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11 Abstract. Objective: This study investigated the effects of a combinatorial treatment, consisting of a brief period of nerve electrical stimulation (ES) and systemic supraphysiologic testosterone, on functional recovery following a crush of the recurrent laryngeal nerve (RLN). Study design: Prospective, controlled animal study. Methods: After a crush of the left RLN, adult male Sprague-Dawley rats were divided into four treatment groups: 1) no treatment, 2) ES, 3) testosterone propionate (TP), and 4) ES + TP. Each group was subdivided into 1, 2, 3, or 4 weeks post-operative survival time points. Groups had an n of 4-9. Recovery of vocal fold mobility (VFM) was assessed. Results: Brief ES of the proximal nerve alone or in combination with TP accelerated the initiation of functional recovery. TP administration by itself also produced increased VFM scores compared to controls, but there were no statistical differences between the ES-treated and TP-treated animals. Treatment with brief ES alone was sufficient to decrease the time required to recover complete VFM. Animals with complete VFM were seen in treatment groups as early as 1 week following injury; in the untreated group, this was not observed until at least 3 weeks post-injury, translating into a 66% decrease in time to complete recovery. Conclusions: Brief ES, alone or in combination with TP, promise to be effective therapeutic interventions for promoting regeneration following RLN injury. 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3–5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1G93A mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS. J. Comp. Neurol. 523:2752–2768, 2015. © 2015 Wiley Periodicals, Inc.

Locomotion analysis is now widely used across many animal species to understand the motor defects in disease, functional recovery following neural injury, and the effectiveness of various treatments. More recently, rodent locomotion analysis has become an increasingly popular method in a diverse range of research. Speed is an inseparable aspect of locomotion that is still not fully understood, and its effects are often not properly incorporated while analyzing data. In this hybrid manuscript, we accomplish three things: (1) review the interaction between speed and locomotion variables in rodent studies, (2) comprehensively analyze the relationship between speed and 162 locomotion variables in a group of 16 wild-type mice using the CatWalk gait analysis system, and (3) develop and test a statistical method in which locomotion variables are analyzed and reported in the context of speed. Notable results include the following: (1) over 90% of variables, reported by CatWalk, were dependent on speed with an average R2 value of 0.624, (2) most variables were related to speed in a nonlinear manner, (3) current methods of controlling for speed are insufficient, and (4) the linear mixed model is an appropriate and effective statistical method for locomotion analyses that is inclusive of speed-dependent relationships. Given the pervasive dependency of locomotion variables on speed, we maintain that valid conclusions from locomotion analyses cannot be made unless they are analyzed and reported within the context of speed. Anat Rec, 297:1839–1864, 2014. © 2014 Wiley Periodicals, Inc.

After injury or insult to a motor system, gonadal steroids play a key role in regeneration and repair of motor function primarily through interactions with their intracellular receptors. This chapter highlights the protective and therapeutic effects that gonadal steroids have on neuronal functioning, ranging from motoneuron survival to enhancement of axonal and dendritic growth, as well as peripheral maintenance of bone and muscle. The systemic actions of gonadal steroids are truly multifaceted, modifying the entire synaptic response as well as targeting multiple tissues. We discuss the effects of gonadal steroids in both the central and the peripheral nervous systems ranging from their role in establishing important neuromuscular sex differences and their ability to protect against motoneuron death and disease, to triggering a regenerative response from both axons and dendrites, to enhancing bone growth and muscle mass after injury.

Amyotrophic lateral sclerosis is a motoneuron degenerative disease that is challenging to diagnose and presents with considerable variability in survival. Early identification and enhanced understanding of symptomatic patterns could aid in diagnosis and provide an avenue for monitoring disease progression. Use of the mSOD1G93A mouse model provides control of the confounding environmental factors and genetic heterogeneity seen in amyotrophic lateral sclerosis patients, while investigating underlying disease-induced changes. In the present study, we performed a longitudinal behavioral assessment paradigm and identified an early hindlimb symptom, resembling the common gait abnormality foot drop, along with an accompanying forelimb compensatory mechanism in the mSOD1G93A mouse. Following these initial changes, mSOD1 mice displayed a temporary hindlimb compensatory mechanism resembling an exaggerated steppage gait. As the disease progressed, these compensatory mechanisms were not sufficient to sustain fundamental locomotor parameters and more severe deficits appeared. We next applied these initial findings to investigate the inherent variability in B6SJL mSOD1G93A survival. We identified four behavioral variables that, when combined in a cluster analysis, identified two subpopulations with different disease progression rates: a fast progression group and a slow progression group. This behavioral assessment paradigm, with its analytical approaches, provides a method for monitoring disease progression and detecting mSOD1 subgroups with different disease severities. This affords researchers an opportunity to search for genetic modifiers or other factors that likely enhance or slow disease progression. Such factors are possible therapeutic targets with the potential to slow disease progression and provide insight into the underlying pathology and disease mechanisms.

