Functional magnetic resonance imaging of mild traumatic brain injury

doi:10.1016/j.neubiorev.2014.11.016

Neuroscience & Biobehavioral Reviews

Volume 49, February 2015, Pages 8-18

https://doi.org/10.1016/j.neubiorev.2014.11.016 Get rights and content

Highlights

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Long-term consequences of mTBI are a growing health concern.
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Evoked fMRI can capture the dynamic neurobehavioral sequelea of mTBI.
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Trauma can affect many components of the fMRI results.
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We conclude by reviewing overarching clinical challenges in fMRI research of mTBI.

Abstract

Functional magnetic resonance imaging (fMRI) offers great promise for elucidating the neuropathology associated with a single or repetitive mild traumatic brain injury (mTBI). The current review discusses the physiological underpinnings of the blood-oxygen level dependent response and how trauma affects the signal. Methodological challenges associated with fMRI data analyses are considered next, followed by a review of current mTBI findings. The majority of evoked studies have examined working memory and attentional functioning, with results suggesting a complex relationship between cognitive load/attentional demand and neuronal activation. Researchers have more recently investigated how brain trauma affects functional connectivity, and the benefits/drawbacks of evoked and functional connectivity studies are also discussed. The review concludes by discussing the major clinical challenges associated with fMRI studies of brain-injured patients, including patient heterogeneity and variations in scan-time post-injury. We conclude that the fMRI signal represents a complex filter through which researchers can measure the physiological correlates of concussive symptoms, an important goal for the burgeoning field of mTBI research.

Introduction

Recently, there has been a dramatic change in thought regarding the physiological consequences of concussion, also referred to as mild traumatic brain injury (mTBI). It was initially believed that mTBI resulted in limited behavioral and no long-term neurological consequences (Pellman et al., 2004), except for in a small percentage of patients with pre-existing psychiatric conditions. Standard clinical neuroimaging methods (computed tomography scans; T₁- and T₂-weighted images) are typically negative for the majority of concussed patients (Hughes et al., 2004, Iverson, 2006), which helped propagate the view that mTBI did not lead to frank neuronal pathology. However, more recent studies suggest that the life-long effects of concussion, especially when repetitive, may be more severe than initially believed, predominantly a result of the dramatic increase in the diagnoses of chronic traumatic encephalopathy (CTE) amongst recently deceased athletes (McKee et al., 2013). A proliferation of neuroimaging studies of mTBI has also occurred, with different imaging modalities finding that neuronal pathology may be present long after traditional outcome measures (e.g., balance and neuropsychological testing) have returned to pre-morbid levels of functioning (Belanger et al., 2007, Bigler, 2013, Bigler and Maxwell, 2012, Mayer et al., 2011). As a result of these new lines of evidence, it has been suggested that a single concussion can result in lifetime impairment for some individuals. However, a more realistic assessment of the field suggests a nascent understanding of the neuronal and behavioral consequences of both single and repetitive mTBIs in humans, with several key challenges remaining to be resolved.

The goals of the current review are to provide the reader with a more thorough appreciation for the challenges of conducting functional magnetic resonance imaging (fMRI) studies in mTBI. We begin with a discussion of the physiological underpinnings of the blood-oxygen level dependent (BOLD) response, how mTBI may alter it, and the analytic strategies through which researchers attempt to non-invasively capture the effects of neuronal injury. The mTBI literature using both task-based (i.e., evoked) paradigms as well as resting state measurements (i.e., functional connectivity) is reviewed next. Finally, the many methodological challenges associated with fMRI studies of brain-injured patients are discussed from a clinical perspective. Although some groups have made a distinction between the terms concussion and mTBI based on injury severity (reviewed in Harmon et al., 2013), for the purpose of the current paper these terms are used inter-changeably.

Section snippets

fMRI physiology and putative effects of trauma

The relation between neuronal activity and the resultant hemodynamic response (i.e., neurovascular coupling) remains a topic of active investigation. The cerebral metabolic rate of glucose (CMR_glu), the cerebral metabolic rate of oxygen (CMRO₂) and cerebral blood flow (CBF) are tightly coupled in the absence of evoked neuronal activity. There is an increase in metabolic demands/energy requirements following excitatory neuronal transmission, and excess glutamate must be rapidly removed from the

Methodological challenges associated with analyses

Given the known complexity of the BOLD response, there are several analytic considerations in fMRI research of mTBI. Foremost, both region of interest (ROI) and voxel-wise analyses inherently assume that heterogeneous initial injury conditions (e.g. motor vehicle accidents, a blow to the left temple, or a blast in combat) result in a homogeneous pattern (i.e., high degree of spatial overlap) of gray matter abnormalities. Specifically, to survive group-wise statistics, traditional ROI and

Evoked fMRI findings in mTBI

fMRI offers great promise for elucidating the underlying neuropathology associated with neurobehavioral sequelae following mTBI, especially in conjunction with tasks that dynamically tap into higher-order cognitive functioning (McDonald et al., 2012). The seminal fMRI studies of mTBI utilized working memory paradigms, with results suggesting a complex relationship between cognitive load and functional activation. Specifically, McAllister et al., 1999, McAllister et al., 2001 reported

