HUMAN SOCIAL INTERACTION RESEARCH PROPOSAL C8CSNR

Transcription

1 HUMAN SOCIAL INTERACTION RESEARCH PROPOSAL C8CSNR Applicants Principal Investigator Student ID Collaborators Name(s) Thomas Straube Institution(s) University of Jena, Germany Title of project: The influence of fear recognition on phobic response, in patients suffering from spider phobia: an fmri study focusing on the amygdala. Lay Summary (max 200 words): An experiment will look at images of brain areas, in people who have a phobia of spiders. Previously, it has been noted that an area known as the amygdala is activated more intensely when people recognise a facial expression of fear as opposed to other emotions. The amygdala is also known to be more highly activated when spider phobics are exposed to images of spiders in comparison to pictures of other fearful animals (e.g. snakes) or neutral images (e.g. mushrooms). This experiment aims to discover whether, when shown a person watching a spider, a spider phobic will demonstrate more amygdala activation when that person is fearful than if the person is indifferent in their facial expression. Scientific Summary (max 200 words): Using a 2X3, event-related functional magnetic resonance imaging (fmri) paradigm, focusing on the amygdala; patients suffering from spider phobia will be shown video-stimuli that vary on facialexpression (fearful; neutral) and target-object (spider: phobogenic-stimulus; snake: fear-relevantstimulus; leaf: neutral-stimulus). Based on previous findings that both fearful-expressions and exposure to phobogenic stimuli correlate with elevated amygdala activation, and evidence that the amygdala is more responsive to an object paired with a fear-expression than a fear-expression alone; it is expected that fearful-expression will interact with spider-stimuli, resulting in an even stronger Blood-Oxygen- Level Dependent (BOLD) signal from the amygdala. Table of Costs Equipment Participants MRI Scanner + 15 subjects Spider Phobics 150 Equipment Total 450 Participants total 150 Grand Total 600 i

2 PROPOSED RESEARCH PROGRAMME 1. Background of the project 2. Questions to be answered 3. Plan of investigation 4. Details of data analysis 5. Expected outcomes 6. Details of any difficulties that can be foreseen 7. Future purpose and theoretical implications PROPOSED RESEARCH PROGRAMME Page One 1. Background of the project There is a developing area of research concerned with the neurological basis of specific phobias (Straube and Miltner, 2006). This proposed experiment is specifically interested in spider phobia, one of the most commonly occurring anxiety disorders: 1.2% prevalence in males and 5.6% in females (Fredrikson et al, 1996). Several fmri studies have reported greater amygdala activation in spider phobics in response to phobogenic stimuli (spiders), in comparison to other fear-relevant stimuli (e.g. snakes) and neutral stimuli (e.g. mushrooms) (Schienle et al, 2005; Dilger et al, 2003; Sabatinelli et al, 2005; Larson et al, 2006; Goosens et al, 2007). This consistent finding highlights the significance of the amygdala in the processing of phobia-relevant threat; which tends to also be found in patients of other phobias (e.g. social phobia: Birbaumer et al, 1998; post traumatic stress disorder: Gilboa et al, 2004). It must be noted that other brain areas have also been linked with the perception of phobogenic stimuli: increased activation in the dorsolateral and orbitofrontal prefrontal cortex (Dilger et al, 2003; Fredrikson et al, 1995; Johanson et al, 1998; Rauch et al, 1995), the insula (Dilger et al, 2003; Rauch et al, 1995) and the visual association cortex, inparticularly the fusiform gyrus (Dilger et al, 2003, Fredrikson et al, 1995; Paquette et al, 2003), none, however are as consistently noted as the amygdala. There is also extensive research in human neuropsychology which demonstrates the amygdala s involvement in processing signals of fear (review: Calder et al, 2001). Patients with bilateral amygdala damage show deficits in recognition of fearful expression, in comparison with other emotions (Adolphs et al, 1994, 1995; Calder et al, 1996). This concurs with further evidence, which reveals, using human neuroimaging, that viewing facial