This is the first study of brain-behavior relationships in a large TBI sample to combine tissue segmentation, regional brain parcellation, and lesion location analysis. Our focus was on neuropsychological functions sensitive to damage in the ventral frontal cortex, a brain region commonly implicated in TBI. We observed two primary results: Firstly, structural integrity of the ventral frontal cortex was reliably related to smell identification (the SIT), but less reliably so to object alternation (OA) or gambling (IGT) performance. Even in patients with lesions, OA and IGT performance showed stronger associations with residual tissue volumes outside the ventral frontal cortex, including the superior medial frontal lobes, sectors of the temporal lobes, and the posterior cingulate gyrus/retrosplenial cortex. Secondly, although most of our brain-behavior correlations were seen in patients with lesions, we still found smell identification associated with parenchymal integrity in medial ventral frontal cortex without lesions. Thus, extending conventional lesion analysis, our approach suggests some ventral frontal cortex functions may covary with ventral frontal cortex damage caused by diffuse injury in TBI. Importantly, the overall brain-behavior patterns in TBI patients with and without lesions were not only quantitatively but also qualitatively different, underlining the necessity to consider these two types of TBI neuropathology separately.
Previous studies in TBI found associations of neuropsychological dysfunctions and atrophy in regions selected for ease of visualization on imaging or for theoretical reasons, such as corpus callosum, cingulate gyrus or fornix (Gale, Johnson, Bigler, & Blatter, 1995
; Tomaiuolo et al., 2004
; Verger et al., 2001
). However, as demonstrated here, regions outside such pre-determined ROIs may be implicated in neuropsychological test performance. Whole-brain approaches offer an unbiased way of assessing structure-function relationships in this population. Furthermore, sampling across tissue compartments reveals the contribution of cortical volume loss to behavior, in contrast to previous studies where analysis was restricted to measures of white matter loss (Bigler, Anderson, & Blatter, 2002
; Levin et al., 1990
; Serra-Grabulosa et al., 2005
; Wilde et al., 2005
). For instance, we found no significant correlations between behavior and white matter volumes in the diffuse injury group, suggesting that gray matter volume loss is more important to behavior than white matter volume loss in the absence of larger focal lesions. For a similar finding in relation to standard neuropsychological tests, see Levine et al. (submitted-b).
Our results were dominated by effects of smell identification performance, which in the diffuse injury group was the only test significantly associated with brain volume loss. Beside the high frequency of olfactory impairment after TBI (Callahan & Hinkebein, 1999
; Doty et al., 1997
; Levin, High, & Eisenberg, 1985
), smell identification problems are strongly associated with the presence of clinically diagnosed lesions in TBI measured with conventional imaging techniques. In the current study, we additionally confirm a quantitative relationship of smell identification problems and degree of radiological abnormalities even without large focal lesions.
Previous investigations have found high incidences of olfactory bulb and tract damage associated with olfactory deficits after TBI (Yousem et al., 1999
; Yousem, et al., 1996
). As noted above, our imaging parameters were not optimized to the detection of extraparenchymal damage in the olfactory system, so we were unable to empirically assess the contribution of such damage to our results. At minimum, total anosmia due to transection of cranial nerve I (the olfactory tracts) did not contribute to our results, in that patients with self-reported anosmia were excluded from this study; the vast majority of the remaining patients, recruited from consecutive admissions, performed above chance on the SIT, confirming residually intact sensory thresholds. This is contrasted to the previous large-scale study of olfaction and imaging in TBI of patients recruited after presentation to a smell and taste clinic, were 22% performed at or below chance levels on the SIT and 44% were anosmic (Yousem et al., 1999
). In that study, olfactory tract and bulb volumes were correlated with SIT performance only among the anosmic patients; cortical temporal volumes were uncorrelated with performance and frontal volumes were not assessed.
Furthermore, only two of our 18 focal lesion patients scored in the anosmic range on the SIT. Although there was evidence of olfactory tract damage in these patients upon inspection by a neuroradiologist (F.G.), it was restricted to the left hemisphere in both patients, contralateral to the side of the right-hemispheric effects in the PLS and the brain lesion location. Due to the heavily ipsilateral nature of olfactory projections, and the right-sided nature of the ventral frontal cortex involvement, a left olfactory tract lesion is unlikely to be the sole source of an olfactory deficit (cf. Eslinger, Damasio, & Van Hoesen, 1982
). Accordingly, when these two patients were excluded from our analyses the critical findings concerning ventral frontal cortex held.
