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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 43-49

Interactive relationship between neuronal circuitry and glioma: A narrative review

1 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
2 Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, Beijing, China

Date of Submission16-May-2022
Date of Decision07-Jun-2022
Date of Acceptance18-Jun-2022
Date of Web Publication26-Jul-2022

Correspondence Address:
Dr. Yu Lin
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_15_22

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Glioma is the most common primary central nervous system tumor. Despite extensive basic research on the tumor, the overall therapeutic effect of glioma remains unsatisfactory. Glioma grows within the framework of complex neural circuitry, which influences both neural network and tumor biology. On the one hand, the growth of gliomas continuously invades and destroys normal neural structures, which stimulate the dynamic remodeling of neural networks to maintain neural function. On the other hand, glioma can also induce neurons to form synaptic connections with it to promote tumor growth. Interventions targeting the interaction between gliomas and the neuronal circuitry provide opportunities for both tumor therapy and neuroplasticity at the same time. Noninvasive brain stimulation (NiBS) technology can actively regulate the excitability of targeted brain regions which can actively induce the remodeling of neural function and may perturb the interference of neuronglioma synapses. This article will review the interaction between gliomas and neural networks, including tumor-induced neuroplasticity, neuron-glioma synaptic connections, and the application and prospect of NiBS techniques.

Keywords: Functional reorganization, glioma, neural plasticity, neuronal circuitry, neuron-tumor synapse

How to cite this article:
Liu J, Shi W, Lin Y. Interactive relationship between neuronal circuitry and glioma: A narrative review. Glioma 2022;5:43-9

How to cite this URL:
Liu J, Shi W, Lin Y. Interactive relationship between neuronal circuitry and glioma: A narrative review. Glioma [serial online] 2022 [cited 2023 Feb 6];5:43-9. Available from: http://www.jglioma.com/text.asp?2022/5/2/43/352256

  Introduction Top

Glioma is the most common primary brain tumor, among which glioblastoma is the most malignant tumor, accounting for 49.1% of primary malignant tumors of the central nervous system.[1] Therapies targeting the glioma cell have translated to only limited success, and malignant gliomas remain the number one cause of brain tumor-related death in both children and adults.[1],[2] Glioma grows within the framework of complex neural circuitry, which influences both neural network and tumor biology.[3] On the one hand, the growth of gliomas continuously invades and destroys normal neural structures, which stimulate the dynamic remodeling of neural networks to maintain neural function. On the other hand, glioma can also induce neurons to form synaptic connections with it to promote tumor growth.[4] Interventions targeting the interaction between gliomas and the neuronal circuitry provide opportunities for both tumor therapy and neuroplasticity at the same time. Noninvasive brain stimulation (NiBS) technology can actively regulate the excitability of targeted brain regions which can actively induce the remodeling of neural function and may perturb the interference of neuron-glioma synapses.[5] Here, we review the interaction between gliomas and neural networks, including tumor-induced neuroplasticity, neuron-glioma synaptic connections, and the application and prospect of NiBS techniques.

  Retrieval Strategy Top

Literature review was electronically performed using PubMed database. The following combinations of keywords were used to initially select the articles to be evaluated: neuronal circuitry and glioma; neuron-tumor synapse; functional reorganization and glioma; neural plasticity and glioma; and NiBS. Most of the elected studies (90% of all references) were published from 2012 to 2022. An ancient publication from 1976 was included in consideration of its relevance in glioma-associated cerebral function field.

  Glioma-Induced Neural Function Remodeling Top

Glioma-induced neuroplasticity refers to the ability of the brain to reorganize itself structurally or functionally in the face of tumors to maintain neurological homeostasis.[6],[7] Due to the existence of tumor-induced functional remodeling, some glioma patients involving functional areas do not exhibit significant dysfunction, indicating that the tumor has not damaged functional areas and their connections, or the function has been remodeled to compensate for the dysfunction caused by the tumor.[8] In general, tumor-induced functional remodeling can be divided into structural remodeling and functional remodeling. Structural remodeling refers to the re-establishment of new connections between synapses and neurons to rebuild neural function, including synaptic plasticity and neuronal plasticity. Functional remodeling means that a neural function can be replaced by adjacent, distant, contralateral homologous brain regions or even other functional networks to compensate for the function affected by the tumor. Under the influence of glioma, the two remodeling modes often coexist and work together, resulting in changes in brain structure and brain function.

