ABSTRACT
BACKGROUND AND OBJECTIVES: We report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene. METHODS: To address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNACys was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons. RESULTS: The sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele. DISCUSSION: In addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.
ABSTRACT
OBJECTIVE: Low-frequency electrical stimulation of the pedunculopontine nucleus (PPN) is a therapeutic approach aiming to improve motor symptoms such as freezing of gate and postural instability in parkinsonian disorders. Because the PPN is a component of the reticular activating system, we tested whether PPN stimulation directly affects attention and consciousness. METHOD: Eight patients with parkinsonian disorders and implanted with electrodes in the bilateral PPN underwent computerized assessment of attention. Performance in 3 standard reaction time (RT) tasks was assessed at 5 different stimulation frequencies in 5 consecutive sessions. RESULTS: Stimulation of the PPN at low (8 Hz) and therapeutic (20 Hz) frequencies led to a significant improvement of performance in a simple RT task. Patients' RTs were significantly faster at stimulation frequencies of 8 Hz and 20 Hz relative to no stimulation. Stimulation did not affect patients' performance in more complex attentional tasks. CONCLUSION: Low-frequent stimulation of PPN improves basal attentional processing in patients with parkinsonian disorders, leading to an improved tonic alertness. As successful performance in this task requires the intrinsic ability to build up and keep a certain level of attention, this might be interpreted as attentional augmentation related to stimulation features. Stimulation had no effect on more complex attentional processing. Our results suggest an influence of the PPN on certain aspects of attention, supporting attentional augmentation as one possible mechanism to improve motor action and gait in patients with parkinsonian disorders.
Subject(s)
Attention , Deep Brain Stimulation , Parkinsonian Disorders/psychology , Parkinsonian Disorders/therapy , Pedunculopontine Tegmental Nucleus , Aged , Consciousness , Electrodes, Implanted , Female , Gait Disorders, Neurologic/etiology , Gait Disorders, Neurologic/therapy , Humans , Male , Middle Aged , Psychomotor Performance , Reaction Time , Treatment OutcomeABSTRACT
The ventriloquist creates the illusion that his or her voice emerges from the visibly moving mouth of the puppet [1]. This well-known illusion exemplifies a basic principle of how auditory and visual information is integrated in the brain to form a unified multimodal percept. When auditory and visual stimuli occur simultaneously at different locations, the more spatially precise visual information dominates the perceived location of the multimodal event. Previous studies have examined neural interactions between spatially disparate auditory and visual stimuli [2-5], but none has found evidence for a visual influence on the auditory cortex that could be directly linked to the illusion of a shifted auditory percept. Here we utilized event-related brain potentials combined with event-related functional magnetic resonance imaging to demonstrate on a trial-by-trial basis that a precisely timed biasing of the left-right balance of auditory cortex activity by the discrepant visual input underlies the ventriloquist illusion. This cortical biasing may reflect a fundamental mechanism for integrating the auditory and visual components of environmental events, which ensures that the sounds are adaptively localized to the more reliable position provided by the visual input.