Connectomic Networks and Their Impact on Clinical Outcomes in Glioma Treatment: A Review

Abstract The emerging field of connectomics has provided an improved understanding of the structural and functional organization of the human brain into large-scale brain networks. Recent studies have helped define the canonical neurological networks and outline how considering their presence may aid in surgical decision-making in brain tumor patients. Gliomas represent one of the most common types of brain tumor and often involve displacement and/or infiltration of neurological pathways, suggesting an opportunity to use connectomic maps to improve patient morbidity and mortality based on oncofunctional goals. This review aims to provide a working knowledge of important neurological networks, examine the use of networks in surgical planning, and describe the current literature discussing the impact of these networks on clinical outcomes in glioma resection.


Introduction
An integrated understanding of the functional innerworkings of the brain remains a limiting factor in predicting neurological outcomes of diseases like gliomas and defining appropriate neurosurgical intervention. Up to 75% of glioma patients may have neurocognitive deficits; this remains challenging to study due to variability in patient baseline cognitive status, tumor size, and location, as well as limited availability of detailed postoperative neuropsychological testing. 1 Although abundant research has been dedicated to learning about the structural and chemical properties of the brain, the connective organization of the brain is largely unknown. 2 Neuronal tracts within the brain create functional parallel networks to share and process information. 3 Gliomas can impact these multiple, interrelated neurological networks in unclear ways that add complexity to clinical outcome prediction.
Connectomics is the study of the brain's entire set of neural connections ("connectome"), that is, the white matter connections that carry information between cortical and subcortical structures. Since the inception of the Human Connectome Project in 2010, the field Keywords ► connectomics ► glioma ► glioblastoma ► neurooncology ► networks

Abstract
The emerging field of connectomics has provided an improved understanding of the structural and functional organization of the human brain into large-scale brain networks. Recent studies have helped define the canonical neurological networks and outline how considering their presence may aid in surgical decision-making in brain tumor patients. Gliomas represent one of the most common types of brain tumor and often involve displacement and/or infiltration of neurological pathways, suggesting an opportunity to use connectomic maps to improve patient morbidity and mortality based on oncofunctional goals. This review aims to provide a working knowledge of important neurological networks, examine the use of networks in surgical planning, and describe the current literature discussing the impact of these networks on clinical outcomes in glioma resection. of connectomics has garnered great interest in cognitive neuroscience and neurosurgery. 4 This momentum, alongside advances in magnetic resonance imaging (MRI) such as functional MRI (fMRI) and diffusion tensor imaging, has led to tremendous growth in efforts to map the brain's connectivity. 3 Additionally, commercially available software, such as Quicktome by Omniscient (Sydney, Australia), can generate patient-specific connectomic maps that enable presurgical planning and postoperative correlation with functional changes. Connectome data can be used in research of neurodegenerative and neurodevelopmental diseases, managing neuropsychiatric illness, and improving brain tumor therapy. 3,5,6 An improved understanding of the human connectome offers potential avenues to mitigate these challenges and is the next step in defining neurologic disease processes and uncovering better strategies to treat them. 7 This review aims to highlight the significance of the connectome and its major encompassing neuronal networks, as well as discuss its use in surgical planning and clinical outcomes of glioma patients.

The Connectome
The human cerebrum's entire set of structural and functional connections constitutes the human connectome.
While these connections can be represented at various macroscopic, mesoscopic, and microscopic levels, macroscale connections at the level of large white matter bundles are most actionable for neurosurgery at the current time. Importantly, as it has become clearer that functionally distinct regions support human behavior through interacting in dynamic large-scale brain networks, recent anatomic and lesion-based studies have also demonstrated that structural white matter connections often link these functional regions and brain networks-illustrating regions that fire together are wired together (►Fig. 1).
The primary networks are the default mode network (DMN), central executive network (CEN), salience network (SN), dorsal attention network (DAN), limbic/paralimbic network, visual network, and sensorimotor network (►Table 1). 5 The ventral attention network interacts closely with the aforementioned networks; however, its role is beyond the scope of this article. The language network is an additional part of the connectome closely tied to disease outcomes. Among these, the DMN, CEN, and SN are often considered the "cognitive control networks" (►Fig. 2), and damage or dysfunction in these networks often accounts for the majority of identifiable cognitive deficits in large-scale reviews. 5 However, each of the other networks often plays a critical role in information sharing through  interacting with these networks. Additionally, within the connectome are extensive subnetworks that assist in integrating and relaying signals throughout the brain. Surgical corridors avoiding component white matter tracts of these key connectome networks may improve surgical outcomes and postoperative cognitive function (►Fig. 3, ►Table 2). The scope of this review focuses on eight of the networks.