Glioma-induced brain structural changes

Glioma can induce changes in cerebral cortex structure, and some studies suggest that glioma can induce an increase in cortical thickness and volume. Yuan et al.[9] observed that the volume of hippocampus in tumor side of glioma patients increased significantly, suggesting that the hippocampus has significant plasticity in pathological stimulation of glioma. Almairac et al.[10] reported that slow infiltrating insula lesions can induce a significant increase in contralateral homologous gray matter volume, and this homotopic reorganization may be the physiological basis for a high level of functional compensation in glioma patients. Zhang et al.[11] found that low-grade glioma patients had greater gray matter volume in areas with increased brain activity, suggesting a structure-functional coupling change in the cerebellum. The changes in cortical volume may be caused by a combination of factors such as increased cell volume, gliogenesis, axonal sprouting, or angiogenesis. However, not all studies support that glioma can induce an increase in the thickness or volume of the cerebral cortex. A large cluster of voxels with gray matter volume decrease in the contralesional medial temporal lobe in patients with unilateral medial temporal lobe glioma was demonstrated by voxel-based morphometry on MRI which suggest that the contralesional cortex may have decompensation of structure and function in patients with unilateral glioma.[12]

Glioma also can induce structural changes in white matter. Changes in language-related white matter fibers are more common due to the complexity of language pathways. De Witte et al.[13] reported atypical right hemisphere language dominance accompanied with higher fiber density, length, and fractional anisotropy in the right arcuate fasciculus of a right-handed patient harboring left-hemispheric LGG. Patients without language impairment tended to have a symmetric or right-lateralized arcuate fasciculus, whereas patients with significant speech deficits often presented a left-lateralized posterior segment of the arcuate fasciculus.[14] Zheng et al.[15] found that the fractional anisotropy and lateralization index of left inferior longitudinal fasciculus and left inferior fronto- occipital fasciculus were higher in glioma patients compared with healthy controls, which indicates that the ventral pathways of language may harbor more functions in patients than in healthy controls. Tantillo et al.[16] found that language lateralization was associated with increased fractional anisotropy in the corpus callosum and proposed a mechanism by which tumors could facilitate the function plasticity between hemispheres. Changes in motor-related white matter fibers are limited, and the integrity of the anterior corticospinal tract, which originated from the supplementary motor area to the medial medulla may contribute to contralateral motor function when glioma invaded the M1 area.[17]

Glioma-induced brain function changes

Gliomas can induce remodeling of brain function, and impaired functions can be replaced by adjacent, distant, contralateral homologous brain regions or even other functional networks. The functional integrity was exclusively associated with the cortical reorganization.[18] Studies using suggested that essential functional areas can be displaced by glioma.[19],[20] It was observed in patients who underwent repeated awake surgery that some sites originally had positive reactions and did not trigger positive reactions. The loss of function at these sites was not associated with neurological impairment during repeated surgery, suggesting that neural function was preserved through rewiring of neural circuits or activation of redundant functional pathways.[21] In right-handed glioma patients, navigated transcranial magnetic stimulation (nTMS) induces significantly higher rates of speech errors in the right hemisphere, suggesting reorganization in language representation in brain tumor patients.[22] Motor-eloquent points tended to shift toward the tumor by 4.5 ± 3.6 mm if the lesion was anterior to the rolandic region and by 2.6 ± 3.3 mm if it was located posterior to the rolandic region in patients with glioma involving motor systems.[23] Again, using nTMS to map the motor cortex repetitively, long-term reorganization of the motor cortex can be observed.[24] The observational approach also found substantial evidence of functional remodeling. The magnetoencephalogram showed subtle changes in the location of the primary motor cortex, while significant changes could occur in the presence of more intense and prolonged glioma damage in the motor cortex.[25] Low-frequency fluctuations in the contralateral isohippocampus and parahippocampal region were significantly increased in patients with right temporal glioma, suggesting that the contralateral isohippocampus plays an important role in neuroplasticity and functional compensation.[26] In patients with unilateral frontal glioma, invasion of the frontal lobe can cause contralateral functional reorganization of the posterior cognitive control network.[19] Not only the cerebrum, but the cerebellum can also play a role in functional compensation, and contralesional cerebellar activation was increased compared to normal controls, which indicates its contributions to motor functional reorganization in glioma patients.[27]

