The human insula plays a role in a wide range of cognitive functions including interceptive thoughts and salience processing.

Insular gliomas, which comprise roughly 25% of low-grade gliomas (LGG) and 10% of high-grade gliomas (HGG), pose a unique challenge to neurosurgeons given their complex anatomy (Duffau and Capelle, 2004; Renfrow et al., 2023). Cognitive impairment has a profound detrimental impact on long-term outcomes of glioma surgery including quality of life (QoL) and return to work status (Liu et al., 2009; Sanai et al., 2011; Hameed et al., 2018; Noll et al., 2018; Li et al., 2020). Evidence over the past 30 years suggests that insular glioma surgery can be safely performed with an acceptable morbidity profile (Sanai et al., 2011; Wu et al., 2011; Li et al., 2020). However, while most surgical series report perioperative speech and language outcomes, the breadth of recent neuroscience studies examining the functional role of the human insula have not been fully translated to patients with intrinsic tumors in this region. Specifically, there is a paucity of data describing how the vast cognitive functions of the insula are impacted by gliomas and their treatment (Table 1).

Clinically relevant cognitive impairment is caused by insular glioma as well as surgical resection. The higher-level cognition in patients with LGG and HGG involving the insula was first characterized in 2011. Patients with insular gliomas demonstrated poorer preoperative performance on visual confrontational naming tasks compared to matched controls (Baker et al., 2018). There was also a tendency for decline in the domains of learning, memory, executive function, and motor function (Wu et al., 2011). This study first suggested that cognitive deficits often go undetected outside of the research setting.

In this review article, we aim to sketch the cognitive footprint of insular glioma in a way that provides recommendations for neuropsychological testing and management of patients affected by this disease.

Despite tremendous interest from the neuroscience community, the insula remains one of the least understood cerebral regions. In 1955, Penfield and Faulk provided the first clues to insular function when they published findings from direct cortical stimulation (DCS) of the insula after temporal lobectomy in epilepsy patients. Patients reported a spectrum of sensations in contralateral body parts including warmth, numbness, shock, and tightness. Most stimulation sites were in the inferior and posterior insula as the superior region was poorly exposed after temporal lobectomy (Penfield and Faulk, 1955).

In more recent years we have come to realize that the complex anatomical features of the insula are matched by an equally as complex functional role (Table 2). The insula has functionally specific spatial organization. A 2010 large meta-analysis of functional neuroimaging experiments revealed at least three distinct functional regions (Kurth et al., 2010). The dorsal anterior insula (dAI) has connections to the frontal lobe, anterior cingulate, and parietal areas, and is most associated with cognition. The ventral anterior insula (vAI) with connections to limbic areas appears to play a role in socio-emotional processing. The posterior insula (PI) is most associated with sensorimotor processing and there is also a central region which is implicated in olfactory and gustatory function (Figure 1) (Kurth et al., 2010). The emergence of the Human Connectome Project (HCP) and connectomics have led to even further parcellations, with currently 13 insular subdivisions (Glasser et al., 2016; Baker et al., 2018; Morell et al., 2022). While the technical aspects of MRI acquisition vary depending (i.e., oncologic purposes compared to stereotactic electrode implantation or studying healthy populations), standard sequences, including diffusion weighted sequences, performed on 1.5 or 3.0 Telsa machines are adequate (Naidich et al., 2004; Uddin et al., 2014; Nomi et al., 2016; Uddin et al., 2017; Blustajn et al., 2019).

Insular gliomas were historically considered inoperable lesions given the surrounding complex anatomy. The insula is located at the depths of the sylvian fissure and is covered by the opercula of the frontal, parietal, and temporal lobes which are eloquent on the dominant side. It is anatomically segmented by three anteriorly projecting short gyri (posterior, middle, and anterior) and two posteriorly projecting long gyri (anterior and posterior) (Tanriover et al., 2004). The middle cerebral artery, with its perforator branches from the M2 segments, along with lenticulostriate arteries, provides the majority of the blood supply to the insula. These vascular structures often pose the most significant risks in insular glioma surgery and the lenticulostriate arteries in particular limit the medial extent of resection. Additionally, the insula is surrounded by eloquent white matter tracts: arcuate fasciculus (AF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFOF), and the corticospinal tract (CST) (Dziedzic et al., 2022).

Yaşargil et al. (1992) was the first to describe the transsylvian approach to insular tumors which he categorized based on location. The Berger-Sanai Classification has become the most common classification and can be used to predict extent of resection (EOR) and aid surgical planning. In this location-based classification, the insula is divided into zones (I anterior-superior; II posterior-superior; III posterior-inferior; and IV anterior-inferior) using a line along the sylvian fissure and bisected by a perpendicular line through the foramen of Monroe (Wu et al., 2011). Applying modern surgical techniques has extended the range of surgical options, leading to targeted resections with acceptable morbidity profiles, such as permanent speech deficits in 0–5% of patients and motor deficits in 2–10%.

