Functional neuroimaging in specific phobia

Functional neuroimaging in specific phobia

Psychiatry Research: Neuroimaging 202 (2012) 181–197 Contents lists available at SciVerse ScienceDirect Psychiatry Research: Neuroimaging journal ho...

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Psychiatry Research: Neuroimaging 202 (2012) 181–197

Contents lists available at SciVerse ScienceDirect

Psychiatry Research: Neuroimaging journal homepage: www.elsevier.com/locate/psychresns

Review article

Functional neuroimaging in specific phobia Antonio Del Casale a,⁎, Stefano Ferracuti a, Chiara Rapinesi a, b, Daniele Serata a, b, Massimo Piccirilli c, Valeria Savoja a, Georgios D. Kotzalidis a, Giovanni Manfredi a, Gloria Angeletti a, Roberto Tatarelli a, Paolo Girardi a, b a

Sapienza University of Rome, Italy, School of Medicine and Psychology, NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy Department of Neuropsychiatry, Villa Rosa, Suore Hospitaliere of the Sacred Heart of Jesus, Viterbo, Italy c University of Perugia, Department of Psychiatry and Clinical Psychology, Perugia, Italy b

a r t i c l e

i n f o

Article history: Received 1 April 2011 Received in revised form 25 October 2011 Accepted 27 October 2011 Keywords: Specific phobia Functional neuroimaging Functional magnetic resonance imaging (fMRI) Amygdala Prefrontal cortex Anterior cingulate cortex

a b s t r a c t Specific phobias (SPs) are common, with lifetime prevalence estimates of 10%. Our current understanding of their pathophysiology owes much to neuroimaging studies, which enabled us to construct increasingly efficient models of the underlying neurocircuitry. We provide an updated, comprehensive review and analyze the relevant literature of functional neuroimaging studies in specific phobias. Findings are presented according to the functional neuroanatomy of patients with SPs. We performed a careful search of the major medical and psychological databases by crossing SP with each neuroimaging technique. Functional neuroimaging, mostly using symptom provocation paradigms, showed abnormal activations in brain areas involved in emotional perception and early amplification, mainly the amygdala, anterior cingulate cortex, thalamus, and insula. The insula, thalamus and other limbic/ paralimbic structures are particularly involved in SPs with prominent autonomic arousal. Emotional modulation is also impaired after exposure to phobic stimuli, with abnormal activations reported for the prefrontal, orbitofrontal and visual cortices. Other cortices and the cerebellum also appear to be involved in the pathophysiology of this disorder. Functional neuroimaging identified neural substrates that differentiate SPs from other anxiety disorders and separate SP subtypes from one another; the results support current Diagnostic and Statistical Manual of Mental Disorders, 4th edition-Text Revision (DSM-IV-TR) diagnostic subtyping of SPs. Functional neuroimaging shows promise as a means of identifying treatment-response predictors. Improvement in these techniques may help in clarifying the neurocircuitry underlying SP, for both research and clinical-therapeutic purposes. © 2012 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 3.1. Distribution of studies according to technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 3.2. Distribution of studies according to method-design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 3.3. Distribution of studies according to population studied/comparison . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.4. Publication year issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.5. Addressing the drug-intake confounder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.6. Distribution of studies according to stimulus type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.7. The cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.7.1. Prefrontal cortex (PFC): ventral PFC (VPFC), ventromedial PFC (VMPFC) dorsomedial PFC (DMPFC), dorsolateral PFC (DLPFC) . 183 3.7.2. Orbitofrontal cortex (OFC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.7.3. Insula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.7.4. Cingulate cortex: anterior cingulate cortex (ACC), dorsal anterior cingulate cortex (dACC), rostral anterior cingulate cortex (rACC), and posterior cingulate cortex (PCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 3.7.5. Visual cortex and association cortices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

⁎ Corresponding author at: Sapienza University of Rome, Italy, School of Medicine and Psychology, NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy. Tel.: + 39 0633775951; fax: + 39 0633775342. E-mail address: [email protected] (A. Del Casale). 0925-4927/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2011.10.009

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3.8.

Limbic sites . . . . . . . . . . . . . . . . . . . . 3.8.1. Thalamus . . . . . . . . . . . . . . . . . 3.8.2. Amygdala . . . . . . . . . . . . . . . . 4. Discussion: the functional neuroanatomy of patients with SP 4.1. Cortical function in patients with SP . . . . . . . . 4.1.1. PFC: VPFC, VMPFC, DMPFC, DLPFC . . . . . 4.1.2. OFC . . . . . . . . . . . . . . . . . . . 4.1.3. Insula . . . . . . . . . . . . . . . . . . 4.1.4. Cingulate cortex: ACC, dACC, rACC, PCC . . . 4.1.5. Visual cortex and association cortices . . . 4.2. Limbic function in patients with SP . . . . . . . . . 4.2.1. Thalamus . . . . . . . . . . . . . . . . . 4.2.2. Amygdala . . . . . . . . . . . . . . . . 5. Conclusions and perspectives . . . . . . . . . . . . . . . Financial and competing interests disclosure . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The term “phobia” derives from φόβος, the Greek word for fear. Phobos was also the name of the Greek deity provoking fear and panic in one's enemies. Although doctors from Hippocrates onwards have described morbid fears, only since the end of the XIX century has the word phobia been used on its own (Errera, 1962). Patients with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition-Text Revision (DSM-IV-TR) anxiety disorder ‘specific phobia’ (SP) consistently respond excessively to specific fear-inducing stimuli or situations. Responses include anticipatory anxiety, anxiety and distress upon exposure, and avoidance behavior (American Psychiatric Association, 1994). SPs are among the most common psychiatric disorders; cumulative estimated lifetime prevalence reaches 10% (American Psychiatric Association, 1994). According to the focus of fear, SPs are categorized as situational, natural (environmental), animal, and blood–injection–injury (BII). Despite poor understanding of the pathophysiology of SPs (Fyer, 1998), during the past two decades our knowledge increased, mainly due to functional neuroimaging studies, especially those carried-out with functional magnetic resonance imaging (fMRI) (Table 1). In our review of articles published over the past 20 years that focused on functional neuroimaging in patients with SPs, we sought to identify area-specific alterations in cerebral perfusion or metabolic activity as indicating functional neuroanatomical alterations underlying SPs. We also searched for possible differences in neural processing of emotional fear between patients with SP and healthy individuals. 2. Method We searched Medline, Embase and PsycInfo databases using the terms specific phobia, simple phobia, positron emission tomography, functional magnetic resonance imaging, single positron emission computerized tomography, magnetic resonance spectroscopy, and electromagnetic tomography. Original research articles were included if they satisfied standards for adequate methodology, including diagnostic criteria (using Diagnostic Statistical Manual (DSM) or International Classification of Diseases (ICD)), specific inclusion and exclusion criteria, if they were published in peer-reviewed journals, and if they were dealing with functional imaging in SP. Articles were excluded if they failed to clearly specify the method for diagnosing SP or if SP was not the principal diagnosis; if imaging methods were unspecified or inadequately described; and if they were reviews or meta-analyses (but their reference lists were further searched). Additional articles that did not appear in the aforementioned databases were searched from reference lists of retrieved articles. When two or more articles by the same study group investigated partially overlapping populations, we included the one with the larger sample, provided that methodological quality was similar.

3. Results Our search indentified a total of 144 articles. Of these, 34 were excluded because they failed to meet selection criteria. Of the 110

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articles selected, 35 were original research articles enrolling a total of 506 patients with SP. These studies used several neuroimaging techniques, mainly fMRI (65.71%), and less frequently single photon emission computerized tomography (SPECT) (5.71%), and positron emission tomography (PET) (28.57%). Most studies (62.86%) compared patients with healthy controls; other studies used withingroup comparisons without controls (37.14%). Differences in brain activity in SP with respect to healthy controls were most frequently found in the amygdala (51.43%), cingulate (37.14%), and prefrontal/ orbitofrontal (40%), visual (20%) and other cortices (37.14%), including insular cortex (40%), whereas differences occurred less frequently in the hippocampal/parahippocampal area (25.71%), thalamus (22.85%), and striatum (putamen, 5.71%; caudate nucleus, 5.71%). 3.1. Distribution of studies according to technique PET has strengths and weaknesses regarding the visualization of cortical metabolic changes. Combined with magnetic resonance imaging (MRI), PET may yield high resolution images, more or less not different from fMRI (Feng et al., 2004), and witnesses more persistent modifications, while responses recorded with fMRI are more timelimited and fleeting; on the other hand, chronometry may render them more useful and show better the course of an activation or a deactivation. However, over the past 10 years, PET has been largely superseded for clinical and research purposes by the less expensive fMRI technique. PET uses various radioligands, like 18F-fluorodeoxyglucose (0 of the 10 PET studies included in this review, 0%), H215O (five studies, 15.15%), 15O-CO2 (one study, 3.03%), and 15O-butanol (four studies, 12.12%) and is suitable for studying receptor occupancy through radio-labeled specific receptor agonists or antagonists, like the NK1 antagonist 11C-GR205171, used here in one study (3.03%). The radioligands may be administered intravenously (i.e. H215O, 15Obutanol) or inhaled (i.e. 15O-CO2, 133Xe). The SPECT studies dealing with specific phobia used the radioligand 99mTc-Exametazime (one study, 3.03%) and 133Xe (one study, 3.03%). All fMRI studies we considered here used the blood oxygen level dependent (BOLD) technique (23 studies, 65.71% of the whole sample). 3.2. Distribution of studies according to method-design In functional MRI studies, block design-adopting studies are likely to detect hypothesis-driven, strong and persistent activations or deactivations, but may be prone to miss fleeting, transient activations in unexpected areas, which could have been important for triggering activities elsewhere; these could have been detected through eventrelated designs (Caseras et al., 2010a). It has been argued that design is likely to affect the results of studies reporting data from the

