Physical activity of men with chronic prostatitis/chronic pelvic pain syndrome not satisfied with conventional treatments--could it represent a valid option? The physical activity and male pelvic pain trial: a double-blind, randomized study

PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome is a major healthcare burden. Affected patient quality of life is poor and currently no investigated treatments have significant long-term benefit. We performed a preliminary investigation of the role of physical activity and its effects on select patients with chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: Between 2002 and 2004 we recruited a volunteer sample of 231 eligible males 20 to 50 years old with chronic prostatitis/chronic pelvic pain syndrome who were unresponsive to conventional treatments and free of any contraindication for moderate intensity physical exercise. This group was screened and, if in accordance with study inclusion/exclusion criteria, patients were randomized into 2 groups. Participants were randomly assigned to the aerobic exercise group (52) and the placebo/stretching and motion exercises group (51). Main outcome measures were the Italian version of the National Institutes of Health Chronic Prostatitis Symptom Index, Beck Depression Inventory, State Anxiety Inventory-Y and a pain intensity visual analog scale administered at baseline, and 6 and 18 weeks. RESULTS: At 18 weeks 36 subjects (75%) in the aerobic exercise group vs 40 (81.63%) in the placebo/stretching and motion exercises group completed the 18-week program and evaluation. Differences between the 2 groups were found in total National Institutes of Health Chronic Prostatitis Symptom Index, pain and quality life impact subscales, and pain visual analog score (ANCOVA p = 0.006, 0.0009, 0.02 and 0.003, respectively). CONCLUSIONS: Improvements in the aerobic exercise group were significantly superior compared to those in the placebo/stretching and motion exercises group. Aerobic exercise represents a valid treatment option and it should be further investigated in a larger study with longer followup.     

The variability of intracortical inhibition and facilitation

OBJECTIVE: To assess the variability of transcranial magnetic stimulation paired pulse measurements of cortical excitability between subjects, between sessions and within subjects within sessions. METHODS: In experiment 1, intracortical inhibition and facilitation were assessed with a fixed conditioning stimulus intensity (CSI) of 80% of active motor threshold (AMT) whereas in experiment 2, the effect of different CSIs (60-110% of AMT) was investigated. RESULTS: Experiment 1 revealed that subjects differed significantly in the degree of inhibition and facilitation. Between sessions the variability was substantial as predicted by high within session variability. Experiment 2 allowed determination of individual thresholds for inhibition and facilitation. These thresholds were the best predictor of the amount of inhibition or facilitation at a given CSI. Across subjects we observed a high correlation of the threshold for inhibition (expressed in terms of maximum stimulator output) with AMT (r=0.93). Results for facilitation were more variable. CONCLUSIONS: The variability was high if a single CSI was used to compare the percent intracortical inhibition or facilitation between subjects, or between sessions. Much less variable was the threshold for intracortical inhibition/facilitation, which was highly correlated to AMT. We suggest that the ratio of CSI:AMT is a robust and useful additional measure of the integrity of neuronal circuits underlying intracortical inhibition/facilitation.     

Human Somatosensory Cortex Is Modulated during Motor Planning

Recent data and motor control theory argues that movement planning involves preparing the neural state of primary motor cortex (M1) for forthcoming action execution. Theories related to internal models, feedback control, and predictive coding also emphasize the importance of sensory prediction (and processing) before (and during) the movement itself, explaining why motor-related deficits can arise from damage to primary somatosensory cortex (S1). Motivated by this work, here we examined whether motor planning, in addition to changing the neural state of M1, changes the neural state of S1, preparing it for the sensory feedback that arises during action. We tested this idea in two human functional MRI studies (N = 31, 16 females) involving delayed object manipulation tasks, focusing our analysis on premovement activity patterns in M1 and S1. We found that the motor effector to be used in the upcoming action could be decoded, well before movement, from neural activity in M1 in both studies. Critically, we found that this effector information was also present, well before movement, in S1. In particular, we found that the encoding of effector information in area 3b (S1 proper) was linked to the contralateral hand, similarly to that found in M1, whereas in areas 1 and 2 this encoding was present in both the contralateral and ipsilateral hemispheres. Together, these findings suggest that motor planning not only prepares the motor system for movement but also changes the neural state of the somatosensory system, presumably allowing it to anticipate the sensory information received during movement.SIGNIFICANCE STATEMENT Whereas recent work on motor cortex has emphasized the critical role of movement planning in preparing neural activity for movement generation, it has not investigated the extent to which planning also modulates the activity in the adjacent primary somatosensory cortex. This reflects a key gap in knowledge, given that recent motor control theories emphasize the importance of sensory feedback processing in effective movement generation. Here, we find through a convergence of experiments and analyses, that the planning of object manipulation tasks, in addition to modulating the activity in the motor cortex, changes the state of neural activity in different subfields of the human S1. We suggest that this modulation prepares the S1 for the sensory information it will receive during action execution.     

