Cerebellar repetitive transcranial magnetic stimulation restores pharyngeal brain activity and swallowing behaviour after disruption by a cortical virtual lesion

Despite evidence that the human cerebellum has an important role in swallowing neurophysiology, the effects of cerebellar stimulation on swallowing in the disrupted brain have not been explored. In this study, for the first time, the application of cerebellar neurostimulation is characterized in a human model of disrupted swallowing (using a cortical virtual lesion). It is demonstrated that cerebellar stimulation can reverse the suppressed activity in the cortical swallowing system and restore swallowing function in a challenging behavioural task, suggesting the findings may have important therapeutic implications.

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title: Dysphagia in Acute Stroke: Incidence, Burden and Impact on Clinical Outcome
abstract: Reported frequency of post-stroke dysphagia in the literature is highly variable. In view of progress in stroke management, we aimed to assess the current burden of dysphagia in acute ischemic stroke.  We studied 570 consecutive patients treated in a tertiary stroke center. Dysphagia was evaluated by using the Gugging Swallowing Screen (GUSS). We investigated the relationship of dysphagia with pneumonia, length of hospital stay and discharge destination and compared rates of favourable clinical outcome and mortality at 3 months between dysphagic patients and those without dysphagia.  Dysphagia was diagnosed in 118 of 570 (20.7%) patients and persisted in 60 (50.9%) at hospital discharge. Thirty-six (30.5%) patients needed nasogastric tube because of severe dysphagia. Stroke severity rather than infarct location was associated with dysphagia. Dysphagic patients suffered more frequently from pneumonia (23.1% vs. 1.1%, p<0.001), stayed longer at monitored stroke unit beds (4.4±2.8 vs. 2.7±2.4 days; p<0.001) and were less often discharged to home (19.5% vs. 63.7%, p = 0.001) as compared to those without dysphagia. At 3 months, dysphagic patients less often had a favourable outcome (35.7% vs. 69.7%; p<0.001), less often lived at home (38.8% vs. 76.5%; p<0.001), and more often had died (13.6% vs. 1.6%; p<0.001). Multivariate analyses identified dysphagia to be an independent predictor of discharge destination and institutionalization at 3 months, while severe dysphagia requiring tube placement was strongly associated with mortality.  Dysphagia still affects a substantial portion of stroke patients and may have a large impact on clinical outcome, mortality and institutionalization.

title: Post-stroke dysphagia: A review and design considerations for future trials
abstract: Post-stroke dysphagia (a difficulty in swallowing after a stroke) is a common and expensive complication of acute stroke and is associated with increased mortality, morbidity, and institutionalization due in part to aspiration, pneumonia, and malnutrition. Although most patients recover swallowing spontaneously, a significant minority still have dysphagia at six months. Although multiple advances have been made in the hyperacute treatment of stroke and secondary prevention, the management of dysphagia post-stroke remains a neglected area of research, and its optimal management, including diagnosis, investigation and treatment, have still to be defined.

title: Heart Disease and Stroke Statistics—2018 Update: A Report From the American Heart Association
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Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. 

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …

title: Recovery of swallowing after dysphagic stroke relates to functional reorganization in the intact motor cortex.
abstract: The aim of this study was to determine the mechanism for recovery of swallowing after dysphagic stroke.



Twenty-eight patients who had a unilateral hemispheric stroke were studied 1 week and 1 and 3 months after the stroke by videofluoroscopy. Pharyngeal and thenar electromyographic responses to magnetic stimulation of multiple sites over both hemispheres were recorded, and motor representations were correlated with swallowing recovery.



Dysphagia was initially present in 71% of patients and in 46% and 41% of the patients at 1 and 3 months, respectively. Cortical representation of the pharynx was smaller in the affected hemisphere (5 +/- 1 sites) than the unaffected hemisphere (13 +/- 1 sites; P </= 0.001). Nondysphagic and persistently dysphagic patients showed little change in pharyngeal representation in either hemisphere at 1 and 3 months compared with presentation, but dysphagic patients who recovered had an increased pharyngeal representation in the unaffected hemisphere at 1 and 3 months (15 +/- 2 and 17 +/- 3 vs. 9 +/- 2 sites; P </= 0.02) without change in the affected hemisphere. In contrast, thenar representation increased in the affected hemisphere but not the unaffected hemisphere at 1 and 3 months (P </= 0.01).



Return of swallowing after dysphagic stroke is associated with increased pharyngeal representation in the unaffected hemisphere, suggesting a role for intact hemisphere reorganization in recovery.

title: Treatment of post‐stroke dysphagia with repetitive transcranial magnetic stimulation
abstract: Up to one‐third of patients experience swallowing problems in the period immediately after a stroke.

title: Therapeutic role of rTMS on recovery of dysphagia in patients with lateral medullary syndrome and brainstem infarction
abstract: There is some evidence for a therapeutic effect of repetitive transcranial magnetic stimulation (rTMS) on dysphagia in hemispheric stroke.  To compare the effect of active or sham rTMS applied to the motor area of both hemispheres in patients with acute lateral medullary infarction (LMI) or other brainstem infarctions.  The study included 22 patients with acute ischaemic stroke who had severe bulbar manifestation. 11 patients had LMI, and 11 had another brainstem infarction. They were randomly allocated to receive active (n=11) or sham (n=11) rTMS of the oesophageal motor cortex. Each patient received 300 rTMS pulses at 3 Hz and an intensity of 130% resting motor threshold to each hemisphere for five consecutive days. Clinical ratings of dysphagia and motor disability were assessed before and immediately after the last session, and then again after 1 and 2 months.  There were no significant differences in baseline clinical assessment of swallowing between active and sham groups. Active rTMS improved dysphagia compared with sham rTMS in both groups of patients, (p=0.001 for both); the LMI group also improved the scores in the Barthel Index. All improvements were maintained over 2 months of follow-up (p=0.001).  These findings suggest that rTMS could be a useful adjuvant strategy in neurorehabilitation of dysphagia due to LMI or other brainstem infarction, although further assessment is necessary in multicentre clinical trials.

title: Effects of Bilateral Repetitive Transcranial Magnetic Stimulation on Post-Stroke Dysphagia
abstract: Optimal protocol of repetitive transcranial magnetic stimulation (rTMS) on post-stroke dysphagia remains uncertain with regard to its clinical efficacy.



