The Regulatory Role of the Human Mediodorsal Thalamus
Authors: Giulio Pergola, Lola Danet, Anne-Lise Pitel, Giovanni A. Carlesimo, Shailendra Segobin, Jérémie Pariente, Boris Suchan, Anna S. Mitchell, Emmanuel J. Barbeau
Journal: Trends in Cognitive Sciences (2018)

The mediodorsal thalamic nucleus is involved in the cognitive deficits observed in several neurological and psychiatric disorders. The long-standing belief in a role of the mediodorsal thalamic nucleus mainly in long-term memory is now being reconsidered. Recent studies emphasize its function in many cognitive tasks related to the prefrontal cortex. The mediodorsal thalamic nucleus is required for the rapid and accurate performance of cognitive tasks and temporally extends the efficiency of cortical networks involving the prefrontal cortex. We propose that the common ground of multiple lines of evidence from human studies points to a role of the mediodorsal thalamic nucleus in regulating prefrontal activity patterns. These hypotheses can be tested by developing specific neuropsychological tasks, parceling the thalamus with high-resolution MRI, and using intracranial recordings in humans. The function of the human mediodorsal thalamic nucleus (MD) has so far eluded a clear definition in terms of specific cognitive processes and tasks. Although it was at first proposed to play a role in long-term memory, a set of recent studies in animals and humans has revealed a more complex, and broader, role in several cognitive functions. The MD seems to play a multifaceted role in higher cognitive functions together with the prefrontal cortex and other cortical and subcortical brain areas. Specifically, we propose that the MD is involved in the regulation of cortical networks especially when the maintenance and temporal extension of persistent activity patterns in the frontal lobe areas are required. The function of the human mediodorsal thalamic nucleus (MD) has so far eluded a clear definition in terms of specific cognitive processes and tasks. Although it was at first proposed to play a role in long-term memory, a set of recent studies in animals and humans has revealed a more complex, and broader, role in several cognitive functions. The MD seems to play a multifaceted role in higher cognitive functions together with the prefrontal cortex and other cortical and subcortical brain areas. Specifically, we propose that the MD is involved in the regulation of cortical networks especially when the maintenance and temporal extension of persistent activity patterns in the frontal lobe areas are required. Nevertheless, Euryclea, take his bed outside the bed chamber that he himself built.Odyssey, Book XXIII, verses 177–178. Butler translation. When faced with the prospect of welcoming a stranger as her long-missing husband, and unable to recognize him, Penelope resorted to her 'thalamus' with the words reported above – the bed had roots in the foundation of the house and could not be moved, a detail her husband would certainly know. Initially entering the scene as something instrumental to recognition, the thalamus (see Glossary) in the Odyssey becomes the center of the scene in the last two books. Likewise, in neuroscience, the investigation of the mediodorsal thalamic nucleus (MD) is gaining momentum. Until recently, the function of the MD has been mapped onto specific cognitive domains, such as memory or executive function. An influential model on a role of the MD in recognition memory for instance suggested it might play a role in familiarity [1Aggleton J.P. Brown M.W. Episodic memory, amnesia, and the hippocampal-anterior thalamic axis.Behav. Brain Sci. 1999; 22: 425-444Crossref PubMed Scopus (1276) Google Scholar]. However, abundant evidence indicates that this view is limited and that the role of the MD in human cognition must be reconsidered. For example, clinicians have known for a long time that the MD and its brain networks are involved in several neurological and psychiatric conditions in which the cognitive deficits are not restricted to memory functions [2Golden E.C. et al.Mediodorsal nucleus and its multiple cognitive functions.Neurology. 