Our results demonstrate that DAI after TBI is associated with altered functional brain response during executive control processing in working memory. Previous studies investigating the functional neuroanatomy of working memory in TBI have been confounded by heterogeneity in patient selection or task characteristics (e.g., references 11
). Focal lesions in our sample were limited to scattered, small hemosiderin deposits, which reflect DAI. It is possible that larger lesions may have been detected using more sensitive sequences, such as susceptibility weighted imaging.25
However, the consistency of the functional brain changes across the TBI sample (figure e-2) suggests that DAI, common to all of our TBI subjects, and not focal lesions, which were inconsistently localized across TBI subjects, accounts for the augmented functional recruitment. We were thus able to specifically examine the impact of DAI on executive control processes to a greater degree than heretofore possible.
Prescan training ensured comparable performance across groups on the working memory task, circumventing potential confounds associated with group differences evident in earlier reports. Even TBI subjects who performed at or above the mean of the control sample on the most challenging condition (alphabetize 5) demonstrated augmented functional recruitment in the right PFC in the alphabetize 5–maintain 5 contrast (figures e-1 and e-2). Thus, executive control processes may be facilitated by supplemental recruitment within this region after DAI. Although group differences in performance cannot explain the group differences in functional activation reported here, this is not to say that performance differences are unrelated to functional activation patterns. We are currently investigating how such brain–behavior correlations are affected by TBI. Moreover, although the patients had sustained moderate to severe brain injury, all had returned to preinjury employment or academic status and were several years after injury, thus avoiding confounds related to recovery phase.
Finally, the functional neuroanatomy of our tasks is well characterized, has good convergent validity with other executive measures, and allowed us to independently manipulate load and executive control demands. By eliminating these sources of patient- and task-related variance, we showed that the functional neuroanatomy of executive control processing is specifically altered by DAI after moderate to severe brain injury. Follow-up analyses indicated that our results were reliable across the TBI sample and could not be attributed to slowing.
These data are consistent with the characterization of working memory as an emergent property of coordinated activity within a distributed network of brain regions.26,27
We have demonstrated that diffuse injury, in the absence of focal brain pathology, is sufficient to alter brain networks subserving working memory processing. Our findings replicate earlier work demonstrating the involvement of PFC and left perisylvian regions during performance of healthy subjects on this task.23
In TBI, however, this network is augmented by additional recruitment of lateral prefrontal regions bilaterally as well as left posterior parietal regions. We observed a significant group × executive demand interaction within lateral PFC regions bilaterally as well as in left posterior parietal cortices. These data demonstrate that DAI is associated with augmented functional recruitment within this network of brain regions, particularly during tasks requiring high executive control. The localization of this augmented functional recruitment implicates interhemispheric frontal and intrahemispheric frontoparietal pathways in the altered functional neuroanatomy of executive control in working memory after TBI. We are currently examining this hypothesis using diffusion tensor imaging data in combination with fMRI.
Altered functional recruitment after brain injury has been characterized as a decline in the efficiency of neural processing operations.28,29
TBI patients often report subjective changes associated with cognitively demanding tasks in spite of normal task performance, a dissociation that presents significant challenges with respect to diagnostics and treatment planning in the absence of measurable signs of cognitive dysfunction in patients with TBI, as well as in patients with other neuropathologies causing diffuse or multifocal damage (e.g., dementia, multiple sclerosis). Reduced cognitive efficiency, as indexed by altered functional recruitment during neuropsychologically normal task performance, may serve as a novel metric, reflecting the costs of normal behavioral performance at the neural level. Indeed, these measures may correlate well with subjective complaints of patients with diffuse damage, but without demonstrable neuropsychological deficits.
Two further clinical implications emerge from these findings. First, although augmented recruitment was observed here in a sample of well-recovered patients without focal injury, we predict that patients with more severe behavioral or functional deficits would similarly demonstrate this pattern of enhanced neural recruitment during cognitively demanding tasks, albeit with diminishing behavioral gains. Such a pattern has recently been reported30
and suggests that these data may have clinical relevance across the spectrum of TBI severity. Second, TBI is commonly associated with deficits in arousal, chronic pain, anxiety and depressive symptomology, each of which has been associated with similar patterns of augmented functional neural recruitment to those reported here (for a review, see reference 31
). Although the cumulative impact of such comorbidity on higher cognitive functions after TBI has yet to be fully investigated, it is plausible that any reduction in neural processing efficiency resulting from brain injury may be exacerbated by secondary impacts of comorbid physical or psychological impairments. The impact of such interactions may impact the pace or extent of recovery in these patients and presents a challenge to both clinicians and researchers in assessing the implications of such comorbidity.