The aim of the present study is to investigate the effects of high-frequency rTMS at the bilateral motor cortices over the cortical representation of the mylohyoid muscles in the patients with post-stroke dysphagia.



This study was a single-blind, randomized controlled study with a blinded observer. Thirty-five stroke patients were randomly divided into three intervention groups: the bilateral stimulation group, the unilateral stimulation group, and the sham stimulation group. For the bilateral stimulation group, 500 pulses of 10 Hz rTMS over the ipsilesional and 500 pulses of 10 Hz rTMS over the contralesional motor cortices over the cortical areas that project to the mylohyoid muscles were administered daily for 2 consecutive weeks. For the unilateral stimulation group, 500 pulses of 10 Hz rTMS over the ipsilesional motor cortex over the cortical representation of the mylohyoid muscle and the same amount of sham rTMS over the contralesional hemisphere were applied. For the sham stimulation group, sham rTMS was applied at the bilateral motor cortices. Clinical swallowing function and videofluoroscopic swallowing studies were assessed before the intervention (T0), immediately after the intervention (T1) and 3 weeks after the intervention (T2) using Clinical Dysphagia Scale (CDS), Dysphagia Outcome and Severity Scale (DOSS), Penetration Aspiration Scale (PAS), and Videofluoroscopic Dysphagia Scale (VDS).



There were significant time and intervention interaction effects in the CDS, DOSS, PAS, and VDS scores (p < 0.05). In the direct comparison of the changes in the swallowing parameters among the three groups, the change in CDS scores at T1 and T2 showed a significantly higher improvement in the bilateral simulation group than in two other groups (p < 0.05). There was a significantly larger change in the DOSS, PAS, and VDS scores at T1 in the bilateral stimulation group than in two other groups (p < 0.05).



The results of the present study provide substantial evidence that 10 Hz rTMS at the bilateral motor cortices over the cortical areas projecting to the mylohyoid muscles is effective as an additional treatment strategy to traditional dysphagia therapies.

title: 
Activation of Cerebellum and Basal Ganglia on Volitional Swallowing Detected by Functional Magnetic Resonance Imaging

abstract: Although regions of the sensorimotor cortex, insula, and anterior cingulate gyrus are reported to be activated during swallowing, findings concerning contributions of the cerebellum and basal ganglia have been contradictory. We investigated cerebellar and basal ganglionic activation using functional magnetic resonance imaging (fMRI). In 11 subjects, single-shot gradient-echo echoplanar image volumes sensitive to BOLD contrast were acquired in block design fashion using an oblique orientation covering both cerebrum and cerebellum. Using statistical parametric mapping, regional activation upon swallowing was observed in the sensorimotor cortex, insula, cerebellum, putamen, globus pallidus, thalamus, anterior cingulate gyrus, supplementary motor area, superior temporal gyrus, and substancia nigra. The cerebellum was activated bilaterally, especially on the left; activation of the putamen and globus pallidus was also found bilaterally. Thus, volitional swallowing involves the cerebellum and basal ganglia as well as cortical structures. The method used was well tolerated by normal subjects and should also be applicable to patients with dysphagia.

title: Exploring the connectivity between the cerebellum and motor cortex in humans
abstract: Animal studies have shown that cerebellar projections influence both excitatory and inhibitory neurones in the motor cortex but this connectivity has yet to be demonstrated in human subjects. In human subjects, magnetic or electrical stimulation of the cerebellum 5–7 ms before transcranial magnetic stimulation (TMS) of the motor cortex decreases the TMS‐induced motor‐evoked potential (MEP), indicating a cerebellar inhibition of the motor cortex (CBI). TMS also reveals inhibitory and excitatory circuits of the motor cortex, including a short‐interval intracortical inhibition (SICI), long‐interval intracortical inhibition (LICI) and intracortical facilitation (ICF). This study used magnetic cerebellar stimulation to investigate connections between the cerebellum and these cortical circuits. Three experiments were performed on 11 subjects. The first experiment showed that with increasing test stimulus intensities, LICI, CBI and ICF decreased, while SICI increased. The second experiment showed that the presence of CBI reduced SICI and increased ICF. The third experiment showed that the interaction between CBI and LICI reduced CBI. Collectively, these findings suggest that cerebellar stimulation results in changes to both inhibitory and excitatory neurones in the human motor cortex.