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amygdala (Caseras et al., 2010a). Nine fMRI SP studies investigating the amygdala (69.23%), which found hyperactivation, used a block design and four used an event-related one (30.77%). However, results were not affected, since both study types agreed on the preferential left amygdala activation induced by fear-related stimuli in patients with SP (Table 2). 3.3. Distribution of studies according to population studied/comparison Of the 35 studies (65.71%) included in this review, 22 compared SP patients with healthy controls; despite the fact that the very first study included a healthy control group (Mountz et al., 1989), the trend in early studies was to use patient populations only. Generally, Swedish studies did not use controls (and were early). Of all specific phobias, few were investigated, namely small animal and needle phobias, overall amounting to 34 studies (97.14%), i.e., all but one (2.86%). The latter included a miscellany of people with various SPs (O'Carroll et al., 1993). Arachnophobia was the most focused upon (24 studies, 68.57%), followed by snake phobia (seven studies, 20%), by small animal phobia in general, including spiders and snakes (five studies, 14.29%), and by needle phobia (two studies, 5.71%). Of the latter, one compared BII phobia with spider phobia (2.86%). Spider phobia and snake phobia were investigated conjointly and comparatively in the same study in three studies (8.57%). Snake phobia and dental phobia were investigated conjointly and comparatively in the same study in one study (8.57%). 3.4. Publication year issues Studies spanned from 1989 to 2011. When diagnoses were based on the Diagnostic and Statistical Manual, studies published until 1998, i.e., 4 years after the introduction of the DSM-IV, used the 1987 DSM-III-R version. Seven studies used the DSM-III-R (20%), 24 used the DSM-IV/DSM-IV-TR (68.57%, in studies published from 2003 and after; there was a noticeable lag between 1998 and 2003). Six studies selected their patients on the basis of interviews and questionnaire cut-offs (17.14%). 3.5. Addressing the drug-intake confounder Of the 35 studies included in this review, 33 were carried-out in patients and/or controls, who either had never taken or were not taking any drugs (94.29%); of these, six included drug-naïve participants (17.14%), one used a double-blind placebo-control design vs. diazepam (2.85%) and only one failed to report drug use (2.85%). A drugfree period was reported by six studies (17.14%), ranging from 3 to 12 weeks. 3.6. Distribution of studies according to stimulus type Procedures involved in most cases the exposure to a specific stimulus that was expected to induce fear in the patient being tested, along with neutral stimuli; variants included the administration of generally fear-inducing stimuli that were not specific for the condition being tested. Most studies used visual stimuli, mostly picture slides (21, 60%). Videos were used in eight instances (22.86%), exposure to true phobic objects (i.e., small animals) in two studies (5.71%), while one study (2.86%) used written words conveying phobic vs. neutral meaning and still another (2.86%) used written words with phobic vs. anxiety-inducing vs. negative-affect-generating vs. neutral meaning. It is noteworthy that the first studies used more videos, while recent studies increasingly use pictures. This is to be taken as indicating study standardization that will hopefully allow metaanalytical studies to be performed. Auditory stimuli were administered in two studies (5.71%), one of which also involved the administration of a visual stimulus (2.86%). In one case the patients were

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subjected to a phobia-unrelated task (2.86%), i.e., implicit vs. random learning (Martis et al., 2004). All the above methodological differences did not apparently bias neuroimaging results. The only SPECT study (O'Carroll et al., 1993) obtained results that cannot be compared to those of other studies, as its results do not match those of the other two studies that used 99m Tc-exametazime as a tracer to investigate anxiety-related issues (Conca et al., 2000; Lucey et al., 1997, not included here). Other SPECT studies of anxiety disorders used markers of serotonergic or GABAergic activity, while exametazime is used exclusively as a blood perfusion tracer. Reduced tracer uptake in right occipital cortex was to be expected, as the design provided for auditory stimuli administered to patients with patched eyes (O'Carroll et al., 1993). Another study standing on its own is the PET study that investigated the uptake of a radio-labeled NK1 receptor antagonist (Michelgard et al., 2007). This study used [ 11C]-GR205171 to trace NK1 receptors, which bind substance P, and focused on the amygdala only. It found decreased tracer uptake in the right amygdala of patients with snake or spider phobia when they were stimulated with their respective phobia-triggering stimulus. The authors conjectured that during a phobic reaction, substance P is released in the amygdala, displacing the tracer, significantly so on the right. GR205171 has been used in animal studies of anxiety disorders and as a therapeutic drug in one human study of social phobia by the same group of investigators (Furmark et al., 2005, not included here), who compared it with the specific serotonin reuptake inhibitor citalopram and placebo according to a double-blind design. This study found the NK1 antagonist to behave similarly to the drug and better than placebo in reducing anxiety symptoms and regional blood perfusion in many brain areas and in the amygdala, consistent with an involvement of substance P transmission in the amygdala in SP. These findings indirectly match those of the PET study of SP (Michelgard et al., 2007), but also indicate that interference with amygdalar substance P transmission may be not specific to one anxiety disorder. Generally, the studies compared the brain activity correlates of stimulus exposure between patients with SP and healthy controls, or between phobia-inducing and neutral stimulation, or before and after a given treatment. Results were rather consistent within each type of investigation, technique and study design. We will now present the results according to the areas involved, reporting the direction of activity modification according to the various studies. A summary of the results is given in Table 1. 3.7. The cortex Significant results were obtained in the executive–evaluative cortex, which comprises the prefrontal cortex, in its ventral, ventromedial, dorsomedial and dorsolateral divisions, the orbitofrontal cortex, the cingulate gyrus and Reil's insula; and in the visual and associative cortices. 3.7.1. Prefrontal cortex (PFC): ventral PFC (VPFC), ventromedial PFC (VMPFC) dorsomedial PFC (DMPFC), dorsolateral PFC (DLPFC) PET studies on spider phobia report reduced activity in prefrontal areas in response to phobic objects (Fredrikson et al., 1993, 1995; Johanson et al., 1998), especially in patients with panic symptoms and no coping strategies (Johanson et al., 1998). In patients experiencing panic, regional cerebral blood flow (rCBF) decreased mainly in frontal areas, especially at the non-dominant (usually right) side, whereas in participants without panic, rCBF increased in the right frontal area (Johanson et al., 1998). Increased activity in the DLPFC was found in fMRI scans of patients with SP, particularly in the left-lateral area (Straube et al., 2004). In another fMRI study, Straube et al. (2006b) investigated brain activation during direct and automatic processing of phobia-relevant threat in 12 women with spider phobia and 12 healthy controls. Participants

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Table 1 Functional imaging studies in specific phobia. Technique/design

Participants

Procedure

Medication

General findings in patients with SP compared to HCs

Mountz et al. (1989)

H215O rCBF PET repeated-measures paradigm, ROI approach

7 SP (DSM-III-R animal): 7 f 8 HC: 8 f All from 24 to 44 years old All right handed

Drug-free and -naïve for at least 1 month prior to the PET scan

SP: global ↓ of CBF during fear scans vs. rest scans

Wik et al. (1993)

15 O-Butanol PET emotional activation paradigm (video)

Drug-free, not used any medication or drugs for at least 3 weeks

O'Carroll et al. (1993)

99m Tc-Exametazime rCBF SPECT symptom provocation paradigm (audio)

↑ rCBF in the secondary visual cortex, ↓ in the hippocampus, orbitofrontal, prefrontal, temporopolar, and posterior cingulated cortex SP: ↓ tracer uptake in the right occipital cortex, right posterior temporal cortex, left ACC

Fredrikson et al. (1993)

15 O-Butanol rCBF PET emotional activation paradigm (video)

6 SP (DSM-III-R snake phobia): 6 f Mean age: 27 All nonsmokers 10 SP (DSM-III-R ‘simple phobia’): 9 f, 1 m Mean age: 51 All right handed 6 SP (DSM-III ‘snake phobia’): 6 f Mean age: 27

Fredrikson et al. (1995)

15 O-Butanol rCBF PET emotional activation paradigm (video)

8 SP (spider) (DSMIII-R ‘simple phobia’): 8 f, postmenopausal Mean age: 29

During repeated 6 min PET scans, participants were confronted with the SP patients' fear object (snakes, spiders and a rat) held at a close distance from participant's chest After 30–60 min resting habituation, participants were alternatively exposed to 4-min fear-inducing, aversive, and neutral videos Participants with patched eyes listened via earphones to a 9-min relaxation tape and to a 4-min participant-specific anxiogenic tape, in which their phobic object was described in detail After 30–60 min rest, alternative exposure to 4-min fear-inducing, aversive, and neutral videos in balanced order After 30–60 min rest, alternative exposure to 4-min couples of neutral and fear-inducing color videos

Rauch et al. (1995)

15 O-labeled CO2 rCBF PET; symptom provocation paradigm; SPM subtraction of provoked minus control condition; ROI approach

7 SP (small animal phobia; DSM-III-R ‘simple phobia’): 6 f, 1 m Mean age: 37

Patient-tailored real life stimulus; patient had to touch the container of innocuous (control) and anxiogenic stimulus (provoked) place at a distance b 2 m to about 6 m (tactile imagery); 1 min PET scan and rate their anxiety on a VAS

Drug-free for at least 4 weeks

Wik et al. (1997)

15 O-Butanol rCBF PET symptom provocation paradigm (video)

After 30–60 min rest, alternative exposure to 4-min fear-inducing, aversive, and neutral videos in balanced order

Drug-free

Johanson et al. (1998)

133 Xe inhalation rCBF SPECT; symptom provocation paradigm (video)

14 SP (snake phobia; DSMIII-R ‘simple phobia’): 14 f Mean age:28 6 HC: 6 f Mean age: 32 16 SP (DSM-III-R spider phobia): 16 f Mean age: 35 All right handed

rCBF during eyes-closed, resting situation, during exposure to neutral video, and during exposure to video with spiders

Drug-free

Dilger et al. (2003)

fMRI BOLD; emotional activation paradigm (visual) 1.5 T; event-related design, ROI approach

Drug-free

Paquette et al. (2003)

fMRI emotional activation paradigm (visual); 1.5 T; block design, ROI approach

Photos of SP (spiders), fear-inducing (snakes), neutral (mushrooms), and ‘null event’ (fixing cross); 56 pictures for each situation, presented in pseudorandom order Exposure to five 30-s film blocks each referring to phobic (spiders) or neutral (butterflies) content. Participants were instructed to watch attentively

10 SP (spider phobia): 10 f Mean age: 25 10 HC: 10 f Mean age 21.3 12 DSM-IV SP (spider): 20 f Mean age: 24.8 years 13 HC: 13 f Mean age: 28.6 years

Drug-free and medication-free for at least 3 months prior to the SPECT scan

Not reported

SP: :↑ rCBF in secondary visual cortex (BA 18,19)

Diazepam 0,1 mg/kg body weight i.v. or placebo after initial PET scans in double blind conditions, the PET scans were then repeated

