Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort.

OBJECTIVE: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI). METHODS: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception. RESULTS: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum. CONCLUSION: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.

Left perirhinal cortex codes for similarity in meaning between written words: Comparison with auditory word input.

Left perirhinal cortex has been previously implicated in associative coding. According to a recent experiment, the similarity of perirhinal fMRI response patterns to written concrete words is higher for words which are more similar in their meaning. If left perirhinal cortex functions as an amodal semantic hub, one would predict that this semantic similarity effect would extend to the spoken modality. We conducted an event-related fMRI experiment and evaluated whether a same semantic similarity effect could be obtained for spoken as for written words. Twenty healthy subjects performed a property verification task in either the written or the spoken modality. Words corresponded to concrete animate entities for which extensive feature generation was available from more than 1000 subjects. From these feature generation data, a concept-feature matrix was derived which formed the basis of a cosine similarity matrix between the entities reflecting their similarity in meaning (called the "semantic cossimilarity matrix"). Independently, we calculated a cosine similarity matrix between the left perirhinal fMRI activity patterns evoked by the words (called the "fMRI cossimilarity matrix"). Next, the similarity was determined between the semantic cossimilarity matrix and the fMRI cossimilarity matrix. This was done for written and spoken words pooled, for written words only, for spoken words only, as well as for crossmodal pairs. Only for written words did the fMRI cossimilarity matrix correlate with the semantic cossimilarity matrix. Contrary to our prediction, we did not find any such effect for auditory word input nor did we find cross-modal effects in perirhinal cortex between written and auditory words. Our findings situate the contribution of left perirhinal cortex to word processing at the top of the visual processing pathway, rather than at an amodal stage where visual and auditory word processing pathways have already converged.