Neuroendocrinology Letters Volume 36 No.

3 2015
ISSN: 0172-780X; ISSN-L: 0172-780X; Electronic/Online ISSN: 2354-4716
Web of Knowledge / Web of Science: Neuroendocrinol Lett
Pub Med / Medline: Neuro Endocrinol Lett

Predictors of poor treatment response to

additional CBT in real panic disorder patients:
The role of DLPF, orbitofrontal cortex, parietal
lobule, frontal eye field and amygdala in PD

O R I G I N A L
Aleš Grambal 1,2,4, Zbyněk Tüdös 2,4, Pavel Hok 3,4, Dana Kamarádová 1,4,
Tomáš Divéky 1,4, Petr Hluštík 3,4, Ján Praško 1,4
1 Department of Psychiatry, University Hospital Olomouc, Czech Republic
2 Department of Radiology, University Hospital Olomouc, Czech Republic
3 Department of Neurology, University Hospital Olomouc, Czech Republic
4 Palacky University Olomouc, Czech Republic

Correspondence to: Ales Grambal

University Hospital Olomouc, Department of Psychiatry
I. P. Pavlova 6, 775 20 Olomouc, Czech Republic.
tel: +420 588 443519; e-mail: ales.grambal@fnol.cz

Submitted: 2015-03-31 Accepted: 2015-04-12 Published online: 2015-08-15

Key words: panic disorder; functional magnetic resonance imaging; DLPFC; amygdala;
treatment response prediction; CBT

Neuroendocrinol Lett 2015; 36(3):269–281 PMID: 26313395 NEL360315A09 © 2015 Neuroendocrinology Letters • www.nel.edu

A R T I C L E
Abstract OBJECTIVE: Previous functional brain imaging studies have described various
and contradictory activation findings in patients with panic disorder (PD). Our
study focused on patients with a chronic PD, who were investigated and treated in
a conventional manner, which represents the real PD patients in clinical practice.
METHODS: Continuing their medication, patients were included in a six-week
cognitive-behavioral therapy (CBT) program in the psychiatry department. At
the onset of the study, participants underwent clinical evaluation using standard
scales and were examined using fMRI while listening to verbal threat-related
stimuli contrasted to neutral words. According to the therapeutic outcome, they
were subsequently divided into two groups, responders, and nonresponders and
the two groups were mutually compared.
RESULTS: In non-responders compared to responders, we found increased pre-
treatment activation in dorsolateral prefrontal cortex bilaterally, left orbitofrontal
cortex, left frontal eye field, right parietal lobule and left amygdala. In addition,
both groups showed negative fMRI BOLD correlation with BAI improvement
and positive correlation with CGI improvement across the ROIs. We suggest that
DLPFC over-activation may reveal a lack of cognitive control over emotional
processing, which makes subsequent CBT less effective.
CONCLUSION: Despite several limitations, we found neuroimaging predictors of
poor CBT response, under the conditions of standard clinical practice, in real PD
patients.

To cite this article: Neuroendocrinol Lett 2015; 36(3):269–281

 Aleš Grambal, Zbyněk Tüdös, Pavel Hok, Dana Kamarádová, Tomáš Divéky, Petr Hluštík, Ján Praško