SP:↑ rCBF in the secondary visual cortex, ↓ in the hippocampus, prefrontal, orbitofrontal, temporopolar and posterior cingulated cortex. Diazepam treatment did not affect the relative rCBF In symptomatic state compared to control state ↑ rCBF in the ACC, left insula, right anterior temporal cortex, left somatosensory cortex, left posteromedial OFC, left thalamus No correlation between VAS anxiety scores and activity in any of the ROIs SP: ↑rCBF in the amygdala, thalamus, putamen, caudate nucleus

Drug-free CBT (4 weeks)

8 SP with severe panic during the spider exposure: ↓rCBF in frontal areas, especially in the right hemisphere 8 SP with more efficient control of their emotions, frightened, but not panic-stricken, during the spider exposure: ↑rCBF in the right frontal area SP vs. HC: ↑ activation of the left amygdala

SP before CBT: activation in the right inferior frontal gyrus (BA-10), parahippocampal gyrus bilaterally (BA 36) left inferior occipital gyrus (BA 19) left fusiform gyrus (BA 20, 37)

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Study

H215O rCBF PET symptom provocation paradigm (auditory–visual)

16 DSM-IV SP (8 spider, 8 snake): 16 f; Mean age spider: 23.25 Mean age snake: 23.87 All right handed

Wright et al. (2003)

fMRI BOLD; emotional activation paradigm (emotionally valenced faces, fearful vs. happy vs. neutral); 1.5 T; block design, ROI approach and VBM

Martis et al. (2004)

fMRI BOLD serial reaction time task paradigm: alternating blocks of random and implicit learning conditions; 1.5 T; ROI approach

10 DSM-IV SP (small animal phobia): 6 f, 4 m; Mean age: 29.8 EY: 17.7 10 HC: 6 f, 4 m Mean age: 29.8 EY: 16.7 All right handed 10 DSM-IV SP (small animal phobia): 6 f, 4 m; Mean age: 29.8 EY: 17.4 10 HC: 6 f, 4 m Mean age: 26.7 EY: 17 All right handed

Straube et al. (2004)

fMRI BOLD; emotional activation paradigm (word); 1.5 T; block design, ROI approach

Veltman et al. (2004)

i.v. H215O rCBF PET Prolonged symptom-provocation paradigm (visual)

11 DSM-IV SP (spider): 11 f Mean age: 20.8 11 HC: 11 f Mean age: 22.4 All right handed university students 12 SP (spider): 11 f, 1 m Mean age: 32.1 6 HC: 4 f, 2 m Mean age: 30.5

Exposure to 25-picture presentations 2–4 s each of phobic (specific) or nonphobic content, separated by 1–3 s blanks each alone or paired with acoustic startle stimulation (500 ms, 80–10 dB white noise bursts separated by 5–17 s intervals) in pseudorandom order Two runs of emotionally valenced faces presented for 200 ms each with a 300-ms interstimulus interval presented in 28-s blocks of alternating happy, fearful, neutral and fixation conditions

Drug-free

Drug-free, no psychotropic medications for at least 8 weeks and naïve to chronic psychotropic medication use by history

SP + HC: significant activation in the left amygdala (ROI) SP: significantly greater activation vs. HC in the right posterior insular cortex; VBM results confirmed ROI findings

Recognition of the position of an asterisk presented in one of four positions for 1 s, followed by a 0.2-s gap; two runs of random and implicit learning, lasting about 7.5 min and composed of 312 trials, administered after 96-trial training (six series of 12-position fixed alternation trials vs. 24 random trials)

Drug-free, no psychotropic medications for at least 6 weeks

Exposure to 14-word spider-related and neutral written word sequences (white in black background); 24 s fixation cross; each word presented in pseudorandom order for 1900 ms

Drug-free

SP and HC did not differ from each other for brain area activations. Implicit learning vs. random conditions showed significant activation in the right caudate, the right putamen, right striatum, left thalamus, left insula, left superior temporal gyrus and midcingulate cortex, bilaterally SP: phobia-related words elicited higher activity than neutral words in left DLPFC, bilateral IFG, bilateral insula, and left PCC HC: no differences in activation between phobia-related and neutral words

Exposure to nine series of 9.5 min blocks of 95 pictures (6 s each, continuously without a break) with a phobic (spiders) and a neutral (butterflies) content, drawn from a 200 picture databank (each photo could be seen three or four times); participants filled-out the SUDS after each series of pictures

Drug-free

SP: activation in left fusiform and right parahippocampal gyrus, right lateral PFC, bilateral perirhinal cortex, right pulvinar, right posterior insula and right medial amygdalar region in phobic vs. neutral condition before habituation HC: no difference, no habituation effects After habituation, SP: signal ↓ as a linear function of time, bilaterally in the anterior MTL; ↓ right amygdala, posterior insular cortex and right hypothalamus. ↓ activity in amygdala: right after a 5–15 min exposure, left after a 15–25 min exposure SUDS scores correlated with activation in the left amygdala and perirhinal cortex, bilaterally, in the right fusiform gyrus, and periaqueductal gray

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Pissiota et al. (2003)

and right occipital gyrus (BA 19) After CBT: activation in the middle occipital gyrus bilaterally (BA 18, 19) HC: activation in the left middle occipital gyrus (BA 19), right inferior temporal gyrus (BA 37). SP vs. HC: activation in the dorsolateral prefrontal gyrus (BA 10) and the parahippocampal gyrus (BA 36) SP: ↑rCBF in the left amygdaloidhippocampal region and medial ACC during the phobic startle stimuli

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Table 1 (continued) Technique/design

Participants

Procedure

Medication

General findings in patients with SP compared to HCs

Schienle et al. (2005)

fMRI Visual emotional activation paradigm: phobia, disgust, fear, neutral; 1.5 T; block design, ROI approach

10 DSM-IV SP (spider): 10 f Mean age: 22.5 13 HC: 13 f Mean age: 23.9 All right handed

Exposure to 160 pictures (1.5 s each), 40-picture blocks, each block corresponding to one of the emotional conditions investigated; every block shown six times, with no pause between blocks

Drug-free and -naïve

Larson et al. (2006)

fMRI BOLD Chronometry, visual emotional activation paradigm (visual); 1.5 T; event-related design, ROI approach fMRI BOLD; emotional activation paradigm (video); 1.5 T; block design, ROI

13 SP (spider): 13 f Mean age:18.46 14 HC: 14 f Mean age: 19.21

Three functional runs; 60 pictures (20 spider, 20 non-spider, 20 neutral) each run presented in a pseudorandom order for 300 ms

Drug-free

SP, phobia > neutral: significant activation in the left middle occipital gyrus, the right parahippocampal gyrus, left lateral OFC, right DLPFC, left fusiform gyrus and both amygdalae. HC > SP: more extended parietal activation SP: strong but brief amygdala response, bilaterally HC: weaker and more sustained response

28 DSM-IV SP (spider): 28 f 14 HC: 14 f Randomly assigned to CBT (N = 14) or to waiting-list (N = 14) Mean age: 22.07 years; university students

Participants were pseudorandomly exposed at a 1 m distance to five neutral (metallic bottom without spider) and four 24-s sequences of specific fear-inducing (the same spider in different positions) videos

Drug-free CBT (two sessions of 4–5 h each)

11 DSM-IV SP (spider): 11 f Mean age: 20.9 12 HC: 12 f All right handed and university students 16 DSM-IV SP (8 spider, 8 snake): 16 f; Mean age 8 spider:23.25 Mean age 8 snake:23.87 All right handed

Exposure to pictures of phobic (spider) and neutral (mushrooms) content. Each block consisted of 40 pictures, each picture shown for 1 s; plus 40 ‘null events’ randomly interspersed Exposure to phobic and to neutral sessions in two different days one week apart, followed suit by PET, in counterbalanced order; 100 pictures with specific phobic content or with control material held for 4–8 s separated by 4–20 s blanks; after each scan, participants filled-out the STAI-Y1 Exposure to specific phobic object, to fear-inducing, and neutral sets of 27 pictures each (spiders, snakes and other, respectively), shown for 1 s

Drug-free and -naïve

Straube et al. (2006a)

Straube et al. (2006b)

fMRI BOLD; identification task; demanding distraction task; 1.5 T; block design, ROI

Michelgard et al. (2007)

11 C-GR205171(NK1 receptor antagonist); H215O rCBF PET; symptom provocation paradigm (visual)

Goossens et al. (2007a)

fMRI BOLD; event-related paradigm (visual); 3 T; block design, ROI and VBM

15 DSM-IV SP (spider): 13 f, 2 m Mean age: 24 14 HC: 12 f, 2 m Mean age:23

Goossens et al. (2007b)

fMRI BOLD; emotional activation paradigm (visual); 3 T; block design, ROI and VBM

20 DSM-IV SP (spider): 20 f Mean age: 24 14 HC: 12 f, 2 m All right handed

Exposure to specific phobic object, to fear-inducing, and neutral sets of 27 pictures each (spiders, snakes and other, respectively), shown for 1 s; before (baseline) and after one CBT session; patients completed an anxiety VAS after CBT

Drug-free CBT, one session treatment

Schienle et al. (2007)

fMRI BOLD; emotional activation paradigm (visual); 1.5 T; block design, ROI

28 DSM-IV SP (spider): 28 f; randomly assigned to CBT (N = 14) or to a waiting list (N = 12); CBT, mean age: 27.2 years; 15.2

Exposure to 160 pictures (1.5 s each), 40-picture blocks, each block corresponding to one of the emotional conditions investigated; every block shown six times, with no pause between blocks

Drug-free CBT (one 4-hour session)

Drug-free

Drug-free

SP: Before CBT: activation in the ACC, insula bilaterally, left extrastriate visual cortex (lingual gyrus). After CBT: CBT: ↓ activation ventral anterior insula Waiting-list: pronounced activation bilaterally in the insula and in the ACC HC: activation in the pre and post central gyri Identification task, SP vs. HC: ↑ left amygdala, left insula, left ACC and left DMPFC Distraction task, SP vs. HC: ↑ left and right amygdala SP: ↓ uptake of the labeled NK1 receptor antagonist in the right amygdala; inverse correlation between NK1 receptor binding and anxiety rated with the STAI-Y1 in right, but not left amygdala

Phobia-related stimuli vs. neutral: SP: significantly higher activation in the left amygdala (ROI), and thalamic pulvinar bilaterally, ACC, supplementary motor cortex (SMA) bilaterally, the fusiform and the lingual gyrus (VBM) vs. HC SP vs. HC: higher activation in the left amygdala (ROI), bilaterally in the ACC and in left insula (VBM) SP: before vs. after CBT: significantly lower activation in all these areas (amygdala, ROI: disappearance of significance of the pre-CBT activation); after CBT, VAS anxiety scores correlated with activation of the amygdala Before CBT: SP and HC showed activation in the right superior occipital gyrus HC: activation in bilateral angular gyrus, right lingual gyrus and left ACC