title: Parallel cortical networks for volitional control of swallowing in humans
abstract: A number of studies have demonstrated the involvement of parallel networks in the control of voluntary sequential motor procedures. We sought to determine whether a parallel network organization may be found for complex, sequentially based motor systems that are the product of both voluntary and automatic control processes. Specifically, we sought to determine whether the cortical organizational scheme for voluntary repetitive swallowing in adult humans is characterized by a hierarchical dual-projection model or by modules organized into parallel systems. We utilized functional magnetic resonance imaging (fMRI) to investigate cortical function during normal swallowing tasks in eight healthy human adults. Subjects performed both dry (saliva) and bolus (3 ml/bolus of water) swallows. Activation during swallowing tasks localized to sensorimotor areas (M1, S1, and SMA), S2, premotor cortex, posterior parietal cortex, cingulate gyrus, inferior frontal gyrus, the cerebellum, the insular cortex, auditory cortex, corpus callosum, and the basal ganglia and thalamus. Principal components analysis (PCA) of these regions revealed five functional clusters or modules: (1) sensorimotor areas and cingulate gyrus; (2) inferior frontal gyrus, S2, corpus callosum, basal ganglia and thalamus; (3) premotor cortex and posterior parietal cortex; (4) cerebellum; and (5) insula. Analysis of the functional relationship between these areas demonstrated two parallel loops defined by connections to either the cerebellum or insula and connected through the sensorimotor-cingulate module. Path analysis was performed to test the hypothesis of modules organized into parallel loops versus a hierarchical dual-projection model consisting of two separate, singular hierarchical serial pathways from the sensorimotor cortex or insula to the thalamus. These results support the model of modules organized into parallel loops (P=0.8), but not the hierarchical dual-projection model (P<0.0001). Organization of the control of voluntary repetitive swallowing into two parallel systems may confer the ability to effectively coordinate and integrate this highly complex sequentially based motor behavior.

title: The pathophysiology of oral pharyngeal apraxia and mutism following posterior fossa tumor resection in children.
abstract: Mutism following posterior fossa tumor resection in pediatric patients has been previously recognized, although its pathophysiology remains unclear. A review of the available literature reveals 33 individuals with this condition, with only a few adults documented in the population. All of these patients had large midline posterior fossa tumors. To better understand the incidence and anatomical substrate of this syndrome, the authors reviewed a 7-year series of 110 children who underwent a posterior fossa tumor resection. During that time, nine (8.2%) of the 110 children exhibited mutism postoperatively. They ranged from 2.5 to 20 years of age (mean 8.1 years) and became mute within 12 to 48 hours of surgery. The period of mutism lasted from 1.5 to 12 weeks after onset: all children had difficulty coordinating their oral pharyngeal musculature as manifested by postoperative drooling and inability to swallow. Further analysis of these cases revealed that all children had splitting of the entire inferior vermis at surgery, as confirmed on postoperative magnetic resonance studies. Lower cranial nerve function was intact in all nine patients. Current concepts of cerebellar physiology emphasize the importance of the cerebellum in learning and language. The syndrome described resembles a loss of learned activities, or an apraxia, of the oral and pharyngeal musculature. To avoid the apraxia, therefore, the inferior vermis must be preserved. For large midline tumors that extend to the aqueduct, a combined approach through the fourth ventricle and a midvermis split may be used to avoid injuring the inferior vermis.

title: Swallowing in degenerative ataxias
abstract: Swallowing consists of oral, pharyngeal and oesophageal phases. In the oral phase, which is voluntary, the bolus to be directed towards the fauces is prepared so initiating the reflexive pharyngeal phase of deglutition. Here the triple protective mechanism of the airway, the downward movement of the epiglottis, closure of the aryepiglottic folds and closure of the vocal cords, prevents the entry of material into the airway, which, on the other hand, may occur if this sequence does not occur perfectly. Whether a swallowing disorder results in the complete expulsion of the material without subsequent problems or in bacterial contamination of the airway leading to bronchitis, aspiration pneumonia or even asphyxia depends on the size and consistency of the bolus and the efficacy of the coughing reflex. It is therefore a mechanism which is of the most vital importance . This complex triple protective mechanism can be affected by several neurological diseases and, especially, by movement disorders. Swallowing abnormalities have been studied in Parkinson’s disease, progressive supranuclear paralysis and Huntington’s disease [2–5]. To the best of our knowledge only two publications have reported deglutition in patients with ataxias but neither of these distinguished between the different types of ataxia in studying this condition [6, 7]. Spinocerebellar ataxias are a group of diseases that are characterised by cerebellar degeneration, which may or may not be associated with neuronal loss in other structures of the central nervous system. The main clinical manifestations of the disease are gait and limb ataxia and dysarthria. In addition to cerebellar neurodegeneration, which makes up the basic clinical picture, a wide range of neurological manifestations including oculomotor, sleep and basal ganglia disorders, dementia, pyramidal signs, autonomic dysfunction, neuropathy and optic atrophy can be found . Swallowing abnormalities are not uncommon in degenerative ataxias although there are considerable inter-series differences [9–18]. In this study we investigated swallowing abnormalities in patients with different types of ataxia and we provide evidence of their high incidence in these patients. We analyse the clinical and radiological characteristics of this dysfunction as well as the long-term prognosis for the related complications.

title: Dysphagia following posterior fossa surgery in adults.
abstract: Our study seeks to assess the incidence of aspiration and prolonged dysphagia needing enteral feeding at discharge (EFD) in adults after posterior fossa (p-fossa) surgery.



A retrospective review was done on 56 patients with p-fossa surgery who needed a swallowing evaluation postoperatively. Questionnaires were sent to patients with EFD. Using univariate and multiple logistic regression analysis, risk factors for aspiration, EFD, and continued enteral feeds were identified.



