Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-19T02:58:14.404Z Has data issue: false hasContentIssue false
  • English
  • Français

Reduced frontostriatal response to expected value and reward prediction error in remitted monozygotic twins with mood disorders and their unaffected high-risk co-twins

Published online by Cambridge University Press:  02 March 2020

Julian Macoveanu Open the ORCID record for Julian Macoveanu [Opens in a new window] ,
Iselin Meluken ,
Henry W. Chase ,
Mary L. Phillips ,
Lars Vedel Kessing ,
Hartwig Roman Siebner ,
Maj Vinberg  and
Kamilla W. Miskowiak
Julian Macoveanu*
Affiliation:
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Iselin Meluken
Affiliation:
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Henry W. Chase
Affiliation:
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Mary L. Phillips
Affiliation:
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Lars Vedel Kessing
Affiliation:
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Hartwig Roman Siebner
Affiliation:
Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark Faculty of Medical and Health Sciences, Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Maj Vinberg
Affiliation:
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Kamilla W. Miskowiak
Affiliation:
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark Department of Psychology, University of Copenhagen, Copenhagen, Denmark
*
Author for correspondence: Julian Macoveanu, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Depressive episodes experienced in unipolar (UD) and bipolar (BD) disorders are characterized by anhedonia and have been associated with abnormalities in reward processes related to reward valuation and error prediction. It remains however unclear whether these deficits are associated with familial vulnerability to mood disorders.

Methods

In a functional magnetic resonance imaging study, we evaluated differences in the expected value (EV) and reward prediction error (RPE) signals in ventral striatum (VS) and prefrontal cortex between three groups of monozygotic twins: affected twins in remission for either UD or BD (n = 53), their high-risk unaffected co-twins (n = 34), and low-risk twins with no family history of mood disorders (n = 25).

Results

Compared to low-risk twins, affected twins showed lower EV signal bilaterally in the frontal poles and lower RPE signal bilaterally in the VS, left frontal pole and superior frontal gyrus. The high-risk group did not show a significant change in the EV or RPE signals in frontostriatal regions, yet both reward signals were consistently lower compared with low-risk twins in all regions where the affected twins showed significant reductions.

Conclusion

Our findings strengthen the notion that reduced valuation of expected rewards and reduced error-dependent reward learning may underpin core symptom of depression such as loss of interest in rewarding activities. The trend reduction in reward-related signals in unaffected co-twins warrants further investigation of this effect in larger samples and prospective follow-up to confirm possible association with increased familial vulnerability to mood disorders.