Central representation of cold-evoked pain relief in capsaicin induced pain: an event-related fMRI study

The termination of an unpleasant or painful somatic condition can produce a rewarding sense of relief, even if the stimulus that causes the termination is itself unpleasant or painful under normal circumstances. We aimed to identify central neural mechanisms of pain relief from capsaicin-elicited heat-hyperalgesia by administering cold stimuli. We hypothesized that cooling might facilitate endogenous descending inhibitory mechanisms. We compared intraindividual neural responses of 15 healthy male volunteers to cold (20, 0 degrees C), intermediate (30 degrees C) and heat stimuli (43 degrees C) on untreated vs. capsaicin-treated skin using event-related fMRI in a 2 x 4 factorial design. Thermal stimuli were applied at the right hand in two separate imaging sessions using a Peltier-element. Psychophysical ratings of the perceived valence and intensity (VAS: 1-100) were obtained after each stimulus. The 43 degrees C-stimulus was perceived as excessively painful on capsaicin-treated skin as opposed to an unpleasant sensation on normal skin. In contrast, the 0 degrees C-stimulus was perceived unpleasant when applied on untreated skin while subjects rated the same stimulus pleasant in the capsaicin-treated condition. When neural responses to the 0 degrees C-stimulus were compared between the untreated and capsaicin-treated skin condition there were stronger BOLD-responses in prefrontal cortex (PFC) and periaqueductal grey (PAG) which correlated with increasing perceived pleasantness (VAS). Based on a connectivity analysis which identified cold-dependent contributions of PFC activity with PAG in heat-hyperalgesia we propose that cold-induced pain relief partly results from activation of endogenous descending inhibition of nociception. The data illustrate that perception of nociceptive input may largely be determined by competing aversive-appetitive motivational states.     

Slow vertical saccades in the frontotemporal dementia with motor neuron disease

BACKGROUND: Ocular motor abnormalities play an important role in differential diagnoses of Pick complex diseases. OBJECTIVES: We evaluated how frequently supranuclear vertical saccadic impairment was observed in patients with frontotemporal dementia with motor neuron disease (FTD-MND). In addition, we tried to characterize their vertical saccadic abnormalities. MATERIALS AND METHODS: Eleven patients with FTD-MND were recruited. Supranuclear vertical saccadic impairment on gross examination was defined as slow saccades with or without reduction in the final amplitude of the movement accompanied by intact oculocephalic reflex. We also recorded their saccades in 6 out of 11 patients using 2-dimensional videooculography (VOG). We measured the amplitude and peak velocity of each saccade. RESULTS: On bedside examination, supranuclear vertical saccadic impairment was observed in 9 of 11 patients. One of the two remaining patients could not be evaluated due to poor cooperation and the other showed normal saccades. Five of nine patients with ocular abnormalities and one patient with normal saccade on gross examination underwent the VOG studies. The results showed that all the five patients with gross ocular abnormalities, compared with age-matched controls, had slowing of vertical saccades. Three out of five patients also showed slowing even in the large horizontal saccades. CONCLUSIONS : Our results showed that slow vertical saccades are common in FTDMND. FTD-MND could be another disease that affects vertical gaze among Pick complex disease. Future pathologic studies are needed to confirm the involvement of the burst neurons in the dorsal midbrain in patients with FTDMND.     

