User:Abdulrahman Alghadhbani/sandbox

Use of fMRI in the diagnosis of anxiety disorders.
= Introduction: =

Functional magnetic resonance imaging (fMRI) is an approach employed to map experiential, affective, and cognitive processes in the brain (Huettel et al., 2004). Anxiety can be defined as an anticipation of a threat in the future (Emilien et al., 2002). This page is an attempt to shed light on the use of fMRI in the diagnosis of anxiety disorders.

= How fMRI can be used in the diagnosis of anxiety disorders? =

One of the most employed behavioural paradigm to analyse dysfunctional neural systems in the different forms of anxiety disorder is emotional face processing (Kim, 2020). However, reaction to emotional face reactions and stimuli is complicated. This encompasses neural circuitry, which may differ in patients with anxiety disorders, compared with normal people (McKay & Storch, 2011). There are cortical areas, close to the extrastriate cortex, very specialised for the processing of facial emotional stimuli (Haxby et al., 1994).

The most important areas responsible for the processing of facial stimuli are the right parahippocampal gyrus and bilateral fusiform/lingual gyri (Kapur et al., 1995). It takes almost 165 ms to process faces in this region (Halgren et al., 2000) and the amygdala is responsible for linking affective representations (e.g., fear) with visual representations of facial stimuli (Adolphs et al., 1995). It was argued that the amygdala has a high level of sensitivity to fear compared with other emotional stimuli (Morris et al., 1996), and the amygdala is involved with awareness of the individual (Whalen et al., 1998), which might be mediated through subcortical paths to the right hemisphere of the amygdala, via thalamus and midbrain (Morris et al., 1999). During the processing of fearful facial stimuli, a large extended circuitry including anterior cingulate, anterior insula, pulvinar, and amygdala are activated (Morris et al., 1998). They are engaged when a judgment of explicit emotion face is needed (Gorno-Tempini et al., 2001). Several researchers stressed that the extended limbic regions and the right and left amygdala are differently engaged in positive versus negative processing of emotional expressions, respectively. For instance, in a response to negative facial expressions, the left amygdala is more activated (Iidaka et al., 2001). On the other hand, when positive facial expressions are evaluated, the right amygdala is more associated than the right amygdala (Iidaka et al., 2001). Others have reported that facial emotional expressions of sadness, fear, and happiness, but not anger, lead to activation of the right hemiface (Indersmitten & Gur, 2003). This is in line with a finding that there was an increase in the activation of the left amygdala to masked facial expressions in patients with depressive symptoms (Sheline et al., 2001). Recently, it was reported that social-emotional stimuli (e.g., flirtatiousness, admiration, and guilt) are processed by the amygdala (Adolphs et al., 2002). Thus, even simple processing (e.g, processing of emotional stimuli) consists of complex cognitive and emotional component processes (Adolphs et al., 2002). Therefore, it is essential to identify which parts of the brain might be dysfunctional in patients with anxiety. The neural layers relative to executive functioning (i.e, anterior cingulate and the dorsolateral prefrontal cortex) modulate the activation of the extended limbic system and the amygdala (Nomura et al., 2001). It was found that there was an inverse correlated activation in these regions relative to the amygdala and it was argued that this contributes to conscious appraisal and evaluation (Hariri et al., 2002; Hariri et al., 2003). This is in line with other evidence of an altered association between the medial prefrontal cortex and amygdala activation (Pezawas et al., 2005). Researchers also paid attention to alterations in the orbitofrontal cortex upon processing of emotional facial expressions (Monk et al., 2003), which might result in representations of several somatic markers (e.g., gut feelings) linked with emotional faces (Winston et al., 2003). Several researchers have argued that the processing of emotional faces can be linked with anxiety. For instance, Bishop et al. (2004) performed an fMRI study with twenty-seven participants in order to investigate whether there is a difference in the responsibility of the amygdala unattended threat-related stimuli based on the anxiety level of the participant. Pairs of faces (both neutral or fearful expressions) and houses were shown to participants, and subjects attended to either the houses or the faces and were asked to match these stimuli on identity (Bishop et al., 2004). The study found that participants with low anxiety levels demonstrated a decreased amygdala reaction to unattended fearful fearful faces compared with attended fearful faces, but subjects with high anxiety levels demonstrated no such decrease, having an increase in the response of the amygdala to fearful facial expressions versus neutral facial expressions regardless attentional focus (Bishop et al., 2004). The findings of this study showed that anxiety might affect the attentional focus, which in turn determine the magnitude of the response of the amygdala to threat-related facial expressions (Bishop et al., 2004).