Keywords

Bipolar disorderexpected valuefamilial riskmajor depressive disorderprediction errortwins
Type
Original Article
Information
Psychological Medicine , Volume 51 , Issue 10 , July 2021 , pp. 1637 - 1646
Check for updates
Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abler, B., Walter, H., Erk, S., Kammerer, H., & Spitzer, M. (2006). Prediction error as a linear function of reward probability is coded in human nucleus accumbens. NeuroImage, 31, 790–795.CrossRefGoogle ScholarPubMed
Arsalidou, M., & Taylor, M. J. (2011). Is 2 + 2 = 4? Meta-analyses of brain areas needed for numbers and calculations. NeuroImage, 54, 2382–2393.CrossRefGoogle ScholarPubMed
Bech, P., Rasmussen, N. A., Olsen, L. R., Noerholm, V., & Abildgaard, W. (2001). The sensitivity and specificity of the Major Depression Inventory, using the Present State Examination as the index of diagnostic validity. Journal of Affective Disorders, 66, 159–164.CrossRefGoogle ScholarPubMed
Berenbaum, H., & Oltmanns, T. F. (1992). Emotional experience and expression in schizophrenia and depression. Journal of Abnormal Psychology, 101, 37–44.CrossRefGoogle ScholarPubMed
Berns, G. S., McClure, S. M., Pagnoni, G., & Montague, P. R. (2001). Predictability modulates human brain response to reward. The Journal of Neuroscience, 21, 2793–2798.CrossRefGoogle ScholarPubMed
Bracht, T., Linden, D., & Keedwell, P. (2015). A review of white matter microstructure alterations of pathways of the reward circuit in depression. Journal of Affective Disorders, 187, 45–53.CrossRefGoogle ScholarPubMed
Chase, H. W., Fournier, J. C., Bertocci, M. A., Greenberg, T., Aslam, H., Stiffler, R., … Phillips, M. L. (2017). A pathway linking reward circuitry, impulsive sensation-seeking and risky decision-making in young adults: Identifying neural markers for new interventions. Translational Psychiatry, 7, e1096.CrossRefGoogle ScholarPubMed
Chase, H. W., Nusslock, R., Almeida, J. R., Forbes, E. E., LaBarbara, E. J., & Phillips, M. L. (2013). Dissociable patterns of abnormal frontal cortical activation during anticipation of an uncertain reward or loss in bipolar versus major depression. Bipolar Disorders, 15, 839–854.CrossRefGoogle ScholarPubMed
Desikan, R. S., Ségonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., … Killiany, R. J. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage, 31, 968–980.CrossRefGoogle ScholarPubMed
Diener, C., Kuehner, C., Brusniak, W., Ubl, B., Wessa, M., & Flor, H. (2012). A meta-analysis of neurofunctional imaging studies of emotion and cognition in major depression. NeuroImage, 61, 677–685.CrossRefGoogle ScholarPubMed
Epstein, J., Pan, H., Kocsis, J. H., Yang, Y., Butler, T., Chusid, J., … Silbersweig, D. A. (2006). Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. American Journal of Psychiatry, 163, 1784–1790.CrossRefGoogle ScholarPubMed
Ernst, M., Nelson, E. E., Jazbec, S., McClure, E. B., Monk, C. S., Leibenluft, E., … Pine, D. S. (2005). Amygdala and nucleus accumbens in responses to receipt and omission of gains in adults and adolescents. NeuroImage, 25, 1279–1291.CrossRefGoogle ScholarPubMed
Gard, D. E., Gard, M. G., Kring, A. M., & John, O. P. (2006). Anticipatory and consummatory components of the experience of pleasure: A scale development study. Journal of Research in Personality, 40, 1086–1102.CrossRefGoogle Scholar
Gotlib, I. H., Hamilton, J. P., Cooney, R. E., Singh, M. K., Henry, M. L., & Joormann, J. (2010). Neural processing of reward and loss in girls at risk for major depression. Archives of General Psychiatry, 67, 380–387.CrossRefGoogle ScholarPubMed
Gottesman, I. I., Laursen, T. M., Bertelsen, A., & Mortensen, P. B. (2010). Severe mental disorders in offspring with 2 psychiatrically ill parents. Archives of General Psychiatry, 67, 252–257.CrossRefGoogle ScholarPubMed
Gradin, V. B., Kumar, P., Waiter, G., Ahearn, T., Stickle, C., Milders, M., … Steele, J. D. (2011). Expected value and prediction error abnormalities in depression and schizophrenia. Brain: A Journal of Neurology, 134, 1751–1764.CrossRefGoogle Scholar
Greenberg, T., Chase, H. W., Almeida, J. R., Stiffler, R., Zevallos, C. R., Aslam, H. A., … Phillips, M. L. (2015). Moderation of the relationship between reward expectancy and prediction error-related ventral striatal reactivity by anhedonia in unmedicated major depressive disorder: Findings from the EMBARC study. American Journal of Psychiatry, 172, 881–891.CrossRefGoogle ScholarPubMed
