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Cerebral control of swallowing: An update on neurobehavioral evidence

  • Ivy Cheng
    Correspondence
    Corresponding author at: Room B210, First Floor, Centre for Gastrointestinal Sciences, Clinical Sciences Building, Salford Royal Foundation Trust Hospital, Eccles Old Road, Salford M6 8HD, UK.
    Affiliations
    Centre for Gastrointestinal Sciences, Division of Diabetes, Gastroenterology and Endocrinology, School of Medical Sciences, University of Manchester, UK
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  • Kazutaka Takahashi
    Affiliations
    Department of Organismal Biology and Anatomy, University of Chicago, USA
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  • Arthur Miller
    Affiliations
    Division of Orthodontics, Department of Orofacial, Sciences, School of Dentistry, University of California at San Francisco, USA
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  • Shaheen Hamdy
    Affiliations
    Centre for Gastrointestinal Sciences, Division of Diabetes, Gastroenterology and Endocrinology, School of Medical Sciences, University of Manchester, UK
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Open AccessPublished:September 22, 2022DOI:https://doi.org/10.1016/j.jns.2022.120434

      Highlights

      • We reviewed neurophysiological and neuroimaging data from animal and human studies.
      • Cortical and subcortical regions that mediate swallowing are functionally connected.
      • Hemispheric dominance for swallowing remains inconsistent across individuals.
      • Activation sites and laterality shift between swallowing preparation and execution.
      • Neurostimulation treatments may be beneficial for dysphagia following brain injury.

      Abstract

      This review aims to update the current knowledge on the cerebral control of swallowing. We review data from both animal and human studies spanning across the fields of neuroanatomy, neurophysiology and neuroimaging to evaluate advancements in our understanding in the brain's role in swallowing. Studies have collectively shown that swallowing is mediated by multiple distinct cortical and subcortical regions and that lesions to these regions can result in dysphagia. These regions are functionally connected in separate groups within and between the two hemispheres. While hemispheric dominance for swallowing has been reported in most human studies, the laterality is inconsistent across individuals. Moreover, there is a shift in activation location and laterality between swallowing preparation and execution, although such activation changes are less well-defined than that for limb motor control. Finally, we discussed recent neurostimulation treatments that may be beneficial for dysphagia after brain injury through promoting the reorganization of the swallowing neural network.

      Keywords

      1. Introduction

      Swallowing is one of the most primitive yet complex functions in mammals. In humans, the swallowing process requires precise coordination of kinematics of approximately 50 pairs of muscles [
      • Hennessy M.
      • Goldenberg D.
      Surgical anatomy and physiology of swallowing.
      ]. It is mediated by the central nervous system, involving the brainstem, cerebral cortex, cranial nerves and motoneurons supplying the swallowing musculature [
      • Miller A.J.
      Deglutition.
      ,
      • Miller A.J.
      Neurophysiological basis of swallowing.
      ]. Studies with animals offer valuable insights into the neurophysiology of swallowing in mammals. These studies have shown that swallowing and related orofacial movements can be elicited through electrical stimulation of the cerebral cortex, brainstem, and peripheral nerves including glossopharyngeal cranial nerve and superior laryngeal nerve in anaesthetized or awake mammals [
      • Miller A.J.
      Deglutition.
      ]. Importantly, several cortical regions, such as the cortical masticatory area (CMA), are found to be involved in the neural control of swallowing, but these regions differ across species. Implanted electrode recordings have shown that neurons in primary motor (M1) and sensory (S1) cortices are specialized for swallowing, mastication or tongue movements in primates [
      • Lin L.D.
      • Murray G.M.
      • Sessle B.J.
      Functional properties of single neurons in the primate face primary somatosensory cortex. I. Relations with trained orofacial motor behaviors.
      ,
      • Murray G.M.
      • Sessle B.J.
      Functional properties of single neurons in the face primary motor cortex of the primate. III. Relations with different directions of trained tongue protrusion.
      ,
      • Murray G.M.
      • Sessle B.J.
      Functional properties of single neurons in the face primary motor cortex of the primate. I. Input and output features of tongue motor cortex.
      ].
      In humans, early understanding of the neurological control of swallowing mainly comes from lesion studies, which allow indirect deduction of the function of the lesioned regions considered to be responsible for swallowing. However, such deduction can be problematic, because lesion data can only infer the remaining functionality of brain control systems in the absence of the lesioned sites rather than its intact normal function. Traditionally, the brainstem was thought to be the primary center for swallowing and the cerebral cortex was not essential for swallowing, based on the observation that encephalic babies with an intact brainstem have retained the ability to suckle [
      • Meadows J.C.
      Dysphagia in unilateral cerebral lesions.
      ]. Such perception has been displaced by clinical reports of dysphagia resulting from supratentorial lesions of a single hemisphere. Since then, growing attention has been given to the cerebral cortex in the investigation of the whole brain neural basis of swallowing. With the advancement in functional neuroimaging technologies, cortical activation during swallowing can be examined in detail with high levels of spatial and temporal resolution. However, there remains considerable uncertainty particularly around how different cerebral regions are functionally connected. Therefore, this review aims to update the current knowledge on the cerebral control of swallowing and the functional connectivity within the cerebral cortex. Evidence from neurophysiological, neuroanatomical and functional neuroimaging studies will be discussed. Finally, we will discuss the therapeutic value of recent treatments in facilitating the rehabilitation of neurogenic dysphagia.

      2. Cerebral control of swallowing in animals

      Animal studies have contributed significantly to our understanding of the swallowing mechanism because they facilitate dissection of individual components of the swallowing control system that would otherwise be restricted in research with humans. In early 1900s, Sir Charles Sherrington and Professor Albert S. F. Grünbaum pioneered the first maps of cortical localization of motor functions in primates [
      • Sherrington C.S.
      • Grünbaum A.
      An address on localisation in the" motor" cerebral cortex.
      ,
      • Sherrington C.S.
      • Grünbaum A.S.
      • Stewart G.N.
      • Campbell A.W.
      • Symington J.
      • May W.P.
      • Thompson W.H.
      A discussion on the motor cortex as exemplified in the anthropoid apes.
      ]. Since then, direct electrical stimulation has been used to stimulate various levels of the corticofugal pathways and the cortex of anesthetized or awake animals to elicit swallowing or swallowing-related movements [
      • Miller A.J.
      Deglutition.
      ]. Microelectrode recordings in sheep and rats have identified that interneurons responsible for swallowing are mainly located in the brainstem, including the solitary tract nucleus (NTS) and the reticular formation surrounding the nucleus ambiguous (NA), and have shown that stimulation of the superior laryngeal nerve can trigger swallowing activity [
      • Jean A.
      • Car A.
      Inputs to the swallowing medullary neurons from the peripheral afferent fibers and the swallowing cortical area.
      ,
      • Jean A.
      Localisation et activité des neurones déglutiteurs bulbaires.
      ,
      • Jean A.
      Localisation et activité des motoneurones oesophagiens chez le mouton. Etude par microélectrodes.
      ,
      • Kessler J.P.
      • Jean A.
      Identification of the medullary swallowing regions in the rat.
      ].
      While the brainstem is often regarded as the most important structure for swallowing, studies have also identified the vital role of the cerebral cortex in mediating swallowing (Table 1). Early studies with anaesthetized sheep found that swallowing can be evoked by repeated stimulation of the orbitofrontal cortex [
      • Jean A.
      • Car A.
      Inputs to the swallowing medullary neurons from the peripheral afferent fibers and the swallowing cortical area.
      ]. Activation of “early” NTS neurons, which fire before or during the oropharyngeal stage of swallowing, following cortical stimulation suggested that this region might be responsible for triggering of swallowing in sheep. In anaesthetized rabbits, Sumi [
      • Sumi T.
      Some properties of cortically-evoked swallowing and chewing in rabbits.
      ] found that the cortical regions for swallowing were located in the anterolateral frontal cortex. Similar findings have been reported in primates. In anaesthetized monkeys, Miller and Bowman [
      • Miller A.J.
      • Bowman J.P.
      Precentral cortical modulation of mastication and swallowing.
      ] found that swallowing can be elicited in posterior regions of the anterolateral primary motor cortex (M1). In awake monkeys, intracortical microstimulation (ICMS) of distinct regions of the cerebral cortex, including the lateral region of face primary somatosensory cortex (face-S1), cortical masticatory area (CMA; see below for descriptions) and frontal operculum, could elicit swallowing [
      • Martin R.E.
      • Kemppainen P.
      • Masuda Y.
      • Yao D.
      • Murray G.M.
      • Sessle B.J.
      Features of cortically evoked swallowing in the awake primate (Macaca fascicularis).
      ]. Studies have shown that “cold-block” of the face-S1 of awake monkeys significantly affects swallowing and tongue-jaw coordination and movements [
      • Yamamura K.
      • Narita N.
      • Yao D.
      • Martin R.E.
      • Masuda Y.
      • Sessle B.J.
      Effects of reversible bilateral inactivation of face primary motor cortex on mastication and swallowing.
      ,
      • Lin L.D.
      • Murray G.M.
      • Sessle B.J.
      The effect of bilateral cold block of the primate face primary somatosensory cortex on the performance of trained tongue-protrusion task and biting tasks.
      ,
      • Narita N.
      • Yamamura K.
      • Yao D.
      • Martin R.E.
      • Sessle B.J.
      Effects of functional disruption of lateral pericentral cerebral cortex on primate swallowing.
      ].
      Table 1Cortical areas that are involved in swallowing and/or orofacial (mainly tongue and jaw) movements as identified by studies with animals across species.
      StudyAnimalMethodsAnaesthetized / AwakeAreas for swallowingAreas for orofacial

      (e.g. jaw, tongue) movements
      Findings on laterality
      Sumi, 1969 [
      • Sumi T.
      Some properties of cortically-evoked swallowing and chewing in rabbits.
      ]
      25 rabbitsOpen skull electrical stimulationAnaesthetized
      • Anterolateral frontal lobe
      • Rostral to insular cortex and lateral to S1


      *Overlapping is great, but areas for swallowing are narrower and more rostrolateral
      • Anterolateral frontal lobe
      • Rostral to insular cortex and lateral to S1
      • Bilaterally controlled even after separation of hemispheres
      Sumi, 1972 [
      • Sumi T.
      Role of the pontine reticular formation in the neural organization of deglutition.
      ]
      53 rabbitsOpen skull electrical stimulationLightly anaesthetized
      • Concurrent stimulation of anterolateral frontal cortex facilitates swallowing evoked by poutine stimulation
      Baldwin et al., 2016 [
      • Baldwin M.K.
      • Cooke D.F.
      • Krubitzer L.
      Intracortical microstimulation maps of motor, somatosensory, and posterior parietal cortex in tree shrews (Tupaia belangeri) reveal complex movement representations.
      ]
      10 treeshrews (Tupaia belangeri)ICMSAnaesthetized
      • Lateral M
      • Lateral S (areas 3a and 3b)
      Bieger & Hockman, 1976 [
      • Bieger D.
      • Hockman C.H.
      Suprabulbar modulation of reflex swallowing.
      ]
      38 catsOpen skull electrical stimulationAnaesthetized
      • Concurrent stimulation of caudal half of the orbital gyrus, internal capsule, caudate nucleus and entopeduncular nucleus, anterior substantia nigra, and rostral pons facilitates SLN elicited swallowing
      Jean & Car, 1979 [
      • Jean A.
      • Car A.
      Inputs to the swallowing medullary neurons from the peripheral afferent fibers and the swallowing cortical area.
      ]
      22 sheepOpen skull electrical stimulationAnaesthetized
      • Orbitofrontal cortex
      Miller and Bowman, 1977 [
      • Miller A.J.
      • Bowman J.P.
      Precentral cortical modulation of mastication and swallowing.
      ]
      13 rhesus monkeys (Macaca Mulatta)Open skull electrical stimulationAnaesthetized
      • Anterolateral M1
      *More posteriorly than the areas for chewing
      • Anterolateral M1
      Huang et al., 1989 [
      • Huang C.S.
      • Hiraba H.
      • Murray G.M.
      • Sessle B.J.
      Topographical distribution and functional properties of cortically induced rhythmical jaw movements in the monkey (Macaca fascicularis).
      ]
      2 monkeys