In a similar vein, Etkin et al. (2004) examined the neural responses linked with the unconscious and conscious perception of fearful facial expressions in healthy participants with variation in the sensitivity of threat. Findings showed that activity of the dorsal amygdala (central nucleus) was activated by conscious processing, whereas activity in the basolateral subarea of the amygdala was modulated by unconscious processing (Etkin et al., 2004). The study found that conscious stimuli activated the dorsal amygdala in a consistent pattern across participants and independent of the level of anxiety (Etkin et al., 2004). On the other hand, the level of the participant's anxiety strongly predicted the participant's reaction times and the extent of the activity of the basolateral amygdala to unconscious stimuli (Etkin et al., 2004). This study provides a means for examining the efficacy and mechanism of treatments for anxiety disorder and a biological basis for how anxiety is associated with unconscious emotional vigilance characteristics (Etkin et al., 2004). Other researchers have argued that the insula has an important role in the processing of threat stimuli among participants with anxiety (Straube et al., 2004). In conclusion, the neural circuitry behind the processing of emotional faces was well delineated and is composed of cortical processing circuits (top-down) and paralimbic and limbic processing circuits “bottom-up”.

Therefore, it is hypothesised that several key parts of the brain modulate the circuitry in patients with anxiety disorders (Paulus, 2008). First, the amygdala plays an important role in assigning salience and valence to internal stimuli and the environment (Paulus, 2008). Second, the insular cortex plays an important role in the processing of predictive interoception and interception (e.g., how the body feels when exposed to an environmental or internal stimulus (Barlow, 2004). Thirdly, the medial prefrontal cortex plays a critical role in self-relevant processing, affective, and cognitive conflict (Simpson et al., 2010). Also, it assesses the extent to which the individual needs to deploy executive control as a response to the demands inferred from the surrounding environment (Bigos et al., 2016).



= Amygdala and the different types of anxiety disorders: =

Several studies sought to analyse the neural correlates of generalised social anxiety disorder or social anxiety disorder (SAD) and used emotionally salient visual stimuli of a social nature. These encompass threatening and negative facial expressions, which leads to activation of the amygdala in patients with generalised social phobia (Stein et al., 2002) and social anxiety disorder (Pompili et al., 2014). For example, when negative affective pictures were shown to patients with generalised anxiety disorders, they experienced an increase in the activity of the bilateral amygdala compared to their normal counterparts (Shah et al., 2009). Interestingly, the study found that the degree of this activation depended on the severity of the anxiety disorders (Shah et al., 2009). Similarly, Blair et al. (2008) used images of fearful faces and found that patients with generalised social phobia experienced an elevation in the responsivity of the amygdala. In addition, an increase in the activity of the amygdala was reported in individuals with a social anxiety disorder when they experienced angry facial expressions, compared to neutral counterparts (Evans et al., 2008). Taken together, these consistent findings showed that patients with anxiety disorders experience a heightened amygdala response to socially stimuli.

Moreover, evidence showed an increase in the activity of the amygdala in response to images of spiders in patients with spider phobia (Schienle et al., 2005). In addition, an increase in the activity of the amygdala in response to the anticipation of talking in public was reported in individuals with generalised social phobia (Lorberbaum et al., 2004).

Studies of patients with Generalised Anxiety Disorder found an increase in the activity of the amygdala. For instance, Whalen et al. (2008) reported that the degree of the amygdala response to fearful facial expressions in a group of patients with GAD, before starting the treatment, were strong predictors of the magnitude of the response to the treatment. Similarly, heightened activation in the amygdala before treatment was a strong predictor of poor treatment response (Whalen et al., 2008).

= Conclusion: =

To sum up, because the different brain regions (e.g., amygdala) in patients with anxiety disorder are differently activated, compared with their healthy counterparts, these differences can be detected and monitored by fMRI. The differences in the activation of those regions can be analysed and used as an indicator for the diagnosis of anxiety disorders.

prepared by: Abdulrahman Alghadhbani

References:
Adolphs, R., Baron-Cohen, S., & Tranel, D. (2002). Impaired recognition of social emotions following amygdala damage. Journal of cognitive neuroscience, 14(8), 1264-1274.

Adolphs, R., Damasio, H., Tranel, D., & Damasio, A. R. (1996). Cortical systems for the recognition of emotion in facial expressions. Journal of neuroscience, 16(23), 7678-7687.