Factors affecting plasticity

Glioma-induced neuroplasticity can be influenced by a variety of factors. For example, the direction of tumor growth can affect the remodeling of neural function. Wunderlich et al.[28] observed that ventral tumors generally did not induce displacement of the motor area compared to tumors growing dorsally.Tumor grade and key molecular signatures can also influence the reshaping of neural function. Compared with patients with IDH1 mutant glioblastoma, patients with IDH1 wild-type glioblastoma have reduced neurocognitive function. For IDH1 wild-type patients, lesion volume is negatively correlated with neurocognitive function, but not with IDH1 mutant tumor volume. Prompt IDH1 wild-type tumors may hinder neural plasticity.[29] In insular gliomas, IDH mutations are associated with greater structural compensation, and patients with insular gliomas with IDH mutations also have larger gray matter volumes throughout the contralateral insula compared with wild-type IDH.[30] Patients with low-grade glioma showed lower local information transmission potential and more decentralized cross-module processing than patients with high-grade glioma. These results indicate that the difference in lesion speed can lead to the difference in topological structure of the contralesional functional network.[31] Tumor size and morphology are also thought to be related to neuroplasticity. Xu et al.[32] found that the gray matter volume in the right cuneus and left thalamus significantly increased in patients with glioma, and the gray matter volume in these areas was positively correlated with the glioma volume in patients. Moreover, glioma morphology can also influence functional remodeling. Cortical tumors with sharp margins promote more effective plasticity mechanisms associated with increased resection range and early restoration of function at reoperation. Tumor invasion of the white matter tract is a major limitation of neuroplasticity: This connectome constraint limits the scope of secondary surgical resection.[33] However, other studies suggested that tumor location has a greater impact on neuroplasticity than tumor size. Smits et al. found a significant correlation between neurological impairment and subcortical tumor location, but no significant correlation between neurological function and tumor volume. These results suggest that even small tumors that invade white matter pathways may lack compensatory mechanisms for functional reorganization.[34] The essence of tumor location's influence on neuroplasticity lies in the difference in intrinsic plasticity in different locations, in general, plasticity is generally high in the cortex (except in primary unimodal areas and a small set of neural hubs) and rather low in connective tracts (especially associative and projection tracts).[35] The plasticity of different brain functions also varies. Motor function reorganization appeared relatively limited and was mostly characterized by intrahemispheric functional changes, including secondary motor cortices. The modes of language function compensation are more adequate and diverse which include recruitment of adjacent, distant, contralateral homologous brain regions, or even other functional networks.[36]

  Neuron-Glioma Synapses Top

Synapses are asymmetric intercellular junctions that mediate rapid point-to-point communication between neurons or between a neuron and a muscle cell, and thereby connect neurons into circuits. The function of the nervous system critically relies on the establishment of precise synaptic connections between neurons and specific target cells.

The relationship between neuronal structures and glioma cells in humans has been described in 2015: Neuronal activity promotes the growth of malignant glioma by regulating the secretion of the synaptic protein neuroligin-3. As a mitogen, synaptic protein neuroligin-3 recruits the PI3K-mTOR pathway to induce the proliferation of glioma cells.[37] Whereafter, Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells through the ADAM10 sheddase. ADAM10 inhibitors prevent the release of neuroligin-3 into the tumor microenvironment and robustly block high-grade glioma xenograft growth.[38] Neurons and oligodendrocyte precursor cells can form bona fide synapses, and electrochemical signaling can regulate the proliferation, differentiation, or survival of oligodendrocyte precursor cells.[39] The resemblance of cellular subpopulation between gliomas and oligodendrocyte precursor cells triggers the hypothesis that similarly, synapses constituted by neurons and gliomas may be the cornerstone of glioma progression. Venkatesh et al.[4] found that in vivo optogenetic evaluation of glioma membrane depolarization promotes proliferation, while pharmacological or genetic blocking of electrochemical signals inhibits glioma xenograft growth and prolongs survival in mice. What's more, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain.[4] Gliomas increase neuronal excitability and thus regulated glioma growth which is the so-called positive feedback mechanism. In gliomas and brain metastases, tumor cells are close to neuron-to-neuron synapses of the brain in a perisynaptic fashion, the similar ways of astrocytes to neurons.[40],[41] Although the certain function of perisynaptic contacts for adult glioma remains unknown. There is one thing we do know, most synapses were found in the infiltration zone of gliomas.[4],[41] Gliomas infiltrate extensively within the surrounding normal brain, which is one of the most important barriers to successful therapy. Therefore, therapies that target the brain tumor synaptic communication (NBTSC) are promising.

