Introduction

The insular cortex (i.e., insula, Latin for "island") is a still poorly understood and hidden structure located deep in the human brain. This telencephalic lobe makes up only about 2% of the complete cortical surface area but is part of complex neural circuitry involving the higher cortex, limbic structures, basal ganglia, and autonomic system. Further, the insula is located adjacent to several critical structures, and pathology originating from this area may risk significant neurological morbidity and even mortality. Care should include a coordinated effort between primary and specialty care alongside strong rehabilitation and social support. These factors make the insula an area of continued basic and clinical neuroscientific research.[1]

Structure and Function

Structure

The insular cortex is a distinct lobe of the cerebral cortex and forms the floor of the lateral sulcus (i.e., Sylvian fissure) bilaterally. It can be grossly observed deep to the insular operculum, which is formed by the parietal, frontal, and temporal lobes. On axial magnetic resonance imaging (MRI) of the brain, the insula can be observed lateral-adjacent to the extreme capsule, with the claustrum, external capsule, then putamen appearing evermore medially. 

The insula is divided into distinct anterior and posterior areas by the insular central sulcus and demarcated by the surrounding peri-insular (circular) sulcus. The anterior insula is composed of the three short gyri (anterior, middle, and posterior) separated by two pre-central sulci, while the posterior insula is composed of two long gyri (anterior and posterior) separated by the singular post-central sulcus. The accessory gyrus is located on the anterior face of the insula, and the transverse gyrus connects the insula to the orbital surface of the frontal lobe. Finally, the limen insulae in the anteroinferior apex of the insula is the point where the mesial surface of the temporal lobe, anterior perforator substance, and inferior insular point come together. This is also where the middle cerebral artery (MCA) generally bifurcates. 

Function

The insula is important for gustatory and sensorimotor processing, risk-reward behavior, autonomics, pain pathways, and auditory and vestibular functioning. Translational work in animals and humans has demonstrated a link between the insula and a number of structures, including the neocortex (i.e., frontal, parietal, and temporal lobes), limbic cortex (i.e., olfactory bulb, anterior cingulum, amygdala, hippocampus, and thalamus), and basal ganglia. Injuries or lesions of the insula can thus manifest with symptoms corresponding to any of these structures. Further, functional magnetic resonance imaging (fMRI) has observed three major functional subdivisions with regard to neural circuitry (dorsal-anterior, ventral-anterior, and mid-posterior), although their specific connections are beyond the scope of this review. In general, the anterior part connects to more anterior structures related to emotional integration, and the posterior part connects to more posterior structures related to cognition. 

Three cytoarchitectonic areas of the insula have been described in the literature: the central agranular zone, the transition dysgranular zone, and the surrounding granular zone. The dysgranular zone has been implicated in executive functioning such as attention and memory.[2][3][4][1]

Embryology

The insula is a paralimbic structure that lies between the neocortex and the paleocortex (sometimes referred to as the mesocortex). Cortical structures begin to form around the sixth week of fetal development, and the sulci fully appear in the second trimester. From an embryological standpoint, the insular cortex is the most primordial structure of the telencephalon, arising from the anterior prosencephalon (i.e., forebrain) during development, with the limen insulae forming as a result of the inferior cortical region folding on itself.

After a series of complex rotations and folds, the insula is housed deep to the lateral sulcus with many connections to surrounding structures. Although isolated reports of insular malformations are rare, the insula's location and development process represent many opportunities for congenital cerebral disruption. Maldevelopment may be associated with lissencephaly, disorders of the adjacent basal ganglia, and others.[5][6][7][8][9]

Blood Supply and Lymphatics

Arterial Supply

The vascular supply to the insular cortex comes from short perforator branches from the superior division of the middle cerebral artery (MCA). These most commonly arise from the M2 segment (i.e., "insular" or "Sylvian" segment), which courses over the lateral surface of the insula within the Sylvian fissure. Some vessels from M1 may supply the limen insulae, while occasionally, branches of the M3 segment supply the peri-insular sulcus. The M3 segment of the MCA travels primarily lateral to the insular cortex and loops around the operculum, supplying the cortex distal to the insula. 