Hamilton, M. (1967). Development of a rating scale for primary depressive illness. The British Journal of Social and Clinical Psychology, 6, 278–296.CrossRefGoogle ScholarPubMed
Hamilton, J. P., Chen, M. C., & Gotlib, I. H. (2013). Neural systems approaches to understanding major depressive disorder: An intrinsic functional organization perspective. Neurobiology of Disease, 52, 4–11.CrossRefGoogle ScholarPubMed
Hasler, G., & Northoff, G. (2011). Discovering imaging endophenotypes for major depression. Molecular Psychiatry, 16, 604–619.CrossRefGoogle ScholarPubMed
Houenou, J., Frommberger, J., Carde, S., Glasbrenner, M., Diener, C., Leboyer, M., & Wessa, M. (2011). Neuroimaging-based markers of bipolar disorder: Evidence from two meta-analyses. Journal of Affective Disorders, 132, 344–355.CrossRefGoogle ScholarPubMed
Jenkinson, M., Beckmann, C. F., Behrens, T. E. J., Woolrich, M. W., & Smith, S. M. (2012). FSL. NeuroImage, 62, 782–790.CrossRefGoogle ScholarPubMed
Jia, T., Macare, C., Desrivières, S., Gonzalez, D. A., Tao, C., Ji, X., … IMAGEN Consortium (2016). Neural basis of reward anticipation and its genetic determinants. Proceedings of the National Academy of Sciences of the United States of America 113, 3879–3884.CrossRefGoogle ScholarPubMed
Joormann, J., & Gotlib, I. H. (2007). Selective attention to emotional faces following recovery from depression. Journal of Abnormal Psychology, 116, 80–85.CrossRefGoogle ScholarPubMed
Keedwell, P. A., Andrew, C., Williams, S. C. R., Brammer, M. J., & Phillips, M. L. (2005). The neural correlates of anhedonia in major depressive disorder. Biological Psychiatry, 58, 843–853.CrossRefGoogle ScholarPubMed
Kendler, K. S., Ohlsson, H., Lichtenstein, P., Sundquist, J., & Sundquist, K. (2018). The genetic epidemiology of treated major depression in Sweden. American Journal of Psychiatry, 175, 1137–1144.CrossRefGoogle ScholarPubMed
Knutson, B., Bhanji, J. P., Cooney, R. E., Atlas, L. Y., & Gotlib, I. H. (2008). Neural responses to monetary incentives in major depression. Biological Psychiatry, 63, 686–692.CrossRefGoogle ScholarPubMed
Kumar, P., Goer, F., Murray, L., Dillon, D. G., Beltzer, M. L., Cohen, A. L., … Pizzagalli, D. A. (2018). Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology, 43, 1581–1588.CrossRefGoogle ScholarPubMed
Kumar, P., Waiter, G., Ahearn, T., Milders, M., Reid, I., & Steele, J. D. (2008). Abnormal temporal difference reward-learning signals in major depression. Brain: A Journal of Neurology, 131, 2084–2093.CrossRefGoogle ScholarPubMed
Linke, J., King, A. V., Rietschel, M., Strohmaier, J., Hennerici, M., Gass, A., … Wessa, M. (2012). Increased medial orbitofrontal and amygdala activation: Evidence for a systems-level endophenotype of bipolar I disorder. American Journal of Psychiatry, 169, 316–325.CrossRefGoogle ScholarPubMed
Liu, Y., Blackwood, D. H., Caesar, S., de Geus, E. J. C., Farmer, A., Ferreira, M. A. R., … Sullivan, P. F. (2011). Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Molecular Psychiatry, 16, 2–4.CrossRefGoogle ScholarPubMed
Liu, W., Roiser, J. P., Wang, L., Zhu, Y., Huang, J., Neumann, D. L., … Chan, R. C. K. (2016). Anhedonia is associated with blunted reward sensitivity in first-degree relatives of patients with major depression. Journal of Affective Disorders, 190, 640–648.CrossRefGoogle ScholarPubMed
Macoveanu, J., Baaré, W., Madsen, K. H., Kessing, L. V., Siebner, H. R., & Vinberg, M. (2018). Risk for affective disorders is associated with greater prefrontal gray matter volumes: A prospective longitudinal study. NeuroImage: Clinical, 17, 786–793.CrossRefGoogle ScholarPubMed
Macoveanu, J., Knorr, U., Skimminge, A., Søndergaard, M. G., Jørgensen, A., Fauerholdt-Jepsen, M., … Kessing, L. V. (2014). Altered reward processing in the orbitofrontal cortex and hippocampus in healthy first-degree relatives of patients with depression. Psychological Medicine, 44, 1183–1195.CrossRefGoogle ScholarPubMed
Macoveanu, J., Miskowiak, K., Kessing, L. V., Vinberg, M., & Siebner, H. R. (2016a). Healthy co-twins of patients with affective disorders show reduced risk-related activation of the insula during a monetary gambling task. Journal of Psychiatry & Neuroscience: JPN, 41, 38–47.CrossRefGoogle Scholar
