This study offers the first demonstration that patients with pure DAI show a compensatory cortical activation during the recovery phase of the condition. We conducted fMRI of 12 patients with pure DAI showing TMB in T2*‐weighted gradient‐echo images in the absence of other traumatic or non‐traumatic MRI abnormalities and compared the result to that for 12 controls of the same age and sex. During the PVSAT task patients with pure DAI showed cortical activations in the bilateral prefrontal region, while controls showed only left prefrontal activation. Activation of the right prefrontal region (BA 45 and 9) was statistically different between the two groups. At the behavioural level, patients with pure DAI had a slightly lower percentage of correct responses than controls during the PVSAT. These findings suggest that compensatory activation of the contralateral (right) prefrontal cortical region was necessary in order for patients with pure DAI to carry out activities similar to controls.
The results of recent studies on cognitive disability of DAI are inconsistent.13,14
Scheid et al15
proposed that the reason for this inconsistency was that diagnosis of DAI relies on cranial computed tomography, although DAI is in fact a neuropathological diagnosis. To further clarify the relationship between DAI and cognitive deficit, they defined pure DAI as the presence of TMBs on T2*‐weighted gradient‐echo images and the absence of other traumatic or nontraumatic MRI abnormalities, and they calculated correlations with detailed neuropsychological test findings for pure DAIs. Pure DAI was confirmed in all patients with impairment of one or more cognitive subfunction, whereas there was no correlation between the number of TMBs and specific or global cognitive performance. Scheid et al15
suggested that functional reorganisation affected performance, such that performance and TMB load were no longer correlated. The same phenomenon has been reported in fMRI studies of other diseases. In patients with multiple sclerosis, cognitive decline was determined to be unrelated to lesion load, reportedly because the patients differed in the ability to recruit resources from brain areas not primarily required for the task. Several recent fMRI studies have shown that during working memory tasks, patients with multiple sclerosis exhibit a higher degree of brain activation than do healthy controls,7,16,17,18,19,20,21
showing that patients with multiple sclerosis and healthy controls use different brain areas to carry out the same cognitive task.
Some of the studies designed to investigate compensatory cortical mechanisms have used the PVSAT task, but there have been no studies of compensatory cortical activation in patients with pure DAI. Many fMRI studies of TBI have focused on mild TBI.22,23,24
Although Christodoulou et al25
reported fMRI data for patients with severe TBI, about 50% of their sample was patients with focal brain contusion. Correlation of cognitive function and traumatic load was inconsistent, because traumatic load included both focal and diffuse injuries. Therefore, the data dealing with functional compensatory mechanisms that included both focal and diffuse injuries was suspected to be inconsistent.
Our data included only patients with pure DAI. No previous reports demonstrating functional mapping of pure DAI were shown. Although patients and controls were matched on age, sex and handedness, cognitive function of the pure DAI patients was slightly inferior to that of controls. Cognitive function could not be matched because all patients with pure DAI showed impairments of one or more cognitive subfunctions.2
sustained attention task, adapted from the PASAT, served as the paradigm during fMRI. This test requires rapid information processing, working memory and arithmetic abilities, and thus can be considered as a test of dual processing. Neither healthy controls nor patients in the early stage of chronic cognitive diseases, such as HIV26,27
or multiple sclerosis,28
have substantial difficulties with the PVSAT.16
We found that patients with pure DAI completing the PVSAT had equal reaction times and only slightly lower performance than control subjects. On average, brain activation in healthy controls during the PVSAT occurred primarily in the frontal and parietal lobes, and these areas were activated in most of the participants, an indication of limited interindividual variation. Brain activation during the PVSAT in these participants depended mainly on left frontal (BA 6 and 9) and parietal areas (BA 7 and 40), with some important activations in the right hemisphere (BA 6) as well. These areas are relevant to performance of oral working memory tasks. The left prefrontal–dorsal region (BA 9) is recruited during the maintenance of information in working memory. Both areas have previously been reported to be components of the central executive system of working memory.29,30
