Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with attention deficit/hyperactivity disorder
Abstract
In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant treatment-naive patients with ADHD (N = 35 boys; N = 46 men) and 23 healthy control subjects (N = 11 boys; N = 12 men). In ADHD patients, we also measured amygdala reactivity 90min after an acute oral challenge with MPH (0.5mg/kg). Mean amygdala reactivity was analyzed for all subjects using a repeated measures analysis of variance (ANOVA). Whole-brain maps were analyzed for the patients only. At baseline, we found a age*diagnosis effect approaching significance (p = 0.05) in the right amygdala due to lower reactivity in children with Attention Deficit/Hyperactivity Disorder (ADHD) vs. controls (-31%), but higher reactivity in adults with ADHD vs. controls (+31%). MPH significantly reduced right amygdala reactivity in all patients, resulting in further reductions in children. In the left amygdala, reduction of amygdala reactivity was confined to adult ADHD patients whereas there was no change in children with ADHD. MPH-induced decrease of amygdala reactivity in adults might be a promising avenue for managing emotional dysregulation when replicated for chronic MPH treatment.
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Other studies found no differences in ADHD children in brain activation to fearful faces or negative emotional pictures, or decreased amygdala activation in children but enhanced activation in adults with ADHD during fearful and angry faces, and reduced activation to verbally instructed fear-conditioning in subgenual ACC and in ventral striatum and subgenual ACC in response to unexpected negative
“However, other studies found no differences in ADHD children in brain activation to fearful faces (Marsh et al., 2008) or negative emotional pictures (Herpertz et al., 2008) or decreased amygdala activation in children but enhanced activation in adults with ADHD during fearful and angry faces (Bottelier et al., 2017) and reduced activation to verbally instructed fear-conditioning in subgenual ACC”
From Cognitive Neuroscience of Attention Deficit Hyperactivity Disorder (ADHD) and Its Clinical Translation (2018) · cites this paper as Bottelier et al., 2017
Cites
1 retracted
Karalunas, S. L., Fair, D., Musser, E. D., Aykes, K., Iyer, S. P., & Nigg, J. T. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.763 · Cited by 340 · see citing works
RetractedAn inventory for measuring depression
BECK, A. T. (1961) · Archives of General Psychiatry · doi:10.1001/archpsyc.1961.01710120031004 · Cited by 38,032 · see citing works
(1998) · The Journal of Clinical Psychiatry · Cited by 19,139 · see citing works
An inventory for measuring clinical anxiety: Psychometric properties.
Beck, A. T., Epstein, N., Brown, G., & Steer, R. A. (1988) · Journal of Consulting and Clinical Psychology · doi:10.1037/0022-006x.56.6.893 · Cited by 14,407 · see citing works
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444 · see citing works
Power, J. D., Barnes, K. A., Snyder, A. Z., Schlaggar, B. L., & Petersen, S. E. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2011.10.018 · Cited by 7,429 · see citing works
Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C. K., Demler, O., Faraone, S. V., Greenhill, L. L., Howes, M. J., Secnik, K., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.4.716 · Cited by 3,886 · see citing works
Children’s Depression Inventory (CDI)
Kovacs, M. (2011) · Springer eBooks · doi:10.1007/978-0-387-79061-9_4285 · Cited by 3,885 · see citing works
Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates
