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2.4.1

Study design considerations and limitations of this work

Individual Feature Maps (IFMs) allow comparisons between a patient and a set of healthy sub- jects to determine regions of interest that are significantly different in the patient with respect to the control group. The nature of the underlying statistical test is to identifypatient-specific ab- normalitiesrather than results that could be extrapolated to the entire patient population using statistics, as achieved by techniques such as voxel-based morphometry [28].

Another important consideration is that IFMs are sensitive to any departure from the con- trol group distribution and not only to those that can be correlated to TLE. For example, dif- ferences in ventricular intensity were found for the MTS+group (Figure 2.7b), however, one of the patients accounting for such differences was diagnosed with ventricular enlargement and periventricular leukomalacia (#8 on Table 2.2). Therefore, interpretation of IFMs should consider the clinical history and other findings accounting for possiblesecondary pathologies

that may appear in addition to TLE. Also, it has been shown that MRI abnormalities associ- ated with TLE can be common in healthy individuals [29]. Therefore, any finding should be examined in clinical context. In particular, no assumptions regarding the level of asymmetry in the control cohort are made. Instead, a baseline for normal asymmetry is established from the control group and it is then applied to evaluate the rarity of individual patient measurements.

I consider that the selection of the control group is an important factor for the applicability of IFMs in similar studies. The control group should match the type of patient (for example, pediatric patients must be compared against similar-aged control group). A large variance of the control group must be avoided to minimize false negatives.

Although a larger patient cohort is not required for individual patient analysis, it could im- prove the applicability ofa posteriorigroup-wise analysis of the kind presented in this chapter.

Though the number of extratemporal (cortical and white matter) intensity abnormalities was higher for R-TLE with respect to L-TLE (Figure 2.7c), no statistical significance was attained. Similarly, a more detailed analysis looking for differences and diagnostic clues for the elusive MTS- group would be possible with a larger MTS- patient sample.

2.4.2

On the role of single-subject statistics

Single-subject t-tests are fundamental to the acquisition of IFMs. There are two considerations (or limitations) regarding the use of these tests in small samples: a) departures from normality and b) statistical power.

Crawford et al.[22] analyzed the effects of lack of normality on normative samples (control group) on single-subject t-tests and conclude that this test behaves better than a regular z- score test (more commonly used by clinicians) for small datasets (N<20) and that departures from normality have low to moderate effects in the test score. If there is concern over the skewness and/or kurtosis of the normative sample, then a smaller significance level than the commonly used 0.05 (i.e. 0.02) could give a higher degree of confidence that the result is not a non-normality artifact, effectively reducing Type I error inflation. A practical consideration is that while patient images are difficult to obtain (patient availability and eligibility), it is much easier to image control volunteers. Therefore, an increased volunteer cohort should ameliorate the quality of the probability distribution.

The second consideration is the statistical power on small datasets. In theory, to increase power the significance level of the test could be less severe 6_{. This would e}ff_{ectively reduce}

the number of false negative (Type II errors), increasing statistical power with the trade-off of increasing the number of false positives (Type I errors). In practice, this does not improve reliability. In our study of TLE, as in most statistical neuroimaging studies, thetrue effect size is commonly unknown[30]. In other words, it is unknown how large a difference between patients and controls needs to be, in order to be declared a pathology. Nonetheless, it is important to note that unlike two-sample t-tests where inferences on a patient group are sought, the goal

of a single-subject t-test is to obtain an estimate of the rarity of a feature for a given subject

with respect to a normative distribution (control group). In other words, the null hypothesis of single-subject t-tests is that the subject being tested belongs to the normative population (control group). Thus, statistically significant results in this scenario, represent regions where the subject departs from the control distribution beyond a given statistical threshold set for the test, and no inferences are made over the patient population.

2.4.3

Comparison with similar studies

The analysis of T1 in the context of TLE has only recently been explored [31]. Our results showed T1 hyperintensities were significantly more common in MTS+ patients (p<0.05), which could be an indication of gliosis and subsequent remyelination (higher signal due to myelin), or iron accumulation associated with microgliosis [32]. More studies are required to investigate the effectiveness of T1 measurements in the study of TLE as well as its correlation with histological findings.

