Dysfunction of proprioceptive sensory synapses is a pathogenic event and therapeutic target in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that SMA patients exhibit impaired proprioception, and their proprioceptive sensory synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show that loss of excitatory afferent synapses and altered potassium channel expression in SMA motor neurons are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.

Signal detection in animal psychoacoustics: analysis and simulation of sensory and decision-related influences.

Signal detection theory (SDT) provides a framework for interpreting psychophysical experiments, separating the putative internal sensory representation and the decision process. SDT was used to analyse ferret behavioural responses in a (yes-no) tone-in-noise detection task. Instead of measuring the receiver-operating characteristic (ROC), we tested SDT by comparing responses collected using two common psychophysical data collection methods. These (Constant Stimuli, Limits) differ in the set of signal levels presented within and across behavioural sessions. The results support the use of SDT as a method of analysis: SDT sensory component was unchanged between the two methods, even though decisions depended on the stimuli presented within a behavioural session. Decision criterion varied trial-by-trial: a 'yes' response was more likely after a correct rejection trial than a hit trial. Simulation using an SDT model with several decision components reproduced the experimental observations accurately, leaving only ∼10% of the variance unaccounted for. The model also showed that trial-by-trial dependencies were unlikely to influence measured psychometric functions or thresholds. An additional model component suggested that inattention did not contribute substantially. Further analysis showed that ferrets were changing their decision criteria, almost optimally, to maximise the reward obtained in a session. The data suggest trial-by-trial reward-driven optimization of the decision process. Understanding the factors determining behavioural responses is important for correlating neural activity and behaviour. SDT provides a good account of animal psychoacoustics, and can be validated using standard psychophysical methods and computer simulations, without recourse to ROC measurements.

Neuronal spike-train responses in the presence of threshold noise.

The variability of neuronal firing has been an intense topic of study for many years. From a modelling perspective it has often been studied in conductance based spiking models with the use of additive or multiplicative noise terms to represent channel fluctuations or the stochastic nature of neurotransmitter release. Here we propose an alternative approach using a simple leaky integrate-and-fire model with a noisy threshold. Initially, we develop a mathematical treatment of the neuronal response to periodic forcing using tools from linear response theory and use this to highlight how a noisy threshold can enhance downstream signal reconstruction. We further develop a more general framework for understanding the responses to large amplitude forcing based on a calculation of first passage times. This is ideally suited to understanding stochastic mode-locking, for which we numerically determine the Arnol'd tongue structure. An examination of data from regularly firing stellate neurons within the ventral cochlear nucleus, responding to sinusoidally amplitude modulated pure tones, shows tongue structures consistent with these predictions and highlights that stochastic, as opposed to deterministic, mode-locking is utilised at the level of the single stellate cell to faithfully encode periodic stimuli.

Location of cells giving phase-locked responses to pure tones in the primary auditory cortex.

Phase-locked responses to pure tones have previously been described in the primary auditory cortex (AI) of the guinea pig. They are interesting because they show that some cells may use a temporal code for representing sounds of 60-300 Hz rather than the rate or place mechanisms used over most of AI. Our previous study had shown that the phase-locked responses were grouped together, but it was not clear whether they were in separate minicolumns or a larger macrocolumn. We now show that the phase-locked cells are arranged in a macrocolumn within AI that forms a subdivision of the isofrequency bands. Phase-locked responses were recorded from 158 multiunits using silicon based multiprobes with four shanks. The phase-locked units gave the strongest response in layers III/IV but phase-locked units were also recorded in layers II, V and VI. The column included cells with characteristic frequencies of 80 Hz-1.3 kHz (0.5-0.8 mm long) and was about 0.5 mm wide. It was located at a constant position at the intersection of the coronal plane 1 mm caudal to bregma and the suture that forms the lateral edge of the parietal bone.

SMN mRNA and protein levels in peripheral blood: biomarkers for SMA clinical trials.

BACKGROUND: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy. OBJECTIVE: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment. METHODS: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein. RESULTS: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity. CONCLUSION: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

Adult botulism type F in the United States, 1981-2002.

