Abstract
ObjectiveWe investigated the nature and neural foundations of pathologic tearfulness in a uniquely large cohort of patients who had presented with autoimmune limbic encephalitis (aLE).MethodsWe recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated correlations of questionnaire scores with demographic, clinical, neuropsychological, and brain imaging data across patients. We also compared patients diagnosed with pathologic tearfulness and those without, along with healthy controls, on gray matter volume, resting-state functional connectivity, and activity.ResultsPathologic tearfulness was reported by 50% of the patients, while no patient reported pathologic laughing. It was not associated with depression, impulsiveness, memory impairment, executive dysfunction in the postacute phase, or amygdalar abnormalities in the acute phase. It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons.ConclusionsPathologic tearfulness is common following aLE, is not a manifestation of other neuropsychiatric features, and reflects abnormalities in networks of emotion regulation beyond the acute hippocampal focus. The condition, which may also be present in other neurologic disorders, provides novel insights into the neural basis of affective control and its dysfunction in disease.
Highlights
It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons
Resting-state amplitude of low frequency fluctuations and functional connectivity We further examined whether resting-state abnormalities in the local amplitude of low-frequency fluctuations and hippocampal functional connectivity were associated with pathologic tearfulness
In our previous study,[24] we identified a series of brain abnormalities (n = 13) that patients showed at group level: volume reduction in the left and right hippocampus, captured by both voxel-based morphometry (VBM) and manual delineation; volume reduction in the anterior-mediodorsal thalamus and right dorsolateral thalamus (VBM) and the left thalamus, as well as the right entorhinal cortex; reduced right hippocampal resting-state functional connectivity (rsFC) with left hippocampus, ventral-posterior posteromedial cortex, and medial prefrontal cortex (BA 10, 32, 24); and reduced rsALFF in the posterior cingulate and the precuneus (BA 23, 31)
Summary
We recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated its relationships with demographic and clinical data, selfreported measures of emotion regulation, and performance on neuropsychological tests. We hypothesized that it is associated with abnormalities in the hippocampus, the amygdala, hippocampal-diencephalic-cingulate networks, and cerebro-ponto-cerebellar loops: aLE results in relatively focal hippocampal atrophy,[11,16] and the limbic system is involved in emotion processing.[17,18,19] Amygdala abnormalities are sometimes observed[20] and have been associated with abnormal autonomic arousal.[21] the hippocampus is embedded within broader hippocampaldiencephalic-cingulate networks supporting emotion regulation.[22] We have recently shown abnormalities in this extended circuitry in aLE.[23,24] in a prominent pathophysiologic account, emotion dysregulation in pseudobulbar affect was caused by disruption to cerebro-pontocerebellar pathways,[7] with which the hippocampus communicates.[25]
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