Intrinsic connectivity findings in mTBI

In addition to studies of evoked BOLD activity, researchers are increasingly turning to measures of intrinsic activity, or functional connectivity (fcMRI), to examine neuronal health following mTBI. Functional connectivity studies are based on neuronal fluctuations that occur synchronously over spatially distributed networks, and are found in both humans and animals. The majority (60–80%) of the brain's energy resources is expended to maintain homeostasis, with intrinsic neuronal activity

Overarching clinical challenges in fMRI research following mTBI

The initial sections briefly introduced several clinical challenges for conducting fMRI studies following mTBI, which are reviewed in greater detail here. Perhaps the largest challenge facing the field are the various definitions for diagnosing mTBI and/or concussion (Ruff et al., 2009, West and Marion, 2013), and the fact that these terms are sometimes used synonymously and at other times denote different injuries. Under these current different diagnostic nosologies, patients who are only

Emotional sequelae following mTBI’

Of all of the challenges faced in mTBI research, operationalizing the psychiatric sequelae of injury may be the most challenging. Episodes of major depression are among the most commonly diagnosed neuropsychiatric complication of TBI across all levels of severity (Dikmen et al., 2004, Kreutzer et al., 2001, Mainwaring et al., 2004), and the diagnoses of mTBI and PTSD are highly co-morbid in military populations (Hoge et al., 2008, Schneiderman et al., 2008). The incidence of anxiety, depression

Conclusions

fMRI provides researchers with a powerful tool for non-invasively measuring the functional integrity and modulation of neuronal circuitry in both animal and human models of mTBI. Evoked fMRI studies capture dynamic changes in brain function during higher-order cognitive and emotional tasks, mimicking the real-world environments under which patients are more likely to complain of symptoms. Thus, fMRI provides a clear advantage relative to other imaging techniques that are only capable of

Acknowledgments

There are no acknowledgments.

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Whole-brain correlates of post-traumatic stress disorder in military-related mild traumatic brain injury: A voxel-wise meta-analysis
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Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used in studying mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) among military service personnel (MSP). The risk for PTSD is greater after mTBI than after non-mTBI trauma, and PTSD is associated with worse biological, psychological, and social (biopsychosocial) outcomes after mTBI. Studying the neural correlates of mTBI-related PTSD in this population may provide insights into the pathophysiology of both conditions and help identify MSPs most at risk of developing persistent symptoms. This voxel-wise meta-analysis aimed to examine the current literature on rs-fMRI in mTBI-related PTSD, collect neuroimaging data, and perform a voxel-wise meta-analysis to identify significant nodes of functional connectivity across studies. We searched the literature using PubMed, EMBASE, and ScienceDirect. The database query yielded 1455 articles, narrowed with specified eligibility criteria to a final cohort of 33 studies, with 1521 experiment group participants and 1369 controls. Article quality was assessed using the QUADAS-2 instrument. Our meta-analysis revealed a robust correlation between PTSD-mTBI and increased whole-brain resting-state functional connectivity (rsFC) in the amygdala. Our meta-analysis also showed strong correlations between PTSD-mTBI and decreased whole-brain rsFC across regions implicated in speech and language processing. Our meta-regression highlighted robust correlations between less time after a recent mTBI and increased whole-brain rsFC in posterior regions of the default mode network. Our meta-regression also showed strong correlations between increased PTSD symptom severity, increased connectivity in the amygdala, and decreased connectivity in Broca's area.
Long-term effects of concussion on relevancy-based modulation of somatosensory-evoked potentials
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The purpose of this investigation was to better understand the effects of concussions on the ability to selectively up or down-regulate incoming somatosensory information based on relevance.
Median nerve somatosensory-evoked potentials (SEPs) were elicited from electrical stimulation and recorded from scalp electrodes while participants completed tasks that altered the relevance of specific somatosensory information being conveyed along the stimulated nerve.
Within the control group, SEP amplitudes for task-relevant somatosensory information were significantly greater than for non-relevant somatosensory information at the earliest cortical processing potentials (N20-P27). Alternatively, the concussion history group showed similar SEP amplitudes for all conditions at early processing potentials, however a pattern similar to controls emerged later in the processing stream (P100) where both movement-related gating and facilitation of task-relevant information were present.
Previously concussed participants demonstrated impairments in the ability to up-regulate relevant somatosensory information at early processing stages. These effects appear to be chronic, as this pattern was observed on average several years after participants’ most recent concussion.
Given the role of the prefrontal cortex in relevancy-based facilitation during movement-related gating, these findings lend support to the notion that this brain area may be particularly vulnerable to concussive forces.
Network topology changes in chronic mild traumatic brain injury (mTBI)
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In mild traumatic brain injury (mTBI), diffuse axonal injury results in disruption of functional networks in the brain and is thought to be a major contributor to cognitive dysfunction even years after trauma.
Few studies have assessed longitudinal changes in network topology in chronic mTBI. We utilized a graph theoretical approach to investigate alterations in global network topology based on resting-state functional connectivity in veterans with chronic mTBI.
50 veterans with chronic mTBI (mean of 20.7 yrs. from trauma) and 40 age-matched controls underwent two functional magnetic resonance imaging scans 18 months apart. Graph theory analysis was used to quantify network topology measures (density, clustering coefficient, global efficiency, and modularity). Hierarchical linear mixed models were used to examine longitudinal change in network topology.
With all network measures, we found a significant group × time interaction. At baseline, brain networks of individuals with mTBI were less clustered (p = 0.03) and more modular (p = 0.02) than those of HC. Over time, the mTBI networks became more densely connected (p = 0.002), with increased clustering (p = 0.001) and reduced modularity (p < 0.001). Network topology did not change across time in HC.
These findings demonstrate that brain networks of individuals with mTBI remain plastic decades after injury and undergo significant changes in network topology even at the later phase of the disease.
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We observed significant age-related changes for a) FNC: changes between 10 pairs of ICNs, mostly involving the default mode (DM) and/or the cognitive-control (CC) domains; b) SMs: intensity decrease in clusters across three domains and intensity increase in clusters across two domains, including the CC but not the DM and c) TC: spectral power decrease within the 0–0.15 Hz range and increase within the 0.20–0.25 Hz range for increasing age within networks located in frontal areas, including the anterior DM. Groups only differed for TC within the 0.065–0.10 Hz range in the cerebellar ICN and no age × group interaction effect was found.
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View full text