Most patients were male and had p-fossa tumors. Multiple swallowing evaluations were needed in 25 (45%) patients. Aspiration was seen in 23 (41%) and 16 (27%) had EFD. Older age and number of evaluations were significantly associated with both aspiration and EFD (P < 0.05). Lateral approach was significantly associated with EFD (P = 0.047). In addition, multiple logistic regression identified aspiration as an independent significant predictor for EFD (P < 0.01). Mean operative time and tumor location did not have a significant correlation with EFD. At mean follow-up (15 months), only 5/16 needed continued enteral feeds.



Although 27% patients had EFD after p-fossa surgery, only 5/56 (9%) required continued enteral feeding. Aspiration, age, and lateral surgical approach is associated with EFD. In patients who demonstrate aspiration, we recommend placement of enteral feeding tube. Although most will not require continued enteral feeding at follow-up, longer follow-ups are needed.

title: Magnetic stimulation over the cerebellum in humans
abstract: Magnetic stimulation performed with a double‐cone coil placed over appropriate positions on the back of the head reduced the size of electromyographic responses evoked by magnetic cortical stimulation in the first dorsal interosseous muscle when it preceded the cortical stimulus by 5, 6, and 7 msec. No suppression of responses to electrical cortical stimulation occurred. Greater suppression was evoked by stronger cerebellar stimuli; lesser suppression was elicited by stronger cortical stimuli. These physiological findings correspond to those obtained with electrical cerebellar stimulation. The most effective position for magnetic stimulation over the back of the head was slightly rostral to the foramen magnum level on the ipsilateral side of the muscle studied. This indicates that the conditioning stimulus activates certain structures at the back of the head on the ipsilateral side of the muscle, consistent with the cerebellum, because the part of the cerebellum regulating limb muscles is positioned about there on the ipsilateral side. In 2 patients with only cerebellar dysfunction, this suppression effect was not elicited, which also supports that the suppression is caused by activity in cerebellar structures. We conclude that magnetic stimulation over the cerebellum with a doublecone coil elicits the same suppressive effect on the motor cortex as electrical stimulation, but with less discomfort; moreover, we believe that this effect is produced by activation of certain cerebellar structures.

title: Modulatory effects of 1 Hz rTMS over the cerebellum on motor cortex excitability
abstract: Clinical observations and data from animal experiments point to a physiological facilitatory influence of the deep cerebellar structures on the motor system through the cerebello-thalamo-cortical pathways. The aim of the present study was to explore the long-term effects of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over the cerebellum on short intracortical inhibition (SICI) and facilitation (ICF) of the motor cortex in normal subjects. Eight healthy subjects (mean age 26.9 ± 3.1) underwent 1 Hz frequency rTMS delivered on the right cerebellar hemisphere. Before and after cerebellar rTMS, SICI and ICF were assessed in the motor cortex contralateral to the stimulated cerebellar hemisphere by means of a paired pulse paradigm with a conditioning subthreshold stimulus set to 80% of the motor threshold (MT) followed by a testing stimulus at 120% of MT intensity. Five different interstimulus intervals (ISIs) were used to assess SICI (2 and 4 ms) and ICF (7, 10 and 15 ms). Amplitude of the responses was expressed as the percentage of motor evoked potential (MEP) to test stimulus alone. Results showed a significant decrease of ICF at 10 ms ISI that persisted up to 20 min after cerebellar rTMS. This was the only significant modulatory effect of cerebellar stimulation on intracortical motor excitability A suppressive effect of the low-frequency TMS on Purkinje cells could be supposed, even if, the lack of effects on other facilitatory ISIs, stands for more complex modulatory effects of rTMS over cerebellum. The study is a further demonstration that rTMS over the cerebellum induces a long-lasting modulatory effect on the excitability of the interconnected motor area.

title: Non‐invasive magnetic stimulation of the human cerebellum facilitates cortico‐bulbar projections in the swallowing motor system
abstract: Animal and human brain imaging studies suggest that the cerebellum plays an important role in the control of swallowing. In this study, we probed the interaction between cerebellar and pharyngeal motor cortical activity with transcranial magnetic stimulation (TMS) to determine if the cerebellum can modulate cortical swallowing motor circuitry.

title: High‐frequency focal repetitive cerebellar stimulation induces prolonged increases in human pharyngeal motor cortex excitability
abstract: Neurostimulation is a rapidly emerging approach to swallowing rehabilitation, but cerebellar stimulation has not been explored as a treatment. Such proposed therapies for post‐stroke dysphagia have required confirmation of physiological effects and optimisation of parameters in healthy humans prior to translational progression into patient groups. There is strong evidence for a role of the cerebellum in swallowing physiology, but this relationship has been under‐explored. Recently, single pulses of cerebellar magnetic stimulation have been shown to directly evoke responses from pharyngeal musculature and produce short‐term enhancement of cortico‐pharyngeal motor evoked potentials, suggesting the feasibility of a cerebellar approach to neurostimulation in the swallowing system. We therefore examined multiple parameters of repetitive cerebellar magnetic stimulation and have described the optimal settings to provoke longer‐lasting changes in swallowing neurophysiology. Based on evidence from the post‐stroke dysphagia neurostimulation literature, these changes may have a therapeutic potential for swallowing rehabilitation.