2016; 87: 2161-2168Crossref PubMed Scopus (3) Google Scholar]. Neuroimaging and neurophysiology studies of the human MD in vivo further support this view change. This review evaluates the latest evidence in humans and aims at formulating hypotheses to elucidate the cognitive functions of the human MD in future studies. We argue that the MD is involved in regulating activity patterns in the frontal lobe that are key to perform cognitive functions characterized by persistent thalamocortical interactions for long delays, in the face of interference, and during multitasking. Disruptions to this thalamofrontal communication may in turn underlie cognitive deficits in several neurological and psychiatric conditions and represent a possible therapeutic target. Animal models emphasizing the role of the MD in recognition memory and familiarity were based on its monosynaptic input from the perirhinal cortex in primates [1Aggleton J.P. Brown M.W. Episodic memory, amnesia, and the hippocampal-anterior thalamic axis.Behav. Brain Sci. 1999; 22: 425-444Crossref PubMed Scopus (1276) Google Scholar] (while this pathway is only weak in rodents [3Furtak S.C. et al.Functional neuroanatomy of the parahippocampal region in the rat: the perirhinal and postrhinal cortices.Hippocampus. 2007; 17: 709-722Crossref PubMed Scopus (0) Google Scholar]). Earlier pioneering work in non-human primates, however, had demonstrated the influence of MD–prefrontal cortex (PFC) interactions on MD activity across delays [4Alexander G.E. Fuster J.M. 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Similarly, in monkeys and humans, MD efferences diverge and make contact with multiple PFC areas [15Ray J.P. Price J.L. The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys.J. Comp. Neurol. 1993; 337: 1-31Crossref PubMed Scopus (278) Google Scholar, 16Klein J.C. et al.Topography of connections between human prefrontal cortex and mediodorsal thalamus studied with diffusion tractography.Neuroimage. 2010; 51: 555-564Crossref PubMed Scopus (102) Google Scholar]. The MD is thus interacting with many frontal areas simultaneously, which in turn have intrinsic connections among multiple cortical layers [17Usrey W.M. Sherman S.M. Corticofugal circuits: communication lines from the cortex to the rest of the brain.J. Comp. Neurol. 2018; (Published online March 10, 2018)https://doi.org/10.1002/cne.24423Crossref PubMed Scopus (1) Google Scholar]. MD neurons may directly facilitate corticocortical communication via trans-thalamic pathways [18Saalmann Y.B. Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition.Front. Syst. Neurosci. 2014; 8: 83Crossref PubMed Scopus (77) Google Scholar], and it would be important to further support this hypothesis with neurophysiological measurements [19Saalmann Y.B. et al.The pulvinar regulates information transmission between cortical areas based on attention demands.Science. 2012; 337: 753-756Crossref PubMed Scopus (335) Google Scholar]. What has been convincingly demonstrated is that persistent PFC activity patterns depend on MD inputs and on recurrent excitation of thalamofrontal circuits [6Bolkan S.S. et al.Thalamic projections sustain prefrontal activity during working memory maintenance.Nat. Neurosci. 2017; 20: 987-996Crossref PubMed Scopus (49) Google Scholar, 20Guo Z.V. et al.Maintenance of persistent activity in a frontal thalamocortical loop.Nature. 2017; 545: 181-186Crossref PubMed Scopus (31) Google Scholar]. Hence the MD may have a role, not limited to long-term memory (LTM), in sustaining delay-related activity in the PFC [21Parnaudeau S. et al.The mediodorsal thalamus: an essential partner of the prefrontal cortex for cognition.Biol. Psychiatry. 2018; 83: 648-656Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Interestingly, while the initial maintenance may be sustained by the PFC alone, its interactions with the MD could extend this activity pattern from several seconds to several minutes and possibly beyond [21Parnaudeau S. et al.The mediodorsal thalamus: an essential partner of the prefrontal cortex for cognition.Biol. Psychiatry. 2018; 83: 648-656Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. The temporal regulation of the mutual interdependence of MD and PFC activity, for example, the rapid adjustment of the phase and frequency of cortical oscillations [7Schmitt L.I. et al.Thalamic amplification of cortical connectivity sustains attentional control.Nature. 2017; 545: 219-223Crossref PubMed Scopus (56) Google Scholar, 9Browning P.G. et al.Evidence for mediodorsal thalamus and prefrontal cortex interactions during cognition in macaques.Cereb. Cortex. 2015; 25: 4519-4534Crossref PubMed Scopus (15) Google Scholar, 13Ouhaz Z. et al.Cognitive functions and neurodevelopmental disorders involving the prefrontal cortex and mediodorsal thalamus.Front. Neurosci. 2018; 12: 33Crossref PubMed Scopus (2) Google Scholar], is an idea also common to other views [18Saalmann Y.B. Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition.Front. Syst. Neurosci. 2014; 8: 83Crossref PubMed Scopus (77) Google Scholar, 22Acsady L. The thalamic paradox.Nat. Neurosci. 2017; 20: 901-902Crossref PubMed Scopus (2) Google Scholar, 23Wang X.J. Synaptic reverberation underlying mnemonic persistent activity.Trends Neurosci. 2001; 24: 455-463Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar]. Thus, the MD when actively engaging with the PFC might support synaptic reverberations in recurrent thalamofrontal loops that promote persistent activity across several cortical regions necessary for efficient cognitive functioning. In other words, the influence of the MD on the cortex may allow for reflections, decisions, and actions relevant to the current task demands to extend over a window of time that is contextually relevant and unfolds at temporal scales distinct in different mammalian species. These ideas, mainly developed through experiments in rodents and monkeys, are plausible in humans too, and these advances call for timely translations into the human field. We are well aware that there is still much to learn in terms of establishing clear homologies between animal models and humans. For example, the primate MD includes an intrinsic population of interneurons releasing GABA that has not been identified in rodents [24Arcelli P. et al.GABAergic neurons in mammalian thalamus: a marker of thalamic complexity?.Brain Res. Bull. 1997; 42: 27-37Crossref PubMed Scopus (156) Google Scholar]. In primates, the MD is also rich in dopamine receptors receiving their input from multiple independent pathways [25Garcia-Cabezas M.A. et al.Distribution of the dopamine innervation in the macaque and human thalamus.Neuroimage. 2007; 34: 965-984Crossref PubMed Scopus (0) Google Scholar, 26Garcia-Cabezas M.A. et al.Dopamine innervation in the thalamus: monkey versus rat.Cereb. Cortex. 2009; 19: 424-434Crossref PubMed Scopus (0) Google Scholar], making it part of well-studied brain networks involved in saliency detection [27Peters S.K. et al.Cortico-striatal-thalamic loop circuits of the salience network: a central pathway in psychiatric disease and treatment.Front. Syst. Neurosci. 2016; 10: 104Crossref PubMed Scopus (26) Google Scholar]. Further, the MD is part of a primate-specific network linking the amygdala with the thalamic reticular nucleus [28Zikopoulos B. Barbas H. Pathways for emotions and attention converge on the thalamic reticular nucleus in primates.J. Neurosci. 2012; 32: 5338-5350Crossref PubMed Google Scholar], one of the main sources of GABA within the thalamus. Importantly, animals are typically overtrained on the tasks they perform, whereas it has been argued that novel, complex tasks, not easily solved based on procedures, expertise, or overlearned knowledge, should particularly tap MD–PFC interactions [13Ouhaz Z. et al.Cognitive functions and neurodevelopmental disorders involving the prefrontal cortex and mediodorsal thalamus.Front. Neurosci. 2018; 12: 33Crossref PubMed Scopus (2) Google Scholar]. Yet we contend that general principles learned from experimental animal models are not undermined by these differences, because of the generally similar connectivity patterns of the MD with the PFC across species. If anything, the primate-specific MD features make it more central in brain networks relevant to cognition (Figure 1). Here we propose that such species-specific adaptations, rather than establishing different functions in the primate context compared to rodents, reflect the phylogenetic adaptation of the interactions between the MD and the PFC in the context of a generally different organization of the primate brain. For example, while saliency detection and persistent PFC activity across delays are affected by MD dysfunction in rodents, the neurochemical basis is likely different to that in primates, since the latter takes advantage of dopamine inputs to the MD. Specifically, we argue that the human MD is in a unique position to participate in the activity of multiple brain networks that exceed the definition of a single cognitive domain – a notion that, in rodents and non-human primates, is supported by multiple lines of evidence [7Schmitt L.I. et al.Thalamic amplification of cortical connectivity sustains attentional control.Nature. 2017; 545: 219-223Crossref PubMed Scopus (56) Google Scholar, 13Ouhaz Z. et al.Cognitive functions and neurodevelopmental disorders involving the prefrontal cortex and mediodorsal thalamus.Front. Neurosci. 