Two types of depolarizing currents were found in glioma cells: Fast excitatory postsynaptic currents and prolonged slow inward currents.[4],[41] Fast excitatory postsynaptic currents can be mainly mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which are the member of the ionotropic glutamate receptor family.[41] AMPAR inhibitors have been used to interfere with glutamatergic NBTSC. Perampanel, as the only noncompetitive AMPAR inhibitor that has been approved by the FDA for the treatment of partial-onset seizures, is used as an alternative or adjunctive therapy to treatment-resistant tumor-related epilepsy. However, progression and survival data of perampanel on glioma are absent. Associated randomized placebo-controlled trials are important to test the anti-tumor function of an AMPAR antagonist in the tumor infiltration zone. N-methyl-D-aspartate receptors (NMDARs), another subtype of ionotropic glutamate receptor, are located in the vicinity of the synaptic cleft within the plasma membrane of breast cancer cells.[42] The signaling of NMDARs is demonstrably instrumental in model systems for metastatic colonization of the brain and is associated with poor prognosis.[42] It is with regret that many approaches to inhibit NMDAR in the brain appear to cause serious adverse effects. Several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity.[43] These allosteric modulators could be tested in controlled trials of brain tumor therapies. Targeting the formation of new malignant synapses may be an alternative. Soluble neuroligin-3 can induce a synaptic gene signature in glioma cells and ADAM10 inhibitors could be a viable approach to decrease malignant synaptogenesis.[37],[38] Pharmacological inhibition of NBTSC has already shown promising results, and further work will help to identify downstream targets of NBTSC and their potential translational relevance.

  Prospect of Neural Modulation Technology Top

In recent years, NiBS has shown great potential in neuroregulatory therapy.[44],[45] Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are the two most commonly used NiBS technologies. Transcranial magnetic stimulation (TMS) is a NiBS technique. The stimulation coil in the TMS device releases a large amount of electric charge in a very short period to generate a magnetic field that is orthogonal to the coil. The magnetic signal travels through the skull and creates an induced current inside the cerebral cortex that affects metabolism and the brain, causing corresponding behavioral changes.[46] Currently, rTMS is the most widely used mode in the field of neural modulation, which can continuously and repeatedly send a series of TMS pulses to the stimulation target at a certain frequency over some time and regulate cortical excitability of the targeted brain region.[47] The stimulation modes of rTMS mainly include high-frequency stimulation, low-frequency stimulation, intermittent theta-burst stimulation (iTBS), and continuous theta-burst stimulation (cTBS). Each stimulation modality produced corresponding neurophysiological effects: low-frequency rTMS and cTBS modalities elicited cortical inhibition, and high-frequency rTMS and iTBS modalities elicited cerebral cortical excitation.[48] tDCS is a NiBS technique that uses a weak current (1–2 mA) to modulate the activity of neurons in the cerebral cortex.[49] When using a tDCS device, its two gel/sponge electrodes (cathodal electrode and anodal electrode) are usually placed on the scalp. Accordingly, the tDCS device outputs anodal and cathodal stimulation. In general, anodal stimulation depolarizes and increases cortical excitability, whereas cathodal stimulation contributes to hyperpolarization and decreases cortical excitability.[50] Transcranial direct current stimulation induces plasticity synaptic changes similar to long-term enhancement or long-term inhibition, and these changes are more durable than the stimulus phase.[51]

Non-invasive brain stimulation-induced neural function plasticity

NIBS can reshape brain structure. cTBS applied over the left anterior temporal lobe decreased gray matter in the left anterior temporal lobe and right cerebellum compared to the control stimulation, supporting fast adapting neuronal plasticity such as synaptic morphology changes.[52] The combination of TMS with specific stimuli can directionally regulate neural functional remodeling.[53] High-frequency TMS can produce transient cortical states with increased excitability and response variability, opening a time window for enhanced plasticity.[54] During the permissible period induced by TMS, a single directional visual stimulus amplifies the selected directional imprint on the visual cortex.[54] This recombination is stable over several hours and is characterized by a systematic shift from directional preference to trained orientation.[54] Thus, TMS can noninvasively trigger targeted large-scale remodeling of basic mature functional structures in the early sensory cortex. This recombination is stable over several hours and is characterized by a systematic shift from directional preference to trained orientation. Thus, TMS can noninvasively trigger targeted large-scale remodeling of the basic mature functional structures of the early sensory cortex.[54]

NIBS stimulation can affect brain functional networks. Two blocks of anodal tDCS at intervals of 48 h, 7 days, and 2 weeks can reliably induce M1 homeostatic plasticity in healthy controls.[55] Bilateral tDCS (left anode and right cathode) reduces left alpha, beta, and gamma power and increases global connectivity in delta, alpha, beta, and gamma frequencies, in a diffuse fashion, which demonstrates that tDCS could reshape resting-state brain networks.[56] Training combined with anodal tDCS of the left motor cortex increased both local and global connectivity in glioma patients.[57] NIBS also presents with a priming effect, facilitatory iTBS priming can make the central nervous system more susceptible to changes elicited by neuromuscular electrical stimulation through sensory recruitment to enhance the facilitation of corticospinal plasticity.[58]