Default Mode Network
The DMN refers to the cortical networks active without externally directed attention or during activities associated with internalized states. 8 Although historically associated with non-goal-directed behavior or mind wandering, 9 the functional role of the DMN has been the source of continued debate and discussion. 10 Early observers described it as the dominant network during the brain's resting or baseline state that functions in the background when the brain is unstimulated. 11 Use of the term "task-negative network," which was previously used interchangeably with the DMN, has decreased as knowledge of the connectome has shown this definition to be mostly inaccurate. 12 The DMN is understood to be involved in a wide variety of goaldirected activities, including visuospatial planning 13,14 and task-switching. 15 Additional studies have also identified the role of the DMN in complex cognitive processes such as memory, sensory integration, and visual integration. 16 A significant amount of clinical interest in the DMN has developed because of its observable relationship with various brain diseases and nonpathological aspects of aging and neurodevelopment. 17,18 The DMN is involved in mental representations of the self and others, and disruptions in its connectivity are associated with changes in social and emotional processing that occur in disorders such as posttraumatic stress disorder, autism spectrum disorder, and schizophrenia. 19,20 Multimodal imaging studies of the DMN indicate its structural organization as multiple interacting hubs and subsystems. 21 In 2008, Buckner et al 21 compared studies mapping the DMN to identify the greatest locations of convergence as the medial prefrontal cortex, the posterior cingulate cortex/retrosplenial cortex, and the inferior parietal lobule. Other subcortical locations are also critical components of the network. An updated review in 2019 by Buckner et al 22 included studies of comparative anatomy using nonhuman primates and rodents that supported the existence of this convergent organization and outlined two primary networks (referred to as "DN-A" and "DN-B"), with separate coupling to the posterior parahippocampal cortex, that together comprise the DMN. The DMN's conceptualization as an interwoven network arrangement has been proposed to account for the contradictions in previously observed discrepancies between functional and structural connectivity. 22 A communicating network model allows a dimensionality layer that consolidates direct and indirect network interactions. In a 2011 review, Sporns 23 noted that this network understanding provides a more dynamic sense of the DMN's place in the connectome, adding that this also explains how aberrations in one network can dysregulate ostensibly unconnected areas of the brain.
The risk of having nontraditional regions of eloquence affected by gliomas may be as high as 93%. 24 These nontraditional areas are extensive throughout the brain's connectome and are involved in higher cognitive functions; their disruption can significantly worsen quality of life by impairing mentalizing and theory of mind in affected individuals. 5 The DMN is often implicated in these nontraditional eloquent areas, 24 in part because of the multiple interacting subsystems within the DMN. 18 Thus, damage to any of its nodes can result in whole-brain functional connectivity decline beyond solely local effects. 25 Additionally, the left parietal and temporal DMN nodes have been implicated as significant contributors to neurocognitive decline when damaged by cytotoxic edema and lesions invading white matter tracts. 26,27 Connectivity loss can also be a consequence of overly extensive resections. Patients with reduced connectivity from regions interacting with the parietal and temporal DMN displayed worse language processing and verbal and visual working memory. 28 In brain tumor patients with akinetic mutism and DMN disruption, restoring DMN synchrony may provide an opportunity to regain function after surgery. 29 The DMN network may play a role in higher cognitive function after glioma surgery, and disruption at any point along the medial prefrontal cortex, cingulate cortex, inferior parietal lobule, and temporal can potentially impact patients.