expressions of fear results in an increase in amygdala activity (Morris et al, 1996, 1998; Breiter et al, 1996). Whalen et al (1998) even reported, using functional magnetic resonance imaging (fmri), increased right amygdala activity in response to masked fearful faces; indicating that even when the expression is not consciously processed, the amygdala is critically involved when perceiving fear in another person. Reports on the etiology of spider phobia suggest that, in most cases, the irrational-fear is attained through learned experience (Merckelbach et al, 1998, 2002; Muris et al, 1997), especially through modelling (Merckelbach et al, 1991). This converges with the literature on social fear-learning; such as Mineka & Cook (1988) who demonstrated that monkeys can acquire a fear of snakes through observation of a conspecific. Similarly, children have been shown to respond aversively to fear-relevant-stimuli e.g. toy snake, spider) after their mother responded fearfully to it. Investigation into the neural correlates of socially-learned fear again highlights the amygdala as the main area of activation. The amygdala was recruited both when observing and experiencing an aversive event (Olsson et al, 2007); suggesting that indirectly acquired fears are as predominant as fears that are directly acquired. The amygdala also reacts more to object-fear association than to fearful expressions alone (Hooker et al, 2006); which is interpreted to be a survival function, as the amygdala is using social signals to learn threatening situations. It seems relevant, therefore, to examine the relationship between a spider-phobic s direct experience of a spider and the indirect experience of another person s fear. There is a paucity of research looking into whether an already established phobic-response can be neurologically heightened in the presence of another s fear to the phobogenic stimulus. With such an established literature demonstrating the involvement of the amygdala in recognising fear in others, and a flourishing area of research revealing that the amygdala is also prominent in phobic responses; an inquiry into whether amygdala-activation is affected by an interaction between the two would be of considerable interest. ii

3 PROPOSED RESEARCH PROGRAMME Page two 2. Questions to be answered - It is consistently found that the amygdala is significantly activated as a result of recognising the expression of fear in another person, in comparison with other emotional expressions. - It is reported that the amygdala, in spider-phobics, is stimulated significantly more when exposed to spider-stimuli, in comparison to other fear-relevant and neutral stimuli. Will both perceiving a spider and experiencing a fearful expression interact on amygdala activation in spider-phobics? I.e. Will recognising someone else s fear of a spider influence a spider-phobic s already-established phobic-response to the spider? 3. Plan of investigation 3.1. Subjects Fifteen female spider phobic participants (age years). Participants will be classified as phobics by scoring greater than 20 (94 th percentile) on a Spider-Phobia-Questionnaire (Klorman et al, 1974) All participants will also be screened with a structured clinical interview for DSM-IV Axis I Disorders (First et al, 1995); this will check whether participants fulfil the criteria for the presence of spider-phobia and to ensure no participant suffers from mood or anxiety disorders. Participants will be under no medication and will have no history of head trauma, drug use or neurological illness. Using similar diagnostic-techniques, it will be ensured that no subject has anxiety towards snakes or butterflies. All subjects will give written informed consent, to be approved by the University of Nottingham Ethics-Committee Design Four-second video-clips shall be produced for each condition. Each clip shall include the view of an actor s face looking directly at a target-object (spider: phobogenic-stimulus; snake: fear-relevent-stimulus; butterfly: emotionally-neutral-stimulus), which will feature between the actor and the camera; e.g. a spider/snake/butterfly will crawl/slither/flutter across the screen, in the foreground. The actor, watching from the background, will