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Study

education years Waiting-list, mean age: 24.3 years; 14 education years 25 HC: 25 f Mean age 24.6; 14.5 EY All right handed

fMRI BOLD; expectation of emotional paradigm (visual); 1.5 T; block design, ROI

16 DSM-IV SP (spider): 16 f Mean age: 21.8 15 HC: 15 f All right handed and university students

Exposure to pictures of phobic (spider) and neutral (mushrooms) content. Each block consisted of 10 pictures, each picture shown for 1.9 s; plus fixation cross for 15 s between each block; after fMRI, participants rated their anxiety on a descriptive 9-point Likert scale

Drug-free

Hermann et al. (2007)

fMRI BOLD; Visual provocation; 1.5 T; block design, ROI

9 DSM-IV BII SP: 9 f Mean age: 22.9 10 HC: 10 f; Mean age: 27.6

Exposure to 160 pictures of phobic (needles and wounds), fear, disgusting, or neutral content. Each block consisted of 40 pictures, each picture shown for 1.5 s; each block seen six times, randomly distributed but avoiding immediate repetition; after fMRI, participants rated how much they were disgusted, anxious, pleasant and aroused on descriptive 9-point Likert scales

Drug-free

Wendt et al. (2008)

fMRI BOLD; sustained symptom provocation paradigm; 1.5 T; block design, ROI

13 SP (spider): 13 f Mean age: 23.2 HC 13: 13 f Mean age: 21.1

Exposure to five blocks of 30 pictures each (spiders, mushrooms, pleasant contents, unpleasant contents, neutral). Each picture

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Straube et al. (2007)

SP vs. HC: ↑ left amygdala and bilateral fusiform gyrus; ↓ right inferior parietal gyrus and IFG, bilateral ACC and medial OFC, and right DLPFC After CBT, in SP CBT: ↓ in the right insula and ↑ in the right medial OFC; Waiting-list: ↓ bilaterally parahippocampal gyrus and in the right lateral and left medial OFC SP vs. HC ↑ activation of the ACC, insula, thalamus, BNST and extrastriate visual cortical areas during the anticipation of phobia-relevant relative to neutral stimulation The subjective anticipatory anxiety ratings of patients with SP correlated with activation in dorsal and rostral ACC, right DMPFC and right insular cortex SP: Phobia > neutral: ↑activation of thalamus bilaterally, left hippocampus, and trend for the left amygdala; Disgust > neutral: ↑activation of the fusiform gyrus (exploratory) and right superior parietal cortex (ROI); Fear > neutral: ↑activation of the right amygdala (ROI) Fear > disgust: ↑activation in left VMPFC (ROI); Disgust > fear: ↑activation superior parietal cortex, bilaterally Phobia > fear: ↑activation in thalamus, bilaterally; Fear > phobia: ↑activation in left VMPFC (ROI) HC: Phobia > neutral: ↑activation in right superior parietal cortex, left inferior parietal cortex, right thalamus and lateral OFC, bilaterally (ROI) Disgust > neutral: ↑activation in occipital cortex (exploratory), right LOFC and left DMPFC (ROI) Phobia > fear: ↑activation in left amygdala and thalamus, bilaterally (ROI) SP vs. HC: ↑ activation in SP in the supplementary motor area and ↑ activation in HC in DMPFC and VMPFC, bilaterally, in the phobia > neutral comparison; ↑ activation in left DLPFC in SP in the disgust > neutral comparison SP: ↑ activation in the amygdalae and the insula bilaterally

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Table 1 (continued) Study

Technique/design

Participants

Procedure displayed for 3 s; 15 s intervals between blocks with a wide fixation cross Exposure to 25-picture presentations 2–4 s each of phobic (specific, spider or snake) or nonphobic (reverse order, snake or spider) content, separated by 1–3 s blanks in pseudorandom order; after each block, patients rated distress through a VAS

General findings in patients with SP compared to HCs

Drug-free

SP: ↑ activation in the extrastriate visual cortex (BA 18), fusiform area (BA 37), right amygdala and circumscribed parts of the prefrontal (BA 10) and temporal cortices (BA 22). During non phobic but fear-relevant stimulation ↓ activation in the prefrontal cortex (BA 46, 47), superior frontal gyrus (BA 10), primary somatosensory (BA 3) and the primary auditory cortices (BA 41), parietal cortex (BA 40), medial orbital gyri (BA 11); VAS distress ratings correlated positively with right amygdala activation SP: ↑ activation in the rostral ACC. Enhanced connectivity between rostral ACC and left amygdala in response to fearful stimuli. HC: ↑ activation in the right amygdala and posterior insula and ↑ deactivation in the thalamus. SP + HC: activations in the anterior cingulate, dorsomedial prefrontal cortex, inferior frontal gyrus/insula, and amygdala and deactivation in the thalamus. SP: ↑ activity in the insula, ↓ in the DMPFC induced by phobic stimulation; emotional up-regulation was effective in SP and induced activation in amygdala, insula, and dorsal ACC, while down-regulation was impaired and accompanied by deactivation in right insula and right ACC

Ahs et al. (2009)

H215O rCBF PET; emotional activation paradigm (visual)

16 SP DSM-IV SP (8 spider, 8 snake): 16 f Mean age: 22.8 Right handed

Britton et al. (2009)

fMRI BOLD; emotional counting Stroop task; 3 T; event-related design, ROI

12 DSM-IV SP (small animal): 7 f, 5 m; Mean age: 25.2 EY: 15.8 12 HC: 8 f, 4 m Mean age: 26.7 EY: 16.2 All right handed

Exposure to 84 words in four separate trials; words were specific phobia-related, anxiety-related, general negative affect and neutral. Each word for 1.45 s, followed by 50 ms fixation

Psychotropic drug-free

Hermann et al. (2009)

fMRI BOLD; Regulation task: down-regulation and up-regulation conditions; 1.5 T; event-related design, ROI

16 DSM-IV SP (spider): 16 f Mean age: 22.1 All right handed

Drug-free

Schienle et al. (2009)

fMRI; emotional activation paradigm; 1.5 T; block design, ROI

10 DSM-IV SP (spider): 10 f Mean age: 29.1 8 HC: 8 f Mean age: 24 All right handed

Participants exposed to phobic (spiders, 54 photos), aversive or neutral (126 affective from an international system and authors' archives) pictures. For each picture, participants were given instructions to downplay the emotional personal meaning of the stimulus (down-regulation of phobic pictures) to increase emotional involvement (up-regulation of negative affect pictures), or to respond naturally (neutral pictures) Exposure to 160 pictures (1.5 s each), 40-picture blocks, each block corresponding to one of the emotional conditions investigated; every block shown six times, with no pause between blocks. The session was repeated 1 week after CBT

Alpers et al. (2009)

fMRI T*2-weighted gradient echo-planar imaging (EPI) sequence; BOLD; emotional

19 DSM-IV SP (spider): 19 f Mean age: 22.5

Exposure to gray-scaled pictures of 32 spiders and 32 birds with fixation cross, task instruction reminder, re-fixation, double-exposure display

Drug-free and -naïve CBT: 6 month follow up session

Drug-free

SP: ↑ activity in the medial OFC, lateral OFC, amygdala and insula during exposure to phobic stimuli vs. neutral; at repeat session, medial OFC activation persisted HC: ↑ activity in the medial OFC during exposure to phobic stimuli vs. neutral; tolerance to the effect at repeat session SP vs. HC: higher insula and lower medial OFC activation; at repeat session no differences. SP and HC, no activations during disgusting stimulation SP: amygdalar activation showed a dose–response relationship: compared to congruent neutral

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Medication

activation; 1.5 T; block design, ROI

with one animal moving and the other still, and a question mark-prompt asking for participants' response

Exposure to nine blocks of 90 pictures (30 spider, 30 needles, 30 neutral), each shown for 3 s; blocks separated by fixation cross (9 s)

Drug-free and -naïve

Two independent 7 min symptom provocation sequences involving 4 s presentations of single visual phobic stimuli

Drug-free

fMRI BOLD; symptom provocation paradigm; 3 T; block design; whole brain and ROI

41 DSM-IV SP: snake phobia: n = 12 mean age: 25.1; 9 f, 3 m; dental phobia: n = 12 mean age: 25.6; 9 f, 3 m; healthy controls: n = 17 mean age: 23.7; 12 f, 5 m

Drug-free and -naïve

fMRI BOLD; symptom provocation paradigm; 1.5 T; block design; whole brain and ROI

15 DSM-IV SP (spider): 13 f, 2 m; mean age: 23.53 14 HC: 12 f, 2 m; mean age: 23.64 All right handed

A video-based paradigm for symptom provocation was used, employing the two anxiety conditions (snake and dental) as both the specific and the non-phobic anxiety control condition (reversed for each subtype). Videos were chosen instead of static pictures to design ecologically valid scenarios of first-person encounters with the feared situation, including dynamic features of the feared stimulus. Exposure to three sets of pictures, each consisting of 16 pictures. The first set contained close-up views of spiders, the second highly aversive scenes, and the third household items.

fMRI BOLD; symptom provocation paradigm; 1.5 T; block design, ROI

Caseras et al. (2010b)

fMRI BOLD; event-related paradigm; 1.5 T; block design, whole brain and ROI

Lueken et al. (2011)

Schweckendiek et al. (2011)

Drug-naïve

SP: showed a quicker time-to-peak in the left amygdala than controls BII: greater activity in the ventral prefrontal cortex compared with controls and lower activity peak in the left amygdala compared with spider phobics. Both phobia groups showed a quicker time-to-peak in the right amygdala than controls SP (snake phobics): activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus; SP (dental phobics): DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP.

SP (spider phobia) ↑ activations within the fear network (medial prefrontal cortex, anterior cingulate cortex, amygdala, insula and thalamus) in response to the phobia-related conditioned stimulus. ↑ Amygdala activation in response to the phobia-related conditioned stimulus than to the non-phobia-related conditioned stimulus.