      (Macaca fascicularis)
      ICMSAwake
      • Face-M1
      • Face-S1
      • CMAp
      • CMAd
      Stepniewska et al., 1993 [
      • Stepniewska I.
      • Preuss T.M.
      • Kaas J.H.
      Architectionis, somatotopic organization, and ipsilateral cortical connections of the primary motor area (M1) of owl monkeys.
      ]
      11 owl monkeys (Aotus trivirgatu)ICMSAnaesthetized
      • Lateral M1
      • Lateral and ventral PMC
      Martin et al., 1999 [
      • Martin R.E.
      • Kemppainen P.
      • Masuda Y.
      • Yao D.
      • Murray G.M.
      • Sessle B.J.
      Features of cortically evoked swallowing in the awake primate (Macaca fascicularis).
      ]
      2 monkeys

      (Macaca fascicularis)
      ICMSAwake
      • Face-M1
      • Face-S1
      • CMA
      • Area ventral to CMAd
      • Lateral face-M1
      • Lateral face-S1
      • Lateral CMA and the region ≥5 mm deep into cortical surface
      • Area for swallowing were greater on the left hemisphere than the right


      • Areas for orofacial movements were greater on the right hemisphere than the left
      Hatanaka et al., 2005 [
      • Hatanaka N.
      • Tokuno H.
      • Nambu A.
      • Inoue T.
      • Takada M.
      Input–output organization of jaw movement-related areas in monkey frontal cortex.
      ]
      7 monkeys (Macaca fuscata)ICMSAnaesthetized
      • CMA
      • Orofacial area of M1
      • Orofacial area of SMA
      Burish et al., 2008 [
      • Burish M.J.
      • Stepniewska I.
      • Kaas J.H.
      Microstimulation and architectonics of frontoparietal cortex in common marmosets (Callithrix jacchus).
      ]
      5 marmosets (Callithrix jacchus jacchus)ICMSAnaesthetized
      • Lateral M1
      • Lateral S (areas 3a and 3b)
      Abbreviations: CMA: cortical masticatory area; CMAp: principal part of cortical masticatory area; CMAd: deep part of cortical masticatory area; ICMS: intracortical microstimulation; M: motor cortex; M1: primary motor cortex; PMC: premotor cortex; SLN: superior laryngeal nerve; S: sensory cortex; S1: primary sensory cortex; SMA; supplementary motor area
      Among all orofacial movements, cortical control of tongue and jaw movements have been studied most extensively given their relevance to swallowing (Table 1). Cortical regions for these movements and those for swallowing are found to be largely overlapping [
      • Sumi T.
      Some properties of cortically-evoked swallowing and chewing in rabbits.
      ,
      • Miller A.J.
      • Bowman J.P.
      Precentral cortical modulation of mastication and swallowing.
      ]. Studies with small mammals such as treeshrews and rabbits showed that jaw movements can be evoked by stimulating the lateral regions of motor and sensory cortices and frontal lobe [
      • Sumi T.
      Some properties of cortically-evoked swallowing and chewing in rabbits.
      ,
      • Baldwin M.K.
      • Cooke D.F.
      • Krubitzer L.
      Intracortical microstimulation maps of motor, somatosensory, and posterior parietal cortex in tree shrews (Tupaia belangeri) reveal complex movement representations.
      ]. In primates, the cortical areas involved in tongue and jaw movements, including M1, S1 and CMA, appear to be more distinct compared to small mammals [
      • Miller A.J.
      • Bowman J.P.
      Precentral cortical modulation of mastication and swallowing.
      ,
      • Martin R.E.
      • Kemppainen P.
      • Masuda Y.
      • Yao D.
      • Murray G.M.
      • Sessle B.J.
      Features of cortically evoked swallowing in the awake primate (Macaca fascicularis).
      ,
      • Huang C.S.
      • Hiraba H.
      • Murray G.M.
      • Sessle B.J.
      Topographical distribution and functional properties of cortically induced rhythmical jaw movements in the monkey (Macaca fascicularis).
      ,
      • Burish M.J.
      • Stepniewska I.
      • Kaas J.H.
      Microstimulation and architectonics of frontoparietal cortex in common marmosets (Callithrix jacchus).
      ,
      • Stepniewska I.
      • Preuss T.M.
      • Kaas J.H.
      Architectionis, somatotopic organization, and ipsilateral cortical connections of the primary motor area (M1) of owl monkeys.
      ,
      • Hatanaka N.
      • Tokuno H.
      • Nambu A.
      • Inoue T.
      • Takada M.
      Input–output organization of jaw movement-related areas in monkey frontal cortex.
      ]. The CMA, of which repetitive stimulation evokes rhythmic jaw movements, comprises two parts: the principal part (CMAp) which is located in the precentral gyrus anterolateral to M1, and the deep part (CMAd) which is located in the inner face of frontal operculum [
      • Huang C.S.
      • Hiraba H.
      • Murray G.M.
      • Sessle B.J.
      Topographical distribution and functional properties of cortically induced rhythmical jaw movements in the monkey (Macaca fascicularis).
      ]. Single neuron recording studies have shown that neurons in the orofacial sensory (S1o) and motor (M1o) cortex are specialized for swallowing, mastication, or tongue protrusion [
      • Lin L.D.
      • Murray G.M.
      • Sessle B.J.
      Functional properties of single neurons in the primate face primary somatosensory cortex. I. Relations with trained orofacial motor behaviors.
      ,
      • Murray G.M.
      • Sessle B.J.
      Functional properties of single neurons in the face primary motor cortex of the primate. III. Relations with different directions of trained tongue protrusion.
      ,
      • Murray G.M.
      • Sessle B.J.
      Functional properties of single neurons in the face primary motor cortex of the primate. I. Input and output features of tongue motor cortex.
      ]. Using chronically implanted multi-electrode arrays, Arce et al., [
      • Arce F.I.
      • Lee J.-C.
      • Ross C.F.
      • Sessle B.J.
      • Hatsopoulo N.G.
      Directional information from neuronal ensembles in the primate orofacial sensorimotor cortex.
      ] investigated the activation patterns of populations of neurons in the orofacial sensorimotor cortex during directional tongue protrusion tasks in 2 monkeys. They found that over 70% of neurons modulate their spiking activity according to the direction of tongue movements (task-modulated neurons). These neurons showed concurrent but different firing patterns in which S1o neurons showed peak activity on or before force onset whereas M1o neurons showed peak activity when peak force was reached. Importantly, this study also found that the direction of tongue-protrusion can be accurately predicted by decoding the firing patterns of M1o and S1o neurons. The finding of distributed population of neurons for directional information processing suggests that direction is likely an important feature for cortical control of tongue movements.
      Of particular interest is the interaction among cortical structures, subcortical structures and brainstem for masticatory movements and swallowing. Histological studies have shown that several cortical regions are interconnected to enable the complex flow for sensory inputs and motor outputs for cortical control of jaw or masticatory movements [
      • Huang C.S.
      • Hiraba H.
      • Murray G.M.
      • Sessle B.J.
      Topographical distribution and functional properties of cortically induced rhythmical jaw movements in the monkey (Macaca fascicularis).
      ,
      • Hatanaka N.
      • Tokuno H.
      • Nambu A.
      • Inoue T.
      • Takada M.
      Input–output organization of jaw movement-related areas in monkey frontal cortex.
      ,
      • Hatanaka N.
      • Tokuno H.
      • Nambu A.
      • Takada M.
      Direct projections from the magnocellular division of the basal nucleus of the amygdala to the principal part of the cortical masticatory area in the macaque monkey.
      ]. Hatanaka et al., [
      • Hatanaka N.
      • Tokuno H.
      • Nambu A.
      • Takada M.
      Direct projections from the magnocellular division of the basal nucleus of the amygdala to the principal part of the cortical masticatory area in the macaque monkey.
      ] found that the CMAp receives direct projections from the amygdala in primates, suggesting that the amygdala may be involved in modulation and generation of masticatory patterns. A further study by Hatanaka et al., [
      • Hatanaka N.
      • Tokuno H.
      • Nambu A.
      • Inoue T.
      • Takada M.
      Input–output organization of jaw movement-related areas in monkey frontal cortex.
      ] found that the CMA, primary orofacial masticatory area (M1o) and supplementary orofacial masticatory area (SMAo) are key cortical components of a dynamic neural network for distinctive masticatory movements. These areas receive projections from the sensory and motor thalamic nuclei, as well as intracortical projections from the frontal, parietal and orbital cortices, and send motor commands to the lateral tegmental field (LTF) in the brainstem directly or indirectly via basal ganglia. This complex network enables execution of the masticatory motor sequence with concurrent modulation through sensory feedback. In anaesthetized rabbits, Sumi [
      • Sumi T.
      Some properties of cortically-evoked swallowing and chewing in rabbits.
      ] found that swallowing and mastication responses were facilitated by stimulation of both hemispheres and such facilitation remained after splitting of the two hemispheres, indicating that swallowing was bilaterally mediated and interhemispheric pathways were absent or dormant for swallowing control. Another study showed that brainstem-evoked swallowing was enhanced by repeated stimulation of the anterolateral frontal cortex in rabbits [
      • Sumi T.
      Role of the pontine reticular formation in the neural organization of deglutition.
      ]. Moreover, reflexive swallowing evoked by peripheral stimulation of superior laryngeal nerve was found to be facilitated by concurrent stimulation to structures along the corticobulbar pathway, including caudal half of the orbital gyrus, internal capsule, caudate nucleus and entopeduncular nucleus, anterior substantia nigra, and rostral pons [
      • Bieger D.
      • Hockman C.H.
      Suprabulbar modulation of reflex swallowing.
      ].
      These animal studies examined the organization of neural networks for swallowing and swallowing-related orofacial movements using electrical stimulation. While some may argue that swallowing evoked by electrical stimulation in a laboratory setting is artificial, and that electrical currents may stimulate all types of nerve fibers (excitatory and inhibitory; sensory and motor) and elicit activity that is not normally seen in a functional central nervous system, this technique allows perturbating the system to obtain a visible outcome (the swallow). Therefore, electrical stimulation to the central nervous system remains a valuable technique for understanding the neurophysiology of swallowing. Although some techniques used in animals such as ICMS are invasive and not applicable to human subjects, advances in magnetic and electrical stimulation technology, for example the development of transcranial magnetic stimulation (TMS), have made similar investigations in humans a realistic possibility. Taken together, these findings highlight the involvement of cerebral cortex in the control of complex swallowing process, which provide valuable implications for the organization of neural networks for swallowing in humans.

      3. Neurodevelopment of swallowing in human brain: from fetus to adolescent

      In humans, neonates at birth have developed the ability to swallow, which is essential for the intake of life-sustaining nutrients. A recent embryology study using real-time ultrasound imaging found that most fetuses displayed swallowing behavior as early as 15 weeks of gestation and showed consistent swallowing by 22 to 24 weeks of gestation [
      • Miller J.L.
      • Sonies B.C.
      • Macedonia C.
      Emergence of oropharyngeal, laryngeal and swallowing activity in the developing fetal upper aerodigestive tract: an ultrasound evaluation.
      ]. Fetal swallowing is important for the regulation of amniotic fluid homeostasis and the development of somatic and gastrointestinal functions [
      • Ross M.G.
      • Nijlang M.J.M.
      Fetal swallowing: relation to amniotic fluid regulation.
      ]. Neurologically, the developmental maturation of cerebral and brainstem pathways involved in swallowing determines the readiness for oral feeding after birth [
      • Delaney A.L.
      • Arvedson J.C.
      Development of swallowing and feeding: prenatal through first year of life.
      ]. Myelination in the brainstem and cranial nerves including facial (VII), glossopharyngeal (IX) and hypoglossal (XII) occurs at 18 to 24 weeks of gestation, and the development of brainstem interneuron network for pharyngeal swallow reaches a functional level before full-term of gestation [
      • Delaney A.L.
      • Arvedson J.C.
      Development of swallowing and feeding: prenatal through first year of life.
      ].
      The cerebral cortex plays an important role in swallowing, as suggested by findings from studies with anencephalic fetuses and infants. Studies have found that swallowing was absent during fetal stages for anencephalic children despite the presence of largely intact medulla, pons and cerebellum [
      • Radford K.
      • Taylor R.C.
      • Hall J.G.
      • Gick B.
      Aerodigestive and communicative behaviors in anencephalic and hydranencephalic infants.
      ]. Although swallowing was seen in an older anencephalic child, this was accompanied by the presence of cerebral tissues with unknown intactness [
      • Dickman H.
      • Fletke K.
      • Redfern R.E.
      Prolonged unassisted survival in an infant with anencephaly.
      ]. Interestingly, an fMRI study found that a 9-year-old child who suffered an anoxic injury at birth and had no normal oromotor control or prior oral feeding experience showed activities in cortical areas identical to age-matched controls while attempting to perform a swallowing task [
      • Hartnick C.J.
      • Rudolph C.
      • Willging J.P.
      • Holland S.K.
      Functional magnetic resonance imaging of the pediatric swallow: imaging the cortex and the brainstem.
      ]. It is possible that abnormal or damaged neural circuits included those beyond the cortical level, such as the cerebellum or brainstem, which were not detected by the fMRI paradigm used in the study. This finding suggested that the integrity of both brain structures and functional connectivity of neural circuits are essential for normal swallowing. In healthy adolescents, it is found that the regions of cortical activation during swallowing, including S1, M1, superior motor cortex, insula, inferior frontal cortex, Heschl's gyrus, putamen, globus pallidus, and the superior temporal gyrus, were comparable to adults, suggesting that maturation of neurological control of swallowing has largely completed [
      • Hartnick C.J.
      • Rudolph C.
      • Willging J.P.
      • Holland S.K.
      Functional magnetic resonance imaging of the pediatric swallow: imaging the cortex and the brainstem.
      ].
      Taken together, these findings highlighted the importance of cerebral cortex for the development of swallowing from the gestation of the fetus to adolescent with much of this completed by mid-childhood.

