Advances in neuroimaging studies of thalamic abnormalities in children with attention deficit hyperactivity disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder whose core pathological mechanism is deeply rooted in the dysfunction of the cortico-striato-thalamo-cortical circuit. This review summarizes recent advances in magnetic resonance imaging (MRI) studies investigating thalamic abnormalities in children with ADHD, highlighting multidimensional pathological changes within the thalamus. Structurally, children with ADHD exhibit delayed overall thalamic volume development and significant atrophy in specific subregions, such as the ventral anterior nucleus, mediodorsal nucleus, and pulvinar. Regarding white matter microstructure, projection pathways from the thalamus to regions such as the motor cortex and striatum are impaired. Both resting-state and task-fMRI consistently demonstrate weakened cortical connectivity between the thalamus and both the default mode and dorsal attention networks. Furthermore, current evidence suggests that mainstream pharmacological treatments, particularly methylphenidate and atomoxetine, effectively promote structural remodeling and the “normalization” of network functions in the aberrant thalamus. Additionally, multidimensional neuroimaging metrics of the thalamus demonstrate substantial potential as objective biomarkers for assessing genetic risk, classifying clinical subtypes, and predicting treatment outcomes. Ultimately, this review emphasizes that the thalamus is not merely a passive sensory relay station, but an active gatekeeper regulating cognition and behavior. Its structural and functional abnormalities constitute a central hub in the pathogenesis of ADHD. Supported by future large-scale machine learning and longitudinal studies, the thalamus holds promise as a crucial biomarker for the precise diagnosis and personalized targeted intervention of ADHD.

Keywords

attention-deficit/hyperactivity disorder / thalamus / MRI / children

References

[1] Agoalikum E, Klugah-Brown B, Wu H, et al. (2023) Structural differences among children, adolescents, and adults with attention-deficit/hyperactivity disorder and abnormal Granger causality of the right pallidum and whole-brain. Front Hum Neurosci 17: 1076873.

[2] Albajara Sáenz A, Van Schuerbeek P, Baijot S, et al. (2020) Disorder-specific brain volumetric abnormalities in attention-deficit/hyperactivity disorder relative to Autism spectrum disorder. PLoS One 15: e0241856.

[3] Alexander AL, Lee JE, Lazar M, et al. (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4: 316-29.

[4] Baboli R, Cao M, Halperin JM, et al. (2022) Distinct thalamic and frontal neuroanatomical substrates in children with familial vs. non-familial attention-deficit/hyperactivity disorder (ADHD). Brain Sciences 13: 46.

[5] Batty MJ, Palaniyappan L, Scerif G, et al. (2015) Morphological abnormalities in prefrontal surface area and thalamic volume in attention deficit/hyperactivity disorder. Psychiatry Res 233: 225-32.

[6] Bouziane C, Caan MWA, Tamminga HGH, et al. (2018) ADHD and maturation of brain white matter: a DTI study in medication naive children and adults. NeuroImage Clin 17: 53-9.

[7] Chen D, Jia T, Cheng W, et al. (2022) Brain signatures during reward anticipation predict persistent attention-deficit/hyperactivity disorder symptoms. J Am Acad Child Adolesc Psychiatry 61: 1050-61.

[8] Christakou A, Murphy CM, Chantiluke K, et al. (2013) Disorder-specific functional abnormalities during sustained attention in youth with attention deficit hyperactivity disorder (ADHD) and with autism. Mol Psychiatry 18: 236-44.

[9] Claesdotter-Hybbinette E, Safdarzadeh-Haghighi M, Råstam M, et al. (2015) Abnormal brainstem auditory response in young females with ADHD. Psychiatry Res 229: 750-4.

[10] Clerkin SM, Schulz KP, Berwid OG, et al. (2013) Thalamo-cortical activation and connectivity during response preparation in adults with persistent and remitted ADHD. Am J Psychiatry 170: 1011-9.

[11] Contreras D, Piña R, Carvallo C, et al. (2022) Methylphenidate restores behavioral and neuroplasticity impairments in the prenatal nicotine exposure mouse model of ADHD: evidence for involvement of AMPA receptor subunit composition and synaptic spine morphology in the hippocampus. Int J Mol Sci 23: 7099.

[12] Córdoba-Claros MA, Rubio-Garrido P, de Lima RRM, et al. (2025) Projection motifs and wiring logic of medial pulvinar thalamocortical axons in the marmoset monkey. J Neurosci 45: e1837242025.

[13] Cubillo A, Halari R, Ecker C, et al. (2010) Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood attention-deficit hyperactivity disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching. J Psychiatr Res 44: 629-39.

[14] Ercan ES, Suren S, Bacanlı A, et al. (2016) Altered structural connectivity is related to attention deficit/hyperactivity subtypes: a DTI study. Psychiatry Res 256: 57-64.