respond to the target-object with a facial expression (either fearful or neutral) (see figure 1). In total 144 video-clips shall be constructed: using a combination of 4 actors (2 male; 2 female); 2 expressions (fearful; neutral); 9 types of target-object (e.g. 3spiders; 3snakes; 3butterflies); 2 directions of Figure1:Stimulus-set-up. An actor(1) will be watching as the target-object(3) travels past(4), while making a facial expression(2). stimulus movement across the screen (left right; right left) [i.e. 2x9x2x2=144]. All clips will be matched for colour, intensity, focus, speed and camera-angle. There will also be 150 null-events: a fixation point on a screen for five seconds; which will serve as a control. All 294 stimuli will be presented twice, in a pseudo-random order, each with a variable interstimulus interval of between 2 and 9 seconds, to control for anticipation. Clips will be projected on a screen behind the subjects and viewed inside the head-coil, by means of a mirror. A passive-viewing fmri paradigm shall be used; subjects will be instructed to watch the video-clips attentively. Functional brain images will be acquired using a 1.5T magnetic resonance scanner(phillips Achieva, whole body imaging/spectroscopy system; Magnetic Resonance Centre, University of Nottingham). 4. Details of data analysis Using a T2* weighted gradient echo-planner sequence, 584 functional images will be acquired for every subject. Each volume will be comprised of 40 axial-slices (thickness= 3mm; no gap), covering the whole brain. Preprocessing and statistical analysis will be carried out using SPM2 statistical and parametric mapping software package (Wellcome Department of Cognitive Neurology, London). The first five volumes will be discarded to allow for signal equilibration. The functional images will be iii

4 PROPOSED RESEARCH PROGRAMME Page three Talairach space (Talairach et al, 1988), after coregistering anatomical and functional volumes. Origin correction, motion correction and smoothing shall also be implemented on the data. First-level statistical analysis will estimate effects, at every voxel, using the general linear model. The expected Blood-Oxygen-Level Dependent (BOLD) signal will be modelled by a hemodynamic response function for each condition: Spider-Fearful(SpF), Spider-Neutral(SpN), Snake- Fearful(SnF), Snake-Neutral(SnN), Butterfly-Fearful(BuF), Butterfly-Neutral(BuN).These images will be entered into second-level analysis, using a two-way (2X3) within subjects ANOVA. Due to the main question of this study, the amygdala shall be defined as a region of interest (ROI) in the analysis. Results will be reported at p<0.05 and Bonferroni correction shall be applied for multiple comparisons. The following subtractions will be carried out to determine the effects of interest: Main-effect of facial-expression (SpF+SnF+BuF) (SpN+SnN+BuN) Main-effect of target-object (SpF+SpN) (SnF+SnN) (BuF+BuN) Simple-main-effect of spider vs. snake (SpF+SpN) (SnF+SnN) Simple-main-effect of spider vs. butterfly (SpF+SpN) (BuF+BuN) Simple-main-effect of snake vs. butterfly (SnF+SnN) (BuF+BuN) Interaction between spider and fear (SpF-SpN) (BuF-BuN) 5. Expected outcomes 5.1. Main-effect of facial-expression Consistent with previous findings (Morris et al, 1996, 1998; Breiter et al, 1996), it will be expected that activation of the amygdala will be significantly larger in conditions involving fearful-expressions than in conditions with neutral-expressions Main-effect of target-object, and simple-main-effects An overall effect of target-object stimulus is also anticipated. Simple-main-effects are expected to show that spider-stimuli cause a significantly larger activation in the amygdala than both snake-stimuli and butterfly(neutral)-stimuli, concurring with earlier studies (e.g. Dilger et al, 2003; Larson et al, 2006; Goosens et al, 2007). Aside from the ROI analysis, within-group analysis may show significant activation of the left and right insula in the spider condition when contrasted with snake and butterfly conditions (as found by Dilger et al); the snake-condition (being fear-relevant) should also show significantly higher amygdala activation than the butterfly-condition. Dilger et al also