Central Executive Network
The CEN-in many ways the opposing network of the DMNis the network mostly associated with goal-directed behavior and planning, decision-making, and externally directed attention. 30 Other terms commonly used to describe the CEN include the frontoparietal and task-positive network, reflecting its structure and function, respectively. 31 The CEN is heavily involved in working memory and task attention, making it a common area of study in relation to conditions such as schizophrenia, where these functions are impacted. 31 As expected, based on its wide variety of functions, altered activity in the CEN is observed in most neuropsychiatric disorders. 30 CEN control is prominent during activities requiring emotional regulation and behavioral inhibition, and connective disruption may contribute to affective symptoms in conditions such as social anxiety disorder and obsessive-compulsive disorder. 32,33 Likewise, the amount of CEN structural dysfunction from disease states or injury may correlate with the level of dysfunction, such as the frequency of antisocial behavior. 34 However, CEN abnormalities may not always lead to psychiatric symptoms. For example, decreased CEN activity is also seen in research participants with a family history of psychosis, even when they do not have psychosis themselves. 35 Originally grouped with the DAN, the anatomy of the CEN has since been primarily localized to the anterior cingulate cortex (ACC), inferior parietal lobe, and posterior middle and inferior temporal gyri. 36,37 As described by Uddin et al, 38 lesser-known areas associated with the CEN include the dorsal precuneus, posterior inferior temporal lobe, dorsomedial thalamus, and head of the caudate. When considered in isolation, the CEN has a uniquely outsized impact on cognitive function, especially in age-related cognitive decline. 39 Interestingly, alterations in the DMN, rather than the CEN, have been implicated in the cognitive deficits and executive dysfunction seen in patients with glioma. 40,41 The CEN is also an important integrator within the connectome, and a comprehensive understanding of its role must include its relationship with other brain networks. Shortened and unbalanced cross-network CEN interactions, particularly between the CEN and the SN, are thought to underlie conditions such as attention-deficit/hyperactivity disorder. 42 Mindfulness training strengthens this functional connectivity, which may explain some of its beneficial effects on executive control and focus. 43,44 Similarly, adaptive changes in CEN connectivity may also predict response to treatment for depression and posttraumatic stress disorder. 45,46 Patients with high-grade tumors may be more susceptible to functional impairments because of the relative absence of neuroplasticity; however, predicting patient outcomes after high-grade glioma surgery is challenged by the pathway variability among tumors. 47 Although slow-growing, low-grade tumors display efficient cortical plasticity and remapping around the lesion, the long-range white matter connections may still be vulnerable. 48 Executive function impairments are among the most frequent impairments after glioma surgery. The CEN can be compromised significantly in patients with diffuse glioma in the frontal, temporal, and parietal lobes. The ability of general processing, critical reasoning, problem-solving, and retaining knowledge and skills through long-term memory can be diminished. In a study of 100 patients by Morell et al, 24 patients with brain tumors and associated neurologic deficits had on average 3.42 affected networks seen on preoperative MRI versus 2.19 affected networks in patients without deficits, and the CEN was most commonly affected (49%), followed by the DMN (43%) and DAN (32%). The frontoparietal cortical areas interconnected by the dorsal perisylvian white matter are important for executive functioning, and damage to the dorsal frontoparietal and intralobar frontal tracts is correlated with worse executive function. Damage to the inferior parietal cortex and its caudal cortical projections leads to verbal fluency impairments. 48 Overall, disruption of the CEN within the ACC, inferior parietal lobule, and temporal gyri can impact attention, cognitive processing, and executive function.

Salience Network
The SN comprises the ventrolateral prefrontal cortex (VLPFC), dorsal ACC, and anterior insula. 49,50 The SN is used in modulating activation of the DMN and CEN by detecting the presence of salient stimuli (cognitive, homeostatic, or emotional). 30,49,[51][52][53][54] Specifically, Goulden et al 52 confirmed that the SN is vital to switching between the CEN and DMN. The ACC and insula maintain reciprocal connectivity to each other and the motor and sensory regions of the brain. Therefore, these regions are ideally located to receive inputs needed to initiate the DMN and CEN switching. 37 This switching process is modulated by specific von Economo neurons found within the SN 55 that have been suggested to rapidly relay simple signals derived from information processed in the ACC and frontoinsular cortex (composed of the VLPFC and anterior insula) to other brain areas. 56 Notably, the SN is particularly weaker in children, and functional and structural maturation of these pathways is critical in brain network maturation. 57 Consequently, damage to vital SN structures, such as the insula, like damage to the DMN and CEN, has been linked to hallucination and psychosis in schizophrenia. 58 A growing interest in the neurosurgical community has been placed on the SN due to its major white matter bundle, the frontal aslant tract (FAT), being implicated in supplementary motor area (SMA) syndrome. 59,60 When operating in the SMA in brain tumor patients, damage to the FAT can cause SMA syndrome while a network-based approach which spares these fibers results in significantly reduced outcomes. 61 Furthermore, transcallosal FAT connections connecting premotor area to the contralateral premotor and SMA through the corpus callosum can facilitate recovery from SMA syndrome. 62,63 It has been hypothesized that a prefrontal cognitive initiation axis exists, where the DMN (linked by the cingulum) and the SN (linked by the FAT) from a strip across the medial frontal lobe extending up until the SMA, and that this axis is responsible for internally modeling goal initiation. 5 Thus, damage to this axis or the FAT fibers may result in a loss of the initiation of spontaneous, internally motivated actions (e.g., as in abulia and akinetic mutism). 61,64 The glioma literature has been less clear in understanding the role of SN resting-state function connectivity. One group found no significant differences in SN in glioma (n ¼ 12), 65 while another group found decreased SN connectivity (n ¼ 13). 66 Neuronal plasticity due to structural reorganization and functional remodeling among these neuronal networks caused by gliomas may alter the clinically observable cognitive manifestations. [67][68][69] Sparacia et al 70 also evaluated the SN in high-grade supratentorial glioma resection. Although their study showed wide variations in functional connectivity before and after surgery on resting-state fMRI (rs-fMRI), they found a significant correlation between the SN and the language network, the SN and the DMN, and the SN and the sensorimotor network.