[15] Fall S, Querne L, Le Moing A-G, et al. (2015) Individual differences in subcortical microstructure organization reflect reaction time performances during a flanker task: a diffusion tensor imaging study in children with and without ADHD. Psychiatry Res 233: 50-6.

[16] Fateh AA, Huang W, Mo T, et al. (2022) Abnormal insular dynamic functional connectivity and its relation to social dysfunctioning in children with attention deficit/hyperactivity disorder. Front Neurosci 16: 890596.

[17] Fu C, Chen S, Qian A, et al. (2021) Larger thalamus correlated with inattentive severity in the inattentive subtype of ADHD without comorbidity. Psychiatry Res 304: 114079.

[18] Hong S-B (2023) Thalamocortical functional connectivity in youth with attention-deficit/hyperactivity disorder. J Psychiatry Neurosci 48: E50-60.

[19] Hua M-H, Chen Y-L, Chen M-H, et al. (2021) Network-specific corticothalamic dysconnection in attention-deficit hyperactivity disorder. J Dev Behav Pediatr 42: 122-7.

[20] Huang AW, Barber AD (2021) Development of lateral pulvinar resting state functional connectivity and its role in attention. Cortex 136: 77-88.

[21] Ivanov I, Bansal R, Hao X, et al. (2010) Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 167: 397-408.

[22] Janmohammadi S, Haghgoo HA, Farahbod M, et al. (2020) Effect of a visual tracking intervention on attention and behavior of children with attention deficit hyperactivity disorder. J Eye Mov Res 12: 8.

[23] Kaiser A, Broeder C, Cohen JR, et al. (2022) Effects of a single-dose methylphenidate challenge on resting-state functional connectivity in stimulant-treatment naive children and adults with ADHD. Hum Brain Mapp 43: 4664-75.

[24] Kim H, Kang D, Jang YH, et al. (2025) Effect of medication on the rostrolateral prefrontal oxygenation and thalamic volume asymmetry in youths with ADHD. Front Integr Neurosci 19: 1591465.

[25] Kim J-S, Lee KH, Hwang C-S, et al. (2022) Subcortical volumetric alterations as potential predictors of methylphenidate treatment response in youth with attention-deficit/hyperactivity disorder. J Psychiatry Neurosci 47: E11-20.

[26] Kowalczyk OS, Cubillo AI, Criaud M, et al. (2023) Single-dose effects of methylphenidate and atomoxetine on functional connectivity during an n-back task in boys with ADHD. Psychopharmacology 240: 2045-60.

[27] Kowalczyk OS, Cubillo AI, Smith A, et al. (2019) Methylphenidate and atomoxetine normalise fronto-parietal underactivation during sustained attention in ADHD adolescents. Eur Neuropsychopharmacol 29: 1102-16.

[28] Kuramoto E, Pan S, Furuta T, et al. (2017) Individual mediodorsal thalamic neurons project to multiple areas of the rat prefrontal cortex: a single neuron-tracing study using virus vectors. J Comp Neurol 525: 166-85.

[29] Lanciego JL, Luquin N, Obeso JA (2012) Functional neuroanatomy of the basal ganglia. Cold Spring Harb Perspect Med 2: a009621.

[30] Lawrence KE, Levitt JG, Loo SK, et al. (2013) White matter microstructure in subjects with Attention-Deficit/Hyperactivity disorder and their siblings. J Am Acad Child Adolesc Psychiatry 52: 431-440.e4.

[31] Li X, Sroubek A, Kelly MS, et al. (2012) Atypical pulvinar-cortical pathways during sustained attention performance in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 51: 1197-1207.e4.

[32] McFarland NR, Haber SN (2002) Thalamic relay nuclei of the basal ganglia form both reciprocal and nonreciprocal cortical connections, linking multiple frontal cortical areas. J Neurosci 22: 8117-32.

[33] Mallas E-J, De Simoni S, Jenkins PO, et al. (2025) Methylphenidate differentially alters corticostriatal connectivity after traumatic brain injury. Brain 148: 1360-73.

[34] Mathiasen ML, Dillingham CM, Kinnavane L, et al. (2017) Asymmetric cross-hemispheric connections link the rat anterior thalamic nuclei with the cortex and hippocampal formation. Neuroscience 349: 128-43.

[35] Metin B, Tas ZC, Çebi M, et al. (2018) Reward processing deficits during a spatial attention task in patients with ADHD: an fMRI study. J Atten Disord 22: 694-702.

[36] Meyer ML, Lieberman MD (2012) Social working memory: neurocognitive networks and directions for future research. Front Psychology 3: 571.

[37] Mills KL, Bathula D, Dias TGC, et al. (2012) Altered cortico-striatal-thalamic connectivity in relation to spatial working memory capacity in children with ADHD. Front Psychiatry 3: 2.

[38] Mizuno K, Yoneda T, Komi M, et al. (2013) Osmotic release oral system-methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder. NeuroImage Clin 2: 366-76.

[39] Parnaudeau S, Bolkan SS, Kellendonk C (2018) The mediodorsal thalamus: an essential partner of the prefrontal cortex for cognition. Biol Psychiatry 83: 648-56.