Individuals respond differently to iTBS, study found gamma-aminobutyric acid receptor-mediated activity measured before stimulation is negatively correlated with the after-effect of cortical excitability induced by iTBS.[59] Combining multiple NIBS techniques may enhance the neuromodulation effect. Preconditioning with cathodal tDCS followed by iTBS showed a greater increase in motor-evoked potential amplitude than sham cathodal tDCS preconditioning and iTBS at each time postintervention point, with longer-lasting after-effects on cortical excitability.[60]

In addition, transcranial-focused ultrasound is another noninvasive ultrasound treatment technology for brain diseases that are currently booming. Ultrasound with a specific center frequency is emitted by an external ultrasound device (the most widely used ultrasound is between 0.2 and 1.5 MHz). The area produces thermal effects, force effects, and cavitation effects to achieve direct or indirect regulation and treatment of intracranial lesions.[61] During the cerebellar transcranial focused ultrasound session, motor-evoked potentials were generated in both forelimbs accompanying excitatory sonication parameters.[62] The sensorimotor recovery of the lateral cerebellar nucleus stimulation group was significantly enhanced compared with that of the nonstimulation group after stroke. This study provides the first evidence that cerebellar modulation induced by transcranial-focused ultrasound may be an important strategy for poststroke recovery.[63] Some invasive brain stimulation techniques also provide ideas for clinical diagnosis and treatment, continuous cortical electrical stimulation, and appropriate behavioral training prior to surgery in WHO grade II and III gliomas affecting functional areas may accelerate plastic change. This can help to maximize tumor removal, thereby improving survival while preserving function.[64]

The research on the application of NiBS technology to the neurological remodeling of glioma patients still needs to expand the sample size, set up a control group, apply different stimulation modes individually according to different situations, and even combine multiple technologies to target induce neural function plasticity.

Noninvasive brain stimulation inhibits glioma growth

Tumor microtubules in glioma cells form functional chemical synapses with normal neurons, and the electrical activity of neurons activates tumor-cell calcium signaling networks through neuroglioma synaptic structures, resulting in multi-level cellular oncogenic signaling levels.[65] The neuronal cytoskeleton remodeling mechanism is activated, which in turn promotes the proliferation and invasion of glioma cells.[66] It is suggested that controlling neuronal excitability in glioma patients may inhibit tumor growth and proliferation, and ultimately prolong patient survival.[4] NIBS techniques can be used to monitor and modulate the excitability of neuronal circuits in the cortex. Prolonged cortical stimulation can have long-lasting effects on brain function, paving the way for the therapeutic application of NIBS in tumor suppression. Low-frequency rTMS stimulation leads to the reduction of presynaptic calcium ion concentration, which in turn causes long-term depression of synaptic function and structure, and reduces neural excitability.[67] The long-term depression-like changes in synaptic excitability may be related to the neuron-glioma interaction. A reduced firing probability of neurons after a presynaptic event reduces Ca2+ AMPAR activation in postsynaptic glioma cells, resulting in a limited influx of Ca2+ signaling that promotes mitosis, which may limit the contribution of nerve cells to glioma growth.[4] NiBS can target and modulate neuronal excitability in specific regions, providing a new therapeutic idea for inhibiting glioma proliferation and migration.

  Limitations Top

There may be some possible limitations in this study. This study is based on the author's own analysis and summary of the literature (although we try to keep objective in the analysis process), but it is still highly subjective, so all the findings are based on personal views. As a review, there may be incomplete retrieval of identified research. Researches focusing on neuron-glioma synapse are also few. This review study covers a period only scientific research (nearly 10 years), and only covers the mainstream in the field study, and not comb research results of recent meetings, so the reader needs to know this review study on the source of the limitations of time and study.

  Conclusion Top

Gliomas induce remodeling of neural function and stimulate neurons to form synaptic connections with them to promote their growth. By understanding the neural circuit integration relationship between neurons and glioma cells, the aim, and direction of glioma treatment can be clarified through regulating the secretion of growth factors, neuron-glioma neural circuit transmission, coupling of ion channel function, and gap junction. NIBS has the characteristics of targeting and regulating cortical excitability in different brain regions, and it is expected to be a therapeutic scheme to induce neural function remodeling and inhibit tumor growth at the same time.



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