Similarly to ROI analyses performed by Pell et al. [25] and VBR analyses by Mueller et al. [26], ipsilateral hippocampal T2 hyperintensities in MTS+ patients were found (Fig- ure 2.8b). However, since our study included several image types, it was assessed that MD asymmetry was comparatively more frequent. In addition, MD hyperintensities were found in the ipsilateral temporal lobe of MTS+patients. This type of finding has also been reported by Shon et al. [11].

Similar to our results, a pattern of ipsilateral FA hypointensity and MD hyperintensity in MTS+ patients (Figure 2.8b) was evidenced by Focke et al. [10] on 33 MTS+ patients. Significant FA reductions in patients with respect to controls were also found, similarly to Ahmadi et al. [9]. In parallel to Liu et al. [33], temporal white matter changes were significantly more frequent in MTS+ than in MTS-. In agreement with Gross et al. [34], no correlation between FA changes and surgical outcome were found.

It has been suggested that DTI abnormalities are not as extensive or as severe in MTS- pa- tients as they are in MTS+patients [35]. This tendency was observed in our results, with more

frequent intensity abnormalities in the MTS+with respect to the MTS-. However, statistical significance was not achieved in our cohort(Figure 2.8a and b, FA and MD plots). In gen- eral, our results show that volume and intensity abnormalities are present to a lesser degree in MTS- patients. Nonetheless, intensity changes in the temporal cortex were significantly more frequent (p<0.01) in this group (Figure 2.7b). The subsequent analysis, revealed that most of these abnormalities originate from MD images (Figure 2.8a and b). This suggests that the anal- ysis of the temporal cortex using MD images could be key for the study of non-lesional cases. In fact Keller et al.[12] have studied this scenario in 10 non-lesional TLE patients, obtaining patterns of FA reduction and MD increase. However, they conclude that larger cohorts are required to obtain more reliable results.

Though extratemporal changes were slightly more common in our R-TLE group, no statis- tical significance was obtained.

The group-wise analysis of volume differences was in agreement with the results shown by Seidenberg et al. [27] and Cohan et al. [8]: hippocampal volume changes were statistically significant between patients and controls. In addition, satisfactory results were obtained using hippocampal volume to distinguish between controls, MTS- and MTS+. Also, extratemporal volume asymmetry on the cortex was found in TLE patients, though it was not significantly higher than that found in our control cohort (Figure 2.9a). Also, in agreement with Pell et al.[1], volume differences between patients and controls were seen in the hippocampus and thalamus (Figure 2.9b). Moreover, our study seems to indicate that both intensity and volumet- ric thalamic changes are significantly more frequent in MTS+patients, which suggests that the thalamus is an interesting region to analyze as a hub in the pathologic network of TLE [36, 37]

2.4.4

Clinical Relevance

Our multi-feature evaluation approach identified hippocampal involvement in all the patients with MTS (Table 2.2). Patient #6 who had been identified as a possible MTS in the presur- gical MRI was later on confirmed negative for MTS by histopathology, which only revealed gliosis. Consistently with the pathological validation, the IFMs did not report any intensity

or or volumetric abnormalities for this patient. No hippocampal involvement was reported in the MTS- with the exception of patient #12, where the volume IFM {V} reported volume re- duction in the left hippocampus. Also, in the MTS- group, significant intensity changes were detected in the temporal cortex with respect to the control group (p-value<0.01) as shown in Figure 2.7b. Focusing on the detection of quantitative intensity changes on the temporal cortex could contribute to a better understanding of non-lesional cases.

Using the laterality score, which measures intensity asymmetry in the temporal lobes, 13 out of 15 patients were lateralized correctly, with the remaining three receiving a lateralization score of zero. These subjects had normal presurgical MRIs (Table 2.2, #13-15) and our method did not find sufficient intensity asymmetry in their respective T1, T2, MD, and FA images.

No clinical correlation was found between the features evaluated in this study and the Engel classification for surgical outcome.