Correlations with neuropsychological dysfunction

3.4.3.1 The role of the uncinate fasciculus in memory

The UF is the major fibre tract connecting the inferior frontal and anterior and mesial temporal lobes (Ebeling and von Cramon, 1992). A multitude of functional neuroimaging data has implicated the temporal lobes, particularly mesial temporal and frontal structures in encoding and retrieval of memories. The anterior temporal area receives information from sensory association areas as well as the limbic nuclei and integrates sensory input (Damasio et al., 1985; Markowitsch et

al., 1985). In healthy subjects, fMRI has confirmed that episodic memory is

associated with both mesial temporal and frontal lobe activation (Brewer et al., 1998; Kirchhoff et al., 2000; Markowitsch et al., 1985; Wagner et al., 1998). There is material specific lateralisation of memory in both healthy volunteers and patients with unilateral mesial temporal lobe lesions. Encoding of verbal information activates the left medial temporal structures, whilst encoding of less verbalisable stimuli, such as patterns, activates the right mesial temporal structures, with encoding of intermediate verbalisable stimuli, such as faces and scenes, resulting in approximately symmetric activation (Brewer et al., 1998; Golby et al., 2001; Golby et al., 2002; Hwang and Golby, 2006). In general, the lateralisation of memory performance regarding verbal material appears stronger; conversely, there is a less firm association of right TLE with disturbed figural learning (Helmstaedter et al., 1995; Powell et al., 2007b).

The medial temporal lobes have been consistently implicated not only in encoding, but also in retrieval (Schacter and Wagner, 1999; Wagner et al., 1998). Pre-frontal regions in the left hemisphere are differentially activated during episodic encoding and semantic retrieval, whereas right pre-frontal areas are differentially involved during episodic memory retrieval. It therefore seems reasonable to assume that the integrity of the UF linking the frontal and anterior and mesial temporal lobes is important for optimal performance on memory tasks.

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3.4.3.2 Correlations of DTI abnormalities in the UF in disease

In line with the above hypothesis, correlations were found between DTI measures suggesting damage to the UF and dysfunction in lateralised memory tasks. Specifically, the current study suggests that in patients with left TLE, left UF diffusivity is related to reduced verbal memory performance, whereas right UF DTI measures are related to reduced visual memory performance. In patients with right TLE, such correlations could not be demonstrated. This may in large part be due to the small sample size in the right TLE group. Although none of the correlations in the right TLE group reached statistical significance, it should be noted that the variance of correlation coefficients observed in this group was large and some of the correlations were in the medium to large range (Table 3.3). This suggests that if the sample sizes had been bigger in the right TLE group, these correlations would likely have reached statistical significance.

In the dominant hemisphere, strong structure and function relationships have been found for both language and memory in a variety of DTI and fMRI studies in temporal lobe epilepsy patients (Focke et al., 2008; Powell et al., 2007a; Powell et

al., 2008; Powell et al., 2007b). Subjects with more lateralised functional

activation had also more highly lateralised DTI values. In left TLE, more symmetrical language activations were seen on fMRI, along with reduced left hemisphere and increased right hemisphere structural connections. fMRI in the patients undergoing non-dominant anterior temporal lobe resection showed no significant correlation between right hippocampal encoding activation for faces or pictures and post-operative change in design learning, suggesting a less strong structure-function relationship in non-dominant TLE. Therefore, lack of correlation between visual memory performance and DTI values in the UF in the smaller right TLE group may not be surprising.

Correlations between lateralised memory performance evaluating both verbal and visual memory paradigms and DTI abnormalities have been shown in other

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diseases. Patients with schizophrenia have reduced levels of functioning across all neuropsychological measures and selective relationships between memory performance and DTI measures have been demonstrated. Reduced left UF FA correlated with reduced scores in measures of declarative-episodic memory, and reduced right UF FA correlated with lower scores on measures of working memory, general intelligence, verbal intelligence and verbal comprehension. The authors felt that the latter finding underscored the widely distributed nature of higher cognition in the brain, thus cautioning against simple isomorphic relationships between function and anatomy (Nestor et al., 2004). Another study reported that lower FA in the right UF correlated with reduced performance on measures of visual attention (Kubicki et al., 2002). In five subjects with schizotypal personality disorder, bilateral reductions of FA in the UF were reported. Correlations were found between right UF abnormalities and clinical symptoms such as restricted affect and social anxiety. Left UF measurements indicative of microstructural damage were correlated with lower performance on measures of verbal and visual memory (Nakamura et al., 2005).

In a group of TLE patients suffering from psychosis (Flugel et al., 2006), a positive correlation was found between verbal fluency and DTI measurements in the left frontal, right frontal, and left temporal regions. Prediction of poor fluency could be made using FA of left frontal and bilateral temporal regions. It was felt that the significant association between impairment on particular executive tests and reductions of frontotemporal FA may reflect the contribution of frontotemporal white-matter abnormalities to the cognitive deficits in these patients. This argument is further strengthened by data from diseases mostly affecting white matter, such as multiple sclerosis, where lesion burden and abnormal diffusivity measures correlate with cognitive performance (Rovaris et al., 2002).

Microstructural abnormalities within the UF therefore could contribute to memory dysfunction in patients with TLE. Furthermore, the UF carries cholinergic fibres from the basal nucleus of Meynert, as part of a cholinergic pathway that supplies

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frontal, parietal and temporal neocortices and the perisylvian division of the frontotemporal operculum, insula and superior temporal gyrus. Altered cholinergic innervation through the UF may contribute to disturbed memory functions (Selden

et al., 1998).

3.4.3.3 Correlations of DTI abnormalities in the UF in epilepsy

Since publication of these results (Diehl et al., 2008), one further study has investigated relationships between memory and DTT and has in part replicated these findings. McDonald et al. (2008) found increased diffusivity of numerous fibre tracts associated with poorer verbal, but not nonverbal memory performances in TLE. These associations were strongly left-lateralised for the UF. McDonald et al. also investigated the parahippocampal cingulum and the inferior occipitofrontal gyrus, which also showed strong correlations with memory performance. The parahippocampal cingulum, the white matter running along the ventral aspect of the parahippocampal gyrus and connecting medial temporal lobe regions to the posterior cingulate cortex is an important part of the limbic circuit and therefore unsurprisingly related to memory function. The authors felt that the damage in the inferior fronto-occipital fasciculus may have affected memory performance through impaired attention.

In the same study, correlations between visual memory and right UF DTT was examined, but did not yield any systematic relation, contrary to the findings of this study. Aside from methodological reasons the authors also discuss that overall the relation between nonverbal memory and right temporal lobe function is known to be more tenuous than the association between verbal memory and left temporal lobe function (Vaz, 2004).

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One of the shortcomings of the current study is that neuropsychological measures were available only for the patient groups and not for the controls. Therefore, it cannot be determined whether similar correlations exist between memory performance and UF diffusion measures in a healthy control population. The current study is also limited by the rather small sample size, and larger prospective studies will need to be undertaken to confirm the results. Furthermore, due to the exploratory nature of the study, no correction for Type I errors were made. However, the strong correlations in the expected direction despite small sample size are a good indicator that the correlation between memory performance and integrity of the UF is a robust finding, particularly in the dominant hemisphere. Regarding tractography, all limitations mentioned in section1.6 apply.

This chapter has shown that in left TLE, strong structure function relationships exist when investigating visual and verbal memory. In the following chapter, results of similar correlation studies between white matter connections and performance in the language domain are presented.

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CHAPTER 4

CORRELATES OF LANGUAGE FUNCTION, DTI MEASURES AND