Effects of Insular Cortex on Post-Stroke Dysphagia: A Systematic Review and Meta Analysis

Objective: To investigate the relationship of lobar and deep brain regions with post-stroke dysphagia (PSD). Method: The databases of Medline, Embase, Web of Science, and Cochrane Library were searched from the establishment to May 2022. Studies that investigated the effects of lesions in lobar and deep brain regions on swallowing function after stroke were screened. The primary outcomes were PSD-related brain regions (including aspiration-related and oral transit time-related brain regions). The secondary outcomes were the incidence rate of PSD. The brain regions with the most overlap in the included studies were considered to be most relevant to PSD, and were presented as percentages. Data were compared utilizing the t-tests for continuous variables and χ2 for frequency-based variables. Result: A total of 24 studies and 2306 patients were included. The PSD-related lobar and deep brain regions included the insular cortex, frontal lobe, temporal gyrus, basal ganglia, postcentral, precentral, precuneus, corona radiate, etc. Among these brain regions, the insular cortex was most frequently reported (taking up 54.2%) in the included studies. Furthermore, the total incidence rate of PSD was around 40.4%, and the incidence of male was nearly 2.57 times as much as that of female (χ2 = 196.17, p < 0.001). Conclusions: In lobar and deep brain regions, the insular cortex may be most relevant to PSD and aspiration, which may be a potentially promising target in the treatment of PSD.


Introduction
Strokes are common diseases; in the aggregate, they are among the leading causes of mortality and long-term disability in developed countries, and their incidence is increasing as the population ages. There are an estimated 100 million individuals living with stroke sequelae worldwide, which has an enormous impact on patients' quality of life and raises the financial burden of medical treatment [1]. Post-stroke dysphagia (PSD) is a major complication or significant sequelae after stroke, which may manifest as aspiration, pharyngeal residual, delayed swallowing initiation, etc., and be closely related to aspiration pneumonia, starvation, and dehydration [2][3][4]. Early data suggest that it affects 29-78% of patients with stroke and is linked to a higher risk of hospital readmissions and death [5,6]. Besides, other PSD-related factors include advanced age, unilateral spatial neglect (USN), etc., because of the decline of physiological functions [7,8].
Full texts of screened publications were examined based on the inclusion criteria and study quality. To comply with the PRISMA statement, the reviewers pilot-tested eligibility criteria and presented a flow diagram of study selection. The characteristics of study included publication year and first author, while characteristics of patients included numbers of patients, locations of stroke, phases of stroke, diagnosis methods of stroke, image analysis methods, evaluation of PSD, days to stroke evaluation, days to PSD evaluation, age, gender, rates of PSD, PSD-related brain regions, aspiration-related brain regions, and oral transit time (OTT)-related brain regions. The primary outcomes were PSD-related brain regions (including aspiration-related and OTT-related regions), and the brain regions related to dysphagia in studies were presented as percentages. The secondary outcomes were the incidence rate of PSD. If data extraction could not be completed, important missing data were first requested from the corresponding author of the studies.

Quality Assessment
We utilized relevant elements from the Cochrane Collaboration's risk of bias checklist [27]. Two authors (QJ and XC) independently evaluated factors as Yes, No, or Unclear. Disagreements were resolved by discussion with the third author (ZMW). We documented additional factors, including study design, timeline for data capture, assessor-blinded, consistent assessment for all patients, declared operational definition for outcome, and outcome addressed for all patients.

Data Synthesis and Analysis
The brain regions with the most overlap in the included studies were considered to be most relevant to PSD. The cortical surface maps were generated by BrainNet viewer software (www.nitrc.org/projects/bnv/ (accessed on 31 October 2017) and Mricon software (www.mccauslandcenter.sc.edu/MRIcro/mricron (accessed on 2 May 2016). Differences between groups were identified by the two-tailed independent-sample t-tests or χ 2 analyses for continuous variables and frequency-based variables (as appropriate). All statistical analyses were performed using SPSS software (version 23.0, SPSS/IBM, Armonk, NY, USA).

Result
A total of 3601 articles were screened, and the full text of 51 articles was reviewed. Finally, 24 studies (2306 patients) meet the inclusion criteria and are included in the final analysis. Figure 1 shows the PRISMA flow diagram. A detailed description and quality assessment of each article is provided in Tables 1-4.