2018; 12: 33Crossref PubMed Scopus (2) Google Scholar, 29Mitchell A.S. The mediodorsal thalamus as a higher order thalamic relay nucleus important for learning and decision-making.Neurosci. Biobehav. Rev. 2015; 54: 76-88Crossref PubMed Scopus (50) Google Scholar]. To this aim, we review the available evidence in human studies from the perspective of clinical, neuroimaging, and neurophysiological studies that highlight the importance of MD–PFC interactions. In humans, the MD has initially been associated with LTM based on its assumed involvement in Korsakoff's syndrome (KS) [30Victor M.A. et al.The Wernicke-Korsakoff syndrome and Related Neurologic Disorder due to Alcoholism and Malnutrition. F. A. Davis, 1989Google Scholar, 31Victor M. et al.The Wernicke-Korsakoff syndrome. A clinical and pathological study of 245 patients, 82 with post-mortem examinations.Contemp. Neurol. Ser. 1971; 7: 1-206PubMed Google Scholar] (Box 1 reports a historical perspective of the function of the MD in memory). Thalamic stroke studies have also historically played an important role in shedding light on the function of individual thalamic nuclei. In particular, ischemia in the paramedian or tuberothalamic artery or hemorrhage causes MD damage [32Schmahmann J.D. Vascular syndromes of the thalamus.Stroke. 2003; 34: 2264-2278Crossref PubMed Scopus (404) Google Scholar, 33Jimenez Caballero P.E. Bilateral paramedian thalamic artery infarcts: report of 10 cases.J. Stroke Cerebrovasc. Dis. 2010; 19: 283-289Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Because of the small size of thalamic nuclei (Box 2), vascular lesions are necessarily unselective and involve multiple nuclei, which also play a role in the ensuing cognitive deficits. For this reason, it is crucial to quantitatively estimate the volume loss separately for different nuclei, an approach that became viable only recently thanks to advances in neuroimaging techniques but that has been too rarely undertaken so far [34Pergola G. et al.Quantitative assessment of chronic thalamic stroke.Am. J. Neuroradiol. 2013; 34: E51-E55Crossref PubMed Scopus (0) Google Scholar, 35Pergola G. et al.The involvement of the thalamus in semantic retrieval: a clinical group study.J. Cogn. Neurosci. 2013; 25: 872-886Crossref PubMed Scopus (19) Google Scholar, 36Danet L. et al.Thalamic amnesia after infarct: the role of the mammillothalamic tract and mediodorsal nucleus.Neurology. 2015; 85: 2107-2115Crossref PubMed Scopus (23) Google Scholar]. Lesion quantification is challenging especially for lesions proximal to the third ventricle: these infarcts tend to merge with the ventricle, or the ventricle itself undergoes progressive enlargement associated with tissue shrinkage, hindering volume measurements in the medial nuclei (see Outstanding Questions).Box 1Familiarity or Recollection? An Historical OverviewThe interest on thalamic nuclei as higher-order cognition substrates enjoyed a widespread increase after Aggleton and Brown's review [1Aggleton J.P. Brown M.W. Episodic memory, amnesia, and the hippocampal-anterior thalamic axis.Behav. Brain Sci. 1999; 22: 425-444Crossref PubMed Scopus (1276) Google Scholar]. The authors described the substrates of the two processes underpinning recognition memory: recollection, the ability to retrieve part of the experience associated with a stimulus, and familiarity, the mere feeling that a stimulus has been experienced. They suggested that the circuit linking the hippocampus with the anterior thalamic nuclei (ATN) along with the mammillary bodies and the mammillothalamic tract (MTT) supported recollection. They also proposed that a second independent circuit involved the perirhinal cortex and the MD processed familiarity due to their direct connections. Although a critical role for the ATN in recollection remains undisputed, the role of the MD in familiarity is still contested. Indeed, studies have typically reported impaired recollection with relatively preserved familiarity following MD damage [38Zoppelt D. et al.Involvement of the mediodorsal thalamic nucleus in mediating recollection and familiarity.Neuropsychologia. 2003; 41: 1160-1170Crossref PubMed Scopus (0) Google Scholar, 99Danet L. et al.Medial thalamic stroke and its impact on familiarity and recollection.eLife. 2017; 6e28141Crossref PubMed Scopus (1) Google Scholar, 100Cipolotti L. et al.The role of the thalamus in amnesia: a tractography, high-resolution MRI and neuropsychological study.Neuropsychologia. 2008; 46: 2745-2758Crossref PubMed Google Scholar, 101Soei E. et al.Involvement of the human thalamus in relational and non-relational memory.Eur. J. Neurosci. 