A recent study by Yang et al 71 suggested that average SN resting-state functional connectivity was lower in patients with gliomas, and the severity of functional connectivity loss was correlated with tumor grade and location. Their group also noted increased amplitude of low-frequency fluctuations on rs-fMRI in specific SN regions, notably the right anterior insula. These findings suggest an explanation for the cognitive deficits these patients experience. 72 Notably, their results indicate that tumors located in the frontal and anterior temporal lobes, near vital SN regions, gave rise to lower SN resting-state functional connectivity compared to healthy controls. Tumors in posterior regions did not produce a significant difference. High-grade gliomas produced more striking overall decreases in SN resting-state functional connectivity. 71 This may be due to increased infiltration and disrupted functional reorganization 73,74 or neurovascular uncoupling resulting in false-negative interpretations. Interestingly, their study also demonstrated only slightly decreased SN resting-state functional connectivity in recurrent gliomas (n ¼ 28) compared to newly diagnosed lesions. Overall, injury to the SN involving the VLPFC, ACC, anterior insula, and FAT can diminish higher cognitive function, switching between CEN and DMN function and spontaneous activity. However, the role of the SN in gliomas remains to be better uncovered.

Dorsal Attention Network
The DAN is organized bilaterally, composed of the dorsolateral prefrontal cortex, middle temporal motion complex, superior parietal lobule, intraparietal sulcus, and frontal eye fields within each hemisphere. [75][76][77][78] The DAN is necessary to orient focus to a particular task. 79 Therefore, these areas become active when attention is overtly or covertly oriented in space during visual attention (i.e., spatial attention, feature attention, and object attention). [80][81][82][83][84] Corbetta and Shulman 77 also suggested that the DAN is vital in goaldirected top-down processing. Rajan et al 85 suggested the organization of top-down attentional control signals within the DAN, arguing against previously proposed models of the DAN (domain-general and supramodal models). They proposed a functional microstructure of attentional control mechanisms within the DAN that could serve as precise topdown projections to sensory structure. These projections may function as part of stimulus processing requirements according to behavioral goals.
The DAN is involved in multiple diseases, including gliomas. In 2021, Tordjman et al 86 aimed to understand the disruption of the DAN (in addition to DMN and CEN) using seed-based connectivity analysis and independent component analysis. Their study indicated that functional connectivity in the DAN is altered in glioma patients at rest, with consistently increased connectivity in the occipital region and medial prefrontal cortex and decreased connectivity in the subcallosal cortex and anterior cingulate gyrus.
Sparacia et al 70 evaluated the use of rs-fMRI in detecting this altered functional connectivity after high-grade glioma resection. rs-fMRI has been demonstrated to be useful in preoperatively localizing the eloquent cortex in an effort to reduce surgery-induced neurologic deficits. 87-90 Among their cohort undergoing left temporal glioblastoma resection, postoperative rs-fMRI revealed that functional connectivity tended to decrease in the DAN, demonstrating a functional disconnection. 70 This decrease in functional connectivity was more dramatic when compared with the sensorimotor network, language network, and DMN in the same patients. These data confirm that tumor presence can impact the connectivity of the DAN.
Patients with damage to their right-sided attentional networks, including the DAN, often experience left visual neglect, behaving as though the left part of the world does not exist. 91 This neglect may improve with time, although slowed response times to targets in their left visual field may persist. 92 A study of patients with low-grade glioma with lesions producing neglect (i.e., visual) confirmed the disconnection of the intermediate branch of the superior longitudinal fasciculus, the segment connecting the caudal node of the ventral attentional network to the rostral node of the dorsal network. [93][94][95] Preoperative brain plasticity and reorganization of the DAN and other attenuation networks in the setting of a lowgrade glioma may contribute to a patient's normal results on standard neuropsychological assessments, as surrounding regions may take on the eloquent roles and function of the invaded tissue. [96][97][98][99][100][101] This can be seen in patients with lowgrade glioma undergoing surgical resection who receive intraoperative electrical stimulation to assist in surrounding white matter tract preservation. Even during acute-phase postoperative deficits, complete recovery among these patients was possible within 3 months. 102 In sum, damage to the DAN within the prefrontal cortex, temporal lobe, superior parietal lobule, intraparietal sulcus, and frontal eye fields inhibits attention orientation and activity, which may impair higher cognitive function in glioma patients.