      4. Clinical lesion studies in humans

      Numerous studies and clinical reports have demonstrated the impacts of cortical lesions on swallowing in humans. Based mainly on animal data, the early concept around the brain's role in swallowing was that there was bilateral hemispheric control. It was thus believed that lesions in the supratentorial regions must be bilateral to cause neurological disturbances of swallowing [
      • Meadows J.C.
      Dysphagia in unilateral cerebral lesions.
      ]. This belief was questioned by a clinical report of six cases of dysphagia associated with unilateral cerebral stroke [
      • Meadows J.C.
      Dysphagia in unilateral cerebral lesions.
      ]. This report began to change the conventional perception on the role of cerebral cortex in swallowing and triggered further investigation into the functions of supratentorial structures. Indeed, much of the recent advancements in neuroimaging technology allowing detailed investigation on the relationship between lesion characteristics, including location, lateralization and size, and dysphagia, has consolidated this contention. Here, we will first discuss the observations obtained from neuroanatomical data ensuing from clinical lesion studies.

      4.1 Lesion location and dysphagia

      It is now well-established that damage to the cerebral hemispheres, such as following cerebral vascular disease (CVA or stroke), can result in dysphagia [
      • Crary M.A.
      • Humphrey J.L.
      • Carnaby-Mann G.
      • Sambandam R.
      • Miller L.
      • Sillima S.
      Dysphagia, nutrition, and hydration in ischemic stroke patients at admission and discharge from acute care.
      ,
      • Daniels S.K.
      • Huckabee M.-L.
      Dysphagia Following Stroke.
      ]. The relationship between lesion location and dysphagia is of particular interest as it indirectly informs the roles of lesioned regions in swallowing, and it can potentially be used to predict the likelihood of dysphagia and its recovery. Given the relatively focal nature of ischemic infarction, studies on this relationship are predominantly based on retrospective review of the magnetic resonance imaging (MRI) and computerized topography (CT) scans of ischemic stroke patients. Although an early study by Albert et al., [
      • Alberts M.J.
      • Horner J.
      • Gray L.
      • Brazer S.R.
      Aspiration after stroke: lesion analysis by brain MRI.
      ] failed to identify significant relationship between lesion location and occurrence of aspiration in acute stroke patients, the majority of studies in the literature have reported significant correlations [
      • Daniels S.K.
      • Foundas A.L.
      Lesion localization in acute stroke patients with risk of aspiration.
      ,
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ,
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ,
      • Cola M.G.
      • Daniels S.K.
      • Corey D.M.
      • Lemen L.C.
      • Romero M.
      • Foundas A.L.
      Relevance of subcortical stroke in dysphagia.
      ,
      • Gonzalez-Fernandez M.
      • Kleinman J.T.
      • Ky P.K.S.
      • Palmer J.B.
      • Hillis A.E.
      Supratentorial regions of acute ischemia associated with clinically important swallowing disorders: a pilot study.
      ,
      • Im I.
      • Jun J.-P.
      • Hwang S.
      • Ko M.-H.
      Swallowing outcomes in patients with subcortical stroke associated with lesions of the caudate nucleus and insula.
      ,
      • Daniels S.K.
      • Foundas A.L.
      The role of the insular cortex in dysphagia.
      ,
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ,
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ] (Table 2).
      Table 2Relationship between lesion location and dysphagia symptoms.
      Lesion locationDysphagia symptomsReferences
      SupratentorialPrimary

      somatosensory cortex
      • Aspiration
      • Pharyngeal residue
      • Impaired swallowing response
      • Impaired cough reflex
      • Poor laryngeal vestibule closure
      [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ]
      Primary

      motor cortex
      • Aspiration
      • Pharyngeal residue
      • Impaired swallowing response
      • Impaired laryngeal elevation
      [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ]
      Limbic structure
      • Impaired cough reflex
      [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ]
      Insula
      • Elevated risk of aspiration
      • Prolonged pharyngeal transit time
      • Impaired laryngeal elevation
      • Impaired laryngeal vestibule closure
      • Prolonged risk of aspiration (with the presence of opercular lesion)
      [
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ,
      • Im I.
      • Jun J.-P.
      • Hwang S.
      • Ko M.-H.
      Swallowing outcomes in patients with subcortical stroke associated with lesions of the caudate nucleus and insula.
      ,
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ]
      Operculum
      • Elevated risk of aspiration
      • Prolonged risk of aspiration (with the presence of insular lesion)
      [
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ]
      Basal ganglia
      • Elevated risk of aspiration
      [
      • Daniels S.K.
      • Foundas A.L.
      Lesion localization in acute stroke patients with risk of aspiration.
      ,
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ]
      InfratentorialBrainstem
      • Impaired laryngeal elevation
      • Prolonged pharyngeal delay time
      [
      • Jeon W.H.
      • Park G.W.
      • Lee J.H.
      • Jeong H.J.
      • Sim Y.J.
      Association between location of brain lesion and clinical factors and findings of videofluoroscopic swallowing study in subacute stroke patients.
      ,
      • Daniels S.K.
      • Pathak S.
      • Mukhi S.V.
      • Stach C.B.
      • Morgan R.O.
      • Anderson J.A.
      The relationship between lesion localization and dysphagia in acute stroke.
      ]
      Cortical regions that have been found associated with dysphagia include, primary and secondary somatosensory and motor (SM1 and SM2) cortices, supplementary motor area, inferior frontal gyrus, anterior cingulate cortex, orbitofrontal cortex and supramarginal gyrus [
      • Daniels S.K.
      • Foundas A.L.
      Lesion localization in acute stroke patients with risk of aspiration.
      ,
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ,
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ]. Among these regions, lesions to the somatosensory and motor areas are most frequently identified and associated with dysphagia. However, the correlation between these regions and dysphagia is inconsistent across studies, potentially due to differences in analysis methods and patient characteristics. Daniels et al., [
      • Daniels S.K.
      • Foundas A.L.
      Lesion localization in acute stroke patients with risk of aspiration.
      ] found that lesions to the M1 were associated with higher risks of aspiration than lesions to the S1. The involvement of SM1 in swallowing is further suggested by a large study with 200 stroke patients [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ], which found that among several cortical and subcortical regions, the SM1 was associated with severe swallowing impairments. Studies have also attempted to correlate specific dysphagia symptoms with lesion location. Lesions to the SM1 and SM2 were associated with aspiration, residues, and delayed or missing swallowing response which increased the risk of aspiration, whereas sensory regions and limbic structures were associated with impaired cough reflex [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ]. More detailed spatial segmentation of the SM1 with fMRI showed that S1 lesions were related to impaired laryngeal vestibule closure and pharyngeal residues whereas M1 lesions were related to impaired laryngeal elevation [
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ].
      Apart from cortical lesions, other studies have reported relatively strong associations between dysphagia and deep brain lesions, including the insula, basal ganglia, corona radiata, thalamus, internal capsule, and periventricular white matters [
      • Daniels S.K.
      • Foundas A.L.
      Lesion localization in acute stroke patients with risk of aspiration.
      ,
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ,
      • Cola M.G.
      • Daniels S.K.
      • Corey D.M.
      • Lemen L.C.
      • Romero M.
      • Foundas A.L.
      Relevance of subcortical stroke in dysphagia.
      ,
      • Gonzalez-Fernandez M.
      • Kleinman J.T.
      • Ky P.K.S.
      • Palmer J.B.
      • Hillis A.E.
      Supratentorial regions of acute ischemia associated with clinically important swallowing disorders: a pilot study.
      ,
      • Im I.
      • Jun J.-P.
      • Hwang S.
      • Ko M.-H.
      Swallowing outcomes in patients with subcortical stroke associated with lesions of the caudate nucleus and insula.
      ,
      • Daniels S.K.
      • Foundas A.L.
      The role of the insular cortex in dysphagia.
      ,
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ,
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ]. Recent studies have suggested that subcortical lesions are associated with higher rate of dysphagia than cortical lesions [
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ]. Among all subcortical structures, the insula is the most consistently identified region to be associated with dysphagia. Daniels et al., [
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ] first reported that damage to the insular cortex is most common among the 16 stroke patients studied. In a further study with 4 patients with insular lesions, they found that all three patients with dysphagia had a lesion in the anterior insula, whereas the non-dysphagic patient had lesions restricted to the posterior region [
      • Daniels S.K.
      • Foundas A.L.
      The role of the insular cortex in dysphagia.
      ]. This finding suggests that the anterior portion of insula may be more important for swallowing than the posterior insula. Other studies also found that lesions to the insula and operculum were associated with elevated risk of aspiration [
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ] and that the association was strongest among all the supratentorial regions assessed [
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ]. Importantly, infarction of the frontal operculum in addition to insula increased the likelihood of extended risk of aspiration due to impaired recovery in the subacute phase [
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ]. However, a negative correlation between insula and dysphagia was reported by Gonzalez-Fernandez et al., [
      • Gonzalez-Fernandez M.
      • Kleinman J.T.
      • Ky P.K.S.
      • Palmer J.B.
      • Hillis A.E.
      Supratentorial regions of acute ischemia associated with clinically important swallowing disorders: a pilot study.
      ]. With respect to dysphagia symptoms, lesions to the insula are associated with prolonged pharyngeal transit time [
      • Im I.
      • Jun J.-P.
      • Hwang S.
      • Ko M.-H.
      Swallowing outcomes in patients with subcortical stroke associated with lesions of the caudate nucleus and insula.
      ], impaired laryngeal elevation and laryngeal vestibule closure [
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ].
      When comparing the likelihood of dysphagia between supratentorial and infratentorial lesions, Jeon et al., [
      • Jeon W.H.
      • Park G.W.
      • Lee J.H.
      • Jeong H.J.
      • Sim Y.J.
      Association between location of brain lesion and clinical factors and findings of videofluoroscopic swallowing study in subacute stroke patients.
      ] found that dysphagia was associated with brainstem lesions, but not with cortical or subcortical lesions. In particular, brainstem lesions are associated with pharyngeal phase dysfunction, including reduced laryngeal elevation and prolonged pharyngeal delay time. A similar relationship was reported by Daniels et al., [
      • Daniels S.K.
      • Pathak S.
      • Mukhi S.V.
      • Stach C.B.
      • Morgan R.O.
      • Anderson J.A.
      The relationship between lesion localization and dysphagia in acute stroke.
      ]. Using diffusion-weighted imaging, they revealed that lesions to the infratentorial structures are associated with more severe penetration and aspiration, whereas lesions to the supratentorial structures have no such association. However, these findings were challenged by a recent study which reported no association between dysphagia and infratentorial lesions [
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ].
      In summary, damage to supratentorial structures can result in dysphagia. However, the relationship between lesion location and dysphagia symptoms remains poorly defined. This is unsurprising given the distributed neural circuits related to swallowing, the likely compensation mechanisms that exist in preserving swallowing after brain injury and the variability in stroke manifestations. Nonetheless, understanding the impacts of lesions to these regions can provide insights into potential swallowing difficulties that may occur in patients prior to swallowing assessments.