Venous Drainage

The venous drainage of the insula is complex and somewhat variable as a majority of cadaveric specimens demonstrate a mix of superficial and deep venous connections. The precentral insular vein is the most common drainage area of the superficial system, while the deep middle cerebral vein (DMCV) represents the predominant deep venous drainage conduit.[3][4][10]

Nerves

For surgery to the insula and Sylvian fissure, superficial nerves of the scalp should be preserved when possible during superficial dissection. For example, in a pterional (frontotemporal) craniotomy, the temporal branches of the facial nerve (CN VII) should be respected, given their supply to the frontalis muscle. The auriculotemporal (from CN V3) and zygomaticotemporal (from CN V2) nerves represent the somewhat variable sources of overlying superficial sensation of this area.[11][12]

Muscles

Similar to the superficial nerves, the superficial muscles overlying a chosen craniotomy site should be well known to the neurosurgeon. Interfascial dissection of the temporalis muscle for a pterional or subtemporal craniotomy is a common step required for a surgical approach to the insula.[13]

Surgical Considerations

The surgical management of insular lesions is particularly challenging, given the difficulty of accessing this region via the overlying eloquent operculae of the frontoparietal and temporal lobes and the intricate MCA vascular supply. Nevertheless, a better understanding of both gross and microsurgical insular anatomy, preoperative fMRI and diffusion tensor imaging (DTI) tractography, awake cortical mapping, and stereotactic and fluorescein guidance have collectively improved the ability of neurosurgeons to resect lesions in this area while respecting eloquent structures. 

Speech and motor areas are of particular concern when attempting to gain access to the insula. In a patient's dominant hemisphere (typically the left), the major language areas overlie the insula. Care is also necessary regarding the arcuate, uncinate, and inferior frontal-occipital fasciculi. The basal ganglia lie medial to the insula. Finally, although short perforators of the M2-MCA can be sacrificed during surgery, long branches must be preserved, as these supply the adjacent corticospinal tract in the corona radiata. Disruption of these vessels may thus lead to hemiplegia.[14]

Berger-Sanai Classification of Insular Gliomas

In 2010, after a growing understanding of the challenges of surgery to the insula, the Berger-Sanai surgical classification system for insular gliomas was developed. This system, which bisects the insula along two perpendicular planes, the lateral sulcus and a line through the Foramen of Monro, divides the insula into four zones. It is useful both for strategizing the surgical approach to the insula and for a pragmatic functional and anatomic understanding of the area. It has been validated as a predictor of the extent of resection and postoperative morbidity in the surgical resection of insular gliomas. The zones are listed below.[15][16]

• Zone I: Anterior-Superior
• Zone II: Posterior-Superior
• Zone III: Posterior-Inferior
• Zone IV: Anterior-Inferior

Surgical Approaches to the Insula

An incision and craniotomy under general anesthesia are required to access the brain parenchyma. Choice of craniotomy (i.e., pterional, temporal) may follow the lesion's location and the preferred surgical approach. The two main surgical approaches to the insula are the transsylvian and transcortical techniques, and there are advantages and risks to both. The ultimate goal is to maximize the extent of resection while minimizing surgical risk to adjacent structures, and thus, the choice is ultimately surgeon-dependent. There remains debate over the preferred approach.[17][18]

Transsylvian Approach

The transsylvian approach to the insula, via a wide exposure through the lateral sulcus, was the first-described technique. It is of particular benefit when accessing lesions in the dominant hemisphere since the operator can better spare the eloquent language areas of the temporal and frontal lobes. Disadvantages include a need for extensive subarachnoid dissection, the manual distraction of the MCA, and opercular retraction for large lesions. 

Transcortical Approach

The transcortical approach is increasingly used for large lesions that may extend beyond the confines of the peri-insular sulcus, especially posteriorly. Cortical and subcortical mapping is important to identify eloquent cortex, whereby exposure windows through non-eloquent areas may be accessed. There appears to be a preference for the transcortical approach for large gliomas and those located in Berger-Sanai Zone III. The transcortical approach may also be associated with lower ischemic morbidity for Berger-Sanai Zone II lesions.[16][14][19][20][15][21]

Clinical Significance

Glioma

Glioma is the most common primary tumor of the central nervous system. The insula is prone to the formation of gliomas, including low- and high-grade astrocytomas and oligodendrogliomas, as well as glioblastoma (GBM). The incidence of intracranial insular gliomas ranges from 10% to 25%, and demographic epidemiology follows that of all intracranial gliomas. Prognosis remains dismal, especially for high-grade tumors, with optimally treated GBMs observing median overall survival around 1 year.

