[ARTICLE] Neuroplasticity: Insights from Patients Harboring Gliomas – Full Text HTML

Abstract

Neuroplasticity is the ability of the brain to reorganize itself during normal development and in response to illness. Recent advances in neuroimaging and direct cortical stimulation in human subjects have given neuroscientists a window into the timing and functional anatomy of brain networks underlying this dynamic process. This review will discuss the current knowledge about the mechanisms underlying neuroplasticity, with a particular emphasis on reorganization following CNS pathology. First, traditional mechanisms of neuroplasticity, most relevant to learning and memory, will be addressed, followed by a review of adaptive mechanisms in response to pathology, particularly the recruitment of perilesional cortical regions and unmasking of latent connections. Next, we discuss the utility and limitations of various investigative techniques, such as direct electrocortical stimulation (DES), functional magnetic resonance imaging (fMRI), corticocortical evoked potential (CCEP), and diffusion tensor imaging (DTI). Finally, the clinical utility of these results will be highlighted as well as possible future studies aimed at better understanding of the plastic potential of the brain with the ultimate goal of improving quality of life for patients with neurologic injury.

1. Introduction

Traditionally, the brain has been considered a static organ, with little potential for plasticity [1]. This concept was centered on the notion that the brain is comprised of discrete sections, each controlling a specific function, and thus localized damage would result in largely irreversible and specific functional deficits. However, recent advances in neuroimaging and direct brain mapping have shown that the brain is capable of significant redistribution of function in response to injury [2–4]. It is believed that this remodeling, termed neuroplasticity, occurs continuously throughout life. Perhaps through similar mechanisms that are activated following brain injury, neuroplasticity is crucial for optimization of neuronal signaling [5].

Neuroplasticity has been extensively documented in developing children and ischemic stroke patients [6–14]. Glioma patients, a less frequently studied population, may represent another group that can give significant insight into neuroplasticity and its mechanisms. For example, it has been reported that lesions that occur in “eloquent” areas, such as Broca’s or Wernicke’s area, may not result in detectable language deficits [15–19], and in fact there have been several reports of resection of presumed critical speech and motor areas in glioma patients [20, 21]. It is believed that injury to these areas may be due to recruiting and reshaping neuronal connections, unmasking latent connections, or creating entirely new pathways [22–24]. On the other end of the plasticity spectrum, a modeling study in low-grade glioma patients suggested that when plasticity potential is exhausted, patients can exhibit seizure activity [25]. Additional research into how and where recruitment and reshaping are occurring in the brain may shed new light on principles governing plasticity of the adult brain. This review will give an overview of the mechanisms involved in neuroplasticity following brain injury, methods utilized to study plasticity, and fundamental questions that remain. Specifically, plasticity will be discussed in the context of patients harboring gliomas, as this group may present an optimal cohort to study neuroplasticity.

2. Mechanisms of Neuroplasticity

The study of neuroplasticity has traditionally focused on synaptic plasticity. Synaptic plasticity occurs in one or more synaptic junctions and is often mediated by the regulation of glutamate receptors—NMDA and AMPA glutamate receptors in particular [26, 27]. The modulation of NMDA and AMPA receptors due to differential neural stimulation is called long-term potentiation (LTP) [28]. LTP is the prevailing paradigm of microscopic neuroplasticity and is the primary mechanism underlying normal learning and memory [29]. This microscopic characterization of plasticity provides a physiological explanation for how synapses are continuously modulated during normal conditions.

In contrast, neuroplasticity following brain injury is less well understood, and although synaptic-level changes presumably play a role in redistribution of function, it is clear that larger-scale macroscopic plasticity plays an important role in cerebral recovery and reorganization following injury.

The brain displays a remarkable capacity for recovery after injury. While it has traditionally been assumed that the brain contains “eloquent” and “silent” areas, it is starting to become clear that the cerebral connectome, consisting of overlapping and independent networks, allows for a much more dynamic view of brain function and reorganization after injury. The understanding of canonical eloquent areas, such as Broca’s area, has even been challenged to include larger and more connected networks [30]. This is to say, damage to an area traditionally considered critical for a given function may not cause irreversible damage, depending on the spatial and temporal features of the injury [31].

2.1. A Hierarchy of Plasticity

A discussion of the hierarchy of cerebral plasticity is important for the context of this review. The first distinction in this hierarchy is between cortical and subcortical plasticity. For the purpose of this review, the term subcortical refers to white matter axonal fiber below the cortical surface. While cortical injury has the potential to recover, lesions of the subcortical white matter tracts are likely irreversible [31, 32]. Clinically, regaining or reestablishing cortical representation of a given function can result in functional recovery. For example, in a Parkinson’s disease patient undergoing chronic deep brain stimulation (DBS), neuroplasticity in sensory-motor and prefrontal/limbic regions is hypothesized to be the reason why the patient’s tremor improved. In addition, ischemic stroke patients have been shown to change the organization of their motor cortex over a six-month span following ischemic injury resulting in improved motor function [7, 33]. Furthermore, glioma patients can remain functionally normal despite tumor infiltrating primary cortical regions. This plasticity is a result of cortical reorganization in response to the glioma as evidenced by direct electrocortical stimulation (DES) data [16, 31, 34, 35]. In contrast to these examples of cortical plasticity, the irreversible nature of subcortical tract damage results in a lack of functional recovery (Figure 1(a)), and there is even evidence that subcortical loss depresses the brain’s ability to adapt to future insults [36]. The critical maintenance of the subcortical white matter pathways was demonstrated in a study that examined neuroplasticity capacity as a function of brain lesion location using DES data from 58 LGG patients. A more recent study by the same group looked at over 230 patients and found that subcortical white matter tracts were far less likely to display neuroplasticity if injured as compared to cortical regions, leading to the hypothesis that these core inviolate tracts compose the “minimal common brain” [31, 37].

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