INTRODUCTION methodologies, small sample sizes, and other limita-

tions, it is not possible to integrate the inconsistently
Panic disorder is a severe and often a disabling condi- published findings. Nevertheless, the functional studies
tion with the lifetime prevalence rate of 4.7% (Kessler together with the morphological findings support the
et al. 2005). Although the pharmacological treatment role of brain structures such as the prefrontal cortex, the
of the panic disorder has repeatedly accomplished an anterior cingulate cortex and limbic areas (hippocam-
effect (Jefferson 1997; Andrisano et al. 2013), around pus and amygdala) in the panic response (de Carvalho
20% to 40% of the patients treated with standard pro- et al. 2010).
cedures remain symptomatic (Black et al. 1993; Bande- Among functional MRI studies using the verbal
low & Rüther 2004). The percentage of chronic panic stimulation task, Maddock et al. (2003) used threat-
patients may be higher in the general clinical practice, related words contrasted with neutral words and in
in comparison with the patients selected in clinical this contrast, the dorsolateral prefrontal cortex (BA 46)
studies, who are often less severely ill, younger, and and the posterior cingulate cortex (BA 23 and 30) were
have less co-morbid conditions (Bandelow et al. 2004). significantly more active in panic patients than control
The reasons for treatment resistance in panic disorder subjects, whereas some other areas showed significantly
patients are not clearly understood yet, but Pollacek less activation in the panic patients. A second fMRI
et al. (2000) found six clinical variables consistently study applied the emotional Stroop test and observed
associated with the high-risk poor outcome including increased neural activation in limbic, and frontal regions
panic severity, presence of agoraphobia, co-morbid in PD patients (van den Heuvel et al. 2005). In contrast,
depression, co-morbid personality disorder, duration another study applying a variation of the emotional
of illness, and female sex (Pollack et al. 2000). Despite Stroop test found decreased activity in the left ACC,
extensive research on the etiology and treatment PFC, insula and thalamus, and higher activation in the
of panic disorder, patients with treatment-resistant right brain stem (Zhang et al. 2011). Recent neurosci-
panic disorder remain a challenge to the psychiatrist. ence approaches suggest that neural biomarkers could
Although cognitive therapy, exposure therapy, and CBT improve accuracy in treatment response prediction
appears to be efficacious and efficient in the treatment beyond demographic and clinical predictors (Ball et al.
of anxiety disorders (Otte 2011; Ougrin 2011), only a 2014), but there is a lack of studies focused on the neural
minority of patients has an access to the suitable psy- biomarkers of therapeutic response in panic disorder.
chotherapy. However, CBT seems to be a promising To our knowledge, no previous fMRI study examined
next-step strategy for patients with panic disorder who the prediction of treatment response to adjuvant CBT
did not remit with drug-based therapies (Rodrigues in pharmacoresistant panic disorder patients. Consid-
et al. 2011). Combining drug treatment with cogni- ering previous research findings, we hypothesized that
tive behavior therapy is the most successful treatment poor treatment response will be associated with an
strategy for them (Bandelow et al. 2013). Gorman as the increased activity in the limbic system and the DLPFC
first proposed and later revised a complex neuroana- by threat-related words compared to neutral words.
tomical model of panic disorder and explained the role
of the brainstem, limbic system, and prefrontal cortex. MATERIALS AND METHODS
He also suggested the theoretical pathways mediat-
ing the influence of prefrontal areas onto the limbic Participants were recruited from patients in the Depart-
system in panic disorder (Gorman et al. 1989, 2000). ment of Psychiatry, University Hospital Olomouc in the
The panic patients manifest specific cognitive abnor- years 2009–2012. Inclusion criteria for study participa-
malities, e.g. an explicit memory bias for physical threat tion included the ICD-10 criteria for panic disorder/
words (Lundh et al. 1997), exhibit significantly better agoraphobia, the diagnosis had to be confirmed by the
episodic memory for threat-related words than healthy MINI scale (Sheehan et al. 1998). Patients were consid-
comparison subjects (Coles & Heimberg 2002) as well ered treatment-resistant after treatment failure in the
as disturbed processing of threat-related and negatively outpatient conditions and referral to our department.
valenced words (Maidenberg et al. 1996). The role of Exclusion criteria were depressive disorder (ICD-10
various categories of positive and negative thoughts in criteria for depressive disorder), risk of suicidality,
panic disorder is being discussed (Casey et al. 2004) organic brain disorders, psychotic disorder in history,
and its relationship to prefrontal cortex impact to sub- substance dependence, severe somatic disease, using
cortical fear response (Berkowitz et al. 2007). Despite non-prescribed medication, gravidity or lactation, epi-
their limitations, morphological neuroimaging studies lepsy or pathological EEG, antisocial personality dis-
repeatedly confirmed the presence of structural changes order. All participants were included at random times,
in specific brain regions associated with anxiety control depending on the fMRI examination availability (fMRI
in panic disorder patients (Bremner 2004; Ferrari et team and free space-time). The study was approved by
al. 2008; Del Casale et al. 2013). Furthermore, dozens the Ethics Committee of University Hospital in Olo-
of articles described functional MRI abnormalities in mouc. Informed written consent was obtained from
panic disorder, but, unfortunately, because of various all participants prior to their inclusion in the study.