Study
Number A total of twelve studies reported the effect of the insular cortex on PSD. These studies were conducted on an acute phase of stroke, investigated the potential lesion pattern related to PSD, and found that the right insular cortex is related to swallowing dysfunction and predictive for the development of dysphagia [11,16,29]. According to Hess et al., the MNI coordinates were X = −39, Y = −11, Z = 10, and the voxels were 799 [11]. Another two studies, conducted on right hemispheric strokes, reported that associations were found in the left insular cortex [29,39]. Furthermore, two studies conducted on supratentorial strokes by VLSM analysis demonstrated that the anterior insular cortex was associated with the prognosis of PSD [17,35]. The anterior insular cortex (MNI coordinates were X = 39, Y = 10, Z = 20) was related to impaired oral intake 4 weeks after stroke, as reported by Galovic et al. [17], and affected 54% of voxels. Besides, Galovic et al. reported the anterior insular cortex was also related to the time before oral feeding [35] and found a significant difference in the anterior insular cortex (MNI coordinates are X = 37, Y = 10, Z = 6) by the comparison between tube-dependency and no tube feeding patients, which affected 70% of voxels. The remaining six studies did not report the specific regions of the insular cortex.
We conducted a secondary analysis according to the data provided in the included articles. The results showed that the incidence rate of PSD was around 40.4%, which was significantly higher in the male than in the female population (χ 2 = 196.17, p < 0.001), while there was no statistical difference in incidence rate between ischemic and hemorrhagic stroke groups (χ 2 = 1.173, p = 0.279), as well as right and left hemispheric stroke groups (χ 2 = 0.648, p = 0.412) ( Table 4).

Discussion
The present study found that the PSD-related lobar and deep brain regions included the insular cortex, frontal lobe, temporal gyrus, basal ganglia, postcentral, precentral, precuneus, corona radiate, etc., in which the insular cortex might be most relevant to PSD and aspiration after PSD and was reported in 54.2% of included studies. Furthermore, the total incidence rate of PSD was around 40.4%, and the incidence of male was nearly 2.57 times as much as that of female.

The Lobar and Deep Brain Regions Participate in the Swallowing Function Regulation
The swallowing function is not only regulated by the medulla oblongata, but by the lobar and deep brain regions. Different lobar and deep brain regions participate in different aspects of swallowing function. For example, lobar regions like the parietal-temporal lobes are associated with oropharyngeal residue, while the somatosensory cortex governs and executes motions by controlling and providing feedback to the brainstem and is responsible for the laryngeal elevation and vestibular closure [13,45]. Besides, the deep brain regions are also involved in PSD. The basal ganglia are considered to participate in the sensory input of swallowing function [34,46], in which the internal capsule is involved in the oropharyngeal residue and aspiration after dysphagia [13,34], while the outer capsule is involved in laryngeal elevation and vestibular closure [13,35]. The periventricular white matter is related to the occurrence of PSD [12,31], and the corona radiata is related to the oropharyngeal residue, laryngeal elevation, and vestibular closure [13].

Insular Cortex May Be Most Relevant to PSD
The present study found that the insular cortex may be most relevant to PSD. The insular cortex is involved in an overwhelming variety of functions, including decision-making, complex social functions, addiction, and sensory processing, to represent feelings [47,48]. It is located in the deep brain part of the lateral fissure and covered by the parietal, frontal, and temporal lobes, which accept the projection fiber from the thalamic nucleus and participate in the swallowing coordination by sensory-motor integration [13]. Therefore, the insular cortex participates in the various aspects of the swallowing process, including OTT, tube dependency, pharyngeal transit time, and aspiration [17,25,31,35,37]. Damage to the insular cortex (e.g., brain trauma) is more likely to manifest as delayed swallowing initiation, decreased laryngeal elevation, and impairment of laryngeal vestibular closure [13,49,50].