Limbic/Paralimbic Network
The limbic system is one of the earliest described networks. In 1878, Broca suggested the limbic system's role was primarily olfactory. 103,104 It was not until Papez discovered the "Papez circuit" that the role of the limbic network expanded to include memory and emotional processing. The hypothalamus, mamillary bodies, and fornix were identified as limbic structures as well as the amygdala, septal area, hippocampus, and cingulate cortex. 104 Moreover, the functions of the limbic system were further understood to include regulation of homeostatic, autonomic, and neuroendocrinological functions. [103][104][105] The limbic system also plays a role in anxiety and aggression as well as reward and addiction. 103,106 Because of the extensive role of the limbic system, its pathways are far-reaching and extend between most of the integral cortices and nodes in the brain. The brainstem and forebrain have limbic nodes with projections to higher cortical areas that contribute to behavioral and action modulation in response to internal and external stimuli. 103,106 As a network involving some of the most primitive brain structures, the foundation of the limbic system is promoting survival through regulating responses to external and internal stimuli. The brainstem and forebrain nodes of the limbic system govern regulatory processes such as respiration and contribute to how we adapt to stressors including emotional, immune, and cognitive stimuli. 105 Classically, the "fight or flight" response is attributed to the limbic network through stimulation of fear, arousal, and behavioral responses. Arousal is stimulated in the median and dorsal raphe and locus coeruleus and emotion in the amygdala. 105 There are also tracts from the orbitofrontal cortex to the amygdala involved in information sharing to regulate emotion and reward. 107 White matter tracts run between limbic structures and the DMN, SN, and CEN to modulate functional processes such as sensory perception, motor commands, spatial reasoning, and decision-making. 108 These tracts begin in nodes at areas including the pons, medulla, midbrain, and travel to the cerebral cortex to create a central homeostatic network. Extrinsic threats and intrinsic metabolic derangement signals are processed, and information is relayed. Interaction with the visual network, sensorimotor network, and CEN results in heightened attention, arousal, and visceral and somatic motor defenses. 105 The limbic system is critical to spatial and long-term memory storage via its hippocampal involvement and memory processing during sleep. 4,106,109 The ventral tegmental area is another important area within the limbic network that plays a role in motivation, reward, and arousal as well as possesses dopaminergic signaling. It has connections to the parabrachial pigmented nucleus and higher cortical regions serving as relay between autonomic and limbic networks to the cortex and other areas. The outcomes of the signal integration are involved in decision-making and reward-seeking behaviors. 110 The cingulate cortex is also part of the limbic network, 111 and its subdivisions including the middle, anterior, and posterior divisions are involved in action-outcome decisions (emotion and object recognition, respectively). 112 As can be inferred, there is no singular function to each structure within the limbic network, and there are many integrated roles and shared connectivity to govern a diverse range of functions. 111 The significance of the functional connectivity of structures within the limbic network can be best illustrated when considering the effects of damage to different pathways. In patients with damage to the ACC, impairment in action-outcome learning and rewardseeking behaviors has been documented. Reward-seeking behaviors relay signals to the hippocampus to form episodic memories, and deficits will be seen if this connectivity is disrupted. 113 Gliomas originating throughout multiple cortices can influence limbic connectivity. In a study of rs-fMRI after cingulate tumor resection, connectomic analysis found that the networks potentially disturbed by the approach and surgical corridor contributed to postoperative development of major depressive disorder. Not only is tumor location an important consideration when identifying adverse outcomes of treatment but also the surgical approach or penumbra affected by radiation can be vital to normal functional connectivity. Avoiding limbic network disruption and connectomic mapping may be useful in avoiding these complications but require further clinical correlation. 114 The insula is a frequent site for primary and secondary tumor resection due to its critical network role and proximity to deeper subcortical regions.
Interestingly, glioma spread within the insula follows stereotypical anatomic patterns, which have been used as prognostication tools. One study found insular gliomas tend to involve the olfactocentric limbic girdle and that those in the hippocampal centric limbic girdle are associated with poorer prognosis. 115 Although surgical approaches to the anterior insula have generally been more favorable in avoiding neurological deficit than posterior insular resection, integrating connectomics and functional mapping may improve outcomes and the extent of resection. 116 Overall, while damage to the limbic structures has a known impact on memory, many recent studies support its role in cognitive processing, arousal, and coordination with other brain networks.