      4.2 Side of lesion, hemisphere and dysphagia

      The effects of a unilaterally lesioned hemisphere have been the center of debate in studies of cerebral control of swallowing. Some studies have reported no association between the side of the lesioned hemisphere and dysphagia severity or characteristics [
      • Alberts M.J.
      • Horner J.
      • Gray L.
      • Brazer S.R.
      Aspiration after stroke: lesion analysis by brain MRI.
      ,
      • Daniels S.K.
      • Foundas A.L.
      Lesion localization in acute stroke patients with risk of aspiration.
      ,
      • Galovic M.
      • Leisi N.
      • Müller M.
      • Weber J.
      • Abela E.
      • Kägi G.
      • Weder B.
      Lesion location predicts transient and extended risk of aspiration after supratentorial ischemic stroke.
      ,
      • Jeon W.H.
      • Park G.W.
      • Lee J.H.
      • Jeong H.J.
      • Sim Y.J.
      Association between location of brain lesion and clinical factors and findings of videofluoroscopic swallowing study in subacute stroke patients.
      ,
      • Daniels S.K.
      • Pathak S.
      • Mukhi S.V.
      • Stach C.B.
      • Morgan R.O.
      • Anderson J.A.
      The relationship between lesion localization and dysphagia in acute stroke.
      ], while others have reported hemispheric bias [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ,
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ,
      • Robbins J.
      • Levine R.L.
      • Maser A.
      • Rosenbek J.C.
      • Kempster G.B.
      Swallowing after unilateral stroke of the cerebral cortex.
      ,
      • May N.H.
      • Pisegna J.M.
      • Marchina S.
      • Langmore S.E.
      • Kumar S.
      • Pearson Jr., W.G.
      Pharyngeal swallowing mechanics secondary to hemispheric stroke.
      ,
      • Wilmskoetter J.
      • Martin-Harris B.
      • Pearson Jr., W.G.
      • Bonilha L.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Differences in swallow physiology in patients with left and right hemispheric strokes.
      ]. Most of these studies report that right hemispheric lesions result in more severe dysphagia involving pharyngeal impairments [
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ,
      • Robbins J.
      • Levine R.L.
      • Maser A.
      • Rosenbek J.C.
      • Kempster G.B.
      Swallowing after unilateral stroke of the cerebral cortex.
      ,
      • May N.H.
      • Pisegna J.M.
      • Marchina S.
      • Langmore S.E.
      • Kumar S.
      • Pearson Jr., W.G.
      Pharyngeal swallowing mechanics secondary to hemispheric stroke.
      ]. The symptoms associated with right hemispheric lesions include altered swallowing mechanics characterized by prominent pharyngeal dysmotility and reduced hyolaryngeal elevation [
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ,
      • May N.H.
      • Pisegna J.M.
      • Marchina S.
      • Langmore S.E.
      • Kumar S.
      • Pearson Jr., W.G.
      Pharyngeal swallowing mechanics secondary to hemispheric stroke.
      ], prolonged pharyngeal events [
      • Robbins J.
      • Levine R.L.
      • Maser A.
      • Rosenbek J.C.
      • Kempster G.B.
      Swallowing after unilateral stroke of the cerebral cortex.
      ], increased pharyngeal residue, impaired swallow response, increased risk of aspiration [
      • Suntrup S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.
      ,
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ,
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Robbins J.
      • Levine R.L.
      • Maser A.
      • Rosenbek J.C.
      • Kempster G.B.
      Swallowing after unilateral stroke of the cerebral cortex.
      ,
      • Wilmskoetter J.
      • Martin-Harris B.
      • Pearson Jr., W.G.
      • Bonilha L.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Differences in swallow physiology in patients with left and right hemispheric strokes.
      ]. Moreover, Li et al., [
      • Li S.
      • Luo C.
      • Yu B.
      • Yan B.
      • Gong Q.
      • He C.
      • He L.
      • et al.
      Functional magnetic resonance imaging study on dysphagia after unilateral hemispheric stroke: a preliminary study.
      ] reported that right hemispheric lesions were associated with pharyngeal dysfunction whereas left hemispheric lesions were associated with oral dysfunction. It should be noted that while these associations are significant at group level, inconsistency has been reported across individuals [
      • Wilmskoetter J.
      • Bonilha L.
      • Martin-Harris B.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Mapping acute lesion locations to physiological swallow impairments after stroke.
      ,
      • Wilmskoetter J.
      • Martin-Harris B.
      • Pearson Jr., W.G.
      • Bonilha L.
      • Elm J.J.
      • Horn J.
      • Bonilha H.S.
      Differences in swallow physiology in patients with left and right hemispheric strokes.
      ].
      Other studies suggested that the effect of hemisphere is region-specific, such that lesions to certain structures in the left hemisphere may be more strongly associated with dysphagia than in the right or vice versa [
      • Suntrup-Krueger S.
      • Kemmling A.
      • Warnecke T.
      • Hamacher C.
      • Oelenberg S.
      • Niederstadt T.
      • Heindel W.
      • Wiendl H.
      • Dziewas R.
      The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.
      ,
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ]. For example, Cola et al., [
      • Cola M.G.
      • Daniels S.K.
      • Corey D.M.
      • Lemen L.C.
      • Romero M.
      • Foundas A.L.
      Relevance of subcortical stroke in dysphagia.
      ] found that left hemispheric lesions in periventricular white matter was associated with dysphagia but right hemispheric lesions were not. Therefore, given the inconsistencies in reported effects of sidedness for each hemisphere, it remains difficult to draw any definitive conclusions on the relationship between lesion laterality and dysphagia.

      4.3 Lesion size and dysphagia

      Compared to lesion location and hemisphere, fewer studies have investigated the relationship between lesion size and dysphagia severity. Similar to the other two stroke characteristics, the reported relationship is mixed, with both positive [
      • Power M.L.
      • Hamdy S.
      • Singh S.
      • Tyrrell P.J.
      • Turnbull I.
      • Thompson D.G.
      Deglutitive laryngeal closure in stroke patients.
      ,
      • Lee S.Y.
      • Han S.H.
      Relationship between subcortical hemorrhage size and characteristics of dysphagia.
      ] and negative [
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ,
      • Daniels S.K.
      • Foundas A.L.
      • Iglesia G.C.
      • Sullivan M.A.
      Lesion site in unilateral stroke patients with dysphagia.
      ,
      • Mihai P.G.
      • Otto M.
      • Domin M.
      • Platz T.
      • Hamdy S.
      • Lotze M.
      Brain imaging correlates of recovered swallowing after dysphagic stroke: A fMRI and DWI study.
      ] findings. A recent study by Hess et al., [
      • Hess F.
      • Foerch C.
      • Keil F.
      • Seiler A.
      • Lapa S.
      Association of lesion pattern and dysphagia in acute intracerebral hemorrhage.
      ] found that the size of hemorrhage is independent of risk of dysphagia as small lesions in the subcortical area could result in substantial dysphagia. By contrast, Lee et al., [
      • Lee S.Y.
      • Han S.H.
      Relationship between subcortical hemorrhage size and characteristics of dysphagia.
      ] found that the hemorrhage size in patients with subcortical stroke is positively correlated with the severity of dysphagia. Several indicators of dysphagia, including, presence of tracheostomy, inadequate lip sealing, tongue protrusion and/or laryngeal elevation, and absence of reflex coughing, were found to be correlated with the size of hemorrhage. Another study by Power et al., [
      • Power M.L.
      • Hamdy S.
      • Singh S.
      • Tyrrell P.J.
      • Turnbull I.
      • Thompson D.G.
      Deglutitive laryngeal closure in stroke patients.
      ] showed that patients who aspirate had larger stroke lesion volume than those who did not aspirate. Although these data did not show definitive relationship between size and dysphagia severity, those positive findings suggest that lesion size may be associated with certain dysphagia symptoms, and such relationship should not be overlooked.