[40] Phillips JM, Kambi NA, Redinbaugh MJ, et al. (2021) Disentangling the influences of multiple thalamic nuclei on prefrontal cortex and cognitive control. Neurosci Biobehav Rev 128: 487-510.

[41] Qiu M-G, Ye Z, Li Q-Y, et al. (2011) Changes of brain structure and function in ADHD children. Brain Topogr 24: 243-52.

[42] Rosch KS, Crocetti D, Hirabayashi K, et al. (2018) Reduced subcortical volumes among preschool-age girls and boys with ADHD. Psychiatry Res 271: 67-74.

[43] Rubia K, Halari R, Cubillo A, et al. (2011a) Methylphenidate normalizes fronto-striatal underactivation during interference inhibition in medication-naïve boys with attention-deficit hyperactivity disorder. Neuropsychopharmacol 36: 1575-86.

[44] Rubia K, Halari R, Mohammad A-M, et al. (2011b) Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder. Biol Psychiatry 70: 255-62.

[45] Schrantee A, Mutsaerts H, Bouziane C, et al. (2017) The age-dependent effects of a single-dose methylphenidate challenge on cerebral perfusion in patients with attention-deficit/hyperactivity disorder. NeuroImage Clin 13: 123-9.

[46] Schweren LJS, de Zeeuw P, Durston S (2013) MR imaging of the effects of methylphenidate on brain structure and function in attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol 23: 1151-64.

[47] Sherman SM (2012) Thalamocortical interactions. Curr Opin Neurobiol 22: 575-9.

[48] Svatkova A, Nestrasil I, Rudser K, et al. (2016) Unique white matter microstructural patterns in ADHD presentations-a diffusion tensor imaging study. Hum Brain Mapp 37: 3323-36.

[49] Sweeney-Reed CM, Buentjen L, Voges J, et al. (2021) The role of the anterior nuclei of the thalamus in human memory processing. Neurosci Biobehav Rev 126: 146-58.

[50] Tsanov M, Vann SD, Erichsen JT, et al. (2011) Differential regulation of synaptic plasticity of the hippocampal and the hypothalamic inputs to the anterior thalamus. Hippocampus 21: 1-8.

[51] Vann SD, Nelson AJD (2015) The mammillary bodies and memory: more than a hippocampal relay. Prog Brain Res 219: 163-85.

[52] Wang T, Liu K, Li Z, et al. (2017) Prevalence of attention deficit/hyperactivity disorder among children and adolescents in China: a systematic review and meta-analysis. BMC Psychiatry 17: 32.

[53] Wang X-K, Wang X-Q, Yang X, et al. (2022) Gray Matter network associated with attention in children with attention deficit hyperactivity disorder. Front Psychiatry 13: 922720.

[54] Wang Y, Xu Q, Li S, et al. (2018) Gender differences in anomalous subcortical morphology for children with ADHD. Neurosci Lett 665: 176-81.

[55] Wang Y, Zuo C, Xu Q, et al. (2021) Attention-deficit/hyperactivity disorder is characterized by a delay in subcortical maturation. Prog Neuropsychopharmacol Biol Psychiatry 104: 110044.

[56] Wilke M, Turchi J, Smith K, et al. (2010) Pulvinar inactivation disrupts selection of movement plans. J Neurosci 30: 8650-9.

[57] Willcutt EG (2012) The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics 9: 490-9.

[58] Wolff M, Vann SD (2019) The cognitive thalamus as a gateway to mental representations. J Neurosci 39: 3-14.

[59] Wu W, McAnulty G, Hamoda HM, et al. (2020) Detecting microstructural white matter abnormalities of frontal pathways in children with ADHD using advanced diffusion models. Brain Imaging and Behav 14: 981-97.

[60] Wu L, Su S, Dai Y, et al. (2024) Disrupted small-world networks in children with drug-naïve attention-deficit/hyperactivity disorder: a DTI-based network analysis. Dev Neurosci 46: 201-9.

[61] Wu Z-M, Wang P, Liu L, et al. (2022) ADHD-inattentive versus ADHD-combined subtypes: a severity continuum or two distinct entities? A comprehensive analysis of clinical, cognitive and neuroimaging data. J Psychiatr Res 149: 28-36.

[62] Xia S, Li X, Kimball AE, et al. (2012) Thalamic shape and connectivity abnormalities in children with attention-deficit/hyperactivity disorder. Psychiatry Res 204: 161-7.

[63] Zhou M, Yang C, Bu X, et al. (2019) Abnormal functional network centrality in drug-naïve boys with attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 28: 1321-8.

[64] Zhu Y, Jiang X, Ji W . (2018) The mechanism of cortico-striato-thalamo-cortical neurocircuitry in response inhibition and emotional responding in attention deficit hyperactivity disorder with comorbid disruptive behavior disorder. Neurosci Bull 34: 566-72.