noted, for phobics, in the spider condition, significantly increased BOLD signals in the bilateral-fusiform-gyrus and the right orbitofrontal cortex, when compared with the snake and neutral conditions; this therefore might also be expected in this study. Furthermore, other brain-areas previously correlated with spider stimuli presentation are the dorsolateral prefrontal cortex and the parahippocampus (Paquette et al, 2003), which should consequently also be noted as possible outcomes Interaction between spider and fear The result of this interaction is the main interest of the study; however it has not been directly investigated before, therefore a prediction is much harder to make. It is widely supported, and therefore anticipated, that both conditions involving fearful-expression and conditions involving a spider as the target-object will correlate with significantly increased activation of the amygdala. The fact that both main-effects centre on the amygdala, suggests that an interaction would occur between them. It will be proposed that when a spider is paired with a fearful-expression (i.e. condition SpF), there will be a significantly larger BOLD-signal from the amygdala, than when a spider (i.e. SpN) or a fearfulexpression (i.e. LeF) are presented without the other (i.e. spider-stimulus and fearful-expression will have an additive interaction on amygdala activation). iv

5 PROPOSED RESEARCH PROGRAMME Page four 6. Details of any difficulties that can be foreseen By the nature of the study, the largest concerns will be regarding participation. The general recruitment of subjects may be an issue; testing will be in one location, so in order to obtain the desired sample, many participants may have to travel quite a way. And of course the selection of subjects is further limited by the fact that each one must meet the criteria of being spider-phobic. Although subjects will be paid a small fee, the testing will be quite lengthy and in a potentially claustrophobic environment; and of course there is the major issue of convincing subjects to enter a study which will expose them to stimuli they are most fearful of: spiders. It is therefore essential to address these matters seriously, as the number of subjects has a large impact on the power of the results. Ways to overcome these problems could include searching for subjects early; making sure they are relaxed and not kept longer than necessary; and highlighting the importance of their participation in terms of furthering the understanding of their anxiety-disorder. In terms of testing, problems may include the stillness of the subjects; movements cannot be completely controlled for, especially when some may be fear-responses to phobogenic stimuli. Spiderphobics are also known to look away or divert their attention from spider stimuli (Rinck et al, 2006), which may result in inaccuracies in brain-imaging. The fmri BOLD-signals can also only be construed as an indirect measure of brain activity and scans may not pick up all activity which can lead to misinterpretation in analysis. Furthermore, there is the fact that results are taken from an artificial environment, where visual field is limited and it is difficult to eliminate all noises from the scanner, which limits their ecological validity. However, fmri is currently one of the most effective non-invasive ways to examine brain activity in this type of paradigm. It just needs to be ensured that precautions are implemented at every stage to uphold accuracy, and vigilance is adopted when interpreting results and generalising them to larger populations. 7. Future purpose and theoretical implications If results turn out as anticipated, they will implicate a number of research areas. Firstly, they will provide support for the amygdala s involvement in fear-recognition, specifically facial-expression (e.g. Morris et al, 1996). Results will also concur with the literature on phobia (e.g. Dilger et al, 2003), by demonstrating that the amygdala is crucially involved in processing phobogenic stimuli, when compared with other fear-relevant (snake) and neutral (butterfly) stimuli. This will converge with other research to emphasise the role of the amygdala in fear (see Calder et al, 2001). The main