2008; 28: 2533-2541Crossref PubMed Scopus (15) Google Scholar]. Aggleton and colleagues [102Aggleton J.P. et al.Unraveling the contributions of the diencephalon to recognition memory: a review.Learn. Mem. 2011; 18: 384-400Crossref PubMed Scopus (0) Google Scholar] thus revised their model integrating the specific connectivity pattern of each thalamic nucleus. The multieffect multinuclei model described a functional continuum, rather than a dissociation, between the MTT/ATN and MD via the midline and intralaminar nuclei. In particular, they proposed recollection to be impaired following MD damage because of the dense connections between this nucleus and prefrontal areas, hence switching the role of this nucleus away from its relation with the medial temporal lobes. A distinction was also drawn between the parvocellular MD, which may be involved in recollection (due to their dense connectivity with the PFC), and the magnocellular MD, whose role remains more elusive [102Aggleton J.P. et al.Unraveling the contributions of the diencephalon to recognition memory: a review.Learn. Mem. 2011; 18: 384-400Crossref PubMed Scopus (0) Google Scholar]. Subsequent studies, including those with more refined imaging approaches to localize lesions, appeared in agreement with these proposals [36Danet L. et al.Thalamic amnesia after infarct: the role of the mammillothalamic tract and mediodorsal nucleus.Neurology. 2015; 85: 2107-2115Crossref PubMed Scopus (23) Google Scholar, 37Pergola G. et al.Recall deficits in stroke patients with thalamic lesions covary with damage to the parvocellular mediodorsal nucleus of the thalamus.Neuropsychologia. 2012; 50: 2477-2491Crossref PubMed Scopus (0) Google Scholar, 51Tu S. et al.Accelerated forgetting of contextual details due to focal medio-dorsal thalamic lesion.Front. Behav. Neurosci. 2014; 8: 320Crossref PubMed Scopus (10) Google Scholar], leaving the purported role of the MD in familiarity unsubstantiated with the exception of a single case study [103Edelstyn N.M. et al.A deficit in familiarity-driven recognition in a right-sided mediodorsal thalamic lesion patient.Neuropsychology. 2016; 30: 213-224Crossref PubMed Scopus (3) Google Scholar] and fMRI studies [74Kafkas A. Montaldi D. Two separate, but interacting, neural systems for familiarity and novelty detection: a dual-route mechanism.Hippocampus. 2014; 24: 516-527Crossref PubMed Scopus (0) Google Scholar, 75Kafkas A. Montaldi D. Familiarity and recollection produce distinct eye movement, pupil and medial temporal lobe responses when memory strength is matched.Neuropsychologia. 2012; 50: 3080-3093Crossref PubMed Scopus (42) Google Scholar, 76Montaldi D. et al.The neural system that mediates familiarity memory.Hippocampus. 2006; 16: 504-520Crossref PubMed Scopus (0) Google Scholar]. Recently, a single case study assessed the impact of MD damage sustained at birth on the Forced Choice Corresponding test, which requires subjects to recognize stimuli among similar foils. Performance on this task is thought to critically depend on the perirhinal cortex, and, by extension, on the MD as a trans-thalamic relay to prefrontal areas. The patient was indeed impaired on trials filled with visual interference, which indicates that the MD may be involved in some visually demanding recognition memory tasks, without necessarily mapping on the classical familiarity/recollection distinction [42Newsome R.N. et al.Dissociable contributions of thalamic nuclei to recognition memory: novel evidence from a case of medial dorsal thalamic damage.Learn. Mem. 2018; 25: 31-44Crossref PubMed Scopus (0) Google Scholar].Box 2Trends in Magnetic Resonance Imaging of Thalamic NucleiFrom an MRI perspective, measurements need precision (the minimum possible error in estimating the signal in a voxel) and accuracy (free of artifacts, well-localized signals). Owing to their small size [104Morel A. Stereotactic Atlas of the Human Thalamus and Basal Ganglia. CRC Press, 2007Crossref Google Scholar] and similarity in terms of relaxation times and/or proton densities, segmenting thalamic nuclei is particularly challenging.Structural ScansManual segmentation of thalamic nuclei depends on good contrast between nuclei of interest and neighboring regions. The optimum choice is to use higher field strength (e.g., 7 T), offering higher contrast and signal-to-noise ratio (SNR). Acquisitions are typically study and nuclei specific. Prior reports employed inversion recovery-turbo spin echo [105Kanowski M. et al.Direct visualization of anatomic subfields within the superior aspect of the human lateral thalamus by MRI at 7T.Am. J. Neuroradiol. 