MT Frequency (Hz) 1 0.3 1; 20 1 versus 5 No. of trains 1 2 30 15 Train duration (s) 1,200 900 60; 2 40 versus 8 Intertrain interval (s) ? 300 na 20 versus 52 Pulses per site per 1,200 270 1,800; 2,400 6,000 session: Psychopathology PTSD symptoms scale CGI, IES, SCL-90, na SCID; HAM-D; POMS; measure instruments USC-REMT; MISS

Time of rating na T0, T1, T24 h na T0, T7 days, T14 days, T30 days,T60 days

Aparative measurement FDG18-PET – – – RESULTS ; Core symptoms ; Core symptoms of Clinically non-relevant 75% of—antidepressant of PTSD PTSD modest and partial response after rTMS ; CGI symptom (3/3) after 50%—response sustain 1 Hz rTMS The effect was rather at 2-month follow-up mild and transient. No effects after 20 Hz ; Anxiety, hostility, and rTMS insomnia (only minimal) Diagnosis Zwanzger et al. Cohen et al. Prasko et al. Mantovani et al. (2002) (2004) (2007) (2007) PD PTSD PD PD

Design Case report Double-blind Double-blind Open label Randomized – ??– Sham – ??– Challenge CCK-4 50 lgiv––– N 1 24156 Sex ratio (M:F) 0:1 17:7 3:3 Age (years) 52 22–68 18–45 50 ± 18.46 Handedness nr nr nr Right Site of stimulation Right DLPFC Right DLPFC Right DLPFC DLPFC No. of sessions 10 10 10 10 Stimulated sites per 1111 session

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Table 1 continued Diagnosis Zwanzger et al. Cohen et al. Prasko et al. Mantovani et al. (2002) (2004) (2007) (2007) PD PTSD PD PD

Shape of the coil Figure 8 nr Figure 8 Figure 8 Intensity (% MT) 110 80 110 100 Frequency (Hz) 1 1 versus 10 versus 11 sham No. of trains pro 1na14 session Train duration (s) 1,200 5 or 2 1,800 300 Intertrain interval (s) ? 55 or 58 ? 120 Pulses per site per 1,200 nr 1,800 1,200 session: Psychopathology API, PSS, HAM-A, Self-report PTSD CGI, HAM-A, SCID; SCRAS; measure BPAS checklist; PDSS, BAI HAM-A; HAM- instruments treatment D; CGI; PDSS; outcome PTSD BDI; SCL-90; scale; clinician SASS administrated PTSD; scale; HAM-A; HAM-D

Time of rating T0, T1 T0, T5 days,T10 days, T0, T14 days, T28 days T0, T7 days,T14 days T24 days Aparative HR, Cortisol, ACTH nr nr nr measurement RESULTS ; Anxiety ; Core symptoms of No differences ; CGI, panic and ; CCK-4-associated PTSD during 10 between activ anxiety (5/6) after panic symptoms daily sessions of versus sham the second week 10-Hz rTMS at rTMS as add on and at 6 month of 80% MT over the SSRI follow-up right DLPFC

DLPFC dorsolateral prefrontal cortex, GAD generalised anxiety disorder, HR heart rate, LPFC lateral prefrontal cortex, MC machine capacity, MDD major depression disorder, MT motor threshold, PD panic disorder, PFC prefrontal cortex, PTSD post traumatic stress disorder, SSRI selective serotonin-reuptake inhibitor; CCK-4 cholecyctokinine tetrapeptide, T0 anxiety rating at baseline before stimulation, T1 anxiety rating immediately after the stimulation, Txmin, Txh, Txd mood rating after n min/h/days (e.g. T30 min anxiety rating 30 min after the stimulation with regard to stimulation frequency. In panic disorder, systematically explored in rTMS studies, which have been most reports showed improvement of symptoms when low following concepts of interhemispheric imbalance. There- frequency rTMS was administered. Nevertheless, most fore, in future studies facilitating TMS protocols might be studies are hampered by small sample size and lack of a applied in order to stimulate prefrontal cortical areas that placebo-controlled design. An overview over all this presumably exert top-down control on the amygdala during studies is provided in the Table 2. emotional processing. With regard to studies in healthy volunteers, it may be generally questionable whether rTMS effects observed in Conclusion and perspectives anxiety-induction paradigms in healthy subjects can be transferred to anxiety disorder patients as cortex excit- Current evidence of anxiolytic effects of rTMS in pre- ability characteristics may diverge between healthy clinical model and pilot patients or studies is still subjects and patients. rTMS-induced effects on cortex inconsistent. However, because of its non-invasive nature, excitability might in turn depend on pre-activation and rTMS is a promising experimental intervention to further excitability of the target region. Thus, future research investigate the function of the PFC and other cortex regions should focus on patients suffering from anxiety disorders in relation to the amygdala. Surprisingly, the established combining rTMS with neuroimaging and other experi- concept of a top-down control by the PFC has not been mental, but also clinical measures of anxiety.

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Table 2 Overview of LF-rTMS anxiety-related studies in healthy volunteers Design d’Alfonso et al. (2000) Schutter et al. (2001) van Honk et al. (2002) Zwanzger et al. (2006) Open label Cross-over Cross-over Cross-over

Randomized – ??? Sham – ??? Challenge – – – CCK-4 50 lgiv N 10 12 8 11 Sex ratio (M:F) 0:10 na 4:4 5:6 Age (years) 18–30 28.4 ± 8.9 20–26 26 ± 1 Handedness nr Right Right nr Site of stimulation Right PFC; left PFC Right DLPFC Right PFC Right DLPFC No. of sessions 2 1 1 1 Stimulated sites per session 1 1 1 1 Shape of the coil Figure 8 nr nr Figure 8 Intensity (% MT) 130 130 130 120 Frequency (Hz) 0.6 1 1 1 No. of trains 1 1 1 1 Train duration (s) 900 1,200 1,200 1,800 Intertrain interval (s) ?? ? ? Pulses per site: 540 1,200 1,200 1,800 Measure instruments POMS STAS, STAI nr API, PSS

Time of rating T0, T1 T0, T1, T65 min na T0, T1

Additional measurement PEST, T10 min EEG PEST, T30 min HR, cortisol, ACTH

Results Right PFC rTMS: ; Anxiety at T35–65 min rTMS reduced the vigilant No signiﬁcant differences : Selective attention : Left hemisphere EEG emotional response to in any of measures the unmasked fearful face toward angry faces theta activity at T25–35 min Left PFC rTMS: and T55–65 min ; Selective attention toward angry faces API acute panic inventory, CCK-4 cholecyctokinin tetrapeptide, DLPFC dorsolateral prefrontal cortex, HR heart rate, PEST pictorial emotional stroop task, PFC prefrontal cortex, PSS panic symptom scale

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