Macoveanu, J., Vinberg, M., Madsen, K., Kessing, L. V., Siebner, H. R., & Baaré, W. (2016b). Unaffected twins discordant for affective disorders show changes in anterior callosal white matter microstructure. Acta Psychiatrica Scandinavica, 134, 441–451.CrossRefGoogle Scholar
Manelis, A., Almeida, J. R. C., Stiffler, R., Lockovich, J. C., Aslam, H. A., & Phillips, M. L. (2016). Anticipation-related brain connectivity in bipolar and unipolar depression: A graph theory approach. Brain, 139, 2554–2566.CrossRefGoogle ScholarPubMed
McClure, S. M., Berns, G. S., & Montague, P. R. (2003). Temporal prediction errors in a passive learning task activate human striatum. Neuron, 38, 339–346.CrossRefGoogle Scholar
McGuffin, P., Rijsdijk, F., Andrew, M., Sham, P., Katz, R., & Cardno, A. (2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry, 60, 497–502.CrossRefGoogle ScholarPubMed
Nelson, H. E., & O'Connell, A. (1978). Dementia: The estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex, 14, 234–244.CrossRefGoogle ScholarPubMed
Nusslock, R., Almeida, J. R. C., Forbes, E. E., Versace, A., Frank, E., Labarbara, E. J., … Phillips, M. L. (2012). Waiting to win: Elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disorders, 14, 249–260.CrossRefGoogle ScholarPubMed
O'Doherty, J. P., Buchanan, T. W., Seymour, B., & Dolan, R. J. (2006). Predictive neural coding of reward preference involves dissociable responses in human ventral midbrain and ventral striatum. Neuron, 49, 157–166.CrossRefGoogle ScholarPubMed
Oldfield, R. C. (1971). The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia, 9, 97–113.CrossRefGoogle ScholarPubMed
Olino, T. M., McMakin, D. L., Morgan, J. K., Silk, J. S., Birmaher, B., Axelson, D. A., … Forbes, E. E. (2014). Reduced reward anticipation in youth at high-risk for unipolar depression: A preliminary study. Developmental Cognitive Neuroscience, 8, 55–64.CrossRefGoogle ScholarPubMed
Oquendo, M. A., Ellis, S. P., Chesin, M. S., Birmaher, B., Zelazny, J., Tin, A., … Brent, D. A. (2013). Familial transmission of parental mood disorders: Unipolar and bipolar disorders in offspring. Bipolar Disorders, 15, 764–773.CrossRefGoogle ScholarPubMed
Ottesen, N. M., Meluken, I., Scheike, T., Kessing, L. V., Miskowiak, K. W., & Vinberg, M. (2018). Clinical characteristics, life adversities and personality traits in monozygotic twins with, at risk of and without affective disorders. Frontiers in Psychiatry, 9, 401.CrossRefGoogle ScholarPubMed
Pizzagalli, D. A., Holmes, A. J., Dillon, D. G., Goetz, E. L., Birk, J. L., Bogdan, R., … Fava, M. (2009). Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. The American Journal of Psychiatry, 166, 702–710.CrossRefGoogle ScholarPubMed
Pizzagalli, D. A., Iosifescu, D., Hallett, L. A., Ratner, K. G., & Fava, M. (2008). Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task. Journal of Psychiatric Research, 43, 76–87.CrossRefGoogle ScholarPubMed
Pornpattananangkul, N., Leibenluft, E., Pine, D. S., & Stringaris, A. (2019). Association of brain functions in children with Anhedonia mapped onto brain imaging measures. JAMA Psychiatry, 76, 624–633.CrossRefGoogle Scholar
Rolls, E. T., McCabe, C., & Redoute, J. (2008). Expected value, reward outcome, and temporal difference error representations in a probabilistic decision task. Cerebral Cortex, 18, 652–663.CrossRefGoogle Scholar
Rothkirch, M., Tonn, J., Köhler, S., & Sterzer, P. (2017). Neural mechanisms of reinforcement learning in unmedicated patients with major depressive disorder. Brain, 140, 1147–1157.CrossRefGoogle ScholarPubMed
Rutledge, R. B., Moutoussis, M., Smittenaar, P., Zeidman, P., Taylor, T., Hrynkiewicz, L., … Dolan, R. J. (2017). Association of neural and emotional impacts of reward prediction errors with major depression. JAMA Psychiatry, 74, 790–797.CrossRefGoogle ScholarPubMed
Schreiter, S., Spengler, S., Willert, A., Mohnke, S., Herold, D., Erk, S., … Bermpohl, F. (2016). Neural alterations of fronto-striatal circuitry during reward anticipation in euthymic bipolar disorder. Psychological Medicine, 46, 3187–3198.CrossRefGoogle ScholarPubMed
Singh, M. K., Kelley, R. G., Howe, M. E., Reiss, A. L., Gotlib, I. H., & Chang, K. D. (2014). Reward processing in healthy offspring of parents with bipolar disorder. JAMA Psychiatry, 71, 1148–1156.CrossRefGoogle ScholarPubMed