270 Copyright © 2015 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu

 Predictors of poor treatment response in PD

Twenty-two patients (15 females), with a mean age of many) with a standard head coil. The subject’s head was
32.4±11.9 years, 11 with agoraphobia participated in immobilized with cushions to assure maximum com-
our study. Twenty patients were right-handed accord- fort and minimize head motion. The MR imaging pro-
ing to the Edinburgh inventory (Oldfield 1971). Some tocol included functional T2*-weighted BOLD images
patients also met diagnostic criteria for additional anxi- during task performance and control state. BOLD
ety disorders and/or personality disorders. Long-term images were acquired with gradient-echo echo-planar
medications almost were not modified during the study imaging (30 axial slices parallel to the AC-PC line,
(Table  4). The intensity of the psychopathology was 5-mm thick, repetition time/echo time=2500/41 ms,
measured with the psychiatric rating scales (general flip angle 80 °, field of view=220 mm, matrix 64×64)
assessment of anxiety and depression with scales CGI, to provide 3.4 mm×3.4 mm×5.0 mm resolution. In
BAI and BDI (Table 3). total, 144 images were acquired per each 6-min func-
tional run. Anatomical spin echo T1-weighted images
Treatment approaches (30 axial 5-mm in-plane slices, repetition time/
Patients were treated with their previous long-term echo time=500/15 ms, flip angle 90 °, field of view =
medication, and with an add-on group CBT accord- 230×173 mm, matrix 192×144) and a high-resolution
ing to the therapeutic guidelines in conventional clinic 3-dimensional scan (magnetization prepared rapid
conditions. The doses and types of medications were acquisition gradient echo, MPRAGE) were acquired to
changed minimally (Table 4); benzodiazepines were provide an immediate overlay with functional data and
gradually reduced (1/8 of doses per week). The CBT better anatomical reference. In-plane fluid-attenuated
was performed in a group format according to the inversion recovery (FLAIR) images were used to screen
structured CBT program. It consisted of 25 standard for unsuspected brain lesions.
therapeutic sessions over 6 weeks, including the vicious
circle of panic disorder and agoraphobia, cognitive Data analysis
restructuring, interoceptive exposure and in vivo expo- fMRI data processing was carried out using FEAT
sure, regular aerobic exercise, communication training, (FMRI Expert Analysis Tool) Version 6.00, part of FSL
problem-solving, adjustment of cognitive schemes and (FMRIB’s Software Library, www.fmrib.ox.ac.uk/fsl)
others. A 25% decrease in BAI scale was considered as (Smith et al. 2004). The following pre-statistics process-
a treatment response. ing was applied; motion correction using MCFLIRT
(Jenkinson et al. 2002) slice timing correction using
Threat-related task in fMRI Fourier-space time-series phase-shifting; non-brain
Threat-related stimuli were 10 words (terror, victim, removal using BET (Smith 2002) spatial smoothing
injury, cancer, panic, dangerous, threatening, emer- using a Gaussian kernel of FWHM 8.0 mm; grand-
gency, violence, destroyed) and the control stimuli mean intensity normalization of the entire 4D dataset
were 10 emotionally neutral words (detect, locate, by a single multiplicative factor; high-pass temporal
track, border, margin, measurement, impression, per- filtering (Gaussian-weighted least squares straight line
tinent, arrangement, translation). Words were trans- fitting, with sigma=30.0 s). Time series statistical analy-
lated into the Czech language and used in accordance sis was carried out using FILM with local autocorre-
with the previous study (Maddock et al. 2003). All lation correction (Woolrich et al. 2001). Registration
participants were Czech native speakers, not suffer- to high-resolution structural and/or standard space
ing from impaired hearing. Each word was presented images was done using FLIRT (Jenkinson et al. 2002)
once in pseudorandom order in each 16 s block of 10 and FNIRT. Higher-level analysis was conducted using
words of the same type. Sixteen alternating blocks of FLAME (FMRIB’s Local Analysis of Mixed Effects)
threat-related and neutral words were given over 256 stage 1 (Beckmann et al. 2003). Z (Gaussian‘s T/F)
s following a 32 s baseline. Subjects were instructed statistic images were thresholded using clusters deter-
to listen passively to the pre-recorded stimuli. Audi- mined by Z>3.1 and a (corrected) cluster significance
tory stimuli were presented through fMRI-compatible threshold of p=0.05.
headphones. Sound volume was adjusted so that each First, within-subject contrasts between the threat-
participant could hear the stimuli properly. Participants related and neutral words were computed. Next, sev-
had their eyes closed during the auditory stimulation. eral group-level contrasts were employed for whole
After the scanning, subjects were questioned about brain analysis in order to fully explore the data: global
stimulus audibility, the words valence (unpleasant, mean pooled across all subjects to compare the effect
pleasant, or neutral) and their emotional state during of threat-related and neutral words, comparison of
the scan. No participant had panic symptoms during non-responders and responders to find expected brain
the investigation. activation differences, and region of interest analysis
focused on amygdala bilaterally. The resulting clus-
Image acquisition ters of activation were superimposed on T1-weighted
Magnetic resonance imaging (MRI) data were acquired Montreal Neurological Institute (MNI) standard brain
on a 1.5-Tesla scanner (Siemens Avanto, Erlangen Ger- (Grabner et al. 2006) and their anatomical locations

Neuroendocrinology Letters Vol. 36 No. 3 2015 • Article available online: http://node.nel.edu 271
 Aleš Grambal, Zbyněk Tüdös, Pavel Hok, Dana Kamarádová, Tomáš Divéky, Petr Hluštík, Ján Praško