Eklund, A., Nichols, T. E., & Knutsson, H. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602413113 · Cited by 3,487 · see citing works
The influence of head motion on intrinsic functional connectivity MRI
Van Dijk, K. R. A., Sabuncu, M. R., & Buckner, R. L. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2011.07.044 · Cited by 2,344 · see citing works
Response and Habituation of the Human Amygdala during Visual Processing of Facial Expression
Breiter, H. C., Etcoff, N. L., Whalen, P. J., Kennedy, W. A., Rauch, S. L., Buckner, R. L., Strauss, M. M., Hyman, S. E., & Rosen, B. R. (1996) · Neuron · doi:10.1016/s0896-6273(00)80219-6 · Cited by 1,711 · see citing works
Emotion Dysregulation in Attention Deficit Hyperactivity Disorder
Shaw, P., Stringaris, A., Nigg, J., & Leibenluft, E. (2014) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.13070966 · Cited by 1,232 · see citing works
The Amygdala Response to Emotional Stimuli: A Comparison of Faces and Scenes
Hariri, A. R., Tessitore, A., Mattay, V. S., Fera, F., & Weinberger, D. R. (2002) · NeuroImage · doi:10.1006/nimg.2002.1179 · Cited by 984 · see citing works
BIEDERMAN, J., MONUTEAUX, M. C., MICK, E., SPENCER, T., WILENS, T. E., SILVA, J. M., SNYDER, L. E., & FARAONE, S. V. (2006) · Psychological Medicine · doi:10.1017/s0033291705006410 · Cited by 850 · see citing works
A Developmental Shift from Positive to Negative Connectivity in Human Amygdala–Prefrontal Circuitry
Gee, D. G., Humphreys, K. L., Flannery, J., Goff, B., Telzer, E. H., Shapiro, M., Hare, T. A., Bookheimer, S. Y., & Tottenham, N. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3446-12.2013 · Cited by 731 · see citing works
Wehmeier, P. M., Schacht, A., & Barkley, R. A. (2010) · Journal of Adolescent Health · doi:10.1016/j.jadohealth.2009.09.009 · Cited by 628 · see citing works
Clinical and Functional Outcome of Childhood Attention-Deficit/Hyperactivity Disorder 33 Years Later
Klein, R. G., Mannuzza, S., Olazagasti, M. A. R., Roizen, E., Hutchison, J. A., Lashua, E. C., & Castellanos, F. X. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2012.271 · Cited by 619 · see citing works
Moffitt, T. E., Houts, R., Asherson, P., Belsky, D. W., Corcoran, D. L., Hammerle, M., Harrington, H., Hogan, S., Meier, M. H., Polanczyk, G. V., et al. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.14101266 · Cited by 618 · see citing works
Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli
Wright, C. I., Fischer, H., Whalen, P. J., McInerney, S. C., Shin, L. M., & Rauch, S. L. (2001) · Neuroreport · doi:10.1097/00001756-200102120-00039 · Cited by 533 · see citing works
Barkley, R. A., & Fischer, M. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.01.019 · Cited by 479 · see citing works
Barkley, R. A., & Fischer, M. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-201005000-00011 · Cited by 479 · see citing works
Lidow, M. S., Goldman-Rakic, P. S., Gallager, D. W., & Rakic, P. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90003-7 · Cited by 394 · see citing works
Sobanski, E., Banaschewski, T., Asherson, P., Buitelaar, J., Chen, W., Franke, B., Holtmann, M., Krumm, B., Sergeant, J., Sonuga‐Barke, E., et al. (2010) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2010.02217.x · Cited by 365 · see citing works
Adult Outcomes of Childhood Dysregulation: A 14-year Follow-up Study
Althoff, R. R., Verhulst, F. C., Rettew, D. C., Hudziak, J. J., & van der Ende, J. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.08.006 · Cited by 303 · see citing works
Dopamine Modulates the Response of the Human Amygdala: A Study in Parkinson's Disease
Tessitore, A., Hariri, A. R., Fera, F., Smith, W. G., Chase, T. N., Hyde, T. M., Weinberger, D. R., & Mattay, V. S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09099.2002 · Cited by 293 · see citing works