Left parietal cortex (BA 7 and 40) has been proposed to be involved in storage processes, in contrast with the maintenance and rehearsal‐related functions thought to be subserved by the prefrontal cortex. Specifically, the posterior parietal cortex participates in phonological storage,31
while the left ventral prefrontal cortex (BA 44, Broca's area) is involved in subvocal rehearsal. Moreover, parietal BA 7 has also been found to be active during arithmetical tasks.17
In our study, healthy controls showed patterns of cortical activation during the PVSAT task similar to those previously reported. The patients with pure DAI also showed right prefrontal activation. We interpret this bilateral activation of the prefrontal region as a cortical compensatory mechanism.18
One of the most important aspects was that the control group outperformed the pure DAI group in the PVSAT. In addition, the patients with DAI who made a few errors tended to show a greater increase in activities of the right prefrontal region. In healthy volunteers, BA 6 has been reported to show bilateral activation during tasks of selective and sustained attention. Likewise, this area has been found to be bilaterally activated in relation to the decision‐making subprocess of working memory, independent of the specific nature of the task (oral or spatial).32
On the basis of the superior performance of the control group in the PVSAT task, we believe that the differences in activation of the right prefrontal cortex are an indication of compensatory mechanisms.
Bilateral activation during a sustained task has been observed in other diseases and conditions. In patients with multiple sclerosis, the primary activation was detected in the right frontal cortex (BA 6, 8, and 9); in addition, the left BA 39 was active.15
In healthy volunteers, tool use activated the right BA44, whereas simple stick use activated only the left BA 44. The right premotor cortex appears to play a greater part than its left‐sided counterpart in sequence production when sequences are performed or learnt using the right hand.33
Maruishi et al34
showed that the right ventral premotor cortex plays an important part in manipulating the electromyographic prosthetic hand. In addition, neuroplasticity—neural changes in response to the disease processes—is also an explanatory factor.
A possible explanation for the difference in parietal activation between patients and controls is that the patients with pure DAI needed greater parietal activation of storage processes during CRT than did the controls. As a result, subtraction of brain activation during CRT from brain activation during PVSAT did not show a significant difference in parietal activation in patients with pure DAI. Specifically, during the PVSAT task, cerebral blood flow in the left parietal region was increased more in patients with pure DAI than in controls.
Our study improved the methods of the fMRI task.7,16,17,18
As in most previous studies, we used an auditory version of the PASAT that resembled the original task. However, the first study used a visual version of the PASAT, called PVSAT.12
As the authors noted, use of the visual modality had the advantage of suppressing interference between scanner noise and auditory stimuli. However, the PVSAT was an easy task because visual presentation of stimuli removed the interference between output and input modalities, leading to better performance.35
A second relevant difference between this study and previous studies was the control task. In the studies by Audoin et al17,18
the control task was repetition, whereas in others it was rest.7,16
Several researchers have criticised the use of rest as a control task based on the notion that it may increase the likelihood of participants engaging in unsolicited cognitive activities that may confound results.36
The third relevant difference from previous studies was the required response. Like Staffen et al
we preferred not to directly control task performance and instructed participants to carry out the task silently. Mainero et al7
instructed participants to carry out the task silently and raise their finger whenever the sum equalled 10. This approach avoided the problems associated with participants responding aloud, but increased the difficulty of the task, converting it to a dual‐task situation. Using a strategy more similar to the PASAT, Audoin et al17,18
instructed participants to respond aloud. Clearly, allowing participants to verbalise in the scanner rather than carry out a motor response would be very desirable when seeking to obtain high‐quality fMRI. However, the risk of movement and magnetic susceptibility artefacts has made the use of oral response prohibitive.
In conclusion, we interpret the differences in brain activation of patients with pure DAI and healthy controls during intact performance of a sustained attention and dual processing task as the consequence of compensatory mechanisms. These findings provide further evidence of the adaptive capacity of neuronal systems and brain plasticity during the recovery stages of DAI.