Visual Network
The visual system controls sight and visual processing, but its coordination with other networks is much more complex. 117 As one of the earliest established networks, the basic pathway of the visual system involves tracts running from the retina, optic nerves, and lateral geniculate nuclei to the visual cortex in the occipital lobe. 118 There are multiple nodes within the visual cortex with unique roles, including V1, which processes the initial signals from the retina, and V2 and V3, which receive relayed information from V1. 118 Many processes in the visual network such as facial recognition and body recognition are signaled along distinct pathways. 119 The dorsal visual circuit is responsible for object perception, global motion perception, and visual stimulus processing, while independently the ventral circuit has a greater role in recognition and is closely integrated with the limbic system for facial, body, and place recognition. The visual system has key relationships with the DAN and sensorimotor network because vision is integral for movement coordination and visuospatial awareness. 118 The limbic system, SN, and visual network have extensive functional connectivity, and integrating these systems plays an important role in eliciting emotion and feelings of empathy. 120 Visual stimuli and memory require signal sharing along pathways in these networks. 121 There are also strong functional connections among nodes in the visual system, amygdala, subcortical network, and hippocampus. This can be seen in studies using verbal versus visual stimuli to elicit memory retrieval and emotional responses. Visual cues engage with many limbic structures to modulate emotional processes. 122 The relationships among the visual system, memory, and emotion are also appreciated in instances of damage to the occipital lobe. Visual processing of emotional stimuli travels between subcortical structures and nodes in the amygdala and can be affected by destruction of V1 nodes in the visual system. 123 Further associations between the limbic and visual networks are recognized with respect to survival and processing of threats. Fear due to implicit and explicit stimuli elicits different responses because of the activation of different pathways. External stimuli from visual cues can send signals through the parahippocampal gyrus and pulvinar, whereas implicit fear activates the cerebellum and amygdala then ascends to the cortex. 124 The dorsal pathway of the visual network is involved in global motion perception 125,126 and is heavily modulated by spatial attentiveness. 127,128 The ventral network tracts relay information for object recognition. 128 The sensorimotor system is also closely integrated with the visual system. For example, children with autism spectrum disorder with greater discrepancies in visual-sensorimotor functional connectivity can show greater social deficits. 125,129 Hypoconnectivity between the DMN and visual and attention networks is also seen in autism spectrum disorder. Visual pathway integration into wider cortical networks remains to be explored in glioma treatment and postsurgical patients.
Focal disruption of the DMN can result in deficits in visual processing. The precuneus of the DMN is an intersection of multiple other networks such that tumors in this region lead to compensatory hyperconnectivity in tracts of the SN, DAN, and visual network. 130 The connectome redistribution of adjacent and remote areas to the tumor region suggests compensatory neuroplasticity that may play a role in function preservation after tumor excision. 131

Sensorimotor Network
First discovered in the 1870s, the sensorimotor network was identified in dogs by Eduard Hitzig alongside Gustav Fritsch, who observed that the electrical stimulation of the dog brain cortex contributed to limb movements. 132 Further classification of facial and upper extremity movement after stimulation of brain cortices was then conducted by David Ferrier. 133 The sensorimotor connectome encompasses brain regions responsible for controlling feeling, audition, and motor functions to integrate sensation inputs into smooth and appropriate coordinated movement and reactions. At a molecular level, these correspond to electrical signals (i.e., action potentials) that propagate physical responses.