Progesterone selectively increases amygdala reactivity in women
van Wingen, G. A., van Broekhoven, F., Verkes, R. J., Petersson, K. M., Bäckström, T., Buitelaar, J. K., & Fernández, G. (2008) · Molecular Psychiatry · doi:10.1038/sj.mp.4002030 · Cited by 273 · see citing works
Emotional Dysregulation in Adult ADHD and Response to Atomoxetine
Reimherr, F. W., Marchant, B. K., Strong, R. E., Hedges, D. W., Adler, L., Spencer, T. J., West, S. A., & Soni, P. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.04.040 · Cited by 258 · see citing works
March, J. S., Swanson, J. M., Arnold, L. E., Hoza, B., Conners, C. K., Hinshaw, S. P., Hechtman, L. T., KRAEMER, H. C., Greenhill, L. L., Abikoff, H., et al. (2000) · Research on Child and Adolescent Psychopathology · doi:10.1023/a:1005179014321 · Cited by 250 · see citing works
Brain habituation during repeated exposure to fearful and neutral faces: A functional MRI study
Fischer, H., Wright, C. I., Whalen, P. J., McInerney, S. C., Shin, L. M., & Rauch, S. L. (2002) · Brain Research Bulletin · doi:10.1016/s0361-9230(02)00940-1 · Cited by 250 · see citing works
Modelling large motion events in fMRI studies of patients with epilepsy
Lemieux, L., Salek‐Haddadi, A., Lund, T. E., Laufs, H., & Carmichael, D. W. (2007) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2007.03.009 · Cited by 240 · see citing works
Dopamine in amygdala gates limbic processing of aversive stimuli in humans
Kienast, T., Hariri, A. R., Schlagenhauf, F., Wrase, J., Sterzer, P., Buchholz, H. G., Smolka, M. N., Gründer, G., Cumming, P., Kumakura, Y., et al. (2008) · Nature Neuroscience · doi:10.1038/nn.2222 · Cited by 177 · see citing works
Rosenberg, D. R., & Lewis, D. A. (1994) · Biological Psychiatry · doi:10.1016/0006-3223(94)90610-6 · Cited by 174 · see citing works
Rösler, M., Retz, W., Thome, J., Schneider, M., Stieglitz, R., & Falkai, P. (2006) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-006-1001-7 · Cited by 171 · see citing works
Criteria and Concurrent Validity of DIVA 2.0: A Semi-Structured Diagnostic Interview for Adult ADHD
Ramos‐Quiroga, J. A., Nasillo, V., Vanesa Richarte, B., Montse Corrales, F., Palma-Álvarez, R. F., Ibáñez, P., Michelsen, M., van de Glind, G., Casas, M., & Kooij, J. J. S. (2016) · Journal of Attention Disorders · doi:10.1177/1087054716646451 · Cited by 170 · see citing works
Self-citationMood lability and psychopathology in youth
Stringaris, A., & Goodman, R. (2009) · Psychological Medicine · doi:10.1017/s0033291708004662 · Cited by 162 · see citing works
Swartz, J. R., Williamson, D. E., & Hariri, A. R. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2014.14020195 · Cited by 144 · see citing works
Lidow, M. S., & Rakic, P. (1992) · Cerebral Cortex · doi:10.1093/cercor/2.5.401 · Cited by 141 · see citing works
Posner, J., Nagel, B. J., Maia, T. V., Mechling, A., Oh, M., Wang, Z., & Peterson, B. S. (2011) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2011.05.010 · Cited by 137 · see citing works
Amygdala habituation: A reliable fMRI phenotype
Plichta, M. M., Grimm, O., Morgen, K., Mier, D. U., Sauer, C., Haddad, L., Tost, H., Esslinger, C., Kirsch, P., Schwarz, A. J., et al. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.09.059 · Cited by 131 · see citing works
Spencer, T. J., Faraone, S. V., Surman, C. B. H., Petty, C., Clarke, A., Batchelder, H., Wozniak, J., & Biederman, J. (2011) · Postgraduate Medicine · doi:10.3810/pgm.2011.09.2459 · Cited by 127 · see citing works
Comparison of acute behavioral effects of sustained-release and immediate-release methylphenidate.