were derived from the Harvard-Oxford brain atlas (Fra- improvement was 56.5±19.5% and 39.9±38.8% in
zier et al. 2005; Desikan et al. 2006) and probabilistic responders. Responders (R) and non-responders (N)
cerebellar atlas (Diedrichsen et al. 2009) incorporated differed significantly in BDI 1 (pretreatment), BDI-R 1
in FSL. The analysis of between-group differences was was 13±7 (BDI-N 1 was 23.4±9.5), age-R was 29.7±6.1
carried out using a two-sample paired t-test, yield- (age-N 40.4±9.5) and gender (number of females in
ing two contrasts: non-responders > responders. In a R/N groups was 9/6). None of the patients met the
post-hoc analysis, we inspected the underlying group clinical criteria for depression. No significant differ-
effects within each cluster by extracting their mean Z ences were found in objective CGI 1, BAI 1, handedness
scores from the contrasts. Next, we transformed the (right-handed R/N was 10/10), medication. No signifi-
clusters into each subject’s functional space and calcu- cant changes in the used medication were made during
lated the single-subject mean Z scores and beta value, the CBT treatment (Table 4). After the six weeks of CBT
as implemented by Featquery tool in FSL. Each cluster treatment, responders and non-responders differed sig-
was classified as arising from activation, deactivation or nificantly in BAI 2, BDI 2, CGI 2 (post-treatment). CGI
as a combination of both. This classification was done improvement was 2.1±0.7 in responders and 4.3±0.6 in
based on the sign of the calculated mean Z scores and non-responders. BAI-R improvement was 56±19.8%
beta scores and the difference between the correspond- against –9.6±24% of BAI-N and BDI changes was
ing absolute values, as measured in the underlying con- 39.9±38.8% for BDI-R and 8.3±23.6% for BDI-N.
trasts. To find a correlation between the subjects, the
individual comparison of Z scores and beta scores to Threat-related vs. neutral words fMRI
clinical scales was performed. Global mean analysis of within-subject contrasts pooled
across all 22 participants demonstrated significant dif-
RESULTS ferences in response to threat-related words compared
to neutral words (Figure 1). Both responders and
Groups characteristics and treatment outcomes non-responders showed stronger activation in the left
50% of panic patients included in our study showed frontal and temporale pole, left frontal orbital cortex,
a  sufficient response to adjuvant CBT treatment (BAI left dorsolateral prefrontal cortex, left inferior frontal
improvement of 25% at least) and mean BAI and BDI gyrus – pars triangularis, left middle frontal and supe-

Tab. 1. Threat-related words compared to neutral words across all PD subjects. For corresponding visualization see the Fig. 1.
Structure Claster Cluster Volume X Y Z
Structure Voxels
index index volume % CV (mm) (mm) (mm)
GM Broca’s area BA45 L 14 6 2715 1200 44.2 –52 26 –12
Left Inferior Frontal Gyrus, pars triangularis 8 6 2715 377 13.9 –48 36 0
Left Temporal Pole 14 6 2715 921 33.9 –40 26 –32
Left Frontal Orbital Cortex 64 6 2715 435 16.0 –52 26 –12
Left Frontal Pole 0 6 2715 597 22.0 –46 38 0
Left Superior Frontal Gyrus 4 5 921 332 36.0 –4 38 48
Right Superior Frontal Gyrus 5 5 921 197 21.4 6 46 40
Left Frontal Pole 0 5 921 143 15.5 –8 48 40
Left Middle Frontal Gyrus 6 4 346 342 98.8 –40 12 48
GM Broca’s area BA44 L 12 4 346 213 61.6 –40 12 48
GM Premotor cortex BA6 L 90 4 346 81 23.4 –40 6 52
Left Angular Gyrus 40 3 318 185 58.2 –38 –56 38
GM Anterior intra-parietal sulcus hlP1 L 0 3 318 111 34.9 –38 –56 38
GM Inferior parietal lobule PFm L 30 3 318 83 26.1 –40 –58 40
GM Inferior parietal lobule Pga L 36 3 318 81 25.5 –40 –60 40
Left Supramarginal Gyrus, posterior division 38 3 318 76 23.9 –52 –48 36
Right Crus I (CRBL) 9 2 265 176 66.4 24 –80 –34
Right Crus II (CRBL) 12 2 265 89 33.6 22 –80 –34
Left Cingulate Gyrus, posterior division 58 1 247 157 63.6 0 –40 22
Right Cingulate Gyrus, posterior division 59 1 247 86 34.8 2 –42 22

272 Copyright © 2015 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu

 Predictors of poor treatment response in PD

rior frontal gyrus, bilateral posterior cingulate cortex, BAI, BDI, and fMRI correlation
parietal cortex and cerebellum (Table 1). Post hoc analysis showed an individually variable rela-
tionship between fMRI signal and anxiety change after
Group comparison fMRI the CBT. Given the small number of subjects, only an
Patients were divided into responders and non- apparent trend for negative correlation between the
responders according to decrease in BAI scale, using fMRI signal and BAI, BDI, and CGI improvement was
the 25% threshold. Contrast analysis showed no sig- observed in responders and non-responders in BA 46
nificant activation increase in responders compared bilaterally and right superior parietal lobule – BA 5/7
to non-responders in pretreatment activation. On (Figure 3). When we compared all individual fMRI data
the other hand, when we compared non-responders (22 PD subjects) across the cluster-based regions of
to responders, stronger activation in five clusters was interests (ROIs) to BAI (CGI) score improvement, a sig-
found in the non-responder group (Figure 2). Group nificant negative (positive) correlation was present for
differences in response to the threat-related words and BA 46 bilaterally, right superior parietal lobule (BA 5/7),
neutral words were mainly found in the right and left left BA 11 and left frontal eye fields. In the left amyg-
middle frontal gyrus (BA 9/46 – DLPFC), left and right dala, we found significant negative correlation between
inferior frontal gyrus (pars opercular and triangularis, BAI improvement and BOLD signal but only in non-
Broca’s BA 44 a BA 45), left frontal orbital cortex (BA responders. In the right amygdala, there was a positive
11), left frontal eye field (middle frontal and precentral correlation between the severity of anxiety, measured
gyrus), right superior parietal lobule (BA 5/7) and the by BAI 1 and fMRI response before the treatment. Fur-
cortex along the intraparietal sulcus (Table 2). Post hoc thermore, mean fMRI response was significantly nega-
analyzes indicate that this interaction effect was driven tively correlated with BAI improvement (Figure 4) and
by an increase of activation in non-responders and acti- positively correlated with CGI improvement (Figure 5),
vation reduction in responders. No significant differ- across all the ROIs. On the other hand, whereas high
ences were found in the amygdala in ROI analysis; only BDI 1, as a clinical factor predicted a poor response
the trends in higher activity in non-responders were to CBT, BDI change post-treatment showed no cor-
found bilaterally. relation with the measured BOLD signal in the ROIs.

