Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and -acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development. Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates.

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To study the demographics of Leber's hereditary optic neuropathy (LHON) using a large international database of people affected by LHON.Design: Cross-sectional study.Participants: One thousand five hundred seventeen people affected by LHON with a known pathogenic genetic mutation.Methods: Self-reported genetic and demographic data were collected. The data were de-identified and then analyzed.Main Outcome Measures: Leber's hereditary optic neuropathy mutation, gender, age at vision loss onset, and geographical region.Results: The data showed that both females and males can experience symptom onset at any age. We found a 3:1 male-to-female ratio. Interestingly, at younger than 5 years and older than 45 years, the male-to-female ratio of those becoming affected was approximately 1:1. A dramatic peak in age at onset of vision loss was found among males between 14 and 26 years of age. Disease onset in females occurred across all age groups, without any comparable dramatic peak of onset age. This study found that 10% of individuals become affected with LHON after 50 years of age. According to the literature, we found that the m.11778, m.14484, and m.3460 mutations were the most common LHON point mutations in both males and females, with a similar age at onset distribution.Conclusions: This was the largest study of LHON demographics to date. It showed that women carrying an LHON mutation are at higher risk of losing vision than is generally expected. Unlike the traditional 5:1 male-tofemale ratio commonly reported in the literature, we found a 3:1 male-to-female ratio. Earlier studies may have harbored an ascertainment bias of overemphasizing the confirmation of this being a disease of young men. However, our data suggest that LHON is a disease that affects both females and males of all ages. This should prompt physicians to conduct genetic testing for LHON in all patients who meet the clinical criteria, regardless of whether they fit the demographics traditionally associated with the disease. Counseling about LHON should be offered to all maternal bloodline relatives, females and males of all ages, because they are at risk of sudden-onset legal blindness.