title: Unilateral suppression of pharyngeal motor cortex to repetitive transcranial magnetic stimulation reveals functional asymmetry in the hemispheric projections to human swallowing
abstract: Inhibitory patterns of repetitive transcranial magnetic stimulation (rTMS) were applied to pharyngeal motor cortex in order to establish its role in modulating swallowing activity and provide evidence for functionally relevant hemispheric asymmetry. Healthy volunteers underwent single pulse TMS before and for 60 min after differing intensities of 1 Hz rTMS (n= 9, 6 male, 3 female, mean age 34 ± 3 years) or theta burst stimulation (TBS) (n= 9, 6 male, 3 female, mean age 37 ± 4 years). Electromyographic responses recorded from pharynx and hand were used as a measure of cortico‐motor pathway excitability. Swallowing behaviour was then examined with a reaction time protocol, before and for up to 60 min after the most effective inhibitory protocol (1 Hz) applied to each hemisphere. Interventions were conducted on separate days and compared to sham using ANOVA. Only high intensity 1 Hz rTMS consistently suppressed pharyngeal motor cortex immediately and for up to 45 min (−34 ± 7%, P≤ 0.001). Adjacent hand and contralateral pharyngeal motor cortex showed no change in response (−15 ± 12%, P= 0.14 and 15 ± 12%, P= 0.45, respectively). When used to unilaterally disrupt each hemisphere, rTMS to pharyngeal motor cortex with the stronger responses altered normal (−12 ± 3%, P≤ 0.001) and fast (−9 ± 4%, P≤ 0.009) swallow times, not seen following rTMS to the contralateral cortex or after sham. Thus, suppression of pharyngeal motor cortex to rTMS is intensity and frequency dependent, which when applied to each hemisphere reveals functionally relevant asymmetry in the motor control of human swallowing.

title: "Virtual" lesioning of the human oropharyngeal motor cortex: a videofluoroscopic study.
abstract: To use focal cortical inhibition and create a "virtual" lesion in the oropharyngeal motor cortex in healthy subjects to determine whether this provokes swallowing dysfunction.



Intervention study: before and after cortical stimulation.



Tertiary care center.



Healthy adult volunteers (N=9; age range, 21-44y) participated in the study.



Active or sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the cortical sites in each hemisphere evoking the largest mylohyoid motor-evoked potentials (mMEPs) to single pulse transcranial magnetic stimulation.



Videofluoroscopic assessment was performed before and 5, 30, and 60 minutes after rTMS.



The motor threshold was 83%±10% for the hemisphere with the larger mMEP (dominant) and 92%±9% for the hemisphere with the smaller mMEP (nondominant). When rTMS was performed over the dominant hemisphere, there was a decrease in oral transit time (P=.05), an increase in swallow reaction time (P=.0001), but no change of pharyngeal transit time or laryngeal closure duration. When rTMS was performed on the nondominant hemisphere, there was also a decrease in oral transit time (P=.05), but no change in any of the other swallowing measures. Neither active intervention produced any signs of aspiration or penetration. Sham stimulation had no effect.



Inhibiting the human oropharyngeal motor cortex using rTMS transiently modifies swallowing behavior in a way reminiscent to that seen in stroke patients.

title: Reversal of a virtual lesion in human pharyngeal motor cortex by high frequency contralesional brain stimulation.
abstract: Excitatory brain stimulation with repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for dysphagia after stroke. Moreover, 1-Hz rTMS can induce a "virtual lesion" in the human pharyngeal motor cortex that suppresses brain activity and temporarily disrupts swallowing. We thus examined if rTMS could reverse the disrupted brain and swallowing functions following a unilateral virtual lesion in the pharyngeal motor cortex, such that rTMS might be developed as a therapy.



Healthy subjects (n = 23) were given varying conditions of 5-Hz rTMS over the pharyngeal motor cortex to determine the most effective excitatory parameters. Thereafter, a unilateral virtual lesion was made in the pharyngeal motor cortex using 1-Hz rTMS, followed by contralateral active or sham 5-Hz rTMS. Motor evoked potentials and serial swallowing reaction times were recorded before and for 60 minutes postlesion to assess reversibility of the disruption to the brain and swallowing.



The greatest increase in pharyngeal motor cortex excitability was seen following 250 pulses of 5-Hz rTMS (F(1,11) = 10.3, P = .008), an effect that lasted over 2 hours. In contrast to sham rTMS, active contralateral 5-Hz rTMS completely abolished the cortical suppression induced by the virtual lesion, with effects occurring for up to 50 minutes in both unlesioned (F(1,11) = 6, P = .03) and lesioned (F(1,11) = 67, P < .001) hemispheres. Active rTMS also reversed the changes in swallowing behavior (F(1,8) = 9, P = .018), restoring function to prelesional levels.



Contralesional-targeted neurostimulation modulates brain activity and swallowing motor behavior after experimental disruption and might be usefully applied in stroke-affected patients as a therapy for dysphagia.

title: Induction of long-term plasticity in human swallowing motor cortex following repetitive cortical stimulation
abstract: The excitability of corticobulbar projections to swallowing musculature undergoes remarkable long-term increases after short periods of pharyngeal stimulation. The aim of this study was to investigate the excitability of swallowing motor cortex following repetitive transcranial magnetic stimulation (rTMS).



Twelve healthy subjects were given 100 rTMS pulses over motor cortex at frequencies of 1, 5 and 10 Hz at an intensity of 80% threshold for corticobulbar activation. The excitability of the corticobulbar projection was assessed before and after rTMS and compared both to sham stimulation and to the corticospinal projection.



Stimulation at 5 Hz, but not 1 Hz, 10 Hz or sham stimulation increased the excitability of the corticobulbar projection to the pharynx, reaching a peak 60 min after rTMS (Delta increase: 65%, P=0.016). Excitability in the projection from the opposite hemisphere also increased, suggesting the presence of inter-hemispheric interactions, whereas excitability in the projection to thenar muscles was unchanged.