      5. Neurophysiologic and functional imaging of the cerebral cortex for swallowing in healthy humans

      The structure of the human cerebral cortex was first studied in the mid-19th century and the most notable work was done by Korbinian Brodmann who classified the human brain into 52 discrete areas based on its cytoarchitectonic features [
      • Brodmann K.
      Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues.
      ,
      • Strotzer M.
      One century of brain mapping using Brodmann areas.
      ]. Since then, the functional organization of human cerebral cortex was initially investigated using direct electrical stimulation during open brain surgery [
      • Penfield W.
      • Boldrey E.
      Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation.
      ]. Penfield and Boldrey [
      • Penfield W.
      • Boldrey E.
      Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation.
      ] first reported findings from systematically mapping of cortical areas during neurosurgery in over 120 cases. They showed that electrical stimulation of anterolateral M1 could induce rhythmic swallowing movements. This type of study is invasive and can only be done when there is a justified medical need for brain mapping. With the introduction of transcranial magnetic stimulation (TMS) in 1985 [
      • Barker A.T.
      • Jalinous R.
      • Freeston I.L.
      Non-invasive magnetic stimulation of human motor cortex.
      ], mapping studies of the human brain have become more amenable. TMS is a non-invasive brain stimulation technique that induces electric current within the brain through electromagnetic induction [
      • Pascual-Leone A.
      • Tormos J.M.
      • Keenan J.
      • Tarazona F.
      • Cañete C.
      • Catalá M.D.
      Study and modulation of human cortical excitability with transcranial magnetic stimulation.
      ]. When applied over the motor cortex, TMS can trigger electromyographic (EMG) responses, termed motor evoked potential (MEP), in the corresponding muscles [
      • Pascual-Leone A.
      • Tormos J.M.
      • Keenan J.
      • Tarazona F.
      • Cañete C.
      • Catalá M.D.
      Study and modulation of human cortical excitability with transcranial magnetic stimulation.
      ]. Different characteristics of MEP, such as amplitude, latency, or intracortical inhibition, can inform different properties of the central nervous system, hence it has been used extensively to study human motor neurophysiology pathways [
      • Pascual-Leone A.
      • Tormos J.M.
      • Keenan J.
      • Tarazona F.
      • Cañete C.
      • Catalá M.D.
      Study and modulation of human cortical excitability with transcranial magnetic stimulation.
      ,
      • Rothwell J.
      • Day B.L.
      • Thompson P.D.
      • Kujirai T.
      Short latency intracortical inhibition: one of the most popular tools in human motor neurophysiology.
      ]. Using TMS, Aziz et al., [
      • Aziz Q.
      • Furlong P.L.
      • Barlow J.
      • Hobson A.
      • Alani S.
      • Bancewicz J.
      • Ribbands M.
      • Harding G.F.A.
      • Thompson D.G.
      Topographic mapping of cortical potentials evoked by distension of the human proximal and distal oesophagus.
      ] found that stimulation of the face-associated area of the M1 or vagal cranial nerve could elicit early and late EMG responses from esophageal muscles. The early responses were thought to result from direct stimulation of motor fibers whereas the late responses were likely mediated by polysynaptic extrapyramidal pathways that were involved in swallowing control [
      • Aziz Q.
      • Furlong P.L.
      • Barlow J.
      • Hobson A.
      • Alani S.
      • Bancewicz J.
      • Ribbands M.
      • Harding G.F.A.
      • Thompson D.G.
      Topographic mapping of cortical potentials evoked by distension of the human proximal and distal oesophagus.
      ]. A further study by Hamdy et al., [
      • Hamdy S.
      • Aziz Q.
      • Rothwell J.C.
      • Singh K.D.
      • Barlow J.
      • Hughes D.G.
      • Tallis R.C.
      • Thompson D.G.
      The cortical topography of human swallowing musculature in health and disease.
      ] demonstrated that cortical representation of mylohyoid, pharynx and esophagus were organized somatotopically in the motor and premotor cortex. Specifically, mylohyoid muscles are represented in the lateral precentral and inferior frontal gyri, pharyngeal muscles are represented in the anterolateral precentral and middle frontal gyri and esophageal muscles are represented in the anterolateral precentral and superior frontal gyri [
      • Hamdy S.
      • Aziz Q.
      • Rothwell J.C.
      • Singh K.D.
      • Barlow J.
      • Hughes D.G.
      • Tallis R.C.
      • Thompson D.G.
      The cortical topography of human swallowing musculature in health and disease.
      ].
      Functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetoencephalography (MEG), functional near-infrared spectroscopy (fNIRS), electroencephalogram (EEG) and electrocorticography (ECoG) are functional neuroimaging/ neuromapping techniques that have been used to study cortical activation during swallowing. Each of these techniques has its own unique advantages and disadvantages, such that their findings can be complementary. FMRI measures changes in cerebral blood oxygenation which reflects the underlying neural activity during tasks [
      • Logothetis N.K.
      • Pauls J.
      • Augath M.
      • Trinath T.
      • Oeltermann A.
      Neurophysiological investigation of the basis of the fMRI signal.
      ]. It has good spatial resolution of 3-4 mm but relatively low temporal resolution (seconds) [
      • Glover G.H.
      Overview of functional magnetic resonance imaging.
      ]. PET detects radioactive tracers such as carbon-11, oxygen-15, nitrogen-13, and fluorine-18 within the region of interest [
      • Ziegler S.I.
      Positron emission tomography: principles, technology, and recent developments.
      ]. It has lower spatial (5-10 mm) and temporal (minutes) resolution than fMRI but it is useful for imaging the subcortical structures [
      • Glover G.H.
      Overview of functional magnetic resonance imaging.
      ]. MEG detects changes in electrical current induced by the varying neuromagnetic field related to brain (mainly cortex) activation [
      • Glover G.H.
      Overview of functional magnetic resonance imaging.
      ,
      • Lewine J.D.
      • Orrison W.
      Magnetoencephalography and magnetic source imaging.
      ]. The spatial resolution of MEG is limited to 10-20 mm, but it has excellent temporal resolution (milliseconds) [
      • Glover G.H.
      Overview of functional magnetic resonance imaging.
      ,
      • Lewine J.D.
      • Orrison W.
      Magnetoencephalography and magnetic source imaging.
      ]. FNIRS measures changes in the concentration of oxygenated and deoxygenated hemoglobin molecules in the blood within the brain, but the measurement is restricted to the cortex due to limited probing depth (3 cm) [
      • León-Carrión J.
      • León-Domínguez U.
      Functional near-infrared spectroscopy (fNIRS): principles and neuroscientific applications.
      ]. It has low spatial (10-20 mm) and temporal (seconds) resolutions, but it is more portable compared to fMRI, allowing flexibility in studying various swallowing protocols [
      • Glover G.H.
      Overview of functional magnetic resonance imaging.
      ]. Recently, researchers have explored the use of EEG and ECoG in detecting swallowing-related cortical activations and reported encouraging findings [
      • Koganemaru S.
      • Mizuno F.
      • Takahashi T.
      • Takemura Y.
      • Irisawa H.
      • Matsuhashi M.
      • Mima T.
      • Mizushima T.
      • Kansaku K.
      Event-related desynchronization and corticomuscular coherence observed during volitional swallow by electroencephalography recordings in humans.
      ,
      • Hashimoto H.
      • Takahashi K.
      • Kameda S.
      • Yoshida F.
      • Maezawa H.
      • Oshino S.
      • Tani N.
      • et al.
      Motor and sensory cortical processing of neural oscillatory activities revealed by human swallowing using intracranial electrodes.
      ,
      • Cuellar M.
      • Harkrider A.W.
      • Jenson D.
      • Thornton D.
      • Bowers A.
      • Saltuklaroglu T.
      Time–frequency analysis of the EEG mu rhythm as a measure of sensorimotor integration in the later stages of swallowing.
      ]. EEG measures brain electrical activity through scalp electrodes. Similar to MEG, although EEG has poor spatial resolution, it offers excellent temporal resolution (1–5 milliseconds), making it a suitable candidate for measuring timing-related neural activity [
      • Gevins A.
      • Smith M.E.
      • McEvoy L.K.
      EEG and ERP imaging of brain function.
      ]. Finally, ECoG measures cortical electrical potentials directly from the exposed brain. Although invasive in nature, ECoG offers better spatial and temporal resolution compared to EEG [
      • Keene D.
      • Whiting S.
      • Ventureyra E.
      Electrocorticography.
      ].
      The imaging protocols used in functional neuroimaging studies have been diverse and increasingly complex. Early studies tended to only investigate cortical activation during two conditions, swallow versus rest [
      • Hamdy S.
      • Mikulis D.J.
      • Crawley A.
      • Xue S.
      • Lau H.
      • Henry S.
      • Diamant N.E.
      Cortical activation during human volitional swallowing: an event-related fMRI study.
      ,
      • Hamdy S.
      • Rothwell J.C.
      • Brooks D.J.
      • Bailey D.
      • Aziz Q.
      • Thompson D.G.
      Identification of the cerebral loci processing human swallowing with H-2 O-15 PET activation.
      ,
      • Abe S.
      • Wantanabe Y.
      • Shintani M.
      • Tazaki M.
      • Takahashi M.
      • Yamane G.-Y.
      • Ide Y.
      • Yamada Y.
      • Shimono M.
      • Ishikawa T.
      Magnetoencephalographic study of the starting point of voluntary swallowing.
      ,
      • Suzuki M.
      • Asada Y.
      • Ito J.
      • Hayashi K.
      • Inoue H.
      • Kitano H.
      Activation of cerebellum and basal ganglia on volitional swallowing detected by functional magnetic resonance imaging.
      ,
      • Watanabe Y.
      • Abe S.
      • Ishikawa T.
      • Yamada Y.
      • Yamane G.-Y.
      Cortical regulation during the early stage of initiation of voluntary swallowing in humans.
      ,
      • Toogood J.A.
      • Barr A.M.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      • Martin R.E.
      Discrete functional contributions of cerebral cortical foci in voluntary swallowing: a functional magnetic resonance imaging (fMRI) “Go, No-Go” study.
      ,
      • Toogood J.A.
      • Smith R.C.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      • Theurer J.
      • Weisz S.
      • Affoo R.H.
      • Martin R.E.
      Swallowing preparation and execution: insights from a delayed-response functional magnetic resonance imaging (fMRI) study.
      ,
      • Paine T.L.
      • Conway C.A.
      • Malandraki G.A.
      • Sutton B.P.
      Simultaneous dynamic and functional MRI scanning (SimulScan) of natural swallows.
      ,
      • Babaei A.
      • Ward B.D.
      • Siwiec R.M.
      • Ahmad S.
      • Kern M.
      • Nencka A.
      • Li S.-J.
      • Shaker R.
      Functional connectivity of the cortical swallowing network in humans.
      ,
      • Inamoto K.
      • Sakuma S.
      • Ariji Y.
      • Higuchi N.
      • Izumi M.
      • Nakata K.
      Measurement of cerebral blood volume dynamics during volitional swallowing using functional near-infrared spectroscopy: an exploratory study.
      ,
      • Kamarunas E.
      • Mulheren R.
      • Palmore K.
      • Ludlow C.
      Timing of cortical activation during spontaneous swallowing.
      ]. More recent studies have attempted to explore activations during saliva swallow versus water swallow [
      • Mosier K.
      • Liu W.-C.
      • Maldjian J.A.
      • Shah R.
      • Modi B.
      Lateralization of cortical function in swallowing: a functional MR imaging study.
      ,
      • Martin R.E.
      • Goodyear B.G.
      • Gati J.S.
      • Menon R.S.
      Cerebral cortical representation of automatic and volitional swallowing in humans.
      ,
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ], oral and jaw muscles movement versus swallow [
      • Zald D.H.
      • Pardo J.V.
      The functional neuroanatomy of voluntary swallowing.
      ,
      • Kern M.
      • Birn R.
      • Jaradeh S.
      • Jesmanowicz A.
      • Cox R.
      • Hyde J.
      • Shaker R.
      Swallow-related cerebral cortical activity maps are not specific to deglutition.
      ,
      • Furlong P.L.
      • Hobson A.R.
      • Aziz Q.
      • Barnes G.R.
      • Singh K.D.
      • Hillebrand A.
      • Thompson D.G.
      • Hamdy S.
      Dissociating the spatio-temporal characteristics of cortical neuronal activity associated with human volitional swallowing in the healthy adult brain.
      ,
      • Malandraki G.A.
      • Sutton B.P.
      • Perlman A.L.
      • Karampinos D.C.
      • Conway C.
      Neural activation of swallowing and swallowing-related tasks in healthy young adults: an attempt to separate the components of deglutition.
      ,
      • Mihai P.G.
      • von Bohlen Und Halbach O.
      • Lotze M.
      Differentiation of cerebral representation of occlusion and swallowing with fMRI.
      ], swallowing imagery versus swallow execution [
      • Kober S.E.
      • Bauernfeind G.
      • Woller C.
      • Sampl M.
      • Grieshofer P.
      • Neuper C.
      • Wood G.
      Hemodynamic signal changes accompanying execution and imagery of swallowing in patients with dysphagia: a multiple single-case near-infrared spectroscopy study.
      ,
      • Kober S.E.
      • Grossinger D.
      • Wood G.
      Effects of motor imagery and visual neurofeedback on activation in the swallowing network: a real-time fMRI study.
      ,
      • Kober S.R.
      • Wood G.
      Changes in hemodynamic signals accompanying motor imagery and motor execution of swallowing: a near-infrared spectroscopy study.
      ], swallow versus oral stimulation (or anesthesia) [
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ,
      • Teismann I.K.
      • Steinstraeter O.
      • Stoeckigt K.
      • Suntrup S.
      • Wollbrink A.
      • Pantev C.
      • Dziewas R.
      Functional oropharyngeal sensory disruption interferes with the cortical control of swallowing.
      ], as well as voluntary versus reflexive swallowing [
      • Kern M.
      • Birn R.
      • Jaradeh S.
      • Jesmanowicz A.
      • Cox R.
      • Hyde J.
      • Shaker R.
      Swallow-related cerebral cortical activity maps are not specific to deglutition.
      ,
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ,
      • Dziewas R.
      • Sörös P.
      • Ishii R.
      • Chau W.
      • Henningsen H.
      • Ringelstein E.B.
      • Knecht S.
      • Pantev C.
      Neuroimaging evidence for cortical involvement in the preparation and in the act of swallowing.
      ].
      Despite the diversity in imaging techniques and protocols, studies have collectively shown that swallowing, whether reflexive or volitional, is represented in spatially and functionally distinct cortical and subcortical foci. The areas that have been reported to be activated during swallowing include (in descending order of occurrence in studies): M1, S1, insula, cingulate cortex, supplementary motor area, premotor cortex, auditory cortex, inferior frontal gyrus, parietooccipital and prefrontal cortex, operculum, putamen, thalamus, global pallidus, internal capsule, cerebellum, corpus callosum, basal ganglia, caudate, pons and midbrain, inferior parietal lobule [
      • Hartnick C.J.
      • Rudolph C.
      • Willging J.P.
      • Holland S.K.
      Functional magnetic resonance imaging of the pediatric swallow: imaging the cortex and the brainstem.
      ,
      • Li S.
      • Luo C.
      • Yu B.
      • Yan B.
      • Gong Q.
      • He C.
      • He L.
      • et al.
      Functional magnetic resonance imaging study on dysphagia after unilateral hemispheric stroke: a preliminary study.
      ,
      • Hamdy S.
      • Mikulis D.J.
      • Crawley A.
      • Xue S.
      • Lau H.
      • Henry S.
      • Diamant N.E.
      Cortical activation during human volitional swallowing: an event-related fMRI study.
      ,
      • Hamdy S.
      • Rothwell J.C.
      • Brooks D.J.
      • Bailey D.
      • Aziz Q.
      • Thompson D.G.
      Identification of the cerebral loci processing human swallowing with H-2 O-15 PET activation.
      ,
      • Abe S.
      • Wantanabe Y.
      • Shintani M.
      • Tazaki M.
      • Takahashi M.
      • Yamane G.-Y.
      • Ide Y.
      • Yamada Y.
      • Shimono M.
      • Ishikawa T.
      Magnetoencephalographic study of the starting point of voluntary swallowing.
      ,
      • Suzuki M.
      • Asada Y.
      • Ito J.
      • Hayashi K.
      • Inoue H.
      • Kitano H.
      Activation of cerebellum and basal ganglia on volitional swallowing detected by functional magnetic resonance imaging.
      ,
      • Toogood J.A.
      • Barr A.M.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      • Martin R.E.
      Discrete functional contributions of cerebral cortical foci in voluntary swallowing: a functional magnetic resonance imaging (fMRI) “Go, No-Go” study.
      ,
      • Toogood J.A.
      • Smith R.C.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      • Theurer J.
      • Weisz S.
      • Affoo R.H.
      • Martin R.E.
      Swallowing preparation and execution: insights from a delayed-response functional magnetic resonance imaging (fMRI) study.
      ,
      • Paine T.L.
      • Conway C.A.
      • Malandraki G.A.
      • Sutton B.P.
      Simultaneous dynamic and functional MRI scanning (SimulScan) of natural swallows.
      ,
      • Babaei A.
      • Ward B.D.
      • Siwiec R.M.
      • Ahmad S.
      • Kern M.
      • Nencka A.
      • Li S.-J.
      • Shaker R.
      Functional connectivity of the cortical swallowing network in humans.
      ,
      • Inamoto K.
      • Sakuma S.
      • Ariji Y.
      • Higuchi N.
      • Izumi M.
      • Nakata K.
      Measurement of cerebral blood volume dynamics during volitional swallowing using functional near-infrared spectroscopy: an exploratory study.
      ,
      • Kamarunas E.
      • Mulheren R.
      • Palmore K.
      • Ludlow C.
      Timing of cortical activation during spontaneous swallowing.
      ,
      • Mosier K.
      • Liu W.-C.
      • Maldjian J.A.
      • Shah R.
      • Modi B.
      Lateralization of cortical function in swallowing: a functional MR imaging study.
      ,
      • Martin R.E.
      • Goodyear B.G.
      • Gati J.S.
      • Menon R.S.
      Cerebral cortical representation of automatic and volitional swallowing in humans.
      ,
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ,
      • Zald D.H.
      • Pardo J.V.
      The functional neuroanatomy of voluntary swallowing.
      ,
      • Kern M.
      • Birn R.
      • Jaradeh S.
      • Jesmanowicz A.
      • Cox R.
      • Hyde J.
      • Shaker R.
      Swallow-related cerebral cortical activity maps are not specific to deglutition.
      ,
      • Furlong P.L.
      • Hobson A.R.
      • Aziz Q.
      • Barnes G.R.
      • Singh K.D.
      • Hillebrand A.
      • Thompson D.G.
      • Hamdy S.
      Dissociating the spatio-temporal characteristics of cortical neuronal activity associated with human volitional swallowing in the healthy adult brain.
      ,
      • Malandraki G.A.
      • Sutton B.P.
      • Perlman A.L.
      • Karampinos D.C.
      • Conway C.
      Neural activation of swallowing and swallowing-related tasks in healthy young adults: an attempt to separate the components of deglutition.
      ,
      • Mihai P.G.
      • von Bohlen Und Halbach O.
      • Lotze M.
      Differentiation of cerebral representation of occlusion and swallowing with fMRI.
      ,
      • Kober S.E.
      • Grossinger D.
      • Wood G.
      Effects of motor imagery and visual neurofeedback on activation in the swallowing network: a real-time fMRI study.
      ,
      • Kober S.R.
      • Wood G.
      Changes in hemodynamic signals accompanying motor imagery and motor execution of swallowing: a near-infrared spectroscopy study.
      ,
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ,
      • Teismann I.K.
      • Steinstraeter O.
      • Stoeckigt K.
      • Suntrup S.
      • Wollbrink A.
      • Pantev C.
      • Dziewas R.
      Functional oropharyngeal sensory disruption interferes with the cortical control of swallowing.
      ,
      • Dziewas R.
      • Sörös P.
      • Ishii R.
      • Chau W.
      • Henningsen H.
      • Ringelstein E.B.
      • Knecht S.
      • Pantev C.
      Neuroimaging evidence for cortical involvement in the preparation and in the act of swallowing.
      ,
      • Kern M.K.
      • et al.
      Cerebral cortical representation of reflexive and volitional swallowing in humans.
      ,
      • Martin R.E.
      • MacIntosh B.J.
      • Smith R.C.
      • Barr A.M.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      Cerebral areas processing swallowing and tongue movement are overlapping but distinct: a functional magnetic resonance imaging study.
      ,
      • Mosier K.
      • Patel R.
      • Liu W.-C.
      • Kalnin A.
      • Maldjian J.
      • Baredes S.
      Cortical representation of swallowing in normal adults: functional implications.
      ,
      • Peck K.K.
      • Branski R.C.
      • Lazarus C.
      • Cody V.
      • Kraus D.
      • Haupage S.
      • Ganz C.
      • Holodny A.I.
      • Kraus D.H.
      Cortical activation during swallowing rehabilitation maneuvers: a functional MRI study of healthy controls.
      ,
      • Satow T.
      • Ikeda A.
      • Yamamoto J.-I.
      • Begum T.
      • Thuy D.
      • Matsuhashi M.
      • Mima T.
      • et al.
      Role of primary sensorimotor cortex and supplementary motor area in volitional swallowing: a movement-related cortical potential study.
      ,
      • Yuan X.-D.
      • Zhou L.
      • Wang S.
      • Zhao Y.
      • Wang X.
      • Zhang L.
      • Wang S.
      • Zhang Y.
      • Chen L.
      Compensatory recombination phenomena of neurological functions in central dysphagia patients.
      ] (Fig. 1). Most of these regions have been identified in lesion studies. Interestingly, motor imagery of swallowing appears to activate similar regions as swallowing execution [
      • Kober S.R.
      • Wood G.
      Changes in hemodynamic signals accompanying motor imagery and motor execution of swallowing: a near-infrared spectroscopy study.
      ]. The following discussion will not cover all brain regions purported to have been involved in swallowing control but focuses on the most consistently reported (> 50% of all studies; Fig. 1) regions, including M1, S1, insula, cingulate cortex and basal ganglia. Table 3 presents a summary of findings from neuroimaging and neurophysiology studies on the involvement of these areas during swallowing.
      Fig. 1
      Fig. 1Summary of cerebral regions found to be activated during swallowing. The percentage represents the frequency of occurrence across 30 functional neuroimaging studies.
      Table 3Summary of findings from neuroimaging and neurophysiology studies in healthy humans on the involvement of sensorimotor cortex, insula, frontal operculum, cingulate cortex and basal ganglia during swallowing.
      Brain regionsNeuroimaging / neurophysiology techniqueStimulation / swallowing taskMain findingsProposed roles in swallowingReference
      SM1fMRIAir-pulse stimulation of posterior oral area