Kollins, S. H., Rush, C. R., Pazzaglia, P. J., & Ali, J. A. (1998) · Experimental and Clinical Psychopharmacology · doi:10.1037//1064-1297.6.4.367 · Cited by 117 · see citing works
Anxiety in Children With Attention-Deficit/Hyperactivity Disorder
Sciberras, E., Lycett, K., Efron, D., Mensah, F. K., Gerner, B., & Hiscock, H. (2014) · PEDIATRICS · doi:10.1542/peds.2013-3686 · Cited by 115 · see citing works
Takahashi, H., Yahata, N., Koeda, M., Takano, A., Asai, K., Suhara, T., & Okubo, Y. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2005.05.039 · Cited by 114 · see citing works
Wagner, A. K., Kline, A. E., Ren, D., Willard, L. A., Wenger, M. K., ZAFONTE, R. D., & Dixon, C. E. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.04.006 · Cited by 99 · see citing works
Comparison of acute behavioral effects of sustained-release and immediate-release methylphenidate.
Kollins, S. H., Rush, C. R., Pazzaglia, P. J., et al. (1998) · Experimental and Clinical Psychopharmacology · doi:10.1037/1064-1297.6.4.367 · Cited by 95 · see citing works
Schrantee, A., Tamminga, H. G. H., Bouziane, C., Bottelier, M. A., Bron, E. E., Mutsaerts, H.-J. M. M., Zwinderman, A. H., Groote, I. R., Rombouts, S. A. R. B., Lindauer, R. J. L., et al. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.1572 · Cited by 77 · see citing works
Self-citationThe effects of Psychotropic drugs On Developing brain (ePOD) study: methods and design
Bottelier, M. A., Schouw, M. L. J., Klomp, A., Tamminga, H. G. H., Schrantee, A., Bouziane, C., de Ruiter, M. B., Boer, F., Ruhé, H. G., Denys, D. A. J. P., et al. (2014) · BMC Psychiatry · doi:10.1186/1471-244x-14-48 · Cited by 36 · see citing works
Self-citationChanges in Emotions Related to Medication Used to Treat ADHD. Part I: Literature Review
Manos, M. J., Brams, M., Childress, A. C., Findling, R. L., López, F. A., & Jensen, P. S. (2011) · Journal of Attention Disorders · doi:10.1177/1087054710381230 · Cited by 28 · see citing works
Fagundes, A. O., Aguiar, M. R., Aguiar, C. S., Scaini, G., Sachet, M. U., Bernhardt, N. M., Rezin, G. T., Valvassori, S. S., Quevedo, J., & STRECK, E. L. (2010) · Neurochemical Research · doi:10.1007/s11064-010-0229-9 · Cited by 27 · see citing works
Effects of methylphenidate during emotional processing in amphetamine users: preliminary findings
Bottelier, M. A., Schouw, M. L. J., de Ruiter, M. B., Ruhé, H. G., Lindauer, R., & Reneman, L. (2015) · Brain Imaging and Behavior · doi:10.1007/s11682-014-9350-8 · Cited by 10 · see citing works
Self-citation
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Cited by
Sorted by citations
Rubia, K. (2018) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2018.00100 · Cited by 384 · see citing works
“…(Herpertz et al., 2008) or decreased amygdala activation in children but enhanced activation in adults with ADHD during fearful and angry faces (Bottelier et al., 2017) and reduced activation to verbally instructed fear-conditioning in subgenual ACC (Maier et al., 2014) and in ventral striatum…”
BackgroundEmotional Dysregulation in Children and Adolescents With Psychiatric Disorders. A Narrative Review
Paulus, F. W., Ohmann, S., Möhler, E., Plener, P. L., & Popow, C. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.628252 · Cited by 335 · see citing works
Tamon, H., Fujino, J., Itahashi, T., Frahm, L., Parlatini, V., Aoki, Y. Y., Castellanos, F. X., Eickhoff, S. B., & Cortese, S. (2024) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20230270 · Cited by 30 · see citing works
Viering, T., Naaijen, J., van Rooij, D., Thiel, C. M., Philipsen, A., Dietrich, A., Franke, B., Buitelaar, J. K., & Hoekstra, P. J. (2021) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-021-01809-3 · Cited by 29 · see citing works
Grossman, A., & Avital, A. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2023.1118937 · Cited by 21 · see citing works