Corticobulbar and corticospinal projections may differ in response to rTMS, implying differences in relative thresholds of inhibitory and excitatory elements in hand versus swallowing cortex.



This might be a useful approach in the motor rehabilitation of dysphagic stroke patients who have damage to sensory projections to the swallowing cortex.

title: Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996.
abstract: Single-pulse transcranial magnetic stimulation (TMS) is a safe and useful tool for investigating various aspects of human neurophysiology, particularly corticospinal function, in health and disease.  TMS (rTMS), however, is a more powerful and potentially dangerous modality, capable of regionally blocking or facilitating cortical processes. Although there is evidence that rTMS is useful for treating clinical depression, and possibly other brain disorders, it had caused 7 known seizures by 1996 and could have other undesirable effects. In June 1996 a workshop was organized to review the available data on the safety of rTMS and to develop guidelines for its safe use. This article summarizes the workshop's deliberations. In addition to issues of risk and safety, it also addresses the principles and applications of rTMS, nomenclature, and potential therapeutic effects of rTMS. The guidelines for the use of rTMS, which are summarized in an appendix, cover the ethical issues, recommended limits on stimulation parameters, monitoring of subjects (both physiologically and neuropsychologically), expertise and function of the rTMS team, medical and psychosocial management of induced seizures, and contra-indications to rTMS.

title: Transcranial magnetic stimulation and the challenge of coil placement: A comparison of conventional and stereotaxic neuronavigational strategies
abstract: The combination of transcranial magnetic stimulation (TMS) with functional neuroimaging has expanded the potential of TMS for human brain mapping. The precise and reliable positioning of the TMS coil is not a simple task, however. Modern frameless stereotaxic systems allow investigators to base navigation either on the subject's structural magnetic resonance imaging (MRI), functional MRI data, or the use of functional neuroimaging data from the literature, so‐called “probabilistic approach.” The latter assumes consistency across individuals in the location of task‐related “activations” in standardized stereotaxic space. Conventional nonstereotaxic localization of brain areas is also a common method for defining the coil position. Our aim was to evaluate the accuracy of five different localization strategies in one single study. The left primary motor cortex (left M1‐Hand) was used as target region. Three approaches were based on real‐time frameless stereotaxy using information based on either anatomical or functional MRI. The remaining two strategies relied either on standard cranial landmarks (i.e., the International 10–20 EEG system) or a standardized function‐guided procedure (i.e., the spatial relationship between the left and right M1‐Hand). The results were compared to a TMS‐based mapping of the primary motor cortex; center of gravity of motor‐evoked potentials (MEP‐CoG) was calculated for each subject (n = 10). Our findings suggest that highest precision can be achieved with fMRI‐guided stimulation, which was accurate within the range of millimeters. Very consistent results were also obtained with the “probabilistic” approach. In view of these findings, we discuss the methods and special characteristics of each localization strategy.

title: Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor threshold and motor evoked potentials
abstract: Transcranial magnetic stimulation (TMS) can be used for non-invasive assessment of cortical physiology and descending motor pathways. However, the focus/exact site of cortical activation is considerably widespread in traditional TMS. When combined with MRI-based navigation, it allows specific anatomical areas of the cortex to be stimulated. The peripheral muscle responses to TMS are commonly measured as motor evoked potentials (MEPs). We compared the accuracy of cortical mapping, as well as the congruity of the motor thresholds (MT) and MEPs between navigated and non-navigated TMS procedures. Eight volunteers were studied in two sessions. In each session both hemispheres were stimulated with and without navigation. Non-navigated TMS: Both hemispheres were mapped without navigation to find the representation area of the thenar muscles based on induced MEP amplitudes. MT was then determined at the optimum coil location. Navigated TMS: Individual MR-images were used for the on-line navigation procedure. The cortical representation area of the thenar musculature was mapped at the "hand knob". The optimum stimulus target was used for MT determination. The order of these two procedures was randomized. Following the MT determination, MEPs were recorded from 20 consecutive stimuli. The MTs were similar from session-to-session with no inter-hemispheric differences, and with and without navigation. The stimulus location was more spatially discrete in navigated TMS producing more stable MEPs with significantly higher amplitudes and shorter latencies. In summary, MEPs exhibit significant differences depending on whether navigation is used. However, the MTs are not significantly dependent on the discrete stimulation site.

title: Theta Burst Stimulation of the Human Motor Cortex
abstract: It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.

title: The human cerebellum: a review of physiologic neuroanatomy.
abstract: The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is anatomically and physiologically divided into distinct functional compartments and is composed of highly regular arrays of neuronal units, each sharing the same basic cerebellar microcircuitry. Its circuitry is critically involved in motor control and motor learning, and its role in nonmotor cognitive and affective functions is becoming increasingly recognized. This article describes the cerebellar gross and histologic neuroanatomy in relation to its function, and the relevance of cerebellar circuitry and firing patterns to motor learning.

title: Cerebellar fastigial nucleus: from anatomic construction to physiological functions
abstract: Fastigial nucleus (FN) is the phylogenetically oldest nucleus in the cerebellum, a classical subcortical motor coordinator. As one of the ultimate integration stations and outputs of the spinocerebellum, the FN holds a key position in the axial, proximal and ocular motor control by projecting to the medial descending systems and eye movement related nuclei. Furthermore, through topographic connections with extensive nonmotor systems, including visceral related nuclei in the brainstem, hypothalamus, as well as the limbic system, FN has also been implicated in regulation of various nonsomatic functions, such as feeding, cardiovascular and respiratory, defecation and micturition, immune, as well as emotional activities. In clinic, FN lesion or dysfunction results in motor deficits including spinocerebellar ataxias, and nonmotor symptoms. In this review, we summarize the cytoarchitecture, anatomic afferent and efferent connections, as well as the motor and nonmotor functions of the FN and the related diseases and disorders. We suggest that by bridging the motor and nonmotor systems, the cerebellar FN may help to integrate somatic motor and nonsomatic functions and consequently contribute to generate a coordinated response to internal and external environments.