Adolphs, R., Tranel, D., Damasio, H., & Damasio, A. R. (1995). Fear and the human amygdala. Journal of neuroscience, 15(9), 5879-5891.

Armony, J. L., Corbo, V., Clément, M. H., & Brunet, A. (2005). Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. American Journal of Psychiatry, 162(10), 1961-1963.

Barlow, D. H. (2004). Anxiety and its disorders: The nature and treatment of anxiety and panic. Guilford press.

Bigos, K. L., Hariri, A. R., & Weinberger, D. R. (Eds.). (2016). Neuroimaging genetics: Principles and practices. Oxford University Press.

Bishop, S. J., Duncan, J., & Lawrence, A. D. (2004). State anxiety modulation of the amygdala response to unattended threat-related stimuli. Journal of Neuroscience, 24(46), 10364-10368.

Blair, K., Shaywitz, J., Smith, B. W., Rhodes, R., Geraci, M., Jones, M., ... & Pine, D. S. (2008). Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders. American Journal of Psychiatry, 165(9), 1193-1202.

Buxton, R. B. (2009). Introduction to functional magnetic resonance imaging: principles and techniques. Cambridge university press.

Dolan, R. J., Fletcher, P., Morris, J., Kapur, N., Deakin, J. F. W., & Frith, C. D. (1996). Neural activation during covert processing of positive emotional facial expressions. Neuroimage, 4(3), 194-200.

Emilien, G., Durlach, C., Lepola, U., & Dinan, T. (2002). Anxiety disorders: pathophysiology and pharmacological treatment. Springer Science & Business Media.

Etkin, A., Klemenhagen, K. C., Dudman, J. T., Rogan, M. T., Hen, R., Kandel, E. R., & Hirsch, J. (2004). Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces. Neuron, 44(6), 1043-1055.

Evans, K. C., Wright, C. I., Wedig, M. M., Gold, A. L., Pollack, M. H., & Rauch, S. L. (2008). A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depression and anxiety, 25(6), 496-505.

Gorno-Tempini, M. L., Pradelli, S., Serafini, M., Pagnoni, G., Baraldi, P., Porro, C., ... & Nichelli, P. (2001). Explicit and incidental facial expression processing: an fMRI study. Neuroimage, 14(2), 465-473.

Halgren, E., Raij, T., Marinkovic, K., Jousmäki, V., & Hari, R. (2000). Cognitive response profile of the human fusiform face area as determined by MEG. Cerebral cortex, 10(1), 69-81.

Hariri, A. R., Mattay, V. S., Tessitore, A., Fera, F., & Weinberger, D. R. (2003). Neocortical modulation of the amygdala response to fearful stimuli. Biological psychiatry, 53(6), 494-501.

Hariri, A. R., Tessitore, A., Mattay, V. S., Fera, F., & Weinberger, D. R. (2002). The amygdala response to emotional stimuli: a comparison of faces and scenes. Neuroimage, 17(1), 317-323.

Haxby, J. V., Horwitz, B., Ungerleider, L. G., Maisog, J. M., Pietrini, P., & Grady, C. L. (1994). The functional organization of human extrastriate cortex: a PET-rCBF study of selective attention to faces and locations. Journal of neuroscience, 14(11), 6336-6353.

Helsley, J. D., & Vanin, J. R. (2008). Anxiety disorders a pocket guide for primary care. Humana Press.

Hofmann, S. G. (Ed.). (2012). Psychobiological approaches for anxiety disorders: treatment combination strategies. John Wiley & Sons.

Huettel, S. A., Song, A. W., & McCarthy, G. (2004). Functional magnetic resonance imaging (Vol. 1). Sunderland, MA: Sinauer Associates.

Iidaka, T., Omori, M., Murata, T., Kosaka, H., Yonekura, Y., Okada, T., & Sadato, N. (2001). Neural interaction of the amygdala with the prefrontal and temporal cortices in the processing of facial expressions as revealed by fMRI. Journal of Cognitive Neuroscience, 13(8), 1035-1047.

Indersmitten, T., & Gur, R. C. (2003). Emotion processing in chimeric faces: hemispheric asymmetries in expression and recognition of emotions. Journal of Neuroscience, 23(9), 3820-3825.

Kapur, N., Friston, K. J., Young, A., Frith, C. D., & Frackowiak, R. S. J. (1995). Activation of human hippocampal formation during memory for faces: a PET study. Cortex, 31(1), 99-108.

Kim, Y. K. (Ed.). (2020). Anxiety Disorders: Rethinking and Understanding Recent Discoveries (Vol. 1191). Springer Nature.