A. Del Casale et al. / Psychiatry Research: Neuroimaging 202 (2012) 181–197

14 DSM-IV SP (spider): 11 f, 3 m Mean age: 22.71 12 BII: 9 f, 3 m Mean age: 24.58 14 HC: 10 f, 3 m Mean age: 23 All undergraduate students SP: n = 14 mean age: 21.50 ± 2.73; 12 f, 2 m; BII phobics: n = 15 Mean age: 22.40 ± 2.32; 13 f, 3 m; Control: n = 17 Mean age: 21.76 ± 2.88; 15 f, 2 m (participants different from Caseras et al., 2010a)

Caseras et al. (2010a)

displays (two birds), activation of the amygdala was most pronounced in response to congruent phobic displays (two spiders) and less, but still significant, in response to mixed displays (spider and bird) when attention was focused on the phobic component. These results challenge the notion that amygdala activation in response to briefly presented phobic cues is independent from attention. SP: ↑ activation in dorsal ACC and left anterior insula BII: ↑ activation in the thalamus and visual/attention areas (occipito-temporo-parietal cortex)

ACC = anterior cingulate cortex; BA = Brodmann's area; BII = blood–injection–injury phobia; BNST = bed nucleus of the lamina terminalis; BOLD = blood oxygen level dependent; CBF = cerebral blood flow; CBT = cognitive-behavioral therapy; DLPFC = dorsolateral prefrontal cortex; DMPFC = dorsomedial prefrontal cortex; EY = education years; f = female; HC = healthy control; IFG = inferior frontal gyrus; m = male; MTL = medial temporal lobe; NK = neurokinin receptor, binding substance P; PCC = posterior cingulate cortex; rCBF = regional cerebral blood flow; ROI = regions of interest; SP = specific phobia; STAI-Y1 = State–Trait Anxiety Inventory-State; SUDS = Subjective Units of Distress Scale; VAS = Visual Analog Scale; VBM = voxel-based morphometry.

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Table 2 Lateralization of the activation of the amygdala in patients with specific phobia after exposure to fearful stimulation prior to treatment (only studies finding an activation are cited). Study

Technique

Activation Left

Wik et al. (1997) Wright et al. (2003) Dilger et al. (2003) Pissiota et al. (2003) Veltman et al. (2004) Larson et al. (2006) Straube et al. (2006a,b) Goossens et al. (2007a,b) Schienle et al. (2007) Hermann et al. (2007) Wendt et al. (2008) Schienle et al. (2009) Britton et al. (2009) Ahs et al. (2009) Alpers et al. (2009) Caseras et al. (2010b) Lueken et al. (2011) Schweckendiek et al. (2011)

Right

15

PET rCBF [ O]butanol i.v. BOLD fMRI b.d. BOLD fMRI e.-r.d. PET H215O i.v. PET H215O i.v. Chronometry fMRI BOLD e-r.d. BOLD fMRI e.-r.d. BOLD fMRI b.d. BOLD fMRI b.d. BOLD fMRI b.d. BOLD fMRI b.d. BOLD fMRI b.d. BOLD fMRI e.-r.d. PET H215O i.v. fMRI b.d. BOLD fMRI b.d. BOLD fMRI b.d. BOLD fMRI b.d.

Bilateral ✓

✓ ✓ ✓ ✓ Identification task ✓ ✓ ✓ ✓ ✓a

Distraction task ✓

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

✓ ✓

I.v., Intravenous; b.d., block design; e.-r.d., event-related design. a Trend level (p = 0.053).

were exposed to a series of pictures displaying spiders and mushrooms during two different tasks. In the identification task they were asked to identify the object, spider or mushroom, whereas in a demanding distraction task, they had to match geometric figures displayed at the pictures' foreground. In patients, fMRI scans showed a stronger response to spiders, compared to mushrooms, in the left DMPFC during the identification task, but not during the distraction task. Activation increased in the DMPFC when patients were required to evaluate threat-relevant stimulation. In a study comparing phobia-relevant pictures, activity in the DMPFC and VMPFC was lower in nine patients with BII phobia than in controls (Hermann et al., 2007). Disgust- but not fear-inducing pictures also elicited lower activity in the VMPFC in patients than in controls. Sixteen patients with spider phobia participated in a fMRI study, in which they used a reappraisal strategy to voluntarily up-regulate and down-regulate their emotions elicited by spiders and generally aversive pictures (Hermann et al., 2009). Diminished activity in the DMPFC, which probably reflects a phobia-specific down-regulation deficit in patients suffering from spider phobia (Ochsner and Gross, 2005), is in line with a previous study by the same investigators (Hermann et al., 2007). Hermann et al. (2007) compared nine patients with BII phobia with 10 healthy controls exposing them to specific phobia-relevant stimuli, generally disgusting, generally fear-evoking, and neutral pictures, reporting lower DLPFC and VMPFC activations in patients than in controls for both phobia-relevant and disgust-inducing pictures. An interesting clinical use of functional neuroimaging could be therapeutic monitoring. Cognitive-behavioral therapy (CBT) has been tested in five studies included in this review and showed to be effective in correcting activation abnormalities of patients with SP (Paquette et al., 2003; Straube et al., 2006b; Goossens et al., 2007b; Schienle et al., 2007, 2009). After successful CBT, the attenuated hyperactivity in Brodmann's area (BA) 10, which Paquette et al. (2003) include in the DLPFC, could be interpreted as a reduction in the use of coping strategies and a decrease in cognitive misattributions and catastrophic thinking. In their later study, Straube et al. (2006b) found no DLPFC hyperactivation in patients, as compared with healthy controls, nor evidence indicating a therapeutic effect in this area. Interestingly, the abnormal activation in the DMPFC and anterior cingulate cortex in people with SP normalized after CBT (Straube et al., 2006a).

Overall, more studies (six vs. two) using PET (N = 3) or fMRI (N = 5) reported hypoactivation than hyperactivation in SP. CBT studies showed “normalization” of activation patterns, but are few for drawing conclusions. 3.7.2. Orbitofrontal cortex (OFC) In an early PET study, Rauch et al. (1995) showed that during a symptomatic state, induced by tactile imagery of the feared stimulus, rCBF increased significantly in the left posterior medial OFC, compared with the control state. Activation was also found in the middle and inferior (lateral) orbitofrontal gyri and in the superior frontal gyrus with fMRI, which was greater in dental, compared to snake phobia (Lueken et al., 2011). In fMRI studies in patients with SP undergoing CBT, after successful outcome, baseline OFC hypoactivity was found to be potentiated (Schienle et al., 2007, 2009). In pre-treatment scans, decreased activation was found in the medial OFC. The therapeutic benefits of CBT correlated with the increased medial OFC activity in the CBT group, compared to a waiting-list group, possibly reflecting cognitive restructuring. Increased medial OFC recruitment was paralleled by diminished activation in the lateral OFC. The OFC has been investigated in few studies. The only PET study showed hyperactivation, while the fMRI studies were controversial; the two studies by the same group of investigators who studied the effect of CBT on brain activation at the OFC level showed ‘normalization’ of the pattern of brain activity. 3.7.3. Insula Again, Rauch et al.'s (1995) pioneering PET study was the first to report increased insular rCBF in patients with SP. The study showed greater activation in the left insula in patients than in healthy controls and patients with other anxiety disorders (mainly obsessive– compulsive disorder and post-traumatic stress disorder (PTSD)). Investigating left insular activation with fMRI, Martis et al. (2004) showed it to be higher in patients with phobia than in healthy controls. Straube et al. (2004) also showed bilateral insular activation (measured with fMRI) when patients with SP were exposed to phobia-related words, whereas healthy controls were unaffected. Using fMRI, other investigators (Straube et al., 2006b; Goossens et al., 2007a) confirmed abnormally prominent left insular activation in patients with SP exposed to visual phobia-related stimuli. Comparing fMRI BOLD responses to spider pictures (phobic-related stimulus)

A. Del Casale et al. / Psychiatry Research: Neuroimaging 202 (2012) 181–197 Table 3 Comparison of the response to fear between healthy controls and SP patients. The table presents successive steps of the modifications in activity of specific brain areas and nuclei immediately after exposure to a fear-inducing stimulus, the short-term adaptation to the stimulus before activity sets-off when the stimulus is dealt or coped with, and the long-term adaptation when the stimulus persists. The amygdala presumably results in recruitment of other brain areas that subsequently set-off amygdalar hyperactivity. This is ineffective in patients with SPs, who fail to recruit the prefrontal cortex in the short-term, and even in the long-term they do so less effectively than healthy controls.

Immediate reaction Ventral PFC DMPFC DLPFC Amygdala

Healthy controls

SP patients

− − − +

− − − ++

Physiological response to fear Ventral PFC + DMPFC + DLPFC + Amygdala −

− − − +

Continuous stimulation Ventral PFC DMPFC DLPFC Amygdala

+ + + ± (> contralateral)

+ + + −

(> righta) (> righta) (> righta) +

−, no activation; +, activation; ±, small activation; >activity higher at the side indicated. a In right-handed patients. Reversal may occur in left or mixed handed individuals

and BOLD responses to snake (fear-related) or mushroom (neutral) pictures in patients with SP and healthy controls, Dilger et al. (2003) detected significant fMRI-BOLD activations in the right and left insula in SP patients. In an fMRI study comparing 10 patients with small animal SP with 10 matched healthy controls subjected to emotionally expressive and neutral faces, Wright et al. (2003) found significantly greater BOLD responses to the fearful vs. neutral faces in the right insular cortex in the SP group than in the healthy control group. Extending these fMRI results, Wendt et al. (2008) found significantly greater bilateral insular activation during viewing of pictures with spiders than during neutral pictures in patients with small animal SP and compared with healthy controls. Insular activation is also important in distinguishing between the neural substrates underlying snake phobia (hyperactivation) and dental phobia (hypoactivation), as shown in a recent fMRI study (Lueken et al., 2011). Successful CBT reduced insular activation during exposure to feared objects in patients with animal phobia (Veltman et al., 2004; Straube et al., 2006a; Schienle et al., 2009). All eight studies investigating the amygdala agreed in finding hyperactivation in SP patients compared to controls; amygdalar hyperactivation subsided after successful CBT in all three studies investigating this aspect. 3.7.4. Cingulate cortex: anterior cingulate cortex (ACC), dorsal anterior cingulate cortex (dACC), rostral anterior cingulate cortex (rACC), and posterior cingulate cortex (PCC) The fMRI studies reviewed here point to an involvement of the ACC in anticipatory anxiety of SP patients, which is characterized by negative affect, autonomic arousal and hypervigilant environmental monitoring. Using fMRI, Straube et al. (2004) investigated brain activation to phobia-related versus phobia-unrelated words in spider phobia patients and healthy controls. Phobia-related vs. neutral words elicited increased activation in the inferior frontal cortex, DLPFC, insula, and PCC. These investigators proposed that the greater activation in the left DLPFC and PCC reflects enhanced memory processing of phobia-relevant information. In the same study, patients with spider phobia showed greater responses to spider vs. neutral