Insular gliomas are classified by the aforementioned Berger-Sinai system, with "giant" status given to those involving all four zones. Neuro-functional and survival outcomes are dependent on a host of factors. Survival is associated with tumor characteristics such as pathologic grade, molecular genetics, resection rate, and utilization of adjuvant chemotherapy and patient characteristics such as age and functional status. Resection typically occurs by either the transsylvian or transcortical approaches. 

Complications of insular glioma resection include motor and executive dysfunction. Temporary and permanent motor deficits occur at rates of 11% and 4%, respectively, while temporary and permanent aphasia occurs at rates of 11% and 2%, respectively.[22][23][24][25][26][27]

Arteriovenous Malformation

Arteriovenous malformations (AVMs) are challenging to treat, and optimal therapy remains somewhat controversial depending on rupture status, location, and other factors. All AVMs can be classified by the Spetzler-Martin grading system (I-V) depending on the lesion's size, draining vein, and presence of regional eloquent cortex. Sylvian fissure AVMs near the insula represent a significant source of potential morbidity or mortality, especially for younger patients. Symptoms can present acutely with rupture or chronically due to mass effect. Sylvian AVMs can thus be further classified based on the location of their nidus by the Sugita system: medial, lateral, pure, and deep. The majority of Sylvian AVMs are either medial (40%) or lateral (40%). With improvements in radiosurgery technology and microsurgical techniques, the ability to manage Sylvian AVMs is becoming an increasingly interprofessional and successful venture.[28][29][30][31]

Stroke

Insular stroke can occur due to hemorrhagic (i.e., vessel rupture) or ischemic (i.e., thrombotic, embolic, or iatrogenic) insult. The MCA is the most commonly affected cerebral artery in acute stroke and presents with a wide range of symptoms, and thus it may be difficult to localize insular involvement based on the clinical exam alone. Further, strokes involving only the insular cortex are abundantly rare, with only 49 reports noted in the literature. Nevertheless, insular-confined strokes manifest as dysfunction of its anatomical-functional properties, including somatomotor deficits, dysarthria, aphasia, vestibulocochlear dysfunction, gustatory change, and behavioral-psychiatric disturbance. In general, insular stroke should be suspected in patients with paresis, speech deficit, and dizziness, with more proximal MCA strokes manifesting with the signs and symptoms of other areas accordingly. Diagnosis and treatment follow that of MCA strokes. [32][33][34]

Seizure and Epilepsy

Seizures arising from the aberrant and excessive neuronal activity may be provoked or unprovoked. Insular seizures may occur due to stroke or glioma but may also follow etiologically from genetic epileptogenic foci, metabolic derangements, or inflammation. With regard to insular epilepsy, manifestations are similar to that of temporal lobe epilepsy. Indeed, debate remains over the true epileptogenic origin of insular seizures (i.e., spread from temporal foci). This uncertainty is complicated by the deep location of the insula, making it difficult to observe seizure activity other than through invasive Phase II electroencephalography (EEG). There is some evidence of true insular epilpetogenic foci provided by video-EEG studies. Nevertheless, patients with insular seizures present with an ictal syndrome characterized by sensory and gustatory auras, dysautonomia, dysphagia, laryngeal constriction, aberrant movements (tonic-clonic or myoclonus), and/or vestibulopathy (i.e., nystagmus). Patients will tend to remain conscious of the event. Diagnosis and treatment follow that of other epileptic pathologies.[35][36]

Other Issues

As previously noted, the insula remains one of the least understood cortical structures of the human brain. Given its deep location and involvement in many neural circuits, there is an impetus to continue improving our understanding both through clinical and translational studies. New and improved diagnostic technologies such as EEG, fMRI, DTI, machine learning, and brain-computer interfaces (BCI) may elucidate the anatomic and functional characteristics of the insula to improve outcomes for patients. 

Depending on the pathologic entity, a patient may present to their primary care physician or the emergency department. Coordinated interprofessional care should subsequently involve neurology, neurosurgery, physiatry, occupational and physical therapy (OT/PT), and dedicated nursing care.