There has been a shift in operative approach over the past 20 years. The transcortical method through non-functional “windows” is a common technique given the increased risk of retraction-induced ischemic damage from the transsylvian approach (Duffau et al., 2006; Menon and Uddin, 2010; Wu et al., 2011; Przybylowski et al., 2019; Pitskhelauri et al., 2021). The existing literature suggests that the morbidity profile for modern insular glioma surgery is acceptable (Table 3). While new or worsening language and motor deficits immediately after surgery are common, these symptoms are often transient with the majority of patients having resolution several months after surgery (Kurth et al., 2010; Wu et al., 2011; Ham et al., 2013; Glasser et al., 2016). Permanent speech and motor deficits are observed in 0–5% and 2–10%, respectively. It is important to note, however, that a new language deficit particularly speech, is associated with worse overall survival (OS). Speech deficits are commonly expressive in nature; however, with such limited data describing the effect of insular resection on NTENs, additional studies are needed. While preserving speech and motor function has been a central tenant of neurosurgical oncology, with respect to insular glioma, these neurologic functions merely scratch the surface of the functional capacity of the human insula. In fact, there is evidence that the human insula plays vital role in cognition and behavior, but the clinical impact of intrinsic neoplasms in this critical cerebral region remains poorly understood.

The steady flow of new studies describing the function of the insula has outpaced our ability to translate this knowledge towards management of insular glioma patients. Despite the complex functional role of the insula, many patients with insular glioma present without a noticeable clinical deficit. It is possible, however, that if they were examined by neuro-psychological testing, the presence of cognitive deficits could be identified. Addressing this problem is challenging because of obstacles to widespread and routine cognitive testing for glioma patients. Additionally, patients might have poor insight to their degree of cognitive impairment (Tucha et al., 2000). Functional plasticity is a phenomenon that likely explains these findings (Sanai et al., 2008; Satoer et al., 2016). An example is absence of apparent language impairment in dominant hemisphere of insular glioma patients despite tumor invasion of the operculum. Plasticity however often does not fully preserve function (Berzero et al., 2021).

The potential for radiographic biomarkers of cognitive function in brain tumor patients is emerging. Tumor volume was associated with effect on preoperative cognitive function in patients with LGG, including insula, as quantified by standard MRI sequences and voxel-based lesion symptom mapping (VLSM) The study consisted of 8 patients with dominant hemisphere insular glioma, and they demonstrated significantly poor performance in object naming. Additionally, VLSM revealed that for both left and right hemispheric glioma groups, 36% of patients with working memory (verbal and visual) impairment had insular involvement (Guarracino et al., 2022).

In a similar study using resting state fMRI, ipsilateral and contralateral connectivity in treatment-naive patients with insular LGG were examined and demonstrated the functional plasticity specifically exhibited by the dominant insula. The authors report significantly increased functional connectivity in 33 edges originating from the dominant insular lobe in patients with non-dominant insular gliomas. This suggests that when glioma cells infiltrate the non-dominant insula, the dominant hemisphere compensates by strengthening original functional connections. In contrast, when LGG originates in the dominant insular lobe, the non-dominant insular lobe must compensate by increasing connectivity to nodes in bilateral hemispheres (Fang et al., 2021). Identifying the biologic factors that alter network dynamics will help to define the cognitive impact of insular glioma.

Understanding of cognitive outcomes in insular glioma patients has evolved yet remains incomplete. The insula’s function as a hub for multimodal sensory processing and emotional regulation further complicates the assessment of these deficits. Modern surgical techniques have decreased the rate of permanent speech and motor deficits. Despite these advances, a significant gap persists in understanding the long-term cognitive and subclinical impacts on patients, especially as survival rates improve. Promising avenues for future research include the use of advanced neuroimaging to characterize cognition radiographically and studies aimed at elucidating the biological factors that alter network dynamics. As the focus shifts toward supramaximal safe resections, further exploration is warranted in three specific areas: 1) the complex functions of the insula to better predict cognitive outcomes, 2) the impact of surgical techniques on cognitive functions, and 3) the development of reliable methods for longitudinal cognitive assessment. Such comprehensive research will allow us to have a meaningful impact on the quality of life for insular glioma patients by understanding with greater clarity the cognitive burden of their disease and risk–benefit profile of surgical intervention.

NN: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. BE: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. AW: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing. FP: Conceptualization, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing. RY: Conceptualization, Investigation, Supervision, Writing – original draft, Writing – review & editing. IG: Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.