interest will be the interaction between fearful-emotion and spider-stimuli. This will really highlight how much someone else s fear can influence your own fear, since the increased amygdala activation from perceiving a phobogenic stimulus is increased even further when you are aware that another person is also fearful to the stimulus. This finding would fit in nicely with the literature on social fearlearning (Mineka & Cook, 1988), and neuropsychological literature which reports that the amygdala is more highly activated when subjects are exposed to a fearful-expression paired with an object-of-fear, than a fearful-expression alone (Hooker et al, 2006). This might suggest that the amygdala is recruited to analyse facial expressions with the intention of learning an association to a potentially threatening stimulus. This concurs with the idea that the amygdala uses negative social signals to facilitate avoidance behaviour to enhance survival (Keltner and Kring, 1998). The results may therefore imply that the amygdala is not simply responding to the negative facial emotion, it is analysing expression for the purpose of learning. The results of this investigation will have a major impact on spider-phobia. A more comprehensive understanding of the phobia s etiology can be gained by noting the significant influence of fear-learning on phobic-response, which is important in terms of stopping transference of phobias. Neuroimaging methods can also help to formulate a reliable neurobiological model of phobia, which is still lacking (Schienle & Schafer, 2006); as anxiety-disorders are not only characterised by emotional and cognitive behavioural changes, they also have a neurological basis. Moreover, brain-imaging results can also inform psychotherapists application of therapeutic interventions, and facilitate new techniques to combat spiderphobia, e.g. newly-developing neuropsychotherapy (e.g. Gauggel, 2006) From here, research could see whether results apply to other phobias. It would also be interesting to see whether other emotional-expressions interact with perceiving a phobogenic stimulus and whether a positive emotion might reduce an already established phobic-response. v

6 PROPOSED RESEARCH PROGRAMME Page five TO BE USED FOR REFERENCES ONLY vi

7 Adolphs R, Tranel D, Damasio H, Damasio A (1994): Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature, vol.372, p Adolphs R, Tranel D, Damasio H, Damasio A (1995): Fear and The human amygdala. Journal of Neuroscience, vol.15, p Birbaumer, N, Grodd,W, Diedrich, O, Klose, U, Erb, M, Lotze, M, Schneider, F, Weiss, U, Flor, H (1998). MRI reveals amygdala activation to human faces in social phobics. NeuroReport, vol.9(6), p Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, et al (1996): Response and habituation of the human amygdala during visual processing of facial expression. Neuron, vol.17, p Calder AJ, Lawrence, AD, Young, AW (2001). Neuropsychology of Fear and Loathing. Nature Reviews. Neuroscience, vol.2, p Calder AJ, Young AW, Rowland D, Perrett DI, Hodges JR, Etcoff NL (1996): Facial emotion recognition after bilateral amygdala damage: Differentially severe impairment of fear. Cognitive Neuropsychology, vol.13, p Dilger S, Straube T, Mentzel HJ, Fitzek C, Reichenbach JR, Hecht H, Krieschel S, Gutberlet I, Miltner WH (2003). Brain activation to phobia-related pictures in spider phobic humans: an event-related functional magnetic resonance imaging study. Neuroscience Letters, vol.348, p First MB, Spitzer RL, Gibbon M, Williams JBW (1995). Structured Clinical Interview for DSM-iv Axis I Disorders Non-patient Edition (SCID/NP, Version 2.0). New York State Psychiatric Institute: Biometrics Research Department Fredrikson M, Annas P, Fischer H, Wik G (1996). Gender and age differences in the prevalence of specific fears and phobias, Behaviour Research and Therapy, vol34, p Fredrikson M, Wik G, Annas P, Ericson K, Stone-Elander S (1995). Functional neuroanatomy of visually elicited simple phobic fear: Additional data and theoretical analysis. Psychophysiology, vol.32, p Gauggel S (2006). Neuropsychotherapy: Comments of a Neuropsychologist. Verhaltenstherapie, vol.16(2), p Gerull FC, Rapee RM. (2002). Mother knows best: effects of maternal modelling on the acquisition of fear and avoidance behaviour in toddlers. Behaviour Research and Therapy, vol.40(3), p Gilboa, A, Shalev, AY, Laor, L, Lester, H, Louzoun, Y, Chisin, R, Bonne, O (2004). Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biological Psychiatry, vol.55, p vii