White matter lesions in the brain with frontotemporal lobar degeneration with motor neuron disease: TDP-43-immunopositive inclusions co-localize with p62, but not ubiquitin

Recently, TDP-43 was established as a major component of the ubiquitinated inclusions found in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). However, differences in the underlying pathogenesis between ALS and FTLD-MND remain yet to be elucidated. Originally, TDP-43-immunopositive inclusions were found in neuronal cells and reported to be ubiquitinated. This study shows that TDP-43-positive inclusions were distributed throughout the subcortical white matter except for the occipital lobe in the FTLD-MND brain, but not in the ALS brain. TDP-43-positive inclusions were also prominent features of pathologically proven FTLD-MND cases (p-FTLD-MND) without history of apparent clinical cognitive decline. A substantial fraction of these inclusions was also p62-immunoreactive, and another noteworthy feature was that those inclusions did not stain positively for ubiquitin. Significant correlations between immunoreactivity for TDP-43 and p62 were observed, particularly in p-FTLD-MND (Pearson correlation coefficient, 0.976). Furthermore, TDP-43 extracted from white matter appeared to be uncleaved. These results indicate that pathological changes might take place within the white matter also in the brain with FTLD-MND, but in a different manner than within the gray matter.     

Identification of a battery of tests for drug candidate evaluation in the SMNDelta7 neonate model of spinal muscular atrophy

Spinal muscular atrophy (SMA) is characterized by selective loss of α-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNΔ7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2^+/+;SMNΔ7^+/+;Smn^−/− mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials.     

A clinical study of Hirayama disease in Taiwan

The purpose of this study was to review the clinical manifestations of 40 patients who fulfilled the clinical criteria for Hirayama disease (juvenile muscular atrophy of distal upper extremities), identified in our neuromuscular clinic between February 1995 and December 2005. Of these 40 patients, 87.5% were male. The mean age at onset was 16.8 years, which was 4.5 years later than the peak age of the normal growth curve. Progressive muscle weakness and wasting were characteristic and occurred predominantly in the distal part of the right upper limb. Neurogenic symptoms ceased to progress within 5 years in most patients (92.5%). About one third of patients had participated frequently in heavy physical activity before onset of muscle symptoms. Reduced amplitude of the compound muscle action potential of the ulnar nerve was the most prominent finding in nerve conduction studies. Electromyography showed acute or chronic neurogenic changes, most frequently in muscles supplied by the C7-T1 segments. Magnetic resonance imaging showed anterior shifting of the posterior dura and engorged posterior venous plexus at the cervical level in 95% of patients. Our results support the belief that Hirayama disease is a self-limited, focal lower motor neuron disease involving the lower cervical segments. Disproportionate growth between the vertebral column and the contents of the spinal canal may be the underlying cause, and strenuous physical activity may be a precipitating factor.     

Coupling of minor motor events and epileptiform discharges with arousal fluctuations in NFLE

Purpose: We recently demonstrated that in nocturnal frontal lobe epilepsy (NFLE) highly stereotyped minor motor events (MMEs, in the form of short‐lasting stereotyped movements involving the limbs, the axial musculature, and/or the head), could occur in either the presence or absence of an epileptiform discharge (ED). In lack of a systematic analysis, both MMEs and EDs were frequently observed to occur in association with arousal fluctuations. Hereby, in the same group of refractory NFLE subjects, we report a methodical neurophysiolgical investigation set out to investigate whether, and how, the arousal mechanism, monitored through visual scoring of the cyclic alternating pattern, modulates the expression of MMEs and EDs. Methods: The relationship of MMEs, EDs and arousal fluctuation was assessed in subjects explored using implanted electrodes. Results: The occurrence of both EDs and MMEs was associated with higher level of arousal (p < 0.0001). Multivariate logistic regression analysis shows a significant effect of interaction of EDs and MMEs during CAP sleep (p < 0.001). Conclusions: Both MMEs and EDs are associated with arousal. We suggest that recurrence of EDs in itself can induce an increase in arousal level, which in turn, through a gate effect, facilitate the occurrence of MMEs. Thus, MMEs wouldn't be a direct effect of EDs, but rather originate from an indirect effect related to loss of cortical inhibition, which is secondary to arousal. In this perspective MMEs may be regarded as the result of aspecific dishinibition, triggered by internal epileptiform stimuli, of innate motor patterns generated by central pattern generators (CPGs). The CPG system might represent, through arousal facilitation, the substrate of the heterogeneous expression of MMEs in NFLE.