title: Cerebellar networks with the cerebral cortex and basal ganglia
abstract: The dominant view of cerebellar function has been that it is exclusively concerned with motor control and coordination. Recent findings from neuroanatomical, behavioral, and imaging studies have profoundly changed this view. Neuroanatomical studies using virus transneuronal tracers have demonstrated that cerebellar output reaches vast areas of the neocortex, including regions of prefrontal and posterior parietal cortex. Furthermore, it has recently become clear that the cerebellum is reciprocally connected with the basal ganglia, which suggests that the two subcortical structures are part of a densely interconnected network. Taken together, these findings elucidate the neuroanatomical substrate for cerebellar involvement in non-motor functions mediated by the prefrontal and posterior parietal cortex, as well as in processes traditionally associated with the basal ganglia.

title: Central Nervous System Control of Voice and Swallowing
abstract: This review of the central nervous control systems for voice and swallowing has suggested that the traditional concepts of a separation between cortical and limbic and brain stem control should be refined and be more integrative. For voice production, a separation of the nonhuman vocalization system from the human learned voice production system has been posited based primarily on studies of nonhuman primates. However, recent humans studies of emotionally based vocalizations and human volitional voice production have shown more integration between these two systems than previously proposed. Recent human studies have shown that reflexive vocalization as well as learned voice production not involving speech involve a common integrative system. However, recent studies of nonhuman primates have provided evidence that some cortical activity vocalization and cortical changes occur with training during vocal behavior. For swallowing, evidence from the macaque and functional brain imaging in humans indicates that the control for the pharyngeal phase of swallowing is not primarily under brain stem mechanisms as previously proposed. Studies suggest that the initiation and patterning of swallowing for the pharyngeal phase is also under active cortical control for both spontaneous as well as volitional swallowing in awake humans and nonhuman primates.

title: The anatomy and physiology of normal and abnormal swallowing in oropharyngeal dysphagia
abstract: Eating and drinking are enjoyable activities that positively impact on an individual's quality of life. The ability to swallow food and fluid is integral to the process of eating. Swallowing occupies a dual role being both part of the enjoyment of eating and being a critically important utilitarian activity to enable adequate nutrition and hydration. Any impairment to the process of swallowing can negatively affect a person's perception of their quality of life. The process of swallowing is highly complex and involves muscles in the mouth, pharynx, larynx, and esophagus. The oropharynx is the anatomical region encompassing the oral cavity and the pharynx. Food must be masticated, formed into a bolus and transported to the pharynx by the tongue whereas fluids are usually held within the mouth before being transported ab‐orally. The bolus must then be transported through the pharynx to the esophagus without any matter entering the larynx. The muscles needed for all these steps are coordinated by swallowing centers within the brainstem which are supplied with sensory information by afferent nerve fibers from several cranial nerves. The swallowing centers also receive modulatory input from higher centers within the brain. Hence, a swallow has both voluntary and involuntary physiologic components and the term dysphagia is given to difficult swallowing while oropharyngeal dysphagia is difficult swallowing due to pathology within the oropharynx.

title: Characterizing the Mechanisms of Central and Peripheral Forms of Neurostimulation in Chronic Dysphagic Stroke Patients
abstract: Swallowing problems following stroke may result in increased risk of aspiration pneumonia, malnutrition, and dehydration.  Our hypothesis was that three neurostimulation techniques would produce beneficial effects on chronic dysphagia following stroke through a common brain mechanism that would predict behavioral response.  In 18 dysphagic stroke patients (mean age: 66 ± 3 years, 3 female, time-post-stroke: 63 ± 15 weeks [±SD]), pharyngeal electromyographic responses were recorded after single-pulse transcranial magnetic stimulation (TMS) over the pharyngeal motor cortex, to measure corticobulbar excitability before, immediately, and 30 min, after real and sham applications of neurostimulation. Patients were randomized to a single session of either: pharyngeal electrical stimulation (PES), paired associative stimulation (PAS) or repetitive TMS (rTMS). Penetration-aspiration scores and bolus transfer timings were assessed before and after both real and sham interventions using videofluoroscopy.  Corticobulbar excitability of pharyngeal motor cortex was beneficially modulated by PES, PAS and to a lesser extent by rTMS, with functionally relevant changes in the unaffected hemisphere. Following combining the results of real neurostimulation, an overall increase in corticobulbar excitability in the unaffected hemisphere (P = .005, F1,17 = 10.6, ANOVA) with an associated 15% reduction in aspiration (P = .005, z = −2.79) was observed compared to sham.  In this mechanistic study, an increase in corticobulbar excitability the unaffected projection was correlated with the improvement in swallowing safety (P = .001, rho = −.732), but modality-specific differences were observed. Paradigms providing peripheral input favored change in neurophysiological and behavioral outcome measures in chronic dysphagia patients. Further larger cohort studies of neurostimulation in chronic dysphagic stroke are imperative.

title: Effects of non-invasive brain stimulation on post-stroke dysphagia: A systematic review and meta-analysis of randomized controlled trials
abstract: The primary aim of this review is to evaluate the effects of non-invasive brain stimulation on post-stroke dysphagia.



