Neurodevelopmental associations of prenatal and postnatal methylmercury exposure among first-grade children in the Kinan region, Japan.

The most severe effects of methylmercury (MeHg) exposure during child development are thought to result from exposure during fetal life and childhood. However, comparing the neurodevelopmental effects of prenatal and postnatal MeHg exposure (PreMeHg and PostMeHg, respectively) remains unclear. We aimed to investigate the associations between neurodevelopmental indicators and PreMeHg or PostMeHg. The participants were 134 children in the first grade of elementary schools aged 7-8 years from the Kinan region, an area with high consumption of MeHg-rich whales and tunas in Japan. We measured MeHg levels in preserved umbilical cord tissues and total mercury (T-Hg) levels in children's hair to estimate PreMeHg and PostMeHg levels, respectively. Neuropsychological (intelligence quotient testing and Boston Naming Test) and neurophysiological (brainstem auditory evoked potential [BAEP], visual evoked potential [VEP], and color vision tests) studies were performed to evaluate the neurodevelopmental status. Multiple regression analyses were conducted according to sex. The geometric mean MeHg levels in preserved umbilical cord tissues and T-Hg levels in children's hair were 0.11 µg/g and 2.94 µg/g, respectively. Neither PreMeHg nor PostMeHg was related to neuropsychological indicators. Some associations between MeHg exposure and neurophysiological results were observed only in boys. N145 latency in VEPs was significantly prolonged with increasing PreMeHg (ß: 12.01, 95% confidence interval [CI]: 0.648, 23.38). The III-V interpeak intervals in BAEP were significantly prolonged with increasing PreMeHg or PostMeHg (ß [95% CI]: 0.142 [0.041, 0.243] and 0.159 [0.052, 0.265], respectively). After adjusting for PreMeHg, the association between PostMeHg and BAEP latencies disappeared. In conclusion, the latency in the auditory and visual pathways was significantly prolonged with increasing PreMeHg in boys. These findings suggest that male fetuses may be more susceptible to MeHg exposure.

Single-trial neuromagnetic analysis reveals somatosensory dysfunction in chronic Minamata disease.

Methylmercury pollution is a global problem, and Minamata disease (MD) is a stark reminder that exposure to methylmercury can cause irreversible neurological damage. A "glove and stocking type" sensory disturbance due to injured primary sensory cortex (SI) (central somatosensory disturbance) is the most common neurologic sign in MD. As this sign is also prevalent in those with polyneuropathy, we aimed to develop an objective assessment for detecting central somatosensory disturbances in cases of chronic MD. We selected 289 healthy volunteers and 42 patients with MD. We recorded the sensory nerve action potentials (SNAPs) and somatosensory evoked magnetic fields (SEFs) to median nerve stimulation with magnetoencephalography. Single-trial epochs were classified into three categories (N20m, non-response, and P20m epochs) based on the cross-correlation between averaged sensor SEFs and individual epochs. We assessed SI responses (the appearance rate of P20m [P20m rate] and non-response epochs [non-response rate]) and early somatosensory cortical processing (N20m amplitude, reproducibility of N20m in single-trial responses [cross-correlation value], and induced gamma-band oscillations of the SI [gamma response] of single epochs excluding non-response epochs). Receiver operating characteristic curve analyses were used to examine the diagnostic accuracy of each parameter. We found that SNAPs exerted a marginal effect on the N20m. The N20m amplitude, cross-correlation value, and gamma response were significantly reduced in the MD group on either side (p < 0.0001), suggestive of altered early somatosensory cortical processing. Interestingly, the P20m rate and non-response rate were significantly increased in the MD group on either side (p < 0.0001), thereby suggesting impaired SI responses. Notably, P20m and absent N20m peaks were observed in 6 and 11 patients with MD, respectively, which may be attributed to increased numbers of P20m epochs. The cross-correlation value exhibited the highest correlation with the P20m rate or non-response rate. Thus, reduced reproducibility of N20m may play an important role in chronic MD. The cross-correlation value exhibited the highest correlation with the gamma response for both SI parameters in early somatosensory cortical processing. The area under the curve was > 0.77 (range: 0.77-0.79) for all parameters. Their confidence intervals overlapped with each other; thus, each SEF parameter likely had an approximately equivalent discrimination ability. In conclusion, chronic MD is characterized by impaired SI responses and alterations in early somatosensory cortical processing. Thus, single-trial neuromagnetic analysis of somatosensory function may be useful for detecting central somatosensory disturbance and elucidating the relevant pathophysiological mechanisms even in the context of chronic MD.

Cerebellar Transcranial Magnetic Stimulation Improves Ataxia in Minamata Disease.

Minamata disease (MD) is a form of intoxication involving the central nervous system and is caused by ingesting seafood from methylmercury-contaminated areas in Japan. In MD, cerebellar ataxia is a cardinal feature observed in approximately 80% of MD patients. Although cerebellar transcranial magnetic stimulation (TMS) has recently been used for treating cerebellar ataxia, the optimal stimulation conditions remain unclear. Here, we report the first case of cerebellar ataxia in an MD patient that was significantly improved after high-frequency cerebellar TMS. To determine the optimal stimulation conditions, we examined the excitability of the primary motor cortex (M1) using resting-state functional magnetic resonance imaging (rs-fMRI). rs-fMRI revealed M1 hyperconnectivity, which was indicative of activation of the dentato-thalamo-cortical (DTC) pathway. Thus, high-frequency cerebellar TMS was applied to inhibit the DTC pathway. Improvement of cerebellar ataxia was only observed after real TMS, not sham stimulation. As this effect was consistent with inhibition of hyperconnectivity of M1, the effectiveness of high-frequency cerebellar TMS for cerebellar ataxia was thought to be caused by inhibition of the DTC pathway. Therefore, we suggest that the evaluation of M1 excitability using rs-fMRI can be effective for determining the optimal TMS stimulation conditions for cerebellar ataxia.