Fig. 1. Threat-related words compared to neutral words across all PD subjects. For corresponding data see the Tab. 1.

Neuroendocrinology Letters Vol. 36 No. 3 2015 • Article available online: http://node.nel.edu 273
 Aleš Grambal, Zbyněk Tüdös, Pavel Hok, Dana Kamarádová, Tomáš Divéky, Petr Hluštík, Ján Praško
Treatment response prediction and left amygdala predicts poor CBT treatment out-
In our chronic PD patient sample, higher score of comes. Moreover, there is a correlation between fMRI
pretreatment BDI predicted the lack of a response to signal before the CBT and BAI (CGI) improvement
psychotherapy. The CBT response measured by BAI in response to therapy. The role of individual regions
decrease (CGI improvement), negatively (positively) of interest will be discussed in the context of clinical
correlates with BOLD activity for treat-related words experience and previous studies. At present, there is
compared with neutral words in all mentioned regions. no consensus yet about the role of brain hemispheres
The higher the activation, the lower the BAI improve- in the performance of specific brain functions. In
ment is and the more pronounced the deactivation, the word processing, Abbassi and co-authors propose the
larger is the improvement. Regional response to panic- hypothesis that the left hemisphere is answerable for the
specific words in the BA 46 bilaterally, left frontal eye automatic early response in emotion words processing,
fields, left BA 11, right parietal lobule and left amygdala whereas the right hemisphere responds to emotional
predicts poor response to CBT. words slowly when attention is recruited by the mean-
ing of these words in a controlled manner. Connection
DISCUSSION between emotion-related structures and attention-
related structures is essential in the elaborated process-
Patients with panic disorder showed significantly ing of emotional words (Abbassi et al. 2011). Regions
greater activation in many regions when listening to with more pronounced activation in non-responders,
threat-related words compared to neutral words. Global associated with the poor CBT response, create compo-
mean analysis results are in accordance with previous nents of attention networks remarkably.
study that used the same stimulation paradigm (Mad-
dock et al. 2003). As we predicted, the BA 46 was acti- Role of the dorsolateral prefrontal cortex
vated by anxiety-prone stimuli, which suggests that BA DLPFC is involved in a range of cognitive and execu-
46 plays a significant role in panic disorder. Higher acti- tive functions, and all complex mental activity requires
vation of DLPFC, right parietal, left prefrontal regions the additional cortical and subcortical circuits with

Tab. 2. Comparison Non-responders > Responders for threat-related words compared to neutral words. For corresponding visualization see
the Fig. 2.
Structure Cl aster Cluster Volume X Y Z
Structure Voxels
index index volume % CV (mm) (mm) (mm)
Right Superior Parietal Lobule (BA 5/7) 35 5 548 369 67.3 26 –48.9 59
Right Postcentral Gyrus (BA 3,1,2) 33 5 548 112 20.4 41.2 –33.1 55.3
Right Precuneous Cortex (BA 7) 61 5 548 27 4.9 11 –49.3 60.3
Right Lateral Occipital Cortex, superior division 43 5 548 15 2.7 35.9 –57.6 49.5
Right Angular Gyrus (BA39) 41 5 548 10 1/8 38 –55.2 49.6
Right Middle Frontal Gyrus (BA 9/46 - DLPFC) 7 4 395 331 83.8 48.3 24.6 30.9
Right Inferior Frontal Gyrus, pars triangularis 9 4 395 36 9.1 54.1 28.7 21
(BA 45 )
Right Frontal Pole - ne BA - orientační 1 4 395 18 4.6 49 35.7 23.6
Right Inferior Frontal Gyrus, pars opercularis 11 4 395 10 2.5 52.5 22.3 26
Left Inferior Frontal Gyrus, pars opercularis 10 3 261 103 39.5 –51.9 17.7 22
(BA 44 - Broca)
Left Middle Frontal Gyrus (BA 9/46 - DLPFC) 6 3 261 81 31.0 –49.7 28 25.9
Left Inferior Frontal Gyrus, pars triangularis 8 3 261 41 15.7 –51.5 31 17.8
(BA 45 broca)
Left Frontal Pole 0 3 261 32 12.3 –47.8 38.3 16.9
Left Frontal Orbital Cortex (BA 11) 64 2 247 174 70.4 –44.8 28.4 –12.3
Left Inferior Frontal Gyrus, pars triangularis 8 2 247 41 16.6 –54.7 30.7 –1.56
(BA 45 Broca)
Left Frontal Pole 0 2 247 25 10.1 –47.1 37.2 –12.6
Left Middle Frontal Gyrus (FEF) 6 1 215 114 53.0 –33.3 1.23 51.1
Left Precentral Gyrus (FEF) 12 1 215 99 46.0 –33.1 –6.5 52