Insular Cortex May Be Relevant to Aspiration after PSD
The aspiration is a common but serious sequela after PSD and is associated with abnormal swallow-breathing coordination [51]. The insular cortex may be involved in the aspiration process by participating in the swallow-breathing coordination. The swallowbreathing coordination center is often considered the medulla oblongata, in which the swCPG and respiratory center pattern generator (rCPG) participates in the regulation of swallow-breathing coordination directly [9,10]. A core aspect of swallow-breathing coordination is the reciprocal inhibition between swCPG and rCPG, and any injury or damage to the brainstem may lead to PSD and aspiration [52].
Meanwhile, the lobar and deep brain neural networks also play an important role in swallow-breathing coordination. On the one hand, the insular cortex participates in the coordination of swallowing function. The previous studies adopted fMRI to explore the features of the cerebral cortex for PSD patients and found that the insular cortex was activated obviously during the swallowing task [50]. For healthy volunteers, the insular cortex was also activated, and the functional connection was enhanced between the insular cortex and other brain regions during swallowing tasks, including the sensorimotor cortex, frontal lobe, and parietal lobe [49]. Besides, damage to the anterior insular would cause more serious symptoms, manifesting as severely impaired oral intake requiring acute tube insertion [35].
On the other hand, the insular cortex also participates in the coordination of respiratory function. Brain imaging studies have provided evidence that dyspnea is associated with activation of the insular cortex [53]. Meanwhile, Trevizan-Baú et al. adopted holera toxin subunit B (CT-B) for the retrograde tracing of the neural regulation of breathing and found that insular exists alongside a great number of neurons with CT-B labeled [54]. Van et al. used the pseudorabies virus (PRV) inoculation into the thyroarytenoid muscle, which participates in the breathing-swallowing coordination, showing that the PRV transfer from the peripheral to the swCPG, rCPG, hypothalamus, insular, and motor cortex. Besides, the different insular cortex regions might be involved in different breathing patterns, and damage to the posterior insular cortex is more likely to manifest as respiratory excitatory responses, while the anterior insular manifests as inhibitory respiratory responses [55]. Therefore, the insular cortex (especially the anterior insular) might be involved in the occurrence of aspiration after PSD by participating in the regulation of swallow-breathing coordination.
According to the previous research, we proposed a new hypothesis for the mechanism of the insular cortex on aspiration after PSD. Firstly, the brainstem receives input signals from peripheral organs (including the tongue, bronchial, and esophagus), in which the swCPG and rCPG located in the brainstem are reciprocal inhibition. Secondly, the thalamus receives input signals from the brainstem. Eventually, the insular cortex receives input signals from the thalamus. The stroke in the insular cortex may disturb the reciprocal inhibition relationship of swCPG and rCPG, which may lead to PSD and aspiration after PSD ( Figure 3).  A hypothesis for the mechanism of the insular cortex on aspiration after PSD based on previous studies. Firstly, the brainstem receives input signals from peripheral organs (including the tongue, bronchial, and esophagus), in which the swCPG and rCPG located in the brainstem are reciprocal inhibition. Secondly, the thalamus receives input signals from the brainstem. Eventually, the insular cortex receives input signals from the thalamus. The stroke in the insular cortex may disturb the reciprocal inhibition relationship of swCPG and rCPG, which may lead to PSD and aspiration after PSD. Note: PSD, post-stroke dysphagia; swCPG, swallowing center pattern generator; rCPG, respiratory center pattern generator. Green arrow, promotion; red arrow, inhabitation.

Clinical/Rehabilitative Implication of Normal Function for Insular Cortex
Several suggestions can be recommended according to our results. Firstly, the insular cortex participates in the various aspects of swallowing and can be a potentially promising target for the treatment of aspiration. For example, noninvasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct cur- A hypothesis for the mechanism of the insular cortex on aspiration after PSD based on previous studies. Firstly, the brainstem receives input signals from peripheral organs (including the tongue, bronchial, and esophagus), in which the swCPG and rCPG located in the brainstem are reciprocal inhibition. Secondly, the thalamus receives input signals from the brainstem. Eventually, the insular cortex receives input signals from the thalamus. The stroke in the insular cortex may disturb the reciprocal inhibition relationship of swCPG and rCPG, which may lead to PSD and aspiration after PSD. Note: PSD, post-stroke dysphagia; swCPG, swallowing center pattern generator; rCPG, respiratory center pattern generator. Green arrow, promotion; red arrow, inhabitation.

Clinical/Rehabilitative Implication of Normal Function for Insular Cortex
Several suggestions can be recommended according to our results. Firstly, the insular cortex participates in the various aspects of swallowing and can be a potentially promising target for the treatment of aspiration. For example, noninvasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), is a practical technique which has proved effective, and is widely used to promote the recovery of PSD [56]. However, the rTMS relies on accurate stimulation at specific brain regions to achieve clinical efficacy [57]. Therefore, the insular cortex may become the target in the treatment of PSD and aspiration. Secondly, brainstem stroke is reportedly the main incentive of PSD [58], however, the lobar and deep brain regions also participate in the swallowing function regulation [59]. After lobar and deep brain regions stroke, a comprehensive assessment may be needed to avoid serious complications according to our results.

Limitations
The present study has several limitations. First, the relationship between the brain stem and dysphagia is not investigated in the present study. Second, only studies that presented detailed stroke lesion sites were included, while those on the large areas of the brain regions were excluded, which might cause potential bias. Third, the studies included in the present research were limited to those in English, which may lead to bias. Fourth, the relationship between brain lesions and dysphagia after stroke was investigated based on qualitative analysis rather than quantitative analysis due to the limited data. Therefore, high-quality quantitative analysis studies are needed.

Conclusions
The PSD-related lobar and deep brain regions included the insular cortex, frontal lobe, parietal lobe, basal ganglia, etc., in which insular cortex may be the area most relevant to PSD and aspiration after PSD.