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words in the insula and the ACC compared to controls. In another fMRI study, the same group of investigators found higher dACC activation in patients affected by spider phobia than in controls; this difference increased when patients anticipated phobia-relevant, rather than neutral stimulation (Straube et al., 2007). In an event-related fMRI study, Goossens et al. (2007a) explored the anxiety/fear pathway by exposing people with spider phobia to pictures of their feared animal, comparing them to a healthy control group. When patients looked at phobia-specific pictures, ACC activation increased bilaterally. ACC activation, particularly in the left hemisphere, as observed during fMRI with identification tasks, supports a role of this brain region in threat processing in SP (Straube et al., 2006b). Other fMRI studies examined the role of the ACC in emotional regulation during a word task. In a study using an event-related emotional counting Stroop task to examine the neural activation response patterns to distracting threat-related words during a cognitive task in patients with specific small animal phobias and in healthy controls, fMRI showed greater rostral ACC activation to phobiarelated than to neutral words in patients, but not in controls (Britton et al., 2009). ACC modulation is also central in BII phobia. Caseras et al. (2010a) compared the neural response to phobia-specific stimuli in patients with BII phobia, patients with animal phobia, and healthy controls. Patients with spider phobia showed significantly more prominent activation in the dorsal ACC and anterior insula than patients with BII phobia. In addition, as previously reported (Fredrikson et al., 1995), patients with spider phobia showed lower activation in the rostral ACC (BA 32) and in the medial frontal gyrus (BA 10), with respect to patients with BII phobia and healthy controls. ACC activity may help in separating other SP subgroups, particularly snake and dental phobias, as reported by Lueken et al. (2011). These investigators showed elevated BOLD responses in snake phobia patients in the anterior and middle cingulate gyrus, supplementary motor area, superior frontal gyrus, parietal cortex (supramarginal and superior parietal gyrus), superior temporal gyrus, and cerebellum. CBT normalized activation in the ACC; this treatment-induced reduction of ACC activation might be coupled to attenuate fearassociated arousal (Straube et al., 2006a). All studies reporting changes in ACC activation agreed in finding hyperactivation upon exposure to phobic stimuli; the only study that focused on the effects of CBT showed normalization of activation patterns in successfully treated cases.

3.7.5. Visual cortex and association cortices Early evidence implying a role for visual and associative cortices in brain activity alterations of patients with SP stem mainly from rCBF PET studies (Table 1). In a PET study of spider phobia, Fredrikson et al. (1993) showed increased activity in the secondary visual cortex during a stimulation paradigm. In a similar study, Fredrikson et al. (1993) found higher rCBF in secondary visual cortex (BA 18 and 19) during visual phobia-inducing stimulation in patients with snake phobia. Fear and anxiety associated with phobic stimulation seem to increase rCBF in the visual associative cortex, while decreasing it in other corticolimbic structures (Wik et al., 1993; Fredrikson et al., 1995). Recent studies point to a role of the occipital cortex, which is differentially activated in different SP subgroups (e.g., BII phobia, dental phobia, snake phobia, etc.). Investigating differences in regional brain activation between people with BII phobia and healthy controls, Schienle et al. (2003) exposed the two groups to disgust-provoking images, but unrelated to the patients' phobic object, finding higher occipital cortex activation in the BII phobia sample, and no other difference whatsoever. Lueken et al. (2011) reported phobic stimuliinduced hyperactivity in the occipito-parietal cortex (supra-marginal

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and angular gyrus) of patients with dental phobia and higher activity compared to patients with snake phobia. Both the three early PET studies and the two recent fMRI studies agree in reporting hyperactivation in the occipital and associative cortices in patients with SP. Hyperactivation was found to be more pronounced in the BII group than in the snake phobia group. 3.8. Limbic sites The limbic system or Papez circuit is considered to represent the site of emotional processing, although it does so in collaboration with other brain areas. The original circuit comprised many hypothalamic nuclei, the mammillary bodies, the anterior thalamus, septum, nucleus accumbens septi-ventral striatum, hippocampus, amygdala, as well as some cortical sites and the tracts connecting these nuclei. We will present here only the two major sites for which consistent findings were obtained with neuroimaging techniques in SP. 3.8.1. Thalamus In spite of a heterogeneity of findings, several functional neuroimaging studies show a thalamic involvement in the pathophysiology of SP, for example, higher thalamic rCBF with PET (Rauch et al., 1995; Wik et al., 1997), higher bilateral thalamic activation during the anticipation of phobia-relevant relative to neutral stimulation with fMRI (Straube et al., 2007), and activation in the left thalamus during implicit vs. random learning (Martis et al., 2004). In two studies investigating the neural correlates of phobic fear (Goossens et al., 2007a,b), patients with spider phobia who were exposed visually to spiders showed increased fMRI-BOLD activation in the amygdala and in the pulvinar of the thalamus. Investigators proposed that the involvement of the pulvinar in the sub-cortical visual pathway enabled fear-relevant stimuli to reach the amygdala. These findings support the involvement of an extrageniculostriate pathway in phobic fear (Goossens et al., 2007a). In a study comparing phobia-related versus neutral words in patients with SP and healthy controls completing an event-related emotional counting Stroop task (ecStroop), Britton et al. (2009) reported greater thalamic fMRI-BOLD deactivation in patients, compared to controls. Recently, Lueken et al. (2011) reported thalamic hyperactivation in snake phobia and hypoactivation in dental phobia patients. These results support thalamic involvement in SP, but the direction of the activation may differ among SP subtypes and depend on the task used in the study.

fMRI study showing increased left amygdala activation in patients with SP confronted with a picture of their feared object, but no between-group differences in activation of the amygdala for the other stimulus categories (potentially fear-relevant and neutral stimuli). Studies designed to avoid amygdala habituation also showed increased left amygdala activity at baseline (Goossens et al., 2007b) and right medial hyperactivation (Veltman et al., 2004) in response to visual stimulation in patients with SP. Summarizing, these findings underline that fMRI studies investigating the function of the amygdala in response to phobic and other emotional stimuli should present stimuli in intermittent unpredictable time blocks to prevent habituation. Based on the established role of the amygdala in attention and negative affect, early studies of emotional fear processing predicted that activity would increase in the amygdala during fear provocation in SP patients compared to healthy controls (Mountz et al., 1989; Fredrikson et al., 1993). In an fMRI study directly examining the role of attention in activating the amygdala, Vuilleumier et al. (2001) found that attention activated the fusiform facial area, but left the activation of the amygdala unchanged; on the other hand, the vision of fearful faces induced higher activation in the amygdala compared to neutral faces. In another study, fear-related distractors did not affect the activity of the amygdala (Bishop et al., 2004); however, the protocol of this study was not optimized for detecting signal changes in the amygdala. In a PET study measuring rCBF in patients with SP and controlling for visual input, Ahs et al. (2009) used matched phobic cues. To minimize habituation, they presented various pictures intermittently. In response to fear-relevant cues, fMRI BOLD activation increased in the right amygdala, cerebellum, left visual cortex, fusiform area and circumscribed frontal areas of SP patients. Subjective distress ratings were positively correlated with amygdalar activity. In a recent fMRI study, Schweckendiek et al. (2011) showed that learned phobic fear is based on exaggerated responses in structures of the fear network (medial prefrontal cortex [mPFC], anterior cingulate cortex, amygdala, insula, and thalamus), hence emphasizing the importance of the amygdala in the processing of phobic fear. Increased activity in the left amygdala at baseline diminished significantly after patients with SP received one CBT session (Goossens et al., 2007b; Schienle et al., 2009). However, other studies did not confirm this finding (Straube et al., 2006b; Schienle et al., 2007). Globally, most studies agree with a central role of amygdalar hyperactivation in SP, particularly at the non-dominant side (Table 2). 4. Discussion: the functional neuroanatomy of patients with SP

3.8.2. Amygdala Most early imaging studies and some recent ones failed to show enhanced amygdala activation in patients with SP presented with fear-related cues (Rauch et al., 1995; Wik et al., 1997; Paquette et al., 2003; Straube et al., 2006b). Comparing responses to phobia-related and neutral pictures (spiders and mushrooms), Straube et al. (2006b) showed greater responses to spiders (phobic stimuli) vs. mushrooms (neutral) in the left amygdala of patients with SP than in healthy controls. Further evidence suggests bilateral amygdala activation in similar conditions (Wendt et al., 2008). In an fMRI study investigating the duration of BOLD activation in response to a phobic stimulus, Larson et al. (2006) confirmed the importance of the duration of the amygdalar response by showing strong, but brief amygdalar activation in patients with SP and weaker and more sustained activation in healthy controls. In a study designed to confirm the involvement of the amygdala in phobic fear, Goossens et al. (2007b) exposed participants to a series of spider (phobia-relevant), snake (potentially fear-relevant) and neutral stimuli. To reduce possible amygdala habituation, pictures were presented in random order for 1 s each with a variable inter-stimulus interval (2.25 s to 9 s). Left amygdala activity resembled the one described by Dilger et al. (2003) in an event-related

This discussion will focus on results of studies included in Table 1, following the same order we used in Section 3, according to the areas showing activation changes upon presentation of phobia-inducing stimuli, or showing differences in activation between patients with SPs and healthy controls, or displaying differences between baseline and post-treatment/task assessment. 4.1. Cortical function in patients with SP 4.1.1. PFC: VPFC, VMPFC, DMPFC, DLPFC The PFC is involved in all executive functions; however, it is also involved in emotional regulation (Davidson et al., 2000). It lies rostrally to the motor and premotor cortices in the frontal lobe; it receives inputs from, and projects to, most other brain regions. Its ventral parts belong to a system which is important for identifying the emotional meaning of stimuli, producing affective states and regulating autonomic responses (Phillips et al., 1997). Effortful regulation of affective states seems to be modulated by a dorsal system, including the DMPFC and DLPFC (Phillips et al., 1997; Ochsner and Gross, 2005), along with the ACC (Ochsner and Gross, 2005). The DLPFC is activated by processes like reappraisal and anticipation, in