Surgeons are especially careful when operating around the primary motor and somatosensory cortices. These brain regions include the primary motor and sensory cortex (and respective premotor and parietal lobe cortices), subcortical gray motor areas (e.g., thalamus, caudate, putamen, pallidum), cingulate cortex, inferior occipital gyrus, and SMA. [134][135][136][137] The developmental trajectories of these topological modifications are system specific: sensorimotor systems develop adult-like topological properties by late childhood, while integral connection topology of connected brain regions continues to develop into early adulthood. 138 It has been shown that the primary motor, somatosensory, auditory, and visual cortices demonstrate interregional plasticity that may impact recovery after glioma surgery. 139 Although this plasticity is greatest in children, it can occur even in adulthood; for instance, fine motor skills/movements lead to cortical reorganization in sensorimotor and related learning connectomes. 140 Interestingly, this motor learning process also occurs during sleep, particularly during the active rapid eye movement stage of sleep, which improves and maintains the sensorimotor connectome. 141 Increased resolution and accuracy of these underlying neural connections has led to the discovery and new understanding of functional motor and sensory areas. 142 Primary sensorimotor areas contain nodes responsible for tactile and sensory stimulus processing, including the fine motor movements that proceed, accounting for implications in visual learning: (1) The cingulate cortex is responsible for motor planning and coordinates movement of muscles with the SMA and the spinal cord. (2) The SMA is implicated in post-visual cue processing (i.e., goal-oriented behavior coordination); further, this process appears to have directional functionality. (3) The dorsal premotor cortex participates in association of information cues to bodily movements. (4) The ventral premotor cortex is involved in active movements and their associated learned behaviors and also includes the language processing center, Broca's area. 134,[143][144][145] The sensorimotor connectome has functional significance and relationship with the hearing/vestibular, visual, and limbic systems, as well as the SN, CEN, DAN, and DMN. [146][147][148][149][150][151][152] When these systems are dysregulated by too much or too little activity, physical and mental illnesses can ensue. 153 Diffuse low-grade gliomas are often found in functional brain regions, such as the frontal lobe involving the SMA. Because of the relationship with other connectomes and subnetworks, indirect implications of sensorimotor dysregulation are possible, although many patients can have mild to no deficits. This is likely related to the progressive slow-growing course of these tumors giving time for remapping. Neuroplasticity of the connectomes surrounding tumors may manifest in different ways such as remapping within the tumor, redistribution around the tumor, remote area compensation, and contralateral hemisphere compensation. 130 This directly contrasts highgrade tumors, or acute pathology (e.g., infarcts), where abrupt onset leads to neuronal cell death.
The handling of low-grade versus high-grade gliomas can differ with the knowledge that networks affected by lowgrade tumors have greater neuroplastic potential to remap. 154 Treating gliomas with a connectome-based resection can lead to resection of structures previously thought of as inoperable while yielding good neurological recovery. Mapping has led to refinement of awake surgery. 155 The philosophy has evolved from resecting diffuse gliomas from oncological boundaries to maximal safe resection according to functional limits. 156 rs-fMRI can be reliably used to map sensorimotor function preoperatively. 157 As we look to the future, advances in connectomic mapping with real-time function monitoring with awake surgery for gliomas in the motor strip and sensorimotor regions will be essential. 154 Nevertheless, the determination of which brain areas should be targeted for gross total resection in glioma patients is multifaceted and highly individualized. It depends on numerous factors (e.g., tumor size, location, patient goals, primary vs. secondary recurrence, and patient age).

Language Network
The language connectome is mainly responsible for articulating and delivering verbal and written thought while simultaneously participating in the comprehension and processing of received input. 158,159 Moreover, the language connectome is not understood to be one of the seven main human connectomes because of the many required integrations with other brain networks and rich connectivity along with postprocessing that is essential for appropriate function (i.e., there is no particular brain region responsible for these actions). 160 Uniquely, language is a coveted network that requires multiple dependent and independent connectomes in precise orchestration to achieve as simple an output as "hello." 143 As one of the connectomes that has been described for centuries, the language network has received special attention from surgeons because of its rich connections with the visual and sensorimotor connectomesparticularly, protecting this connectome is essential to preserving independent function of language and associated processing but also has implications in vision and movement. 161 The associated brain regions of the language connectome include the lateral prefrontal cortex, left temporal regions, left dorsomedial prefrontal cortex, inferior frontal gyrus, superior temporal cortex, and anteroinferior left temporal gyrus. 162 These anatomic connections implicate connectivity with the visual, auditory, and sensorimotor connectomes, which describe functional significance for hearing and listening, reading, and speech. Furthermore, connection of the language connectome with the CEN connectome implicates a task specification role, connection with the DAN connectome implicates focus, and connection with the DMN connectome implicates contemplation. 162 As we further develop understanding of this involved connectome, novel implications regarding verbal and written word delivery, comprehension, and language processing may help us understand deficits and find treatment options.
Because of recent connectomic analysis, the concept that language is primary left-sided is being adapted to a new dorsal-ventral stream model, which has recently been further improvised to describe pairs of dorsal and ventral streams, connecting the prefrontal and temporal areas via connections between the temporal and premotor cortices as well as the temporal cortex and Broca's area, respectfully (e.g., patients with left-sided slow-growing lesions may develop right-sided language function in response to localized pathology). 163,164 These new insights provide understanding into the language connectome that challenge traditionally accepted methodologies and have the potential to provide novel breakthroughs in treatment and our understanding of neuroscience.
