Traumatic Brain Injury //
Traumatic Brain Injury Research at MRN
Mild traumatic brain injury (mTBI) represents a natural union of MRN’s interests in attention, advanced neuroimaging and clinical care. Although there has been much debate about long-term cognitive outcome following mTBI (Dikmen et al., 2009), a recent meta-analysis suggests a moderate effect size (d = .54) for executive, working memory and attention dysfunction during the semi-acute injury phase (Belanger et al., 2005). Laboratory measures suggest that attentional disengagement and selective attention are particularly affected (Drew et al., 2007; Halterman et al., 2006), providing a natural bridge for our in these fields. Second, routine clinical imaging scans (MRI and CT) are usually negative (Belanger et al., 2007; Bigler, 2008; Iverson, 2005), suggesting that these techniques are not sensitive to the pathophysiological changes commonly reported in animal injury models. As a result, alternative neuroimaging techniques are well-positioned to provide unique information about putative “silent lesions” and their impact on cognition functioning.
To this end, published data from MRN provides preliminary evidence of tissue-specific dysfunction and self-reported neuropsychiatric disturbances.This includes increased fractional anisotropy in white matter, likely secondary to cytotoxic edema, secondary inflammatory processes and potential structural alterations in neurofilaments and myelin (Mayer et al., 2010; Ling et al., 2011). White matter creatine and the combined glutamate/glutamine peak (Glx) are also increased (Figure 1), possibly indicative of increased energetics for cell repair (Gasparovic et al., 2009; Yeo et al., 2011). Grey matter is characterized by reduced Glx, potentially representing an adaptive response to avoid excitotoxicity (Gasparovic et al., 2009; Yeo et al., 2011). A tight coupling exists between the release of glutamate into the synaptic cleft, the cycling of glutamate and glutamine between neurons and astrocytes, and the hemodynamic response (Hyder et al., 2006; Mangia et al., 2009; Schummers et al., 2008). Therefore, it is no surprise that mTBI was also associated with hypoactivation of the frontoparietal reorienting network during spatial orienting (Mayer et al., 2009), hypoactivation within the dMFC and lateral PFC during multisensory selective attention (Mayer et al., manuscript in preparation), and behavioral deficits. The balance of intrinsic neuronal fluctuations also appears to be affected by injury (Figure 2), with reduced connectivity in the DMN and increased connectivity in frontoparietal attention networks (Mayer et al., 2011). Given that approximately 80% of the brain’s energy budget is devoted to the cycling of glutamate and glutamine (Hyder et al., 2006; Shulman et al., 2004) and maintaining intrinsic neuronal activity (Raichle and Mintun, 2006; Fox and Raichle, 2007), these functions may be particularly susceptible to diffuse injury following mTBI.
Thus, our current working hypothesis is that a tissue-specific pattern of injury characterizes semi-acute injury, and that these underlying neuronal changes contribute to attentional dysfunction. A key goal of our future work is to determine which changes are most deleterious to cognition. Are orienting and selective attention deficits following mTBI the result of decreased neuronal/metabolic/hemodynamic grey matter response or secondary to a disconnection between frontoparietal sites? Or are cognitive deficits/increased errors following mTBI the result of an imbalance between primary cortical networks mediating internal mentations (DMN) and attention to external events?
Mild TBI also presents an ideal “natural experiment” for examining both the initial consequences of the lesion and the substrate for cognitive recovery (usually 3-6 months post-injury). Results from our lab and others suggest a partial recovery in white matter (Arfanakis et al., 2002; Mayer et al., 2010), with a more robust recovery (Figure 1) of biochemical markers (Vagnozzi et al., 2010; Yeo et al., 2011). We also observed that biochemical recovery is impacted by general cognitive status (Yeo et al., 2011), representing an intriguing possibility about the role of cognitive reserve in mTBI. Finally, reports of persistent hemodynamic abnormalities in clinically asymptomatic mTBI patients (Mayer et al., 2011; McAllister et al., 2006) may explain why a second, temporally proximal mTBI results in greater cognitive deficits than a single injury of comparable severity (Vagnozzi et al., 2008; Wall et al., 2006; Vagnozzi et al., 2005).