Two studies were conducted to explore the hypothesis that Broca's and Wernicke's aphasics have deficits arising from the processes involved in activating the lexicon from phonological form. The first study explored whether phonologically similar lexical entries differing only in their initial consonants show “rhyme priming.” Results revealed that Broca's aphasics failed to show facilitation when the target was identical to the prime (i.e. identity priming) and they showed significant inhibition when targets were preceded by rhyming words. Wernicke's aphasics showed a pattern of results similar to that of normal subjects, i.e., identity priming and rhyme priming as well as significantly slower reaction-times in the rhyming condition compared to the identity condition. The second study investigated form-based repetition priming in aphasic patients at a number of intervals including when no other stimuli intervened between repeated stimuli (0 lag) or when 4, 8, or 12 stimuli intervened. Results showed that, unlike old normal subjects who showed repetition priming for both words and nonwords, both Broca's and Wernicke's aphasics showed repetition priming for word targets only. Moreover, in contrast to old normal subjects who showed a greater magnitude of priming at 0 lag for word targets, neither Broca's aphasics or Wernicke's aphasics showed priming at 0 lag. Implications of these findings are considered with respect to the hypotheses that Broca's and Wernicke's aphasics have deficits in the nature of the activation patterns within the lexicon itself and in auditory (working) memory.

Over the past decade, our laboratory has been investigating the now well-established neurotrophic capabilities of gonadal steroids in the context of peripheral nerve injury and repair. The focus of our work has been on the hamster facial motoneuron (FMN) system (Kujawa & Jones, 1995), although we have recently begun to explore two additional motoneuron injury paradigms, the rat sciatic and hamster rubrospinal systems (Kujawa et al., 1993). In this brief review, we will discuss the effects of androgens and estrogens on the regenerative properties and the molecular programming of injured hamster FMN. This will be followed by a discussion of the effects of androgens on the glial response to injury in the facial nucleus. Finally, a working model of the mechanism by which gonadal steroids enhance neuronal reparative processes will be advanced. Our proposed mechanism involves a neuroprotective role for gonadal steroids, in that we hypothesize that exposure to these agents at the time of injury reduces the need for the injured neuron to mount a classical “stress response” involving the production of heat shock protein 70. Finally, a series of future directions for our work will be presented.

Purpose: To investigate the effects of the androgen testosterone propionate (TP), on regeneration of the recurrent laryngeal nerve (RLN) after unilateral crush injury using assessment of vocal fold mobility (VFM) as a measure of behavioral recovery. Methods: 48 adult male rats underwent standardized crush injury of left RLN and received treatment in the form of 2 silastic capsules containing TP or controls receiving a blank capsule (untreated). Direct laryngoscopic assessment of vocal cord mobility was performed before, immediately following and 1, 2, 3, 4, 5 or 6 weeks post injury. Results: Treatment with TP enhanced the recovery of full VFM following crush injury of the RLN compared to controls. There was statistically significant improvement in VFM seen at the 1 and 2 week time points (p < 0.05). By 4 weeks TP-treated rats displayed a 100% recovery of VFM function, compared to only 50% by the control group. Conclusions: TP enhances RLN functional recovery following a crush injury, which further supports its potential general applicability as a therapeutic agent in peripheral nerve injury.

Two auditory lexical decision semantic priming experiments were conducted to examine the extent to which the automaticcontrolled processing dichotomy can characterize lexical access deficits in Broca's and Wernicke's aphasics. In Experiment 1, prime-target predictability was varied while the interval between prime and target (ISI) was held constant. In Experiment 2, ISI was varied while prime-target predictability was held constant. The pattern of semantic facilitation and inhibition results for Experiment 1 showed that Broca's aphasics were influenced by prime-target predictability, whereas Wernicke's aphasics were not. In contrast in hperiment 2, manipulations of ISI at 150 and 2000 msec did not affect patterns of semantic facilitation for either Broca's or Wernicke's aphasics. Taken together, the results of these two experiments suggest that Broca's aphasics use heuristic strategies more so than old and young normal subjects. In addition, they seem to have an automatic processing deficit affecting the level of activation of lexical entries, with a spared time course of activation. Wernicke's aphasics show a pattern of results consistent with the view that automatic processing is unimpaired in these patients, while they fail to use heuristic strategies in these tasks.

PURPOSE: Testosterone (T) treatment accelerates recovery from facial paralysis after facial nerve crush in hamsters. In this study, we extended those studies to another injury model and asked the following question: Will T treatment accelerate recovery from lower limb paralysis following sciatic nerve crush in the rat? METHODS: Castrated adult male rats received a right side sciatic nerve crush at the level of the sciatic notch, with the left side serving as control. Half the animals received a subcutaneous implant of a propionated form of T (TP), the others were sham-implanted. Weekly testing using the Sciatic Functional Index (SFI), a quantitative measure of locomotion, was done for 7 weeks postoperative (wpo). RESULTS: Between 3 and 5 weeks post-op, the average SFI score of the TP-treated group was higher than controls. This difference was significant at 4 wpo, indicating an accelerated degree of functional recovery. At these timepoints, the differences were attributable to the footprint or paw length and associated with calf muscle reinnervation rather than the toespreading component associated with intrinsic foot muscle rein-nervation. Beyond 5 wpo, there were no differences in the SFI scores. CONCLUSION: The results indicate that, as with facial nerve regeneration in the hamster, testosterone accelerates functional recovery from hind limb paralysis following sciatic nerve injury in the rat. While the responses of spinal motoneurons to injury can differ from those of cranial motoneurons, in this case it appears that they share a similar response to the trophic actions of androgen. This is important in the context of designing therapeutic strategies for dealing with direct trauma to motoneurons resulting from both peripheral and central nervous system trauma, such as spinal cord injury.