Lorberbaum, J. P., Kose, S., Johnson, M. R., Arana, G. W., Sullivan, L. K., Hamner, M. B., ... & George, M. S. (2004). Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport, 15(18), 2701-2705.

McKay, D., & Storch, E. A. (Eds.). (2011). Handbook of child and adolescent anxiety disorders. Springer Science & Business Media.

Monk, C. S., McClure, E. B., Nelson, E. E., Zarahn, E., Bilder, R. M., Leibenluft, E., ... & Pine, D. S. (2003). Adolescent immaturity in attention-related brain engagement to emotional facial expressions. Neuroimage, 20(1), 420-428.

Morris, J. S., Friston, K. J., Büchel, C., Frith, C. D., Young, A. W., Calder, A. J., & Dolan, R. J. (1998). A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain: a journal of neurology, 121(1), 47-57.

Morris, J. S., Frith, C. D., Perrett, D. I., Rowland, D., Young, A. W., Calder, A. J., & Dolan, R. J. (1996). A differential neural response in the human amygdala to fearful and happy facial expressions. Nature, 383(6603), 812-815.

Morris, J. S., Öhman, A., & Dolan, R. J. (1999). A subcortical pathway to the right amygdala mediating “unseen” fear. Proceedings of the National Academy of Sciences, 96(4), 1680-1685.

Nomura, M., Ohira, H., Haneda, K., Iidaka, T., Sadato, N., Okada, T., & Yonekura, Y. (2004). Functional association of the amygdala and ventral prefrontal cortex during cognitive evaluation of facial expressions primed by masked angry faces: an event-related fMRI study. Neuroimage, 21(1), 352-363.

Paulus, M. P. (2008). The role of neuroimaging for the diagnosis and treatment of anxiety disorders. Depression and anxiety, 25(4), 348-356.

Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., Verchinski, B. A., Munoz, K. E., Kolachana, B. S., ... & Weinberger, D. R. (2005). 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature neuroscience, 8(6), 828-834.

Pine, D., Rothbaum, B. O., & Ressler, K. (Eds.). (2015). Primer on anxiety disorders: translational perspectives on diagnosis and treatment. Primer on.

Pompili, M., Innamorati, M., Gonda, X., Serafini, G., Erbuto, D., Ricci, F., ... & Girardi, P. (2014). Pharmacotherapy in bipolar disorders during hospitalization and at discharge predicts clinical and psychosocial functioning at follow‐up. Human Psychopharmacology: Clinical and Experimental, 29(6), 578-588.

Schienle, A., Schäfer, A., Walter, B., Stark, R., & Vaitl, D. (2005). Brain activation of spider phobics towards disorder-relevant, generally disgust-and fear-inducing pictures. Neuroscience letters, 388(1), 1-6.

Shah, S. G., Klumpp, H., Angstadt, M., Nathan, P. J., & Phan, K. L. (2009). Amygdala and insula response to emotional images in patients with generalized social anxiety disorder. Journal of psychiatry & neuroscience: JPN, 34(4), 296.

Sheline, Y. I., Barch, D. M., Donnelly, J. M., Ollinger, J. M., Snyder, A. Z., & Mintun, M. A. (2001). Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biological psychiatry, 50(9), 651-658.

Simpson, H. B., Neria, Y., Lewis-Fernández, R., & Schneier, F. (Eds.). (2010). Anxiety disorders: Theory, research and clinical perspectives. Cambridge University Press.

Stein, M. B., Goldin, P. R., Sareen, J., Zorrilla, L. T. E., & Brown, G. G. (2002). Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Archives of general psychiatry, 59(11), 1027-1034.

Straube, T., Kolassa, I. T., Glauer, M., Mentzel, H. J., & Miltner, W. H. (2004). Effect of task conditions on brain responses to threatening faces in social phobics: an event-related functional magnetic resonance imaging study. Biological psychiatry, 56(12), 921-930.

Whalen, P. J., Johnstone, T., Somerville, L. H., Nitschke, J. B., Polis, S., Alexander, A. L., ... & Kalin, N. H. (2008). A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biological psychiatry, 63(9), 858-863.

Whalen, P. J., Rauch, S. L., Etcoff, N. L., McInerney, S. C., Lee, M. B., & Jenike, M. A. (1998). Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. Journal of neuroscience, 18(1), 411-418.

Winston, J. S., O'doherty, J., & Dolan, R. J. (2003). Common and distinct neural responses during direct and incidental processing of multiple facial emotions. Neuroimage, 20(1), 84-97.