Objective: The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA.Methods: Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Fortyseven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA.Results: Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle.Conclusions: PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a "dysmetria" of emotional expression resulting from cerebellar dysmodulation. Neurology ® 2014;83:620-627 GLOSSARY ALS 5 amyotrophic lateral sclerosis; ALSbi 5 amyotrophic lateral sclerosis with mild behavioral impairment; ALSci 5 amyotrophic lateral sclerosis with mild cognitive impairment; ALSFRS-R 5 Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; BDI-II 5 Beck Depression Inventory-II; DRS-2 5 Mattis Dementia Rating Scale-2; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; FSL 5 FMRIB's Software Library; PBA 5 pseudobulbar affect; PLS 5 primary lateral sclerosis; TFCE 5 threshold-free cluster enhancement; UCLA 5 University of California Los Angeles.Pseudobulbar affect (PBA) is a syndrome of involuntary emotional expression dissociated from one's true emotional experience.1 It occurs in several neurologic disorders, including amyotrophic lateral sclerosis (ALS).2,3 In one retrospective series, PBA occurred in 50% of patients with ALS. 4 There have been case reports of PBA in patients with primary lateral sclerosis (PLS), a motor neuron disorder variant with relatively selective degeneration of upper motor neurons. However, the prevalence of PBA in PLS has not been evaluated in a large patient series. 2,6 To assess the occurrence of PBA in PLS, we reviewed the charts of all patients seen in an upper motor neuron disorder clinic.Two hypotheses have been proposed regarding the neural circuits that produce PBA. Wilson 7 proposed that brainstem centers controlling laughter and crying were separately controlled by volitional a...
Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.
Introduction Patients with mutations in C9orf72 can have amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or ALS-FTD. The goals were to establish whether cortical hyperexcitability occurs in C9orf72 patients with different clinical presentations. Methods Cortical thresholds and silent periods were measured in thenar muscles in 19 participants with C9orf72 expansions and 21 healthy controls using transcranial magnetic stimulation (TMS). El Escorial and Rascovsky criteria were used to diagnose ALS and FTD. Fourteen participants with C9orf72 expansions were re-tested 6 months later. Correlations with finger-tapping speed, timed peg test, the ALS functional rating scale, and Dementia Rating Scale were examined. Results Most participants with C9orf72 expansions had normal or low cortical thresholds. Among them, ALS patients had the lowest thresholds and significantly shorter silent periods. Thresholds correlated with timed peg-test scores. TMS did not correlate with the Dementia Rating Scale. Conclusion TMS measures of cortical excitability may serve as non-invasive biomarkers of ALS disease activity.
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