We acknowledge however, that TBI forces sufficient to damage the ventral medial prefrontal cortex may also cause olfactory tract or nerve shearing in the nasal cavity. Subtle olfactory tract or bulb damage cannot be ruled out as contributing to our results as the integrity of these extraparenchymal stuctures was not empirically assessed. Our finding of superior sensitivity of SIT to ventral medial prefrontal cortex damage may therefore be caused by the fact that in TBI, unlike in other patient populations with exclusively focal lesions, ventral medial prefrontal damage is necessarily correlated with extraparenchymal, primary sensory damage. Nonetheless, our findings replicate previous research on patients with ventral frontal damage in the absence of olfactory tract or bulb damage (Jones-Gotman et al., 1997
) as well as recent findings from our own laboratory in a sample of 32 patients with focal lesions due to strokes or tumors, where SIT performance was related to bilateral ventral frontal and right dorsolateral damage (Wiederkehr et al., in preparation).
Smell identification performance closely paralleled the location of focal lesions. It was further associated with residual integrity of a predominantly right-hemispheric combination of brain regions composed of ventral frontal cortex, medial temporal lobes and posterior cingulate gyrus/retrosplenial cortex. The primary olfactory cortex on the medial surface of the temporal lobe receives input from the ipsilateral olfactory bulb. Via thalamic, perirhinal and entorhinal regions, the ventral prefrontal cortex receives secondary and tertiary olfactory projections (Rolls, 2004
). Furthermore, the cingulate gyrus, particularly vulnerable to TBI (Gale, Baxter, Roundy, & Johnson, 2005
; Levine et al., submitted-b
; Yount et al., 2002
), provides a functional contribution to many tasks (Levine et al., submitted-a). In our case, the one may argue that damage to the posterior cingulate gyrus/retrosplenial cortex, intricately connected to medial frontal cortex (Cavada, Company, Tejedor, Cruz-Rizzolo, & Reinoso-Suarez, 2000
) may have contributed to the smell deficits. Thus, the localization of smell identification problems in TBI patients with focal cortical contusions can be considered in good accordance to previous studies of olfactory problems after ventral prefrontal or medial temporal lobe lesions (Jones-Gotman et al., 1997
; Zatorre & Jones-Gotman, 1991
), functional neuroimaging studies (Dade, Zatorre, & Jones-Gotman, 2002
; Wang, Eslinger, Smith, & Yang, 2005
), and findings of smell loss as reported in other samples of patients with TBI (Green, Rohling, Iverson, & Gervais, 2003
; Levin et al., 1985
; Yousem et al., 1996
). While this lesion-behavior relationship was expected, we showed gradual ventral frontal tissue loss in the absence of focal cortical contusions was likewise associated with smell identification problems following TBI.
An interesting additional finding in the diffuse injury group of patients was the association of smell identification problems to gray matter loss in lateral posterior temporal lobe regions. The SIT requires not only sensory detection of odors but also their classification to semantic verbal labels. The posterior temporal lobes are activated in functional neuroimaging studies involving integration of semantic and multisensory information (Beauchamp, 2005
; Büchel, Price, & Friston, 1998
). Lesions of posterior temporal lobe regions within the ventral visual pathway correspond with difficulties in connecting categorical semantic knowledge to sensory information (Damasio, Tranel, Grabowski, Adolphs, & Damasio, 2004
; Gainotti, Silveri, Daniele, & Giustolisi, 1995
; Humphreys & Forde, 2001
). Reduced lateral posterior temporal lobe gray matter in our diffuse injury group may therefore have reflected inefficient connection of conceptual knowledge about the odor descriptions to the sensory features of the odors themselves (see also: Jones-Gotman & Zatorre 
The OA task was only reliably related to regional tissue volumes outside the ventral frontal cortex, including the medial temporal lobes, posterior cingulate gyrus/retrosplenial cortex and superior medial frontal cortex. These results contrast with studies implicating the importance of the ventral frontal regions to OA and other reward alternation performance in humans (Kringelbach & Rolls, 2004
; Rolls, 2000
) and non-human primates (Mishkin, Vest, Waxler, & Rosvold, 1969
; Pribram & Mishkin, 1956
). The medial temporal lobe and posterior cingulate gyrus/retrosplenial cortex may mediate mnemonic components of OA, such as associative memory for relationships between information presented at different times (Cohen & Eichenbaum, 1993
