Objective: The clinical diagnosis of primary lateral sclerosis can only be made after upper motor neuron symptoms have progressed for several years without developing lower motor neuron signs. The goal of the study was to identify neuroimaging changes that occur early in primary lateral sclerosis, prior to clinical diagnosis. Methods: MRI scans were obtained on 13 patients with adult-onset progressive spasticity for five years or less who were followed longitudinally to confirm a clinical diagnosis of primary lateral sclerosis. Resting state functional MRI, diffusion tensor imaging, and anatomical images were obtained. These ‘pre-PLS’ patients were compared to 18 patients with longstanding, established primary lateral sclerosis and 28 controls. Results: Pre-PLS patients had a marked reduction in seed-based resting-state motor network connectivity compared to controls and patients with longstanding disease. White matter regions with reduced fractional anisotropy were similar in the two patient groups compared to controls. Patients with longstanding disease had cortical thinning of the precentral gyrus. A slight thinning of right precentral gyrus was detected in initial pre-PLS patients’ scans. Follow-up scans in 8 pre-PLS patients 1-2 years later showed increasing motor connectivity, thinning of the precentral gyrus, and no change in diffusion measures of the corticospinal tract or callosal motor region. Conclusions: Loss of motor functional connectivity is an early imaging marker in primary lateral sclerosis. This differs from literature descriptions of amyotrophic lateral sclerosis, warranting further studies to test whether resting-state functional MRI can differentiate between amyotrophic lateral sclerosis and primary lateral sclerosis at early disease stages.

Highlights Functional connectivity changes over 18 months in presymptomatic C9orf72 carriers. Thalamic networks have reduced functional connectivity, but are stable over time. Presymptomatic FC patterns trend toward those of symptomatic C9orf72 carriers. Reduced connectivity of posterior parietal regions occurs in different networks.

BackgroundLittle is known about the effects of social exclusion on youth with bipolar disorder (BD). Understanding these effects and the functional neural correlates of social exclusion in youth with BD may establish differences from healthy youth and help identify areas of intervention.MethodsWe investigated brain function in 19 youth with BD and 14 age and gender matched healthy control (HC) participants while performing Cyberball, an fMRI social exclusion task. Whole brain activation, region-of-interest, and functional connectivity were compared between groups and examined with behavioral measures.ResultsCompared with the HC group, youth with BD exhibited greater activation in the left fusiform gyrus (FFG) during social exclusion. Functional connectivity between the left FFG and the posterior cingulate/precuneus was significantly greater in the HC compared with the BD group. For the HC group only, age and subjective distress during Cyberball significantly predicted mean FFG activation. No significant differences in distress during social exclusion were found between groups.ConclusionAlthough preliminary due to small sample size, these data suggest that youth with BD process social exclusion in a manner that focuses on basic visual information while healthy youth make use of past experiences to interpret current social encounters. This difference may account for the social cognitive issues experienced by youth with BD, which can lead to more severe anxiety and mood symptoms.