Thirteen databases were systematically searched through July 2014. Studies had to meet pre-specified inclusion and exclusion criteria. Each study's methodological quality was examined. Effect sizes were calculated from extracted data and combined for an overall summary statistic.



Eight randomized controlled trials were included. These trials revealed a significant, moderate pooled effect size (0.55; 95% CI=0.17, 0.93; p=0.004). Studies stimulating the affected hemisphere had a combined effect size of 0.46 (95% CI=-0.18, 1.11; p=0.16); studies stimulating the unaffected hemisphere had a combined effect size of 0.65 (95% CI=0.14, 1.16; p=0.01). At long-term follow up, three studies demonstrated a large but non-significant pooled effect size (0.81, p=0.11).



This review found evidence for the efficacy of non-invasive brain stimulation on post-stroke dysphagia. A significant effect size resulted when stimulating the unaffected rather than the affected hemisphere. This finding is in agreement with previous studies implicating the plasticity of cortical neurons in the unaffected hemisphere.



Non-invasive brain stimulation appears to assist cortical reorganization in post-stroke dysphagia but emerging factors highlight the need for more data.

title: Effect of Low-Frequency rTMS and NMES on Subacute Unilateral Hemispheric Stroke With Dysphagia
abstract: To investigate the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) and neuromuscular electrical stimulation (NMES) on post-stroke dysphagia.  Subacute (<3 months), unilateral hemispheric stroke patients with dysphagia were randomly assigned to the conventional dysphagia therapy (CDT), rTMS, or NMES groups. In rTMS group, rTMS was performed at 100% resting motor threshold with 1 Hz frequency for 20 minutes per session (5 days per week for 2 weeks). In NMES group, electrical stimulation was applied to the anterior neck for 30 minutes per session (5 days per week for 2 weeks). All three groups were given conventional dysphagia therapy for 4 weeks. We evaluated the functional dysphagia scale (FDS), pharyngeal transit time (PTT), the penetration-aspiration scale (PAS), and the American Speech-Language Hearing Association National Outcomes Measurement System (ASHA NOMS) swallowing scale at baseline, after 2 weeks, and after 4 weeks.  Forty-seven patients completed the study; 15 in the CDT group, 14 in the rTMS group, and 18 in the NMES group. Mean changes in FDS and PAS for liquid during first 2 weeks in the rTMS and NMES groups were significantly higher than those in the CDT group, but no significant differences were found between the rTMS and NMES group. No significant difference in mean changes of FDS and PAS for semi-solid, PTT, and ASHA NOMS was observed among the three groups.  These results indicated that both low-frequency rTMS and NMES could induce early recovery from dysphagia; therefore, they both could be useful therapeutic options for dysphagic stroke patients.

title: Bilateral Repetitive Transcranial Magnetic Stimulation Combined with Intensive Swallowing Rehabilitation for Chronic Stroke Dysphagia: A Case Series Study
abstract: The purpose of this study was to clarify the safety and feasibility of a 6-day protocol of bilateral repetitive transcranial magnetic stimulation (rTMS) combined with intensive swallowing rehabilitation for chronic poststroke dysphagia. In-hospital treatment was provided to 4 poststroke patients (age at treatment: 56-80 years; interval between onset of stroke and treatment: 24-37 months) with dysphagia. Over 6 consecutive days, each patient received 10 sessions of rTMS at 3 Hz applied to the pharyngeal motor cortex bilaterally, followed by 20 min of intensive swallowing rehabilitation exercise. The swallowing function was evaluated by the Penetration Aspiration Scale (PAS), Modified Mann Assessment of Swallowing Ability (MMASA), Functional Oral Intake Scale (FOIS), laryngeal elevation delay time (LEDT) and Repetitive Saliva-Swallowing Test (RSST) on admission and at discharge. All patients completed the 6-day treatment protocol and none showed any adverse reactions throughout the treatment. The combination treatment improved laryngeal elevation delay time in all patients. Our proposed protocol of rTMS plus swallowing rehabilitation exercise seems to be safe and feasible for chronic stroke dysphagia, although its efficacy needs to be confirmed in a large number of patients.

title: Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research
abstract: This article is based on a consensus conference, which took place in Certosa di Pontignano, Siena (Italy) on March 7-9, 2008, intended to update the previous safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings. Over the past decade the scientific and medical community has had the opportunity to evaluate the safety record of research studies and clinical applications of TMS and repetitive TMS (rTMS). In these years the number of applications of conventional TMS has grown impressively, new paradigms of stimulation have been developed (e.g., patterned repetitive TMS) and technical advances have led to new device designs and to the real-time integration of TMS with electroencephalography (EEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Thousands of healthy subjects and patients with various neurological and psychiatric diseases have undergone TMS allowing a better assessment of relative risks. The occurrence of seizures (i.e., the most serious TMS-related acute adverse effect) has been extremely rare, with most of the few new cases receiving rTMS exceeding previous guidelines, often in patients under treatment with drugs which potentially lower the seizure threshold. The present updated guidelines review issues of risk and safety of conventional TMS protocols, address the undesired effects and risks of emerging TMS interventions, the applications of TMS in patients with implanted electrodes in the central nervous system, and safety aspects of TMS in neuroimaging environments. We cover recommended limits of stimulation parameters and other important precautions, monitoring of subjects, expertise of the rTMS team, and ethical issues. While all the recommendations here are expert based, they utilize published data to the extent possible.