Over the past three years, we received 3 NIH awards (R24, R21 and a challenge grant) for our mTBI work. We have amassed a unique multimodal imaging dataset on 55 well-characterized (full neuropsychological and clinical battery) semi-acutely injured mTBI patients and 55 well-matched healthy controls (data collection complete in March 2011), publishing several papers on our initial FMRI, 1H-MRS and DTI findings from our first cohort of patients (samples varied between 16 to 30 patients). The longitudinal aspect of data collection concludes in the fall of 2011, coincidental with the conclusion of our NIH funding. However, much work remains to be done. Replication is acornerstone of science, and our most immediate goal (1-2 years) is to determine the reproducibility of our initial neuroimaging findings in our second independent cohort (25 patients and controls). MEG data was also collected on the second cohort using identical cognitive (evoked) and resting state (intrinsic) tasks, providing an unparalleled dataset for examining the dynamic relationship between electrophysiological and hemodynamic activity. Finally, a basic multisensory task was employed to ensure that widespread hypoactivation during cognitive tasks was not due to differences in basic properties of the hemodynamic response.
A more long-term goal (3-5 years) is to conduct longitudinal imaging studies on the relatively small percentage of patients with “complicated” mTBI. Patients with complicated mTBI have visible focal lesions on CT scans and are more likely to have chronic neuropsychiatric symptoms/poor outcome following injury (Borgaro et al., 2003; Lee et al., 2008; Kashluba et al., 2008; Lange et al., 2009). Current theories (Bigler, 2010; Smits et al., 2008) suggest the focal lesions cause residual cognitive deficits. While intuitive, support for this theory has been mixed (Hughes et al., 2004; Lee et al., 2008; Smits et al., 2008). An alternative theory supported by our work is that poor cognitive outcomes are the result of diffuse injuries in otherwise healthy appearing tissue.
Current Research //
Mild Traumatic Brain Injury (mTBI)
Mild traumatic brain injury (mTBI) is associated with neurobehavioral deficits in a majority of patients during the semi-acute injury phase, with a minority of patients remaining symptomatic for months to years post-injury. Routine clinical imaging scans (MRI and CT) are usually negative, suggesting that alternative neuroimaging techniques such as fMRI, DTI and 1H-MRS are well-positioned to provide unique information about the putative “silent lesions” of mTBI and their impact on neurobehavioral functioning. To this end, published data from my lab provides preliminary evidence of tissue-specific dysfunction and self-reported neuropsychiatric disturbances in both children and adults following mTBI. These injuries include increased fractional anisotropy in white matter, likely resulting from cytotoxic edema, secondary inflammatory processes, and potential structural alterations in neurofilaments and myelin. The brain’s ability to respond to external stimuli also appears to be reduced in the semi-acute stage of mTBI, with individual brain networks failing to communicate properly with each other. An increased understanding of the mechanisms underlying these injuries and how/when they recover represents the crucial next step for determining when patients can safely resume physical activities.
Consequences of mTBI
Almost all of us will get “hit in the head” at some point in our lives. “How hard” we get hit will likely determine whether we have a life altering experience or just walk away from it. However, emerging evidence suggests that even mild TBI can have prolonged consequences, affecting how we perform at work and make critical daily decisions for months. More importantly, particularly for athletes or soldiers, repeat injuries may make us more vulnerable for experiencing long-term negative outcomes. Unfortunately, mild TBI is not detected using routine clinical brain imaging techniques, nor do we have sufficient understanding of its long-term effects on behavior.
In the Mild TBI Project at MRN, lead by Dr. Andrew Mayer, we are investigating the subtle structural and biochemical consequences of mild TBI using state-of-the-art neuroimaging techniques. Our preliminary findings have shown that mild TBI causes alterations in the brain’s structure, function and chemistry. We are exploring how these alterations correlate with neurobehavioral symptoms, and how these may change as a function of recovery.