      Volitional saliva swallow

      Imaginary swallow
      Increased activation

      Larger activation during volitional saliva swallow than imaginary swallow
      M1 and S1 may function in synchrony[
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ]
      MEGVolitional water swallow

      Oral anaesthesia
      Increased activation during oral stimulation

      Reduced activation after anaesthesia
      [
      • Teismann I.K.
      • Steinstraeter O.
      • Stoeckigt K.
      • Suntrup S.
      • Wollbrink A.
      • Pantev C.
      • Dziewas R.
      Functional oropharyngeal sensory disruption interferes with the cortical control of swallowing.
      ]
      M1fMRIAutomated saliva swallow

      Volitional saliva swallow

      Volitional water swallow
      Increased activation during swallowingInitiation and execution of swallowing[
      • Hamdy S.
      • Mikulis D.J.
      • Crawley A.
      • Xue S.
      • Lau H.
      • Henry S.
      • Diamant N.E.
      Cortical activation during human volitional swallowing: an event-related fMRI study.
      ,
      • Martin R.E.
      • Goodyear B.G.
      • Gati J.S.
      • Menon R.S.
      Cerebral cortical representation of automatic and volitional swallowing in humans.
      ,
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ,
      • Malandraki G.A.
      • Sutton B.P.
      • Perlman A.L.
      • Karampinos D.C.
      • Conway C.
      Neural activation of swallowing and swallowing-related tasks in healthy young adults: an attempt to separate the components of deglutition.
      ,
      • Mosier K.
      • Patel R.
      • Liu W.-C.
      • Kalnin A.
      • Maldjian J.
      • Baredes S.
      Cortical representation of swallowing in normal adults: functional implications.
      ]
      PETVolitional water swallowIncreased activation during swallowing[
      • Hamdy S.
      • Rothwell J.C.
      • Brooks D.J.
      • Bailey D.
      • Aziz Q.
      • Thompson D.G.
      Identification of the cerebral loci processing human swallowing with H-2 O-15 PET activation.
      ]
      TMSCortical mapping:

      Elicits EMG responses by stimulating M1
      Mylohyoid: lateral M1 and inferior frontal gyrus

      Pharynx: anterolateral M1 and middle frontal gyrus

      Esophagus: anterolateral M1 and superior frontal gyrus
      [
      • Aziz Q.
      • Furlong P.L.
      • Barlow J.
      • Hobson A.
      • Alani S.
      • Bancewicz J.
      • Ribbands M.
      • Harding G.F.A.
      • Thompson D.G.
      Topographic mapping of cortical potentials evoked by distension of the human proximal and distal oesophagus.
      ,
      • Hamdy S.
      • Aziz Q.
      • Rothwell J.C.
      • Singh K.D.
      • Barlow J.
      • Hughes D.G.
      • Tallis R.C.
      • Thompson D.G.
      The cortical topography of human swallowing musculature in health and disease.
      ]
      Direct electrical stimulation during open-skull surgeryElicits rhythmic swallowing[
      • Penfield W.
      • Boldrey E.
      Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation.
      ]
      “Virtual lesion” of pharyngeal M1 induced by 1 Hz rTMSDecreased oral transit time, increased swallow response time and reduced swallowing accuracy[
      • Verin E.
      • Michou E.
      • Leroi A.-M.
      • Hamdy S.
      • Marie J.-P.
      "Virtual" lesioning of the human oropharyngeal motor cortex: a videofluoroscopic study.
      ,
      • Mistry S.
      • Verin E.
      • Singh S.
      • Jefferson S.
      • Rothwell J.C.
      • Thompson D.G.
      • Hamdy S.
      Unilateral suppression of pharyngeal motor cortex to repetitive transcranial magnetic stimulation reveals functional asymmetry in the hemispheric projections to human swallowing.
      ]
      S1fMRIPleasant and unpleasant taste stimulationIncreased activation of inferior S1Processing of sensory information during swallowing[
      • Faurion A.
      • Cerf B.
      • Le Bihan D.
      • Pilliasa A.-M.
      fMRI study of taste cortical areas in humans.
      ]
      fMRIRetention of room temperature water in oral cavityIncreased activation[
      • Furlong P.L.
      • Hobson A.R.
      • Aziz Q.
      • Barnes G.R.
      • Singh K.D.
      • Hillebrand A.
      • Thompson D.G.
      • Hamdy S.
      Dissociating the spatio-temporal characteristics of cortical neuronal activity associated with human volitional swallowing in the healthy adult brain.
      ,
      • Zald D.H.
      • Pardo J.V.
      Cortical activation induced by intraoral stimulation with water in humans.
      ]
      fMRI, MEGAir-pulse stimulation of posterior oral area, laryngeal mucosaIncreased activation[
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ,
      • Soros P.
      • Lalone E.
      • Smith R.
      • Stevens T.
      • Theurer J.
      • Menon R.S.
      • Martin R.E.
      Functional MRI of oropharyngeal air-pulse stimulation.
      ,
      • Miyaji H.
      • Hironaga N.
      • Umezaki T.
      • Hagiwara K.
      • Shigeto H.
      • Sawatsubashi M.
      • Tobimatsu S.
      • Komune S.
      Neuromagnetic detection of the laryngeal area: sensory-evoked fields to air-puff stimulation.
      ]
      MEGElectrical stimulation of pharyngeal mucosaIncreased activation[
      • Gow D.
      • Hobson A.R.
      • Furlong P.
      • Hamdy S.
      Characterising the central mechanisms of sensory modulation in human swallowing motor cortex.
      ]
      PETBalloon distention of lower esophagusIncreased activation, increase further with painful stimulation[
      • Aziz Q.
      • Andersson J.L.
      • Valind S.
      • Sundin A.
      • Hamdy S.
      • Jones A.K.
      • Foster E.R.
      • Langstrom B.
      • Thompson D.G.
      Identification of human brain loci processing esophageal sensation using positron emission tomography.
      ]
      Insula and frontal operculumPET, fMRI, MEGGustatory stimulationIncreased activationProcessing and perception of taste information (Taste centre)