In this review, the neuroprotective actions of testosterone on three different populations of injured rat peripheral motoneurons, i.e. facial (FMN), spinal (SMN) and pudendal (PMN), will be discussed. We have extrapolated concepts from the neuroendocrine field regarding the trophic effects of gonadal steroids on target neural tissue to the nerve regeneration field. Exogenous administration of testosterone immediately after nerve injury impacts positively on functional recovery through actions mediated by the androgen receptor. The mechanism by which steroidal enhancement of the regenerative properties of injured motoneurons occurs may involve pre-existing androgen receptors, heat shock proteins, and modulation of the cellular stress response.

Two experiments were conducted exploring on-line processing of filler–gap constructions in aphasia. An auditory–auditory lexical decision paradigm was used to investigate whether Broca's and Wernicke's aphasic patients show, as do normals, reactivation of the filler at the gap site. Experiment I investigated the processing of a number of filler–gap constructions including wh-questions, relative clauses as subject, relative clauses as object, and embedded wh-questions. Broca's aphasics showed reactivation of the filler at the gap site, whereas Wernicke's aphasics did not. Experiment II examined object relative clauses and their processing by Broca's aphasics. In addition, we investigated whether the presence (or absence) of the relative pronoun played any role in on-line processing. Broca's aphasics performed as did normals. In addition, their performance was unaffected by the presence or absence of the relative pronoun. The results of these experiments suggest that Broca's aphasics do not have an impairment in processing or representing thematic relationships of NP arguments to predicates or relating traces to their antecedents.

The histochemical NADPH-diaphorase reaction has identified distinct neuronal populations in the nervous system of several species. Considerable evidence suggests that NADPH-d is a neuronal nitric oxide synthase (NOS). We examined spinal cords of adult and metamorphosing Xenopus laevis (XL) for developmental differences in NADPH-d reactivity. In adult XL, labeling was found in all dorsal root ganglia (DRGs) and in their termination sites within the dorsal horn (cutaneous afferent field) and intermediate gray (muscle afferent field). Cell bodies in the intermediate gray regions containing the autonomic preganglionic neurons were labeled in thoracic and sacral sections. Neurons located in the medial (MMC) and lateral motor columns (LMC) of the ventral horn were also stained. In metamorphosing XL, reactivity was detected in neurons in the intermediate gray, in the MMC and in the LMC as in the adult. Additionally, primary motoneurons including those innervating tail musculature were labeled. Neurons in the DRGs were stained at all stages; in the dorsal horn, the density of staining reflected the development of the sensory afferent fields. The conservation of NADPH-d reactivity in adult and metamorphosing XL spinal neurons suggests that NOS may be involved in processes independent of developmental changes occurring in XL spinal cord.

Lidocaine kinetics were examined during continuous infusions in five healthy subjects using stable isotope lidocaine labeled with two deuterium atoms. During phase 1, lidocaine and stable isotope lidocaine (50 mg IV each) were given as a bolus to confirm that the two species were kinetically identical. Phase 2 consisted of a long-term (30 hr) lidocaine infusion designed to produce a steady-state concentration equal to 1.5 microgram/ml. Twenty-four hours into the infusion, stable isotope lidocaine (50 mg) was given as an intravenous bolus and kinetic parameters were calculated. Phase 3 differed from phase 2 in that target steady-state lidocaine concentration was 4 microgram/ml and the stable isotope lidocaine dose was reduced to 40 mg. A gas chromatograph-mass spectrometer was used to determine lidocaine and stable isotope lidocaine serum concentrations. Compared to phase 1, clearance decreased (P less than 0.05) and half-life increased (P less than 0.025) during phases 2 and 3. The volume of distribution at steady-state remained constant during all three phases. Lidocaine cumulated in serum during long-term infusions in all five patients; repeated decreases in infusion rate were necessary to avoid exceeding desired target concentrations in phases 2 and 3.

A case that utilizes a pharmacokinetic approach to evaluate the need for withdrawal prophylaxis after a phenobarbital overdose is presented. To date, the practitioner has had to rely on an accurate drug-use history to predict which patients may be at risk for withdrawal symptoms. Since this information is often difficult to obtain, some other means of identifying potential withdrawal-syndrome patients would be useful. This case describes the successful use of kinetically determined parameters, the elimination rate constant and half-life, in predicting withdrawal potential. This easily used kinetic approach may provide practitioners with a useful tool for predicting those patients at risk for withdrawal symptoms following phenobarbital overdose.