Identified in the early 1860s, Broca's area in the left posterior interior frontal gyrus was defined as functional unit of word and speech production; this designation was later reclassified in 1874 by Carl Wernicke who identified another brain region located in the left posterior superior temporal gyrus (i.e., Wernicke's area) that impacted language function. 143,159 We now know the functional significance of both these regions with respect to word recognition and phonological action and presentation. 158,165 The connectomic relationship between the two brain regions has led to over a century of significant research. 161 This led to identifying the arcuate fasciculus and other white matter tracks that connect areas of the language connectome. 166 More recently, an area known as 55b was described in the left dorsal premotor cortex, which contains few myelinsurrounded neurons and was shown to be consistently active during language input (i.e., listening). 162,167 Recent advances in anatomic understanding of the language connectome have refined the key brain regions involved: the lateral prefrontal cortex, inferior temporal gyrus, anterior portion of the left inferior temporal gyrus, left temporal regions extending outside of Wernicke's area, left dorsal-medial prefrontal cortex, and superior temporal cortex. 168,169 Of note is that most of the language connectome resides on the left brain; however, right brain interactions have been identified during particular language processes (e.g., metaphor comprehension), indicating the potential language-driven task-dependent activation of the connectome and its associations. 168 Recent discovery of two language hubs has implicated new anatomic brain regions of importance, especially during surgery, due to their direct and anatomical relationship with language connectome components. 170 One of the common insults to occur to the language connectome occurs following a lesion or injury. In particular, when this pathology occurs between functional connections (i.e., white and/or gray matter tracts), this may lead to core cognitive deficits, language difficulties, and comprehension issues. 171 Other consequences with damage include neurological decline and aphasia, including difficulties in recognition and naming, 170,172 alexia, and agraphia; uniquely, agraphia has implications with language processing, motor planning, and visual perception. 167 Similarly, after insult to either the left hemisphere or white matter tracts of the language connectome, aphasia has been demonstrated to cause difficulty with reading, writing, listening, and speaking. 167 Gliomas affecting speech and language can be diverse because of the complex network that involves multiple cortices and extensive functional connectivity. In a cohort of patients with left-sided cerebral glioma, Yuan et al 173 used a machine-learning prediction model to discover how whole brain functional connectivity was altered by tumors in the region of the language network. Variability in the degree of impairment was seen in high-versus low-grade glioma, and long-distance lesion effects were appreciated in the reorganization of different functional networks. Alterations in connectivity seen on fMRI were predictive of language deficits, with changes in the temporal and prefrontal regions predictive of impairments in low-and high-grade glioma. Changes in the cerebellum and limbic system were also predictive of deficits in only high-grade glioma. 173 In a study of plasticity of the language and semantic network, van Dokkum et al 174 found that focusing on changes in one network affected by a tumor may not be suitable because many connectomes work in concert with one another. While analyzing picture naming pre-and postoperatively in patients with low-grade glioma compared with controls, they found extensive adaptive plasticity that may confer some protection to tumor infiltration. Decreased connectivity of middle temporal gyrus with superior temporal gyrus and inferior parietal lobe was compensated with increased input from right to left inferior parietal lobe, which is connected to left inferior temporal gyrus. Decreased connectivity between left middle frontal gyrus and left parahippocampal gyrus was associated with lower scores on picture naming. 174 Awake brain surgery provides for the ability of language monitoring during surgical manipulation to the brain. Still, there are limitations to the use of this surgical method because of the widespread functional significance of the language connectome. Nonverbal deficits that either could not or were not being monitored during awake surgery can appear postoperatively. 161 Using patient-specific brain maps, connectomics can pinpoint areas of specific function and help personalize operating and therapeutic decisions for individual patients. This level of granularity further increases surgical precision regarding understanding areas of language function, allowing for better surgical planning (i.e., the route of least connectomic disruption), and ability to predict for postoperative deficits. Age also has implications with regard to the language connectome; for example, children with congenital damage to the left hemisphere may show ageappropriate language development and a relatively lower incidence of the aphasic symptoms in contrast to adults who sustain similar brain damage in these areas later in life. 175

Conclusion
This study highlights many of the known connectomic networks and their structural areas and functional impacts in patients with gliomas. The literature regarding the impact of gliomas on the structure and function of these neural networks remains an area of active exploration. Future studies aiming to understand these networks will be important to better identify the critical components of a network and predict patient outcome after treatment. These can include evaluating subsets of patients, tumor locations, and standardized surgical approaches. In addition, exploration of the impact of tumor subtypes and mutational patterns on connectomic disruption remains to be explored. And lastly, detailed preoperative and postoperative neuropsychological testing and the impact of resection on specific pattern changes remains to be seen. The new insight into the human connectome offers an exciting future for further understanding the function of the brain and making surgical treatment gentler and safer.