274 Copyright © 2015 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu

 Predictors of poor treatment response in PD

which the DLPFC is connected. There is growing evi- cognitions lead to a greater probability of panic attack
dence that the prefrontal cortex also plays a role in the (Casey et al. 2004). An important difference, which
regulation of emotions in human anxiety disorders. may explain the conflicting findings between the pub-
Emotional dysregulation seems to be caused at least lished studies, is the passive versus active dealing with
in part by differential activity in the prefrontal cortex emotional stimuli. We suggest in our study that DLPFC
(Berkowitz et al. 2007). According to Gorman’s model BOLD response can demonstrate how strongly the PD
of panic disorder, prefrontal cortical areas affect the patients are influenced by passively received negative
response to emotional stimuli. Some studies found stimuli. It is possible that passive listening to negative
reduced (Domschke et al. 2006; Beutel et al. 2010), stimuli leads in non-responders (weak control over
whereas others showed increased (Maddock et al. DLPC) to ruminations of negative topics which is asso-
2003; Dresler et al. 2011, 2012) activity of PFC in PD. ciated with greater prefrontal activity. The suggestion
In our study, we found increased activation of BA 46 is further supported by the fact that observed differ-
bilaterally, which was correlated with poor response ences between responders and non-responders result
to CBT. Moreover, non-responders had more right from increased activation by threat-related words in
greater than left asymmetry in the BA 46. Our results non-responders together with reduced activation in
are ostensibly in contrast with the reported increased responders.
pre-treatment DLPFC activation in responders to brief The significance of the observed relationship
CBT (Reinecke et al. 2014) and the view, that PFC acti- between the treatment response prediction and BDI is
vation might indicate a greater demand for cognitive unclear as well as the cause of high pretreatment BDI
control over emotional responses in PD patients (van values. As we mentioned, none of our patients meet the
den Heuvel et al. 2005). clinical criteria for depression. To consider the under-
The cognitive model of panic disorder (Casey et al. lying mechanisms, we can contrast our results with
2004), emphasizes the role of positive and negative cog- functional imaging in diagnosed depression. In one
nitions in panic disorder. Positive cognitions can mod- study, the major depressive disorder patients showed
erate negative emotions in panic disorder, and negative hypoactivity in the left DLPFC during emotional judg-

Fig. 2. Threat-related words compared to neutral words across all PD subjects. For corresponding data see the Tab. 2.

Neuroendocrinology Letters Vol. 36 No. 3 2015 • Article available online: http://node.nel.edu 275
 Aleš Grambal, Zbyněk Tüdös, Pavel Hok, Dana Kamarádová, Tomáš Divéky, Petr Hluštík, Ján Praško

Tab. 3. Clinical characteristics of subjects.

Sub BAI 1 BAI 2 BDI 1 BDI 2 DES 1 pDES 1 CGI 1 CGI 2 CGIi BAI % BDI %
RI 33 16 21 10 1 0 4 3 2 52 52
R2 36 17 11 6 18 18 5 3 2 53 45
R3 28 19 28 21 4 3 4 3 3 32 25
R4 39 25 12 8 14 11 5 3 3 36 33
R5 17 8 9 7 15 19 3 1 2 53 22
R6 32 6 14 10 3 3 4 1 1 81 29
R7 16 6 20 10 6 1 3 1 2 63 50
R8 17 11 7 11 3 1 3 2 3 35 –57
R9 32 16 9 1 1 0 4 3 2 50 89
RIO 3 1 2 1 3 0 1 1 2 67 50
Rll 25 0 10 0 0 0 3 1 1 100 100
Average 25.3 11.4 13.0 7.7 6 5 3.5 2.0 2.1 56 40
SD 10.4 7.5 7.0 5.7 6 7 1.1 1.0 0.7 20 39
Sub BAI 1 BAI 2 BDI 1 BDI 2 DES 1 pDES 1 CGI 1 CGI 2 CGIi BAI % BDI %
NI 30 35 24 20 7 9 4 4 4 –17 17
N2 32 25 5 2 1 1 4 3 4 22 60
N3 28 27 33 31 10 14 4 4 4 4 6
N4 26 23 31 23 7 1 4 3 3 12 26
N5 29 30 24 28 14 15 4 4 4 –3 –17
N6 16 24 9 10 0 0 3 3 5 –50 –11
N7 30 40 35 30 6 0 4 4 4 –33 14
N8 25 21 26 33 19 18 4 4 5 16 –27
N9 15 13 29 29 34 32 4 4 4 13 0
NIO 32 42 13 9 4 0 4 5 5 –31 31
Nil 32 44 28 30 11 13 4 5 5 –38 –7
Average 26.8 29.5 23.4 22.3 10 9 3.9 3.9 4.3 –10 8
SD 5.8 9.3 9.5 10.1 9 10 0.3 0.7 0.6 24 24
p-value 0.685 0.000 0.012 0.001 0.253 0.252 0.314 0.00004 0.0000003 0.000001 0.04