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conjunction with the ventral system (Ochsner and Gross, 2005). DLPFC activation is proportional to limbic inhibition (for example, amygdala) (Phelps, 2006). Bilateral amygdala is acutely activated when one deals with fearful stimuli; learned experience that a stressor can be coped with, or is under control or no longer worth paying attention to, is characterized by regional prefrontal activation (Ochsner and Gross, 2005; Phelps, 2006). When this prefrontal activation is protracted, it decreases amygdala activation when a solution is lacking, and is higher in the non-dominant hemisphere if the stressor is rated as difficult to cope with (Ochsner and Gross, 2005; Phelps, 2006). The DLPFC is also important for executive and working memory processes, and is implicated, along with the ventrolateral prefrontal cortex (VLPFC) and VPFC, in effortful emotion regulation (Phelps, 2006). The DLPFC has few direct reciprocal connections with emotional appraisal regions (Ochsner and Gross, 2005). The findings of the studies considered here suggest that specific phobias might reflect a deficit in the automatic mechanisms regulating fear responses and difficulties in the effortful cognitive control of emotions. This probably explains why individuals with SP typically manifest irrational cognition in phobic situations in which they realize they should not be afraid. We may speculate that the DLPFC and VLPFC up-regulate and down-regulate emotional responses by modulating activity in the insula and in the amygdala. A deficit in settingoff phobic, compared with generally aversive emotional reactions, may be linked to diminished inhibitory ability of the PFC. Comorbidity with panic disorder may play a role in the differences observed between SP patients with and without panic disorder (Johanson et al., 1998). These differences could imply that the strongly panicking group lacks the efficiently functioning mechanisms needed to handle strong fear, whereas in non-panicking individuals, despite fearfulness, these mechanisms are still effective (Johanson et al., 1998). The decrease in prefrontal rCBF probably reflects a different psychological response to the fear-engendering stimuli (Fredrikson et al., 1993, 1995). The increased left DLPFC activity found with fMRI in SP patients (Straube et al., 2004) may be related to the use of proactive metacognitive strategies, aimed at automatic regulation of anxiety evoked by the phobic stimuli. This activation may also reflect enhanced memory processing concerning phobia-relevant information, and seems to be strongly involved in working memory and in retrieving semantic information (Cabeza and Nyberg, 2000). Activity in the DMPFC may be associated with direct threat evaluation, a process that requires sufficient concentration. In Straube et al.'s (2006b) fMRI study, the left DMPFC showed a greater response to spiders (specific phobic stimulus), compared to an unspecific stimulus only when the task involved identification, which prompts the individual to focus on a target, but not during distraction. Hermann et al.'s (2007) finding of lower VMPFC activity in patients vs. controls may indicate decreased cognitive control of emotions in people suffering from BII phobia during phobic symptom provocation as well as during disgust, hence pointing at an interdependence of these two emotional conditions. CBT trials in SP agree as to the reversal of activation abnormalities in such patients when CBT is successful (Paquette et al., 2003; Straube et al., 2006b; Goossens et al., 2007b; Schienle et al., 2007, 2009). Dampened DLPFC activation could be interpreted as a reduction in the use of coping strategies and a decrease in cognitive misattributions and catastrophic thinking. Straube et al. (2006b) found no differences between SP patients and controls in DLPFC hyperactivation, nor evidence indicating a therapeutic effect in this area. Interestingly, the abnormal activation in the DMPFC and ACC in people with SP, normalized after CBT (Straube et al., 2006a). It would be interesting to observe separately any changes occurring post-treatment in responder vs. non-responder groups in SP, as described previously for depression (Mayberg et al., 2002) and obsessive–compulsive disorder (Yamanishi et al., 2009). Taken together, data on the effect of

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psychotherapy on brain pattern activation in patients with SP converge to indicate that patients who respond undergo a “normalization” of their brain activity in the prefrontal cortex, which is similar to that shown in other psychiatric disorders. 4.1.2. OFC The OFC is involved in emotion and emotion-related learning; it is central for rapid relearning of stimulus–reinforcement associations and for self-regulation of emotions (Kringelbach and Rolls, 2004). Rauch et al.'s (1995) early PET study showed increased rCBF in the left posterior medial OFC, left insular cortex, left thalamus, right anterior temporal cortex, ACC and left somatosensory cortex. Activation of these paralimbic and limbic regions may be associated with autonomic hyperactivity and exaggerated anxiety response to phobic stimuli (Rauch et al., 1995). This prompts us to consider the OFC as part of a circuitry controlling fearful autonomic responses and taste, considering also that these emotions are interdependent in the PFC as well. The middle, inferior (lateral) orbitofrontal, and superior frontal gyri appear to play a key role in the distinction between dental (greater activation) and snake phobia (smaller activation), as reported recently by Lueken et al. (2011). Studies using fMRI to investigate the effect of CBT in SP patients are in the same line with those which found a reversal of activation abnormalities after successful psychotherapy (Schienle et al., 2007, 2009). The finding of increased medial OFC activity in CBT responders along with diminished activation in the lateral OFC indicates different roles for OFC subdivisions (Kringelbach and Rolls, 2004). The medial regions are involved in the representation of positive reinforcers, whereas lateral parts encode negative stimulation (O'Doherty et al., 2001). This neuroanatomical distinction may help in explaining the “normalizing” effects of CBT (Table 3). 4.1.3. Insula The insula is involved in heartbeat and arterial blood pressure regulation, as well as in viscero-motor control, in viscero-sensitive functions, in nociceptive input processing (Guenot et al., 2004), in disgust (Wicker et al., 2003), and in empathy (Singer et al., 2009). It has a unique position in mediating among sensory input, autonomic/ visceral systems, and other brain regions involved in higher order processing (Wright et al., 2003). Hemodynamic brain imaging studies showed insular activation during processing of facial expressions of disgust (Calder et al., 2001), and other disgustrelated stimuli (Murphy et al., 2003), such as pictures of mutilation and contamination (Wright et al., 2003), disgusting food (Calder et al., 2007) and smells (Wicker et al., 2003), and during autobiographical recall of disgusting events (Fitzgerald et al., 2004). Damage to the anterior insula leads to impaired recognition of disgust stimuli (Sprengelmeyer et al., 1998), and the anterior insula volume correlates with disgust recognition in Huntington's disease (Kipps et al., 2007). These findings suggest that the anterior insula has a central, although nonspecific role in disgust processing (Schienle et al., 2002). In fact, Schienle et al. (2006), studying activation of the insula during disgust processing, reported that healthy controls subjected to two types of disgust elicitors rated comparably disgust, fear and arousal. Both elicitors were associated with activation in the occipitotemporal cortex, amygdala, and OFC, while the activity of the insula was not significantly affected. Higher left insular activation in patients with phobia than in healthy controls (Martis et al., 2004) indicates that the pathophysiological mechanisms responsible for SP differ from those underlying obsessive–compulsive disorder, in which functional neuroimaging invariably discloses deficient striatal activity (Rauch et al., 2001; Del Casale et al., 2011). Left (Straube et al., 2006b; Goossens et al., 2007a) and bilateral (Dilger et al., 2003; Straube et al., 2004) insular activation in patients

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with SP during exposure to phobia-related stimuli is consistent with the insula integrating the meaning of perceived threat signals with bodily states of arousal and subsequent triggering of emotional experiences (Critchley, 2003). The insula might also be involved in mediating the emotional consequences of perceived phobia-relevant linguistic information. Neuroanatomically specific fMRI BOLD responses during SP-related tasks provide further evidence that a variety of aversive stimuli, including disgust- or fear-related pictures, activate the insula (Phillips et al., 1997; Schienle et al., 2002). Hence, the insula seems to be involved in the representation of internal bodily states of arousal (Critchley et al., 2002); this brain region might serve an important role in integrating the information from aversive stimuli in the environment with bodily symptoms evoked by feared objects. The role of the insula in interoception suggests a relation between insular hyperactivity, increased awareness of bodily states, and anxiety proneness (Critchley et al., 2004; Paulus and Stein, 2006). Regarding the latter, Straube et al. (2007) reported ACC activation to be a stronger predictor for subjective anticipatory anxiety than insular activation. Insular activation can help to make a distinction between SP and PTSD, as reported in a meta-analysis conducted by Etkin and Wager (2007). The relation between insula activation and anxiety might be enhanced when attention of research participants is explicitly focused on interoceptive signals (Critchley et al., 2004) or when participants are called upon to evaluate explicit threat-related events (Straube et al., 2004, 2006b). As with other brain areas, successful CBT “normalized” insular activation during exposure to feared objects in SP patients (Veltman et al., 2004; Straube et al., 2006a; Schienle et al., 2009), pointing to a complex effect on brain activity related to this type of psychotherapy. 4.1.4. Cingulate cortex: ACC, dACC, rACC, PCC Broca assigned the cingulate gyri and precuneus to the limbic lobe. The cingulate encompasses several specialized subdivisions that subserve a vast array of cognitive, emotional, motor, nociceptive, and visuospatial functions. The ACC differs from the PCC in cytoarchitecture and projection patterns, as well as functioning (Elston et al., 2005). The ACC performs executive and the PCC evaluative functions (Vogt et al., 1992). The ACC comprises two major subdivisions with distinct functions, the dACC (cognitive division) and the rACC (affective division). The cognitive division belongs to a diffuse attentional network. It maintains reciprocal interconnections with the lateral prefrontal cortex (BA 46/9), parietal cortex (BA 7), and premotor and supplementary motor areas (Devinsky et al., 1995). The various functions attributed to the dACC include attention modulation and executive functions. These functions comprise sensory or response selection (or both), competition monitoring, complex motor control, motivation, novelty, error detection, working memory, and cognitive anticipation of demanding tasks. The rACC is connected to the amygdala, periaqueductal gray, nucleus accumbens, hypothalamus, anterior insula, hippocampus, and orbitofrontal cortex. It projects to the autonomic, visceromotor and endocrine systems. It is mainly involved in assessing the salience of emotional and motivational information and in regulating emotional responses (Vogt et al., 1992; Devinsky et al., 1995). Some evidence implicates the dACC in cognitive operations such as performance monitoring, attentional control or response selection (Bush et al., 2000). Correlation analysis showed that subjective anticipatory anxiety in patients with phobia induces activation in dACC, rACC and DMPFC, and the intensity is proportional to the severity of the anticipatory anxiety experienced. This association may reflect a balance between introspective thinking and outwardly directed attention to ensure readiness for adaptively responding to sudden

