Structural and functional hallmarks of amyotrophic lateral sclerosis progression in motor- and memory-related brain regions

Abstract

Previous studies have shown that in amyotrophic lateral sclerosis (ALS) multiple motor and extra-motor regions display structural and functional alterations. However, their temporal dynamics during disease-progression are unknown. To address this question we employed a longitudinal design assessing motor- and novelty-related brain activity in two fMRI sessions separated by a 3-month interval. In each session, patients and controls executed a Go/NoGo-task, in which additional presentation of novel stimuli served to elicit hippocampal activity. We observed a decline in the patients' movement-related activity during the 3-month interval. Importantly, in comparison to controls, the patients' motor activations were higher during the initial measurement. Thus, the relative decrease seems to reflect a breakdown of compensatory mechanisms due to progressive neural loss within the motor-system. In contrast, the patients' novelty-evoked hippocampal activity increased across 3 months, most likely reflecting the build-up of compensatory processes typically observed at the beginning of lesions. Consistent with a stage-dependent emergence of hippocampal and motor-system lesions, we observed a positive correlation between the ALSFRS-R or MRC-Megascores and the decline in motor activity, but a negative one with the hippocampal activation-increase. Finally, to determine whether the observed functional changes co-occur with structural alterations, we performed voxel-based volumetric analyses on magnetization transfer images in a separate patient cohort studied cross-sectionally at another scanning site. Therein, we observed a close overlap between the structural changes in this cohort, and the functional alterations in the other. Thus, our results provide important insights into the temporal dynamics of functional alterations during disease-progression, and provide support for an anatomical relationship between functional and structural cerebral changes in ALS.

Keywords: Amyotrophic lateral sclerosis; Hippocampus; Longitudinal fMRI; Novelty processing.

Fig. 1

Schematic illustration of the experimental design. The paradigm consisted of a modified Go/NoGo-task. Beyond repeated presentation of a target and a highly similar non-target stimulus, the design also included the presentation of novel pictures (each of which occurred only once during the entire experiment). The subjects' task was to make a speeded button-press response upon detection of the target picture, but to withhold their response to the highly similar non-target and novel stimuli.

Fig. 2

Functional changes in motor regions related to ALS disease-progression. A) Motor activity (“Targets > Non-Targets”) from the 1st and 2nd fMRI sessions. Motor-related activations were observed in the bilateral primary motor cortex, cerebellum, inferior frontal gyrus/ anterior insula, striatum, thalamus, and in the supplementary motor area. Note that maximum t-values and the extent of activations are considerably higher for the 1st than for the 2nd session. B) Direct comparison of motor-related activity across sessions. A decrease in motor-related activity from the 1st to the 2nd measurement was evident in the left primary motor cortex and bilateral cerebellum, which was confirmed in a ROI-analysis (see bar graphs). C) Correlation of ROI-results and the patients' clinical data. The decrease in motor-related activity correlated with the patients' ALSFRS-R scores for both cerebellar ROIs, while in the primary motor cortex it correlated with their MRC-Megascores.

Fig. 3

Functional alterations in novelty processing related to ALS disease-progression. A) Novelty-related activity (“Novels >  Non-targets”) from the 1st and 2nd fMRI sessions. Novelty-related activity was observed across multiple ventral occipital and temporal regions, including the middle/superior occipital, fusiform, lingual and parahippocampal gyri. In addition, significant hippocampal novelty-related activations were evident during the 2nd measurement (compare activation maps between the upper and lower rows). B) Direct comparison of novelty-related activity across sessions. A decrease in hippocampal novelty-related activity occurred from the 1st to the 2nd measurement, which was confirmed by a subsequent ROI-analysis (see bar plots). C) Correlation of hippocampal ROI-results and the patients' clinical data. The hippocampal activation-increase showed a negative correlation with the patients' ALSFRS-R scores for both ROIs.

Fig. 4

Comparison of motor- and novelty-related activations between patients and controls. Values denote differences in beta-estimates between A) target and non-target trials or between B) novel and non-target trials. Black and white bars depict values for the 1st and 2nd scanning sessions, respectively. Control subjects' data are shown on the left and the patients' data on the right. Values represent the mean ± standard error of the mean. A) ROI-analysis comparing motor-related activity across sessions and groups. Patients displayed higher motor-related activity in the left primary motor cortex during the 1st scanning session and a significant decrease between sessions, which was absent in controls. B) ROI-analysis comparing novelty-evoked activity across sessions and groups. For both sessions there were no significant differences in hippocampal novelty-evoked activity between groups. Direct within-subject comparisons, however, revealed that – in contrast to controls – the patients' novelty-related hippocampal activity increased from the 1st to the 2nd session.

Fig. 5

Regional atrophy in ALS patients in comparison to controls. Results of the between-group VBM analysis are superimposed on a standard MNI template thresholded at p < 0.001 (uncorrected). Clusters of significantly reduced MTR (ALS < controls) were detected within the bilateral precentral gyrus and several subcortical regions, including the bilateral hippocampus, thalamus and striatum (see Table 6 for MNI-coordinates and maximum t-values).

Fig. 6

Overlap between structural and functional alterations. Results from the VBM analysis (illustrated in red) and for changes in motor- (blue) and novelty-related (green) activity were superimposed onto an anatomical template image. Direct overlap of functional motor-related (fMRI) and structural (VBM) alterations is shown in magenta, while overlap between functional novelty-related and structural alterations is illustrated in yellow.