). OA requires flexible learning and unlearning of correct responses in each trial, whereas other tasks used in patient studies involved a slower rate of reward acquisition and switching (Fellows & Farah, 2003
; Hornak et al., 2004
). Thus OA may be more sensitive to functions associated with dorsal prefrontal regions, such as resolution of response conflict (de Wit, Kosaki, Balleine, & Dickinson, 2006
) and selective attention and working memory (Faw, 2003
) may have had a larger contribution to OA performance than processing of the emotional aspects of this task (reward representation and changing response patterns to obtain reward) considered functions of the ventral frontal cortex (Kringelbach & Rolls, 2004
). Our study is not alone in this respect. Lesions in previous patient studies of reward alternation behavior have not been strictly confined to ventral frontal lobes; they have encroached well into more superior medial brain areas (Fellows & Farah, 2003
; Freedman et al., 1998
; Hornak et al., 2004
). Results from functional neuroimaging studies of object alternation are thus far inconsistent. Whereas some point to a particular involvement of ventral medial frontal cortex regions (Gold, Berman, Randolph, Goldberg, & Weinberger, 1996
; O'Doherty, Kringelbach, Rolls, Hornak, & Andrews, 2001
; Zald, Curtis, Folley, & Pardo, 2002
), other studies – consistent with our findings – show additional, more dorsal frontal regions critically involved (Zald, Curtis, Chernitsky, & Pardo, 2005
), with a particular importance of medial polar frontal cortex (Turner & Levine, 2006
Finally, we failed to confirm the specificity of the Iowa Gambling Task to ventral frontal brain regions. Indeed, IGT performance was not significantly related to structural integrity of most of the assessed regional brain volumes, even in the presence of lesions. Some previous patient studies showed decision-making problems following ventromedial prefrontal cortex lesions, especially if damage was sustained to the right hemisphere (Bechara, et al., 2000
; Tranel, Bechara, & Denburg, 2002
). Such an association might be expected in the present study given the predominance of right ventral frontal lesions. Instead we found, similar to our results with the OA task, the only significant correlation to gambling performance was in the focal lesion group and confined to gray matter volumes in superior medial frontal cortex. The specificity of the Iowa Gambling Task to ventral frontal cortex damage has been challenged (Clark, Manes, Antoun, Sahakian, & Robbins, 2003
; Manes et al., 2002
). For instance, Manes and colleagues (Manes et al., 2002
) reported patients with focal ventral frontal cortex damage performed similar to controls, whereas patients with damage to either dorsolateral, dorsomedial or more extended frontal lobe regions were impaired. We have also found that the IGT is unrelated to focal frontal damage in our sample of 32 patients (Wiederkehr et al., in preparation).
A composite IGT score could be regarded as a limitation since effects involving acquisition slopes may be obscured. The first two blocks of the IGT were differentially influenced in the TBI patients compared to comparison subjects. Comparison subjects started out with lower difference scores in block 1 and TBI patients scored lower in block 2, while all other blocks, when analyzed separately, were statistically identical between patients and comparison subjects. Owing to this result of differential performance patterns across IGT blocks (see also Brand, Recknor, Grabenhorst, & Bechara 
for healthy individuals' differential performance during IGT blocks), we performed two additional PLS analyses using brain volumes and SIT, OA and separate blocks of the IGT in focal lesion patients and diffuse injury patients. None of the analyses from focal lesion patients returned significant LVs, due to the greater variability among now seven instead of three behavioral measures in this relatively small sample. In the diffuse injury group, none of the single IGT blocks was significantly related to brain volumes. Furthermore, conventional correlations between separate IGT blocks and ventral frontal cortex volumes in either focal or diffuse injury group did not reveal any significant results (all p's> 0.05). Finally, also re-analyzing our results by excluding the first two IGT blocks due to their less reliable contribution to the overall IGT outcome (see also: Levine et al., 
, Dunn et al. 
), to rule out contamination of the composite score by these trials did not qualitatively change our results. Thus, it appears safe to say that, at least in our form of analysis, IGT blocks did not covary differentially with brain volumes in our patient group.