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Restructuring the socially anxious brain: Using magnetic resonance imaging to advance our understanding of effective cognitive behaviour therapy for social anxiety disorder
Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Hjärnan formas av psykologisk behandling (Swedish)
Abstract [en]

Social anxiety disorder (SAD) is a common psychiatric disorder associated with considerable suffering. Cognitive behaviour therapy (CBT) has been shown to be effective but a significant proportion does not respond or relapses, stressing the need of augmenting treatment. Using neuroimaging could elucidate the psychological and neurobiological interaction and may help to improve current therapeutics. To address this issue, functional and structural magnetic resonance imaging (MRI) were repeatedly conducted on individuals with SAD randomised to receive CBT or an active control condition. MRI was performed pre-, and post-treatment, as well as at one-year follow-up. Matched healthy controls were also scanned to be able to evaluate disorder-specific neural responsivity and structural morphology. This thesis aimed at answering three major questions. I) Does the brain’s fear circuitry (e.g., the amygdala) change, with regard to neural response and structural morphology, immediately after CBT? II) Are the immediate changes in the brain still present at long-term follow-up? III) Can neural responsivity in the fear circuitry predict long-term treatment outcome at the level of the individual? Thus, different analytic methods were performed. Firstly, multimodal neuroimaging addressed questions on concomitant changes in neural response and grey matter volume. Secondly, two different experimental functional MRI tasks captured both neural response to emotional faces and self-referential criticism. Thirdly, support vector machine learning (SVM) was used to evaluate neural predictors at the level of the individual.

Amygdala responsivity to self-referential criticism was found to be elevated in individuals with SAD, as compared to matched healthy controls, and the neural response was attenuated after effective CBT. In individuals with SAD, amygdala grey matter volume was positively correlated with symptoms of anticipatory speech anxiety, and CBT-induced symptom reduction was associated with decreased grey matter volume of the amygdala. Also, CBT-induced reduction of amygdala grey matter volume was evident both at short- and long-term follow-up. In contrast, the amygdala neural response was weakened immediately after treatment, but not at one-year follow-up. In extension to treatment effects on the brain, pre-treatment connectivity between the amygdala and the dorsal anterior cingulate cortex (dACC) was stronger in long-term CBT non-responders, as compared to long-term CBT responders. Importantly, by use of an SVM algorithm, pre-treatment neural response to self-referential criticism in the dACC accurately predicted (>90%) the clinical response to CBT.

In conclusion, modifying the amygdala is a likely mechanism of action in CBT, underlying the anxiolytic effects of this treatment, and the brain’s neural activity during self-referential criticism may be an accurate and clinically relevant predictor of the long-term response to CBT. Along these lines, neuroimaging is a vital tool in clinical psychiatry that could potentially improve clinical decision-making based on an individual’s neural characteristics.

Abstract [sv]

Social ångest är en av de vanligaste psykiska sjukdomarna. Mer än en miljon svenskar bedöms lida av detta. Social ångest leder ofta till svåra konsekvenser för den som drabbas, men även ökade kostnader för samhället har noterats, t ex i form av ökad sjukfrånvaro. Även om många som drabbas inte söker hjälp så finns effektiva behandlingar för social ångest, både farmakologiska och psykologiska behandlingar rekommenderas av Socialstyrelsen. Kognitiv beteendeterapi (KBT) är en evidensbaserad och rekommenderad psykologisk behandling för social ångest. Trots att nuvarande interventioner är effektiva så är det fortfarande en andel individer som inte blir förbättrade. Det finns en stor andel studier som visar att individer med social ångest, i jämförelse med friska individer, karakteriseras av överdriven aktivitet i ett nätverk som har till uppgift att tolka och reagera på hotfull information. Denna aktivitet är lokaliserad i rädslonätverket där området amygdala spelar en central roll. Det finns ett behov att utveckla nuvarande behandlingar och denna avhandling syftar till att öka vår förståelse för en neurobiologisk verkningsmekanism bakom KBT för social ångest.