      Initiation of swallowing
      [
      • Faurion A.
      • Cerf B.
      • Le Bihan D.
      • Pilliasa A.-M.
      fMRI study of taste cortical areas in humans.
      ,
      • Kinomura S.
      • Kawashima R.
      • Yamada K.
      • Ono S.
      • Itoh M.
      • Yoshioka S.
      • Yamaguchi T.
      • et al.
      Functional anatomy of taste perception in the human brain studied with positron emission tomography.
      ,
      • Zald D.H.
      • Lee J.T.
      • Fluegel K.W.
      • Pardo J.V.
      Aversive gustatory stimulation activates limbic circuits in humans.
      ,
      • Small D.M.
      • M. J.-G
      • Zatorre R.J.
      • Petrides M.
      • Evans A.C.
      Flavor processing: more than the sum of its parts.
      ,
      • Francis S.
      • Rolls E.T.
      • Bowtell R.
      • McGlone F.
      • O'Doherty J.
      • Browning A.
      • Clare S.
      • Smith E.
      The representation of pleasant touch in the brain and its relationship with taste and olfactory areas.
      ,
      • Kobayakawa T.
      • Endo H.
      • Ayabe-Kanamura S.
      • Kumagai T.
      • Yamaguchi Y.
      • Kikuchi Y.
      • Takeda T.
      • Saito S.
      • Ogawa H.
      The primary gustatory area in human cerebral cortex studied by magnetoencephalography.
      ]
      PETBalloon distention of lower esophagusIncreased activation during both painful and non-painful stimulation[
      • Aziz Q.
      • Andersson J.L.
      • Valind S.
      • Sundin A.
      • Hamdy S.
      • Jones A.K.
      • Foster E.R.
      • Langstrom B.
      • Thompson D.G.
      Identification of human brain loci processing esophageal sensation using positron emission tomography.
      ]
      MEGVolitional water swallowIncreased activation before swallowing[
      • Watanabe Y.
      • Abe S.
      • Ishikawa T.
      • Yamada Y.
      • Yamane G.-Y.
      Cortical regulation during the early stage of initiation of voluntary swallowing in humans.
      ]
      Electrical stimulation of right inferior posterior insula using deep electrodesDelayed and irregular swallowing[
      • Soros P.
      • Al-Otaibi F.
      • Wong S.
      • Shoemaker J.K.
      • Mirsattari S.M.
      • Hachinski V.
      • Martin R.E.
      Stuttered swallowing: electric stimulation of the right insula interferes with water swallowing. A case report.
      ] (single case study)
      Cingulate cortexfMRIBalloon distention of lower esophagusIncreased activation in left mid-ACC with increasing pain

      Reduced right mid-ACC activation when pain is distracted, but no changes with left mid-ACC activation
      Higher order cognitive processing and attention to swallowing[
      • Coen S.J.
      • Gregory L.J.
      • Yaguez L.
      • Amaro Jr., E.
      • Brammer M.
      • Williams S.C.R.
      • Aziz Q.
      Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging.
      ,
      • Coen S.J.
      • Aziz Q.
      • Yágüez L.
      • Brammer M.
      • Williams S.C.R.
      • Gregory L.J.
      Effects of attention on visceral stimulus intensity encoding in the male human brain.
      ]
      fMRIAutomate saliva swallow

      Volitional saliva swallow

      Volitional water swallow
      ACC activation is more likely associated with volitional saliva and water swallow than automated saliva swallow[
      • Martin R.E.
      • Goodyear B.G.
      • Gati J.S.
      • Menon R.S.
      Cerebral cortical representation of automatic and volitional swallowing in humans.
      ]
      MEGVolitional water swallowIncreased ACC and PCC activation before swallowing[
      • Watanabe Y.
      • Abe S.
      • Ishikawa T.
      • Yamada Y.
      • Yamane G.-Y.
      Cortical regulation during the early stage of initiation of voluntary swallowing in humans.
      ]
      Basal gangliafMRI, PETAutomated saliva swallow

      Volitional saliva swallow

      Volitional water swallow
      Increased activation during swallowingLargely unknown, but it is proposed to be part of a neural circuit for swallowing which comprises the inferior frontal gyrus, S2, corpus callosum, basal ganglia and thalamus[
      • Hamdy S.
      • Mikulis D.J.
      • Crawley A.
      • Xue S.
      • Lau H.
      • Henry S.
      • Diamant N.E.
      Cortical activation during human volitional swallowing: an event-related fMRI study.
      ,
      • Suzuki M.
      • Asada Y.
      • Ito J.
      • Hayashi K.
      • Inoue H.
      • Kitano H.
      Activation of cerebellum and basal ganglia on volitional swallowing detected by functional magnetic resonance imaging.
      ,
      • Toogood J.A.
      • Smith R.C.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      • Theurer J.
      • Weisz S.
      • Affoo R.H.
      • Martin R.E.
      Swallowing preparation and execution: insights from a delayed-response functional magnetic resonance imaging (fMRI) study.
      ,
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ,
      • Zald D.H.
      • Pardo J.V.
      The functional neuroanatomy of voluntary swallowing.
      ,
      • Kober S.E.
      • Bauernfeind G.
      • Woller C.
      • Sampl M.
      • Grieshofer P.
      • Neuper C.
      • Wood G.
      Hemodynamic signal changes accompanying execution and imagery of swallowing in patients with dysphagia: a multiple single-case near-infrared spectroscopy study.
      ,
      • Kober S.E.
      • Grossinger D.
      • Wood G.
      Effects of motor imagery and visual neurofeedback on activation in the swallowing network: a real-time fMRI study.
      ,
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ]
      Abbreviations: ACC: anterior cingulate cortex, EMG: electromyography, fMRI: functional magnetic resonance imaging, MEG: magnetoencephalography, M1: primary motor cortex, PCC: posterior cingulate cortex, PET: positron emission tomography, rTMS: repetitive transcranial magnetic stimulation, S1: primary sensory cortex, S2: secondary sensory cortex, SM1: primary sensorimotor cortex

      5.1 Primary motor cortex (M1) and primary somatosensory cortex (S1)

      Primary motor and somatosensory cortices, often known together as primary sensorimotor cortex (SM1), are well-recognized cortical regions involved in swallowing. These regions are often found activated together during swallowing or oral sensory stimulation [
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ] or reduced in activation during oropharyngeal anesthesia [
      • Teismann I.K.
      • Steinstraeter O.
      • Stoeckigt K.
      • Suntrup S.
      • Wollbrink A.
      • Pantev C.
      • Dziewas R.
      Functional oropharyngeal sensory disruption interferes with the cortical control of swallowing.
      ], suggesting that both M1 and S1 function in synchrony. Separately, M1 has been suggested to be responsible for swallowing initiation and execution [
      • Hamdy S.
      • Mikulis D.J.
      • Crawley A.
      • Xue S.
      • Lau H.
      • Henry S.
      • Diamant N.E.
      Cortical activation during human volitional swallowing: an event-related fMRI study.
      ,
      • Hamdy S.
      • Rothwell J.C.
      • Brooks D.J.
      • Bailey D.
      • Aziz Q.
      • Thompson D.G.
      Identification of the cerebral loci processing human swallowing with H-2 O-15 PET activation.
      ,
      • Martin R.E.
      • Goodyear B.G.
      • Gati J.S.
      • Menon R.S.
      Cerebral cortical representation of automatic and volitional swallowing in humans.
      ,
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ,
      • Malandraki G.A.
      • Sutton B.P.
      • Perlman A.L.
      • Karampinos D.C.
      • Conway C.
      Neural activation of swallowing and swallowing-related tasks in healthy young adults: an attempt to separate the components of deglutition.
      ,
      • Mosier K.
      • Patel R.
      • Liu W.-C.
      • Kalnin A.
      • Maldjian J.
      • Baredes S.
      Cortical representation of swallowing in normal adults: functional implications.
      ]. The activation of M1 during swallowing is in accordance with animal studies which found that ICMS of the face-M1 could induce swallowing [
      • Martin R.E.
      • Kemppainen P.
      • Masuda Y.
      • Yao D.
      • Murray G.M.
      • Sessle B.J.
      Features of cortically evoked swallowing in the awake primate (Macaca fascicularis).
      ], “cold-block” applied to this area could disrupt food preparatory phase [
      • Lin L.D.
      • Murray G.M.
      • Sessle B.J.
      The effect of bilateral cold block of the primate face primary somatosensory cortex on the performance of trained tongue-protrusion task and biting tasks.
      ], and that single neuron firing of tongue-M1 is related to swallowing [
      • Martin R.E.
      • Murray G.M.
      • Kemppainen P.
      • Masuda Y.
      • Sessle B.J.
      Functional properties of neurons in the primate tongue primary motor cortex during swallowing.
      ]. In humans, studies have reported that electrical stimulation of M1 could induce rhythmic swallowing movements [
      • Penfield W.
      • Boldrey E.
      Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation.
      ]. Cortical mapping studies using TMS have demonstrated efferent projections from the M1 to swallowing musculature, including mylohyoid, pharyngeal and esophageal muscles [
      • Aziz Q.
      • Furlong P.L.
      • Barlow J.
      • Hobson A.
      • Alani S.
      • Bancewicz J.
      • Ribbands M.
      • Harding G.F.A.
      • Thompson D.G.
      Topographic mapping of cortical potentials evoked by distension of the human proximal and distal oesophagus.
      ,
      • Hamdy S.
      • Aziz Q.
      • Rothwell J.C.
      • Singh K.D.
      • Barlow J.
      • Hughes D.G.
      • Tallis R.C.
      • Thompson D.G.
      The cortical topography of human swallowing musculature in health and disease.
      ]. A virtual lesion (induced by 1 Hz repetitive TMS) of the M1 seems to result in temporary disruption of swallowing behavior, characterized by decreased oral transit time, increased swallow response time and reduced swallowing accuracy [
      • Verin E.
      • Michou E.
      • Leroi A.-M.
      • Hamdy S.
      • Marie J.-P.
      "Virtual" lesioning of the human oropharyngeal motor cortex: a videofluoroscopic study.
      ,
      • Mistry S.
      • Verin E.
      • Singh S.
      • Jefferson S.
      • Rothwell J.C.
      • Thompson D.G.
      • Hamdy S.
      Unilateral suppression of pharyngeal motor cortex to repetitive transcranial magnetic stimulation reveals functional asymmetry in the hemispheric projections to human swallowing.
      ].
      Processing of sensory information is an integral part of swallowing. It is essential to provide biofeedback on the texture of bolus and dynamics of bolus passage to ensure swallow safety [
      • Miller A.J.
      The neurobiology of swallowing and dysphagia.
      ]. Studies have shown that S1 is activated when different forms of sensory input are presented to the oral, laryngeal, pharyngeal or esophageal areas. Faurion et al., [
      • Faurion A.
      • Cerf B.
      • Le Bihan D.
      • Pilliasa A.-M.
      fMRI study of taste cortical areas in humans.
      ] showed that the inferior regions of S1 were activated when healthy volunteers were presented with liquids of pleasant and unpleasant tastes. Moreover, mechanical sensory inputs from the oral cavity, including retention of room temperature pure water in the oral cavity [
      • Furlong P.L.
      • Hobson A.R.
      • Aziz Q.
      • Barnes G.R.
      • Singh K.D.
      • Hillebrand A.
      • Thompson D.G.
      • Hamdy S.
      Dissociating the spatio-temporal characteristics of cortical neuronal activity associated with human volitional swallowing in the healthy adult brain.
      ,
      • Zald D.H.
      • Pardo J.V.
      Cortical activation induced by intraoral stimulation with water in humans.
      ] and air-pulse stimulation of right posterior oral area [
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ,
      • Soros P.
      • Lalone E.
      • Smith R.
      • Stevens T.
      • Theurer J.
      • Menon R.S.
      • Martin R.E.
      Functional MRI of oropharyngeal air-pulse stimulation.
      ], are also processed in the S1. Apart from the oral cavity, bilateral activation of S1 is observed during air-pulse stimulation of the laryngeal mucosa [
      • Miyaji H.
      • Hironaga N.
      • Umezaki T.
      • Hagiwara K.
      • Shigeto H.
      • Sawatsubashi M.
      • Tobimatsu S.
      • Komune S.
      Neuromagnetic detection of the laryngeal area: sensory-evoked fields to air-puff stimulation.
      ], electrical stimulation of the pharynx [
      • Gow D.
      • Hobson A.R.
      • Furlong P.
      • Hamdy S.
      Characterising the central mechanisms of sensory modulation in human swallowing motor cortex.
      ] and sensory stimulation of the lower esophagus through balloon inflation [
      • Aziz Q.
      • Andersson J.L.
      • Valind S.
      • Sundin A.
      • Hamdy S.
      • Jones A.K.
      • Foster E.R.
      • Langstrom B.
      • Thompson D.G.
      Identification of human brain loci processing esophageal sensation using positron emission tomography.
      ]. The activation was noted to increase during painful lower esophageal stimulation [
      • Aziz Q.
      • Andersson J.L.
      • Valind S.
      • Sundin A.
      • Hamdy S.
      • Jones A.K.
      • Foster E.R.
      • Langstrom B.
      • Thompson D.G.
      Identification of human brain loci processing esophageal sensation using positron emission tomography.
      ].