N - Non-responders and R – Responders. SD - Standard Deviation. 1 – pretreatment, 2 – post-treatment, CGI - Clinical Global Impression,
CGIi – CGI improvement, BAI % and BDI % - percentage improvement. P-values were calculated by Student’s unpaired t-test.

ment and hyperactivity in the right DLPFC during (Wager & Smith 2003). Other authors assume that auto-
attended emotional judgment which correlated with matic processing of semantic information localizes to
depression severity (Grimm et al. 2008). In our study, the left hemisphere and controlled processing to the
firstly, no correlation or trend between the measured right hemisphere (Abbassi et al. 2011). Speculatively,
BOLD response and BDI was found in the studied the stronger activation in right DLPFC observed in our
areas including the right DLPFC. Secondly, there are study may be associated with the stronger emotional
some differences between both the Grimm’s and our meaning in non-responders or the involvement of
studies. In our study, the PD patients engaged in a pas- catastrophic ideas imagination during verbally specific
sive task, and as it was demonstrated, task instructions stimulation.
modulate neural responses to emotional stimuli (Lange
et al. 2003). Wagner and Smith suggested that verbal, Role of Broca’s area and the inferior frontal gyrus
as well as visual working memory processing, leads to Broca’s region, classically considered a motor speech
activation in the DLPFC. Whereas visual tasks usually production area, is involved in action understanding
result in symmetric or right-lateralized activations, and imitation. Current studies converge on a central
verbal tasks activate predominantly the left hemisphere role in Broca’s area as an orchestrator of time-sensitive

276 Copyright © 2015 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu

 Predictors of poor treatment response in PD

perceptual and motor functions underly-

ing verbal and nonverbal communica-
tion (Nishitani et al. 2005). Furthermore,
increased Broca’s activity during execution,
imagination, imitation and observation
may simply be due to inner speech (Heiser
et al. 2003). In our study, Broca´s area and
right BA45 activation were found in non-
responders compared to responders. The
left IFG has been shown to sustain inner
speech and was more frequently recruited
during conceptual tasks (e.g., emotions,
traits) than during perceptual tasks (e.g.,
agency, self-recognition), and has a role in
inner speech within self-reflective processes
(Morin & Michaud 2007). We consider the
possibility that non-responders strongly
Fig. 3 Significant negative correlation between the BAI % improvement and
process the threat-related words, which fMRI signal. Beta values represent individual fMRI signals in left BA 46.
involves the inner speech leading to the
simultaneous activation of IFG. Another
possibility is that PD non-responders are
more attentive to insignificant stimuli than
responders are, and enhance non-specific
sensitivity to multiple regions of the brain
including Broca’s area.
Role of the orbitofrontal cortex
Engagement of bilateral DLPF and OFC
cortex during strategic memory processes
was demonstrated, particularly when
mobilization and effort of efficient use
of strategies are required (Miotto et al.
2006). It has been proposed that the OFC
may be involved in sensory integration,
in representing the practical value of rein-
forcers, in decision-making and expecta-
tion (Kringelbach 2005) and in signaling Fig. 4. Significant negative correlation between the BAI % improvement and fMRI
the expected rewards/punishments of signal. Beta values represent individual means of fMRI signals across all ROIs.
an action given the particular details of a
situation (Schoenbaum et al. 2011). In our
study, a higher activity of the left OFC was
demonstrated. We suggest that the activa-
tion is related to the difficulty to evaluate
the danger and make a decision, and the
left-sided lateralization may be due to the
verbal stimulation task.
Role of frontal eye fields (FEF)
and parietal cortex
The FEF area is traditionally associated
with the activity during the initiation of
eye movements, such as voluntary saccades
and pursuit eye movements. In our study,
we found increased activity in the left FEF
in nonresponders, and this finding in PD
during a verbal task with eyes closed might
be surprising. Vernet et al. suggest that FEF Fig. 5. Significant correlation between the CGI improvement and fMRI signal.
is also as an essential region contributing to Beta values represent individual means of fMRI signals across all ROIs.

Neuroendocrinology Letters Vol. 36 No. 3 2015 • Article available online: http://node.nel.edu 277
 Aleš Grambal, Zbyněk Tüdös, Pavel Hok, Dana Kamarádová, Tomáš Divéky, Petr Hluštík, Ján Praško

Tab. 4. Medication and comorbidity of PD subjects.