I detta forskningsprojekt har magnetresonanstomografi (MRT) använts för att undersöka personer som lider av social ångest. Upprepade mätningar har genomförts, innan, efter, och vid uppföljning ett år efter ångestlindrande behandling. Utöver detta har individer som inte lider av social ångest undersökts för att förstå hur patienter skiljer sig från friska personer, men också för att undersöka om behandlingen normaliserar patientens hjärna. Under tiden som deltagarna undersöktes med MRT genomfördes två experiment för att ta reda på hur hjärnan reagerar på affektiv information. Deltagarna tittade på bilder med ansikten som uttrycker emotioner, t ex arga och rädda ansiktsuttryck, samt information som innehöll kritiska kommentarer riktade till personen själv eller någon annan, t ex ”ingen tycker om dig” eller ”hon är inkompetent”. Strukturella bilder på deltagarnas hjärnor har också samlats in vid varje mättillfälle. Utöver detta fick alla deltagare instruktioner om att de efter MRT skulle hålla en muntlig presentation inför en publik. Denna uppgift är oftast den värsta tänkbara för individer med social ångest, och syftet med uppgiften var att relatera hjärnans struktur och aktivitet till hur mycket ångest som individerna upplevde inför denna situation.

I arbetet med denna avhandling har tre frågor ställts. a) Uppstår strukturella och funktionella förändringar i rädslonätverket direkt efter avslutad KBT (Studie I och II)? b) Är de tidiga förändringarna efter behandlingen även kvarstående ett år senare (Studie III)? c) Kan hjärnans reaktioner i rädslonätverket förutspå vilka individer som kommer att bli förbättrade av en ångestlindrande psykologisk behandling på lång sikt?

Resultat från studierna i denna avhandling sammanfattas nedan:

  1. Reaktioner till självriktad kritik i amygdala är överdrivna hos individer med social ångest, i jämförelse med friska individer
  2. Reaktioner i amygdala minskar efter att individerna blivit behandlade med KBT och minskningarna korrelerar till minskade symptom av social ångest
  3. Den strukturella volymen av amygdala korrelerar positivt med hur mycket ångest individerna upplever inför en muntlig presentation, och minskningen av dessa symptom korrelerar även med hur mycket volymen av amygdala minskar efter KBT
  4. Minskningen av amygdalavolym och den samtidigt minskade reaktiviteten i amygdala till självriktad kritik är korrelerade. Medieringsanalyser antyder att det är den minskade volymen som driver förhållandet mellan minskad reaktivitet och minskad ångest inför att hålla en muntlig presentation
  5. Den strukturella minskningen av amygdala ses både direkt efter behandlingens avslut, men även vid uppföljning ett år senare. Hjärnans reaktivitet till självriktad kritik i amygdala minskar direkt efter behandling, men är inte kvarstående vid uppföljning ett år senare
  6. Kopplingen mellan hjärnans reaktivitet till självriktad kritik i amygdala och dorsala främre cingulum var starkare hos de som inte blev förbättrade (jämfört med de som blev bättre) av en ångestlindrande behandling på lång sikt
  7. Med hjälp av en stödvektormaskin (en. support vector machine learning) och ett mönster av hjärnaktivitet i dorsala främre cingulum innan behandling påbörjades, predicerades (med 92% träffsäkerhet) vilka individer som ett år senare var fortsatt förbättrade av en effektiv psykologisk behandling

Utifrån dessa observationer är slutsatserna att strukturell och funktionell påverkan på amygdala är en möjlig neurobiologisk mekanism för minskad social ångest efter KBT, samt att reaktivitet i främre cingulum kan ge kliniskt relevant data om vem som kommer att bli förbättrad av en psykologisk behandling. Denna information kan potentiellt vara viktig i framtidens psykiatri för att utveckla existerande behandlingar, men även för att stödja klinikers beslutsfattande huruvida en viss individ bör erbjudas en specifik behandling eller ej.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 77 p.
Series
Linköping Studies in Arts and Science, ISSN 0282-9800 ; 694Linköping Studies in Behavioural Science, ISSN 1654-2029 ; 197
Keyword [en]
Social anxiety disorder (SAD); Cognitive behaviour therapy (CBT); Amygdala; Multimodal neuroimaging; Support vector machine learning (SVM)
Keyword [sv]
Social ångest; Kognitiv beteendeterapi; Hjärnavbildning; Amygdala; Magnetresonanstomografi
National Category
Psychology Applied Psychology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:liu:diva-132637DOI: 10.3384/diss.diva-132637ISBN: 9789176856888 (Print)OAI: oai:DiVA.org:liu-132637DiVA: diva2:1047632
Public defence
2016-12-15, VAL, Hus Vallfarten, Campus Valla, Linköping, 13:00 (English)
Opponent
Supervisors
Note

Illustration on the cover by Jan Lööf. Cover image printed with permission from Jan Lööf and Bonnier Carlsen Förlag. The cover was art directed by Staffan Lager.

Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2016-11-23Bibliographically approved
List of papers
1. Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder
Open this publication in new window or tab >>Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder
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2013 (English)In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 214, no 3, 229-237 p.Article in journal (Refereed) Published
Abstract [en]

Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
Amygdala, Cognitive behavior therapy, dlPFC, fMRI, mOFC, vlPFC
National Category
Psychology
Identifiers
urn:nbn:se:liu:diva-102160 (URN)10.1016/j.pscychresns.2013.08.012 (DOI)000327531600008 ()24064198 (PubMedID)
Available from: 2013-12-01 Created: 2013-12-01 Last updated: 2016-11-18Bibliographically approved
2. Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder
Open this publication in new window or tab >>Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder
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2016 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, no e727Article in journal (Refereed) Published
Abstract [en]

Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brains adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure-function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood-oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time x treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected P-FWE = 0.02) and BOLD responsivity (P-FWE = 0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (P-FWE = 0.04), and CBT-induced reduction of amygdala GM volume (pre-post) correlated positively with reduced anticipatory anxiety after treatment (P-FWE <= 0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (P-FWE = 0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P = 0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-127755 (URN)10.1038/tp.2015.218 (DOI)000373892200004 ()26836415 (PubMedID)
Note

Funding Agencies|Linkoping University; Swedish Research Council; Swedish Council for Working Life and Social Research; LJ Boethius Foundation; PRIMA Psychiatry Research Foundation

Available from: 2016-05-12 Created: 2016-05-12 Last updated: 2016-11-18
3. Structural but not functional neuroplasticity one year after effective cognitive behaviour therapy for social anxiety disorder
Open this publication in new window or tab >>Structural but not functional neuroplasticity one year after effective cognitive behaviour therapy for social anxiety disorder
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2017 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 318, 45-51 p.Article in journal (Refereed) Published
Abstract [en]

Abstract Effective psychiatric treatments ameliorate excessive anxiety and induce neuroplasticity immediately after the intervention, indicating that emotional components in the human brain are rapidly adaptable. Still, the interplay between structural and functional neuroplasticity is poorly understood, and studies of treatment-induced long-term neuroplasticity are rare. Functional and structural magnetic resonance imaging (using 3 T MRI) was performed in 13 subjects with social anxiety disorder on 3 occasions over 1 year. All subjects underwent 9 weeks of Internet-delivered cognitive behaviour therapy in a randomized cross-over design and independent assessors used the Clinically Global Impression-Improvement (CGI-I) scale to determine treatment response. Gray matter (GM) volume, assessed with voxel-based morphometry, and functional blood-oxygen level-dependent (BOLD) responsivity to self-referential criticism were compared between treatment responders and non-responders using 2 × 2 (group × time; pretreatment to follow-up) ANOVA. At 1-year follow-up, 7 (54%) subjects were classified as CGI-I responders. Left amygdala GM volume was more reduced in responders relative to non-responders from pretreatment to 1-year follow-up (Z = 3.67, Family-Wise Error corrected p = 0.02). In contrast to previous short-term effects, altered BOLD activations to self-referential criticism did not separate responder groups at follow-up. The structure and function of the amygdala changes immediately after effective psychological treatment of social anxiety disorder, but only reduced amygdala GM volume, and not functional activity, is associated with a clinical response 1 year after CBT.

Place, publisher, year, edition, pages
Elsevier, 2017
Keyword
Amygdala, Neuroplasticity, Long-term, Social anxiety disorder, Cognitive behavior therapy
National Category
Psychology
Identifiers
urn:nbn:se:liu:diva-132638 (URN)10.1016/j.bbr.2016.11.018 (DOI)27838341 (PubMedID)
Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2016-11-23Bibliographically approved
4. Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.
Open this publication in new window or tab >>Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.
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2015 (English)In: Translational psychiatry, ISSN 2158-3188, Vol. 5, e530- p.Article in journal (Refereed) Published
Abstract [en]

Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

National Category
Applied Psychology
Identifiers
urn:nbn:se:liu:diva-117119 (URN)10.1038/tp.2015.22 (DOI)000367654700004 ()25781229 (PubMedID)
Note

Funding agencies: Swedish Research Council; Linkoping University; Swedish Research Council for Health, Working Life and Welfare; PRIMA Psychiatry Research Foundation; Kings College London Centre of Excellence in Medical Engineering - Wellcome Trust; Engineering and Physica

Available from: 2015-04-16 Created: 2015-04-16 Last updated: 2016-11-18

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