ReviewFunctional magnetic resonance imaging of mild traumatic brain injury

Highlights

Abstract

Introduction

Section snippets

fMRI physiology and putative effects of trauma

Methodological challenges associated with analyses

Evoked fMRI findings in mTBI

Intrinsic connectivity findings in mTBI

Overarching clinical challenges in fMRI research following mTBI

Emotional sequelae following mTBI’

Conclusions

Acknowledgments

Neuron

Clin. Sports Med.

Magn. Reson. Imaging

Neuroimage

J. Neurosci. Methods

Arch. Phys. Med. Rehabil.

Neuroimage: Clin.

Neurosci. Biobehav. Rev.

J. Pediatr.

Neuroimage

Neuroimage

Neuroimage

J. Neurosci. Methods

Arch. Phys. Med. Rehabil.

Arch. Phys. Med. Rehabil.

Neuroimage

Neuroimage

Psychiatry Res.

Int. J. Psychophysiol.

Neuroimage

Sensory cortex underpinnings of traumatic brain injury deficits

PLoS One

Animal models of sports-related head injury: bridging the gap between preclinical research and clinical reality

J. Neurochem.

Glial and neuronal control of brain blood flow

Nature

Does a history of mild traumatic brain injury increase suicide risk in veterans with PTSD?

Rehabil. Psychol.

Chronic stress conditions do explain posttraumatic brain injury depression

Res. Theory Nurs. Pract.

Recent neuroimaging techniques in mild traumatic brain injury

J. Neuropsychiatry Clin. Neurosci.

Compensation and malingering in traumatic brain injury: a dose-response relationship?

Clin. Neuropsychol.

Neuropsychology and clinical neuroscience of persistent post-concussive syndrome

J. Int. Neuropsychol. Soc.

Neuroimaging biomarkers in mild traumatic brain injury (mTBI)

Neuropsychol. Rev.

Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings

Brain Imaging Behav.

Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—a unifying hypothesis

Surg. Neurol. Int.

Neural recruitment after mild traumatic brain injury is task dependent: a meta-analysis

J. Int. Neuropsychol. Soc.

The brain's default network: anatomy, function, and relevance to disease

Ann. N. Y. Acad. Sci.

Modeling the hemodynamic response to brain activation

Neuroimage

Visual dysfunctions and symptoms during the subacute stage of blast-induced mild traumatic brain injury

Mil. Med.

A validation of the post concussion symptom scale in the assessment of complex concussion using cognitive testing and functional MRI

J. Neurol. Neurosurg. Psychiatry

Neural substrates of symptoms of depression following concussion in male athletes with persisting postconcussion symptoms

Arch. Gen. Psychiatry

A novel animal model of closed-head concussive-induced mild traumatic brain injury: development, implementation, and characterization

J. Neurotrauma

Sex and age differences in depression and baseline sport-related concussion neurocognitive performance and symptoms

Clin. J. Sport Med.

Persistent differences in patterns of brain activation after sports-related concussion: a longitudinal functional magnetic resonance imaging study

J. Neurotrauma

Depressive symptoms and concussions in aging retired NFL players

Arch. Clin. Neuropsychol.

Prediction of human errors by maladaptive changes in event-related brain networks

Proc. Natl. Acad. Sci. U.S.A.

Do brain activation changes persist in athletes with a history of multiple concussions who are asymptomatic?

Brain Inj.

Neural activation during response inhibition differentiates blast from mechanical causes of mild to moderate traumatic brain injury

Review
Functional magnetic resonance imaging of mild traumatic brain injury