The volumetric 3-D MRI-based measurements of amygdala demonstrated a trend for volume reduction in patients with clinically definite ALS, i.e. a mean decrease by 6.9% in absolute and 7.6% in corrected values. These data are in general accordance with autopsy studies which describe intraneuronal inclusion bodies and marked gliosis in the amygdala of ALS patients [
6], although it has to be held that these histological changes might not influence volumes per se. Another reason for the apparent discrepancy between the marked amygdala alterations in neuropathological studies and the non-significant findings in MRI-based studies might be that the latter including the present one were performed in patients who were moderately disabled and that amygdala changes might be more pronounced in the later stages. The neuropathological findings seem to be more common in ALS patients with dementia [
2], but they are not limited to these cases and are found in non-demented ALS patients as well [
6]. The lower volumes in ALS are obviously a subtle finding in
in vivo studies which was only detected when amygdala volumes were specifically addressed – in contrast, there were no amygdala changes found in previous whole brain-based investigations in ALS using statistical comparisons of 3-D MRI data (voxel-based morphometry), neither in non-demented ALS patients [
10] nor in patients suffering from ALS/frontotemporal lobar degeneration complex [
20]. The trend for lower amygdala volumes is the more remarkable since there was no global atrophy of the ALS patients' brains found here (i.e., the total brain volumes did not differ from controls), opposite to previously used automated techniques [
10]. These discrepant findings might be explained by the basic methodological differences in global atrophy assessment between the two studies. In the present study, a volume-of-based approach was used on 3-D MRI data in native space to determine total brain volumes, for the purpose of correcting absolute amygdala volumes for global brain atrophy in a ratio of absolute volumes. In the previous study [
10], brain parenchymal fractions (BPF) were investigated, i.e. size-normalised proportions of grey matter and white matter volumes to total intracranial volumes, calculated after pre-processing steps including statistical parametric mapping (SPM)-based spatial normalisation to standard space and automatic segmentation. Obviously the manual ROI delineation and automatic growing tool, performed in every tenth slice, within
MRreg on the one hand and the SPM-based automatic processing of normalised data on the other hand produced different results with respect to the statistical significance of the comparison of ALS patients and controls.
The functional impact of the subtle structural amygdala abnormalities is hard to assess. The amygdala is believed to be important among other functions for evaluation of the emotional valence of stimuli in the early phases of sensory processing (assigning emotional significance to specific sensory input [
21]), linkage of perceptual representation to emotional memories and regulation of autonomic responses [
22]. In humans, the amygdala appears to be especially important for processing of emotional information in a social context [
23]. Affection and emotional processing in ALS is poorly understood beyond the general agreement that ALS patients do not develop a depressive disorder despite the severe impact of the disease on their lives. It has been demonstrated that emotional responses of ALS patients tend to be altered towards positive valence [
8], and it seems a plausible concept that alterations of the amygdala might be involved in this process.
Whether the volume reduction implies
per se a loss of function of the amygdala or is just the morphological correlate of a generally altered function, remains unresolved. According to a PET study, a group of non-demented MND patients had a reduced regional cerebral blood flow in limbo-thalamic areas [
24], indicative of functional decrease. With respect to cognitive abilities, the division of human behaviour into emotion and cognition is not as clear as previously suggested, and the finding that brain regions linked to executive function and working memory are correlated with amygdala response suggests one pathway by which complex cognitive manipulations of stimuli might influence the neural circuitry of emotion, so for instance an indirect communication between frontal cortical areas and amygdala exists [
25]. The involvement of amygdala volume decreases in dementia, even as a predictive factor, has been demonstrated, however, only for Alzheimer disease yet [
26], but might be part of the ALS/dementia complex as well.