Campez, M., Raiker, J. S., Little, K., Altszuler, A. R., Merrill, B. M., Macphee, F. L., Gnagy, E. M., Greiner, A. R., Musser, E. D., Coles, E. K., et al. (2021) · Experimental and Clinical Psychopharmacology · doi:10.1037/pha0000446 · Cited by 18 · see citing works
Neural Basis of Impaired Emotion Recognition in Adult Attention-Deficit/Hyperactivity Disorder
Zuberer, A., Schwarz, L., Kreifelts, B., Wildgruber, D., Erb, M., Fallgatter, A. J., Scheffler, K., & Ethofer, T. (2020) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2020.11.013 · Cited by 17 · see citing works
Alkalay, S., & Dan, O. (2022) · Child and Adolescent Psychiatry and Mental Health · doi:10.1186/s13034-022-00526-2 · Cited by 16 · see citing works
Brancati, G. E., Acierno, D., Barbuti, M., Elefante, C., Gemignani, S., Raia, A., & Perugi, G. (2023) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2023.2263645 · Cited by 16 · see citing works
Kim, J.-S., Lee, K. H., Hwang, C.-S., & Kim, J.-W. (2022) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.210074 · Cited by 11 · see citing works
Patino, L. R., Wilson, A. S., Tallman, M. J., Blom, T. J., DelBello, M. P., & McNamara, R. K. (2023) · Journal of Attention Disorders · doi:10.1177/10870547231215292 · Cited by 6 · see citing works
Retz, W., Rösler, M., Fischer, R., Ose, C., & Ammer, R. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02226-7 · Cited by 8 · see citing works
Rode, J., Runnamo, R., Thunberg, P., & Msghina, M. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.05.073 · Cited by 6 · see citing works
Attention deficit hyperactivity disorder (ADHD)
Kohn, M. R., & Griffiths, K. R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-818872-9.00016-9 · Cited by 5 · see citing works
An assessment of the autism neuroimaging literature for the prospects of re-executability
Hodge, S. M., Haselgrove, C., Honor, L. B., Kennedy, D. N., & Frazier, J. A. (2020) · F1000Research · doi:10.12688/f1000research.25306.1 · Cited by 3 · see citing works
Kaiser, A., Bottelier, M. A., de Ruiter, M. B., Solleveld, M. M., Tamminga, H. G. H., Bouziane, C., Geurts, H. M., Lindauer, R., Kooij, J. J. S., Lucassen, P. J., et al. (2021) · Psychoradiology · doi:10.1093/psyrad/kkab013 · Cited by 1 · see citing works
Self-citationAn assessment of the autism neuroimaging literature for the prospects of re-executability
Hodge, S. M., Haselgrove, C., Honor, L. B., Kennedy, D. N., & Frazier, J. A. (2021) · F1000Research · doi:10.12688/f1000research.25306.2 · Cited by 1 · see citing works
Li, Q., Li, F., Qin, K., Lei, D., Tallman, M. J., Patino, L. R., Sweeney, J. A., Gong, Q., DelBello, M. P., & McNamara, R. K. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.122623
- Authors
- Bottelier, M. A., Schrantee, A., Ferguson, B., Tamminga, H. G. H., Bouziane, C., Kooij, J. J. S., de Ruiter, M. B., & Reneman, L.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- PsyQ (NL)
- Corresponding author
- Reneman, Liesbeth
- Venue
- Psychiatry Research Neuroimaging
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 269
- Pages
- 36-42
- ISSN
- 0925-4927 (ISSN-L)
- OpenAlex
- W2754295102
- Cited by
- 19
- References
- 50
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 3 · 2018: 1
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychiatry Research Neuroimaging (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Academic Medical Center, University of Amsterdam
- EU (11.32050.26)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- methylphenidate, attention deficit hyperactivity disorder, amygdala reactivity, age differences, emotional processing, facial expressions, anger, fear, emotional dysregulation, children and adults
- MeSH terms
- Adult, Age Factors, Amygdala, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Brain Mapping, Child, Double-Blind Method, Emotions, Humans, Magnetic Resonance Imaging, Male, Methylphenidate, Photic Stimulation, Treatment Outcome, Young Adult
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