Antisepressants 1 Antisepressants 2 Anxiety
Sub Age Duration Ag Personality Other medication
(mg per day) (mg per day) disorders
R1 24 8 0 0 N
R2 23 4 paroxetin 20 paroxetin 20 A euthyreox
R3 35 4 moklomebid 600 Citalopram 20 N social phobia euthyros
R4 37 5 escitalopram 10, escitalopram 15, A bromazepam 0,75
mirtazapin 30 mirtazapin 15
R5 29 2 paroxetin 20 paroxetin 20 N social phobia prothazine 25
R6 25 0.1 escitalopram 10 escitalopram 10 N
R7 31 1 0 0 A
R8 22 0.2 escitalopram 10 escitalopram 10 N
R9 32 5 setralin 100 setralin 100 A
R10 27 4 setralin 200 setralin 200 N
R11 42 22 escitalopram 10 escitalopram 10 A
N1 40 7 0 0 A
N2 25 3 moclobemid 300 moclobemid 300 A GAD
N3 30 2 setralin 100 setralin 100, N social phobia borderline alprazolam 1, quetiapine
alprazolam 1 300
N4 51 7 paroxetin 20, paroxetin 20, N
mirtazapin 15 mirtazapin 15
N5 40 11 escitalopram 10, escitalopram 10, A anxious
mirtazapin 15 mirtazapin 15
N6 42 4 setralin 25, setralin 25, N
trazodon 225 trazodon 225
N7 36 14 escitalopram 20 escitalopram 20 N borderline olanzapin 5, valproat 1000
N8 52 1 escitalopram 10 escitalopram 10 A social phobia magnesium 1000
N9 34 4 escitalopram 20 escitalopram 20 A social phobia magnesium 500
N10 36 2 0 0 N
N11 58 1 escitalopram 20 escitalopram 20 A GAD

N - Non-responders and R – Responders. Ag – Agoraphobia.

cognitive processes such as attentional orienting, visual vation according with previous findings (Grosbras
awareness, conscious access, perceptual performance, & Paus 2003). Previous studies showed that intrusive
and decision-making and spatial attention (Vernet et al. negative images (involving harm or danger) occur in
2014). Moreover, TMS stimulation over the left FEF sig- 90% of patients with anxiety neurosis (Beck et al. 1974)
nificantly increased the probability of detecting visual as well as negative imaginations of mental or physical
targets presented in the contralateral hemifield (Gros- catastrophe in panic disorder patients (Hibbert 1984;
bras & Paus 2003). A subset of the dorsal frontoparietal Breitholtz et al. 1998). We hypothesize that in the PD,
attentional control network, including the medial supe- threat-related words trigger unwanted catastrophic
rior parietal lobule, intraparietal sulcus, and superior imagination, which is associated with extensive acti-
frontal sulcus/gyrus was jointly activated by deploy- vation of emotional, speech and visual regions of the
ments of external and internal attention, that is, shifting brain. The dorsal convexity of the human frontal and
attention to either a perceptual (vision) or mnemonic parietal lobes forms a network that is crucially involved
domains (Tamber-Rosenau et al. 2011). Stinct areas of in the selection of sensory contents by attention. This
the parietal lobe were activated by visuospatial tasks, system includes cortex along the intraparietal sulcus,
attention and saccades tasks (Simon et al. 2002), as was the inferior parietal lobe, and dorsal premotor cortex,
also demonstrated in our study including the frontal eye field – attention network
In our data, non-responders demonstrated increase (Ptak 2012). The alternative explanation is, that under
left FEF activity and contralateral brain regions acti- the influence of anxiety, PD non-responders strongly

278 Copyright © 2015 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu

 Predictors of poor treatment response in PD

activate the attention system to be ready for a poten- CONCLUSION

tial danger, or both the hypothesis may be combined.
This pathological activation could be higher in non- In the search for fMRI response predictors to add-on
responders and might be associated with stronger CBT in panic disorder, we found increased pre-treat-
emotions and BOLD activation in regions involved in ment activation in DLPFC, right parietal cortex, left
increased cortical excitability. frontal eye field and orbito-frontal cortex and left
amygdala in non-responders. Both groups showed
Role of the amygdala negative fMRI BOLD correlation with BAI and CGI
There is a consensus that the amygdala is an important improvements across the ROIs. The study thus sug-
part of anxiety circuits (Gorman et al. 2000; Fredrik- gested possible predictors of poor CBT response, under
son & Faria 2013; Adhikari 2014; Likhtik & Paz 2015). the conditions of standard clinical practice, in real PD
However, the engagement of amygdala in imaging stud- patients. We hypothesize that the observed increased
ies is inconsistent, and it has also been shown that the activation in specific brain areas reflects unwanted
amygdala rapidly habituates to repeated threat-related catastrophic imagination triggered by the threat-related
stimuli (Maddock & Buonocore 1997). Whereas some words. Alternatively, PD non-responders may strongly
fMRI studies of PD found increased (Pfleiderer et al. activate the attention network in order to be ready for
2007; Spiegelhalder et al. 2009; Ohrmann et al. 2010; a potential danger, or both these hypotheses can be
Lueken et al. 2014) activation of the amygdala, reduc- complementary. This excessive activation to passively
tions (Pillay et al. 2006; Ottaviani et al. 2012; Deme- received emotional stimuli may be the characteristic
nescu et al. 2013) or absence (Dresler et al. 2012; sign of the poorer response possibly reflecting impaired
Killgore et al. 2014; Petrowski et al. 2014) activity was cognitive control of emotions, a crucial skill required
found by others. We found no significant differences for successful CBT treatment.
in amygdala within ROI analysis, only trends to higher
bilateral activity in non-responders. However, we found
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