2014; 35: 1721-1727Crossref PubMed Scopus (0) Google Scholar] for imaging the dorsal thalamus, susceptibility-weighted imaging [106Deistung A. et al.Toward in vivo histology: a comparison of quantitative susceptibility mapping (QSM) with magnitude-, phase-, and R2*-imaging at ultra-high magnetic field strength.Neuroimage. 2013; 65: 299-314Crossref PubMed Scopus (168) Google Scholar] for its ventral intermediate aspects, and MPRAGE sequences that nullify white matter that separates several nuclei [107Tourdias T. et al.Visualization of intra-thalamic nuclei with optimized white-matter-nulled MPRAGE at 7T.Neuroimage. 2014; 84: 534-545Crossref PubMed Scopus (37) Google Scholar]. A trade-off is needed between SNR and acquisition times. Shorter acquisition times help minimize movement artifacts due to head motion or cerebrovascular pulsation [105Kanowski M. et al.Direct visualization of anatomic subfields within the superior aspect of the human lateral thalamus by MRI at 7T.Am. J. Neuroradiol. 2014; 35: 1721-1727Crossref PubMed Scopus (0) Google Scholar], while longer acquisition times allow for higher-resolution images, decreasing the mixture of tissues in a voxel. Typically, 7-T MRI sequences with discernable nuclei had acquisition times of 7–15 min for image resolutions varying from 0.67 mm isotropic to 0.375 × 0.375 × 1 mm3 [107Tourdias T. et al.Visualization of intra-thalamic nuclei with optimized white-matter-nulled MPRAGE at 7T.Neuroimage. 2014; 84: 534-545Crossref PubMed Scopus (37) Google Scholar].Currently, with most data collected at lower field strength (3 T), automatic segmentation is often preferred. It can be achieved through a histological atlas [108Krauth A. et al.A mean three-dimensional atlas of the human thalamus: generation from multiple histological data.Neuroimage. 2010; 49: 2053-2062Crossref PubMed Scopus (101) Google Scholar] and requires normalization of the MRI into atlas-standardized space. Its accuracy is limited to the resolution of both, MRI and atlas, and does not account for intersubject variability of shape and volume for each nucleus, especially in patients [109Pergola G. Thalamic amnesia after infarct: the role of the mammillothalamic tract and mediodorsal nucleus.Neurology. 2016; 86: 1928Crossref PubMed Google Scholar].Structural ConnectivityAutomatic segmentation can also employ diffusion imaging and state-of-the-art tractography algorithms. The connectivity strength in each thalamic voxel is evaluated with respect to a priori-defined regions [110Behrens T.E.J. et al.Probabilistic diffusion tractography with multiple fibre orientations: what can we gain?.Neuroimage. 2007; 34: 144-155Crossref PubMed Scopus (1684) Google Scholar, 111Behrens T.E. et al.Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging.Nat. Neurosci. 2003; 6: 750-757Crossref PubMed Scopus (1371) Google Scholar, 112Rittner, L. et al. (2010) Segmentation of thalamic nuclei based on tensorial morphological gradient of diffusion tensor fields. Proceedings of the 2010 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro, ISBI 2010, pp. 1173–1176, IEEEGoogle Scholar] or every voxel in the brain [113O'Muircheartaigh J. et al.White matter connectivity of the thalamus delineates the functional architecture of competing thalamocortical systems.Cereb. Cortex. 2015; 25: 4477-4489Crossref PubMed Scopus (18) Google Scholar] and then clustered together according to connectivity-based feature similarities to segment the thalamus [114Jbabdi S. et al.Multiple-subjects connectivity-based parcellation using hierarchical Dirichlet process mixture models.Neuroimage. 2009; 44: 373-384Crossref PubMed Scopus (0) Google Scholar].Functional ConnectivityResting-state fMRI studies have segmented the thalamus based on functional connectivity patterns with cortical areas (e.g., independent component analysis [115Hale J.R. et al.Comparison of functional thalamic segmentation from seed-based analysis and ICA.Neuroimage. 2015; 114: 448-465Crossref PubMed Scopus (14) Google Scholar, 116Zhang D. et al.Noninvasive functional and structural connectivity mapping of the human thalamocortical system.Cereb. Cortex. 2010; 20: 1187-1194Crossref PubMed Scopus (185) Google Scholar] or normalized spectral clustering [117Ji B. et al.Dynamic thalamus parcellation from resting-state fMRI data.Hum. Brain Mapp. 2016; 37: 954-967Crossref PubMed Scopus (13) Google Scholar]). Thalamic parcels typically do not have a one-to-one mapping to cortical regions