BACKGROUND: Clostridium botulinum neurotoxin types A, B, and E cause most cases of the paralytic disease botulism. Little is known about the epidemiology, clinical features, or microbiology of botulism type F. METHODS: Cases of adult type F botulism were identified by review of data collected by CDC's National Botulism Surveillance System between 1981 and 2002. A case was either an individual whose serum or stool demonstrated type F toxin or whose stool culture yielded an organism producing toxin type F. A detailed review of cases' medical charts and laboratory data from CDC and local health departments was performed. RESULTS: Between 1981 and 2002, 1,269 cases of botulism among adults and infants were reported to CDC; 13 (1%) were adult type F. The median age of type F cases was 54 years; 7 (54%) were female. None were part of outbreaks. A toxigenic Clostridium baratii was identified in 9 (69%) of 13 cases. Among 11 cases for which clinical data were available, all required mechanical ventilation for a median duration of 17 days (range, 10 to 84); 8 (73%) were intubated within 24 hours of symptom onset. All patients had nearly complete or complete quadriplegia at the nadir of neurologic dysfunction, which occurred on average on day 5. On average by day 8, improvement in neuromuscular function was noted. The median duration of acute hospitalization was 31 days (range, 20 to 60). No deaths were reported. In only one case was a possible foodborne etiology identified. CONCLUSIONS: Toxigenic C baratii are the sole documented causes of type F botulism in the United States since 1981. These cases are characterized by a fulminant course with rapid progression to respiratory failure and paralysis, making early recognition and intervention critical to appropriate management.

Effects of contralateral sound stimulation on unit activity of ventral cochlear nucleus neurons.

The cochlear nucleus (CN) commissural connection represents the first opportunity for convergence of binaural information in the auditory brainstem. All major neuron types in the ventral CN (VCN) are innervated by a diverse population of cells in the contralateral VCN. This study examined the effect of contralateral sound stimulation on the spontaneous rates (SRs) of neurons in the VCN. Unit activity was recorded with silicon-substrate multichannel probes which allowed recordings from up to 16 sites simultaneously. On average, 30% of units showed short-latency (often only 2 ms greater than the latencies of ipsilateral sound-evoked responses) inhibition of SR by wideband contralateral noise bursts. Fewer units (4.5%) were excited by contralateral noise at sound levels low enough to exclude excitation by acoustic crossover. Both regular and irregular units in the anterior VCN (AVCN) and posterior VCN (PVCN) were inhibited by contralateral sound. Decrements in SR followed a monotonic function with increases in contralateral sound level, except where responses could be attributed to acoustic crossover. Restricting the contralateral noise bandwidth resulted in a frequency-specific inhibition, dominated by frequencies at and below the ipsilateral BF of the unit, consistent with anatomical findings of the tonotopic organization of the CN commissural pathway. The latencies of these effects are compatible with mono, di and tri-synaptic connections reflecting CN commissural pathway effects.

The spectrum of neuropathy in diabetes and impaired glucose tolerance.

OBJECTIVE: To compare the neuropathy associated with impaired glucose tolerance (IGT) and diabetes mellitus (DM) determined by oral glucose tolerance testing (OGTT). METHODS: Patients with peripheral neuropathy of unknown cause were prescribed OGTT. Duration of neuropathic symptoms, neuropathic pain, neuropathy classification, nerve conduction test results, and intraepidermal nerve fiber densities (IENFD) were compared between IGT and DM groups. RESULTS: Seventy-three patients completed OGTT; 41 (56%) had abnormal results. Of these 41 patients, 26 had IGT and 15 had DM. Patients with IGT had less severe neuropathy than patients with diabetes, as measured by sural nerve amplitudes (p = 0.056), sural nerve conduction velocities (p = 0.03), and distal leg IENFD (p = 0.01). Patients with IGT had predominantly small fiber neuropathy, compared to patients with DM (p = 0.05), who had more involvement of large nerve fibers. CONCLUSIONS: The neuropathy associated with IGT is milder than the neuropathy associated with DM. Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism. OGTT is appropriate in patients with idiopathic neuropathy.