environmental changes (Straube et al., 2007). These functional neuroimaging research findings provide evidence encouraging psychotherapies to direct their efforts to relieve phobic symptoms in patients with SP. Several studies investigated the role of the ACC in modulating threat-related and other emotion-relevant stimuli in patients with SP. In the Goossens et al. (2007a) study, when patients looked at phobia-specific pictures, their ACC activation increased bilaterally. In healthy subjects, fMRI scans showed ACC activation, especially in the rostral part, during processing of threat-related and other emotion-relevant stimuli (Bush et al., 2000; Phan et al., 2002). ACC activation, particularly in the left hemisphere, observed during fMRI with identification tasks, supports a role for this brain region in threat processing in SP (Straube et al., 2006b). The exaggerated rACC activation found during phobic exposure in SP patients, compared to healthy controls (Britton et al., 2009), may suggest increased salience, heightened sensitivity, or a lower perceptual threshold for detecting fear, which more readily draws attention toward threatening cues. Alternatively, the rACC response could indicate emotion regulation needed to shift attention to the cognitive task (Britton et al., 2009). Increased activation in the inferior frontal cortex, DLPFC, insula, and PCC during phobic exposure in spider phobia led Straube et al. (2004) to propose that the greater activation in the left DLPFC and PCC reflects enhanced mnemonic processing of phobia-relevant information. As in other areas, CBT normalized activation in the ACC (Straube et al., 2006a); however, as this is the only study regarding this area, replication studies are needed. 4.1.5. Visual cortex and association cortices Increased visual associative cortex rCBF may reflect increased visual attention to a possible threat, whereas reduced limbic and paralimbic cortical rCBF activity in SP may indicate impaired conscious cognitive processing during a defense reaction. Altered rCBF in posterior cerebral regions during experimental manipulation of phobic anxiety (O'Carroll et al., 1993) combined with visual association cortex rCBF increase may reflect enhanced processing in the stimulated visual modality (Fredrikson et al., 1993). 4.2. Limbic function in patients with SP 4.2.1. Thalamus The thalamus is a midline paired symmetrical formation. It is the largest structure in the diencephalon, and lies between the cerebral cortex and midbrain surrounding the third ventricle. Its functions include relaying sensation, special sense and motor signals to the cerebral cortex, along with regulating consciousness, sleep and alertness (Percheron, 2004). Britton et al.'s (2009) finding of greater lateral amygdala and posterior insula activation and thalamic deactivation suggested that the sensory input for phobia-related words, relayed via the thalamus to the rACC and the amygdala, may be more salient in patients with animal phobia, and that the cognitive demands of the ecStroop task may alter prefrontal sensory modulation signals through the thalamus (Britton et al., 2009). Recently, Lueken et al. (2011) suggested that, among other brain areas, snake phobia (hyperactivation) may be best differentiated from dental phobia (hypoactivation) in the thalamus. 4.2.2. Amygdala The amygdala is probably a key cerebral structure in stress response, phobia and anxiety mediation. It is localized in the anterior medial portion of the temporal lobes bilaterally and comprises many specialized nuclei, each having wide connections. Its role in emotional processing is comprehensive; some investigators proposed

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to include the main emotional nucleus of the basal ganglia, the nucleus accumbens, in a functional system working conjointly with the amygdala proper, denominating it the “extended amygdala” (Zahm, 1998). The amygdala receives excitatory glutamatergic afferents from the thalamus and sensory cortex (Davis, 1997, 2002). Afferent fibers reach the first lateral portion of the amygdala, then project to two small subregions, i.e., basolateral and basomedial portions, finally reaching the central nucleus. In turn, the central amygdaloid nucleus projects to the hypothalamus (paraventricular and lateral nuclei), to the thalamic reticular nucleus, to the nuclei of the trigeminal and facial nerves, to the ventral tegmental area, to the periaqueductal gray, and to the locus coeruleus. Each structure in this network seems to mediate several components of emotional responses (Charney and Drevets, 2002). Early imaging studies and also some recent ones failed to show enhanced amygdala activation in patients with SP exposed to fearrelated cues (Paquette et al., 2003; Straube et al., 2006b). This was probably due to differences in study design and brain imaging methodology. Several early PET studies probably failed to find amygdala activation in response to phobia-relevant cues because the temporal resolution of the technique during the mid-1990s was insufficiently developed for capturing these relatively fleeting activation patterns (Rauch et al., 1995; Wik et al., 1997). The failure to obtain positive activations in past studies of obsessive–compulsive disorder and aversive conditioning has been attributed to similar methodological issues, for example, to study design implying stimulus presentation in fixed time blocks, which causes habituation of rapid amygdala responses (Breiter et al., 1996; Buchel et al., 1998). Later studies showed that random intermittent and repeated feared stimuli avoid habituation and activate the amygdala better than periodic, predictable stimuli (Straube et al., 2006a,b). Several studies (Mountz et al., 1989; Fredrikson et al., 1993; Vuilleumier et al., 2001) suggest that the amygdala may be automatically activated, independently from attention. This suggestion receives further support from Anderson et al. (2003), who found fearful face recognition to activate the amygdala independently from attention in healthy controls, while disgusted faces activated the insula only when attention was intact. Given that less anxious subjects show stronger amygdalar responses to attended, than to unattended fearful faces, we may hypothesize that anxiety might modulate attention-related changes in amygdalar activation (Pessoa et al., 2002). There is a linear relationship between subjective experience of negative affect and amygdalar activation (Goossens et al., 2007b; Michelgard et al., 2007; Ahs et al., 2009). Interestingly, in a metaanalysis conducted by Etkin and Wager (2007), amygdala hyperactivation was more commonly observed in social anxiety disorder and SP than in PTSD, and may help in distinguishing SP from PTSD. Left amygdalar reduction of hyperactivation after a single CBT session (Goossens et al., 2007b; Schienle et al., 2009) is another result obtained with this type of psychotherapy in the normalization direction. However, it would be premature to propose tolerance to the phobigenic amygdalar activation after treatment as a biological marker for successful treatment in SP, because other studies did not confirm this finding (Straube et al., 2006b; Schienle et al., 2007). Although the amygdala is at the crossroads between phobia-related brain activity (Figs. 1 and 2), its interplay with many other structures may trigger activities elsewhere that may set-off its activity in the context of normal responses to phobic stimulation; hence, the activation may be too transient to be detected. 5. Conclusions and perspectives Clear-cut neurobiological differences between specific phobia and other anxiety disorders are increasingly emerging from functional neuroimaging, pointing to its future usefulness.

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Different brain areas contribute to a specific fear network, composed by the medial prefrontal cortex, anterior cingulate cortex, amygdala, insula and thalamus, in which higher activations were observed in response to phobia-related conditioned stimuli. Limbic and paralimbic structures, such as the thalamus and the insula, are involved in SP-related autonomic dysregulation. The control and evaluative cortices supervising executive functions, such as the VLPFC, OFC, ACC and insular cortices, also determine the kind of neural and behavioral output. For example, the inhibitory influence of the OFC and its habit-formation properties may overcome abnormal amygdalar activation and constitute the target for psychological and pharmacological therapeutic interventions. Functional neuroimaging showed BII and dental phobia to be functionally different. BII phobia shows a biphasic response to fearinducing stimuli; as in other SPs, the initial sympathetic response leads to an increase in heart rate and blood pressure. Unlike other SPs, this is followed by a pronounced parasympathetic response that can lead to fainting (Caseras et al., 2010a). BII phobia is characterized by dysfunction of the PFC (lower DLPFC and VMPFC activations in patients than in controls for both phobia-relevant and disgust-inducing pictures), of the ACC and insula (higher activation in the dorsal ACC and anterior insula in spider phobia compared with BII phobia; lower activation in the rostral ACC and in the medial frontal gyrus in spider phobia compared with BII phobia and healthy controls), and of the occipital cortex (higher activation in BII phobia than in healthy controls). Snake phobia is also characterized by autonomic arousal, with activation of the fear circuitry structures comprising the insula, the anterior cingulate cortex, and the thalamus. Autonomic arousalindependent SPs, like dental phobia, showed lower PFC and OFC activation than snake phobia. Taken together, these findings support the current DSM-IV-TR subtyping of SPs. Functional neuroimaging techniques might identify treatmentresponse predictors and monitor response to drug treatment or CBT, for example, by showing fMRI activation pattern normalization after successful treatment in the ACC, the amygdala, insula, OFC and other prefrontal areas, like the DMPFC. Future improvements in

Fig. 1. The amygdala at the crossroads of fear-related information processing involving the prefrontal cortex. Stimuli are worked-through by entering to the amygdala through the thalamus and then processed to the amygdala, which provides connections to both higher brain function-related cortical areas (light gray) and subcortical nuclei (darker gray); upon receiving their output, the amygdala integrates messages, thus providing feedback to the thalamus and the striatum (not shown) to yield a motor output. DLPFC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; Ventral PFC, ventral frontopolar prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex.

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Fig. 2. Integrated model of the fear-related circuitry involving cortices other than the prefrontal cortex. The interconnections are shown between cortical (light gray) and subcortical structures (darker gray) participating in the response to fearful signals.

functional neuroimaging and other imaging techniques may help in better clarifying neurobiological dissimilarities of various SP subgroups and distinguishing between the neurobiology of SP and other anxiety disorders. Despite substantial convergence of studies focusing on functional neuroimaging of SP, findings come from a relatively small number of investigations. Furthermore, the majority of these investigations focused on small animal phobia and other types of phobia appear to have been relatively neglected. However, from what is already available, we might hypothesize that the various SPs, despite sharing most areas of involvement in their pathophysiology, are endowed with partially different neurobiological mechanisms. Financial and competing interests disclosure In the past 3 years, Stefano Ferracuti has participated in advisory boards for Pfizer and Lilly and received honoraria from Lilly, BristolMyers, Sigma Tau, Schering and Pfizer; Paolo Girardi has received research support from Lilly and Janssen, has participated in Advisory Boards for Lilly, Organon, Pfizer, and Schering and received honoraria from Lilly and Organon; Roberto Tatarelli has participated in Advisory Boards for Schering, Servier, and Pfizer and received honoraria from Schering, Servier, and Pfizer. All other authors of this review article have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the review article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Acknowledgments We gratefully acknowledge the contribution of the Librarians of the School of Medicine and Psychology of Sapienza University, Drs. Mimma Ariano, Felicia Proietti and Tiziana Mattei, in helping us to locate and organize the relevant literature. References Ahs, F., Pissiota, A., Michelgard, A., Frans, O., Furmark, T., Appel, L., Fredrikson, M., 2009. Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake phobia. Psychiatry Research: Neuroimaging 172, 103–108.

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