Smoski, M. J., Felder, J., Bizzell, J., Green, S. R., Ernst, M., Lynch, T. R., & Dichter, G. S. (2009). fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder. Journal of Affective Disorders, 118, 69–78.CrossRefGoogle ScholarPubMed
Snaith, R. P., Hamilton, M., Morley, S., Humayan, A., Hargreaves, D., & Trigwell, P. (1995). A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. The British Journal of Psychiatry: The Journal of Mental Science, 167, 99–103.CrossRefGoogle ScholarPubMed
Spielberger, C. D. (1989). State-trait anxiety inventory: Bibliography (2nd ed.). Consulting Psychologists Press, Palo Alto.Google Scholar
Stalnaker, T. A., Liu, T.-L., Takahashi, Y. K., & Schoenbaum, G. (2018). Orbitofrontal neurons signal reward predictions, not reward prediction errors. Neurobiology of Learning and Memory, 153, 137–143.CrossRefGoogle Scholar
Sullivan, P. F., Neale, M. C., & Kendler, K. S. (2000). Genetic epidemiology of major depression: Review and meta-analysis. American Journal of Psychiatry, 157, 1552–1562.CrossRefGoogle ScholarPubMed
Treadway, M. T., & Zald, D. H. (2011). Reconsidering anhedonia in depression: Lessons from translational neuroscience. Neuroscience and Biobehavioral Reviews, 35, 537–555.CrossRefGoogle ScholarPubMed
Ubl, B., Kuehner, C., Kirsch, P., Ruttorf, M., Flor, H., & Diener, C. (2015). Neural reward processing in individuals remitted from major depression. Psychological Medicine, 45, 3549–3558.CrossRefGoogle ScholarPubMed
Vinberg, M., Miskowiak, K. W., & Kessing L, V. (2013). Risk markers for affective disorder, a seven-years follow up study of a twin cohort at low and high risk for affective disorder. Journal of Psychiatric Research, 47, 565–571.CrossRefGoogle ScholarPubMed
Vrieze, E., Pizzagalli, D. A., Demyttenaere, K., Hompes, T., Sienaert, P., de Boer, P., … Claes, S. (2013). Reduced reward learning predicts outcome in major depressive disorder. Biological Psychiatry, 73, 639–645.CrossRefGoogle ScholarPubMed
Watanabe, N., Sakagami, M., & Haruno, M. (2013). Reward prediction error signal enhanced by striatum-amygdala interaction explains the acceleration of probabilistic reward learning by emotion. The Journal of Neuroscience, 33, 4487–4493.CrossRefGoogle Scholar
White, S. F., Pope, K., Sinclair, S., Fowler, K. A., Brislin, S. J., Williams, W. C., … Blair, R. J. R. (2013). Disrupted expected value and prediction error signaling in youths with disruptive behavior disorders during a passive avoidance task. The American Journal of Psychiatry, 170, 315–323.CrossRefGoogle ScholarPubMed
Wing, J. K., Babor, T., Brugha, T., Burke, J., Cooper, J. E., Giel, R., … Sartorius, N. (1990). SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Archives of General Psychiatry, 47, 589–593.CrossRefGoogle ScholarPubMed
Wise, T., Radua, J., Via, E., Cardoner, N., Abe, O., Adams, T. M., … Arnone, D. (2017). Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis. Molecular Psychiatry, 22, 1455–1463.CrossRefGoogle ScholarPubMed
Woolrich, M. W., Behrens, T. E. J., Beckmann, C. F., Jenkinson, M., & Smith, S. M. (2004). Multilevel linear modelling for fMRI group analysis using Bayesian inference. NeuroImage, 21, 1732–1747.CrossRefGoogle ScholarPubMed
Woolrich, M. W., Ripley, B. D., Brady, M., & Smith, S. M. (2001). Temporal autocorrelation in univariate linear modeling of fMRI data. NeuroImage, 14, 1370–1386.CrossRefGoogle ScholarPubMed
Yacubian, J., Gläscher, J., Schroeder, K., Sommer, T., Braus, D. F., & Büchel, C. (2006). Dissociable systems for gain- and loss-related value predictions and errors of prediction in the human brain. The Journal of Neuroscience, 26, 9530–9537.CrossRefGoogle ScholarPubMed
Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978). A rating scale for mania: Reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429–435.CrossRefGoogle ScholarPubMed
Zhang, B., Lin, P., Shi, H., Öngür, D., Auerbach, R. P., Wang, X., … Wang, X. (2016). Mapping anhedonia-specific dysfunction in a transdiagnostic approach: An ALE meta-analysis. Brain Imaging and Behavior, 10, 920–939.CrossRefGoogle Scholar
Supplementary material: File

Macoveanu et al. supplementary material

Macoveanu et al. supplementary material

Download Macoveanu et al. supplementary material(File)
File 22.2 KB