      5.2 Insula

      Studies with primates have identified the insula and frontal operculum as the primary taste cortex [
      • Scott T.R.
      • Yaxley S.
      • Sienkiewicz Z.J.
      • Rolls E.T.
      Gustatory responses in the frontal opercular cortex of the alert cynomolgus monkey.
      ,
      • Rolls E.T.
      • Yaxley S.
      • Sienkiewicz Z.J.
      Gustatory responses of single neurons in the caudolateral orbitofrontal cortex of the macaque monkey.
      ]. Single neurons located in these regions were found to be responsive to sensory (olfactory, gustatory and visual) stimulation [
      • Rolls E.T.
      • Baylis L.L.
      Gustatory, olfactory, and visual convergence within the primate orbitofrontal cortex.
      ]. Some of these neurons responded to combined modalities, allowing processing of sensory information of different modalities simultaneously [
      • Rolls E.T.
      • Baylis L.L.
      Gustatory, olfactory, and visual convergence within the primate orbitofrontal cortex.
      ]. In humans, convergent findings of increased activation in the insular-opercular region during gustatory stimulation have been reported in studies using PET [
      • Kinomura S.
      • Kawashima R.
      • Yamada K.
      • Ono S.
      • Itoh M.
      • Yoshioka S.
      • Yamaguchi T.
      • et al.
      Functional anatomy of taste perception in the human brain studied with positron emission tomography.
      ,
      • Zald D.H.
      • Lee J.T.
      • Fluegel K.W.
      • Pardo J.V.
      Aversive gustatory stimulation activates limbic circuits in humans.
      ], fMRI [
      • Faurion A.
      • Cerf B.
      • Le Bihan D.
      • Pilliasa A.-M.
      fMRI study of taste cortical areas in humans.
      ,
      • Small D.M.
      • M. J.-G
      • Zatorre R.J.
      • Petrides M.
      • Evans A.C.
      Flavor processing: more than the sum of its parts.
      ,
      • Francis S.
      • Rolls E.T.
      • Bowtell R.
      • McGlone F.
      • O'Doherty J.
      • Browning A.
      • Clare S.
      • Smith E.
      The representation of pleasant touch in the brain and its relationship with taste and olfactory areas.
      ] and MEG [
      • Kobayakawa T.
      • Endo H.
      • Ayabe-Kanamura S.
      • Kumagai T.
      • Yamaguchi Y.
      • Kikuchi Y.
      • Takeda T.
      • Saito S.
      • Ogawa H.
      The primary gustatory area in human cerebral cortex studied by magnetoencephalography.
      ]. Moreover, Aziz et al., [
      • Aziz Q.
      • Andersson J.L.
      • Valind S.
      • Sundin A.
      • Hamdy S.
      • Jones A.K.
      • Foster E.R.
      • Langstrom B.
      • Thompson D.G.
      Identification of human brain loci processing esophageal sensation using positron emission tomography.
      ] found that the insula was activated during both painful and non-painful esophageal stimulation, suggesting that it may also be involved in processing mechanical sensory information transmitted from both vagal and/or spinal afferents. Apart from being the primary taste cortex, the insula is also thought to be a primary integrative area for volitional swallowing [
      • Lowell S.Y.
      • Reynolds R.C.
      • Chen G.
      • Horwitz B.
      • Ludlow C.L.
      Functional connectivity and laterality of the motor and sensory components in the volitional swallowing network.
      ] and is responsible for coordinating visceral sensory and motor information [
      • Dupont S.
      • Bouilleret V.
      • Hasboun D.
      • Semah F.
      • Baulac M.
      Functional anatomy of the insula: new insights from imaging.
      ]. A case report showed that electrical stimulation of the right inferior posterior insular cortex using deep electrodes resulted in irregular and delayed swallows [
      • Soros P.
      • Al-Otaibi F.
      • Wong S.
      • Shoemaker J.K.
      • Mirsattari S.M.
      • Hachinski V.
      • Martin R.E.
      Stuttered swallowing: electric stimulation of the right insula interferes with water swallowing. A case report.
      ]. This finding is contradictory to that reported by Daniels et al., [
      • Daniels S.K.
      • Foundas A.L.
      The role of the insular cortex in dysphagia.
      ] which suggested that lesions in the posterior insula was not associated with dysphagia. However, given that these were single case reports, cautions should be taken when interpreting these results. Watanabe et al., [
      • Watanabe Y.
      • Abe S.
      • Ishikawa T.
      • Yamada Y.
      • Yamane G.-Y.
      Cortical regulation during the early stage of initiation of voluntary swallowing in humans.
      ] found that the insula was activated before swallowing, indicating that this region may be essential for the initiation of swallowing.

      5.3 Cingulate cortex

      The cingulate cortex is part of the limbic system. Within this region, the anterior cingulate cortex (ACC) is frequently identified in functional neuroimaging studies for swallowing. The ACC is considered to be a multifunctional region that is involved in the initiation and motivation of goal-directed behaviors, anticipation of and attention to action, and error detection [
      • Devinsky O.
      • Morrell M.J.
      • Vogt B.A.
      Contributions of anterior cingulate cortex to behaviour.
      ,
      • Carter C.S.
      • Braver T.S.
      • Barch D.M.
      • Botvinick M.M.
      • Noll D.
      • Cohen J.D.
      Anterior cingulate cortex, error detection, and the online monitoring of performance.
      ]. Moreover, ACC may be involved in the processing of visceral pain. Several fMRI studies have found that the level of activation in the left mid-ACC increased with increasing intensity of pain resulted from esophageal electrical stimulation [
      • Coen S.J.
      • Gregory L.J.
      • Yaguez L.
      • Amaro Jr., E.
      • Brammer M.
      • Williams S.C.R.
      • Aziz Q.
      Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging.
      ,
      • Coen S.J.
      • Aziz Q.
      • Yágüez L.
      • Brammer M.
      • Williams S.C.R.
      • Gregory L.J.
      Effects of attention on visceral stimulus intensity encoding in the male human brain.
      ]. Interestingly, Coen et al., [
      • Coen S.J.
      • Aziz Q.
      • Yágüez L.
      • Brammer M.
      • Williams S.C.R.
      • Gregory L.J.
      Effects of attention on visceral stimulus intensity encoding in the male human brain.
      ] found that the activation in the right mid-ACC was reduced when the attention to the pain was distracted, whereas the activation in the left mid-ACC remained unchanged. This finding suggested the potential role of the right ACC in attention or cognition. The PCC is an association area with abundant connections to the thalamus and is suggested to be responsible for attentional focus [
      • Leech R.
      • Sharp D.J.
      The role of the posterior cingulate cortex in cognition and disease.
      ]. An MEG study found that both ACC and PCC were activated before swallowing [
      • Watanabe Y.
      • Abe S.
      • Ishikawa T.
      • Yamada Y.
      • Yamane G.-Y.
      Cortical regulation during the early stage of initiation of voluntary swallowing in humans.
      ]. Furthermore, using fMRI, Martin et al., [
      • Martin R.E.
      • Goodyear B.G.
      • Gati J.S.
      • Menon R.S.
      Cerebral cortical representation of automatic and volitional swallowing in humans.
      ] found that ACC activation is more likely associated with volitional saliva and water swallow than automated saliva swallow. Taken together, these findings suggest that the cingulate cortex may be responsible for higher order cognitive processing of and attention to swallowing.

      5.4 Basal ganglia

      The basal ganglia are a group of subcortical nuclei consisting of the striatum, the globus pallidus, the subthalamic nucleus, and the substantia nigra [
      • Nelson A.B.
      • Kreitzer A.C.
      Reassessing models of basal ganglia function and dysfunction.
      ]. They are involved in a number of cortical-subcortical neural circuits that supports sensorimotor, cognitive and emotional-motivational brain functions [
      • Groenewegen H.J.
      The basal ganglia and motor control.
      ]. Their main roles are thought to be learning and selection of appropriate motor programs [
      • Groenewegen H.J.
      The basal ganglia and motor control.
      ]. Basal ganglia dysfunction can lead to a number of movement disorders, including Parkinson's disease (PD) and Huntington's disease (HD), in which dysphagia is common [
      • Nelson A.B.
      • Kreitzer A.C.
      Reassessing models of basal ganglia function and dysfunction.
      ,
      • Leopold N.A.
      • Daniels S.K.
      Supranuclear control of swallowing.
      ,
      • Hunter P.C.
      • Crameri J.
      • Austin S.
      • Woodward M.C.
      • Hughes A.J.
      Response of parkinsonian swallowing dysfunction to dopaminergic stimulation.
      ,
      • Keage M.
      • Baum S.
      • Pointon L.
      • Lau J.
      • Berndt J.
      • Hopkins J.
      • Maule R.
      • Voge A.P.
      Imaging and clinical data on swallowing function of individuals with Huntington’s disease and dysphagia.
      ]. Although functional neuroimaging studies have demonstrated activation of basal ganglia during swallowing [
      • Hamdy S.
      • Mikulis D.J.
      • Crawley A.
      • Xue S.
      • Lau H.
      • Henry S.
      • Diamant N.E.
      Cortical activation during human volitional swallowing: an event-related fMRI study.
      ,
      • Suzuki M.
      • Asada Y.
      • Ito J.
      • Hayashi K.
      • Inoue H.
      • Kitano H.
      Activation of cerebellum and basal ganglia on volitional swallowing detected by functional magnetic resonance imaging.
      ,
      • Toogood J.A.
      • Smith R.C.
      • Stevens T.K.
      • Gati J.S.
      • Menon R.S.
      • Theurer J.
      • Weisz S.
      • Affoo R.H.
      • Martin R.E.
      Swallowing preparation and execution: insights from a delayed-response functional magnetic resonance imaging (fMRI) study.
      ,
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ,
      • Zald D.H.
      • Pardo J.V.
      The functional neuroanatomy of voluntary swallowing.
      ,
      • Kober S.E.
      • Bauernfeind G.
      • Woller C.
      • Sampl M.
      • Grieshofer P.
      • Neuper C.
      • Wood G.
      Hemodynamic signal changes accompanying execution and imagery of swallowing in patients with dysphagia: a multiple single-case near-infrared spectroscopy study.
      ,
      • Kober S.E.
      • Grossinger D.
      • Wood G.
      Effects of motor imagery and visual neurofeedback on activation in the swallowing network: a real-time fMRI study.
      ,
      • Lowell S.Y.
      • Poletto C.J.
      • B.R. K.-C
      • Reynolds R.C.
      • Simonyan K.
      • Ludlow C.L.
      Sensory stimulation activates both motor and sensory components of the swallowing system.
      ], little is known regarding their specific roles in the control of swallowing [
      • Leopold N.A.
      • Daniels S.K.
      Supranuclear control of swallowing.
      ]. Functional connectivity studies have shown that basal ganglia are part of a neural circuit for swallowing [
      • Mosier K.
      • Bereznaya I.
      Parallel cortical networks for volitional control of swallowing in humans.
      ] (See section 5.6).

      5.5 Hemispheric dominance for swallowing

      Hemispheric dominance or functional lateralization is thought to be a result of brain size expansion during evolution [
      • Ringo J.L.
      • Doty R.W.
      • Demeter S.
      • Simard P.Y.
      Time is of the essence: a conjecture that hemispheric specialization arises from interhemispheric conduction delay.