8 PROPOSED RESEARCH PROGRAMME Page six TO BE USED FOR REFERENCES ONLY Goossens L, Schruers K, Peeters R, Griez E, Sunaert S (2007).Visual presentation of phobic stimuli: Amygdala activation via an extrageniculostriate pathway? Psychiatry Research-Neuroimaging, vol.155(2), p Hooker CI, Germine LT, Knight RT, D'Esposito M (2006). Amygdala response to facial expressions reflects emotional learning. Journal of Neuroscience, vol.26(35), p Johanson A, Gustafson L, Passant U, Risberg J, Smith G, Warkentin S, Tucker D (1998). Brain function in spider phobia. Psychiatry Research: Neuroimaging, vol.84, p Keltner D, Kring (1998) Emotion, social function, and psychopathology. Review of General Psychology, vol.2, p Klorman R, Weerts TC, Hastings JE, Melamed BG, Lang PJ (1974). Psychometric description of some specific-fear questionnaires. Behaviour Therapy, vol.5, p Larson CL, Schaefer HS, Siegle GJ, Jackson CA, Anderle, MJ,Davidson, RJ (2006). Fear is fast in phobic individuals: amygdala activation in response to fear-relevant stimuli. Biological Psychiatry, vol.60, p Merckelbach H, Arntz A, Dejong P (1991). Conditioning experiences in spider phobics. Behaviour Research and Therapy, vol.29(4), p Merckelbach H, Muris P, Schouten E (1996). Pathways to fear in spider phobic children. Behaviour Research and Therapy. vol. 34(11), p Mineka S, Cook M (1993). Mechanisms involved in the observational conditioning of fear. Journal of Experimental Psychology: General, vol.122, p Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, et al (1996): A differential neural response in the human amygdala to fearful and happy facial expressions. Nature, vol.383, p Morris JS, Öhman A, Dolan RJ (1998): Conscious and unconscious emotional learning in the human amygdala. Nature, vol. 393, p Muris P, Merckelbach H, Collaris R (1997).Common childhood fears and their origins. Behaviour Research and Therapy, vol.35(10), p Muris P, Merckelbach H, de Jong PJ, Ollendick TH (2002). The etiology of specific fears and phobias in children: a critique of the non-associative account. Behaviour Research and Therapy, vol.40 (2), p Olsson A, Nearing K, Phelps E (2007). Learning fears by observing others: the neural systems of social fear transmission. Social Cognitive and Affective Neuroscience, vol. 2(3), p3-11. viii

9 PROPOSED RESEARCH PROGRAMME Page seven TO BE USED FOR REFERENCES ONLY Paquette V, L evesque J, Mensour B, Leroux JM, Beaudoin G, Bourgouin P, Beauregard M (2003). Change the mind and you change the brain: effects of cognitive behavioural therapy on the neural correlates of spider phobia. NeuroImage, vol.18, p Rauch SL, Savage CR, Alpert NM, Miguel EC, Baer L, Breiter HC (1995). A positron emission tomography study of simple phobic symptom provocation. Archives of General Psychiatry, vol.52, p Rinck M, Becker ES (2006). Spider fearful individuals attend to threat, then quickly avoid it: Evidence from eye movements Journal of Abnormal Psychology, vol.115(2), p Sabatinelli D, Bradley MM, Fitzsimmons JR, Lang PJ (2005). Parallel amygdala and inferotemporal activation reflect emotional intensity and fear relevance. NeuroImage, vol.24, p Schienle A, Schafer (2006). Neural correlates of exposure therapy in patients suffering from specific phobia. Verhaltenstherapie, vol.16(2), p Schienle, A., Schafer, A., Walter, B., Stark, R., Vaitl, D., Brain activation of spider phobics towards disorder-relevant, generally disgust and fear-inducing pictures. Neuroscience Letters, vol.388, p1 6. Straube T, Miltner WHR (2006). Neural Correlates of the Processing of Threat-Relevant Stimuli in Phobics and Healthy Subjects. Psychologische Rundshau, vol.57(3), p Talairach J, Tournoux P (1988). Co-Planar Stereotactic Atlas of the Human Brain, New York: Thieme. Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA (1998): Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. Journal of Neuroscience, vol.18, p Word Count: 2,472 (+16 words in caption) ix