Brian L. Allman

NEUROMUSCULAR FATIGUE AND AGING: CENTRAL AND PERIPHERAL FACTORS

A limited number of studies have investigated the effect of old age on neuromuscular fatigue, yet a variety of protocols have been used to compare the fatigability of old and young humans. These include voluntary isometric and isokinetic contraction protocols at maximal and submaximal intensities, and electrical stimulation protocols of continuous or intermittent stimulation at a variety of stimulation frequencies. The results of these studies are summarized in this review. Although it seems reasonable to suggest that age‐related changes in muscle morphology and motor unit remodeling, as well as the associated loss of strength and slowed contractile properties, may improve the resistance to neuromuscular fatigue in old humans, the collective results suggest that it is not possible to make this generalization. In fact, it cannot be generalized that the muscles of old humans are either more or less fatigable than young adults because the extent of the difference in fatigability relies strongly on the fatigue task performed (task‐dependency). Age‐related changes that occur within the neuromuscular system may result in some candidate fatigue sites increasing or decreasing their susceptibility to failure under specific task conditions. These candidate fatigue sites include central drive, muscle membrane excitability, excitation–contraction coupling mechanisms, and metabolic capacities. The effect of old age on these various central and peripheral sites is discussed with respect to their relative contribution during different fatigue tasks. Moreover, the impact of the possible confounding effects of subject habituation, physical activity status, and sex on the fatigability comparison is addressed.

Incomplete recovery of voluntary isometric force after fatigue is not affected by old age

The 60‐min recovery profiles of voluntary and electrically stimulated force, contractile speed, surface electromyography, muscle activation via twitch interpolation, and muscle compound action potentials (M‐waves) in the elbow flexors of seven young men (24 ± 2 years) and seven men over 80 years of age (84 ± 2 years) were compared following intermittent (3 s on, 2 s off) contractions at 60% of each subjects maximum voluntary contraction (MVC) force. There was no age‐related difference between groups in the average time to fatigue or the rate of voluntary force loss; both groups lost 40% of their force within approximately 5 min. Despite a rapid increase to ∼83% of the prefatigue MVC by the third minute of recovery for both groups, MVC force did not return to the prefatigue value within 60 min (94 ± 4% young, 91 ± 3% old). These results suggest that the incomplete recovery of voluntary force was likely due to a peripheral limitation in the muscle at the level of excitation–contraction coupling, and was not affected by age. Delayed recovery of voluntary force and a greater degree of low‐frequency fatigue in the old men were not observed and there were no age‐related impairments in any parameter normalized to the prefatigue value during fatigue or recovery. We suggest that the specific fatigue task may be more important to recovery than proposed alterations in the aged neuromuscular system when normalization and matching of the fatigue task criteria occurs.

Single‐unit analysis of somatosensory processing in the core auditory cortex of hearing ferrets

The recent findings in several species that the primary auditory cortex processes non‐auditory information have largely overlooked the possibility of somatosensory effects. Therefore, the present investigation examined the core auditory cortices (anterior auditory field and primary auditory cortex) for tactile responsivity. Multiple single‐unit recordings from anesthetised ferret cortex yielded histologically verified neurons (n = 311) tested with electronically controlled auditory, visual and tactile stimuli, and their combinations. Of the auditory neurons tested, a small proportion (17%) was influenced by visual cues, but a somewhat larger number (23%) was affected by tactile stimulation. Tactile effects rarely occurred alone and spiking responses were observed in bimodal auditory–tactile neurons. However, the broadest tactile effect that was observed, which occurred in all neuron types, was that of suppression of the response to a concurrent auditory cue. The presence of tactile effects in the core auditory cortices was supported by a substantial anatomical projection from the rostral suprasylvian sulcal somatosensory area. Collectively, these results demonstrate that crossmodal effects in the auditory cortex are not exclusively visual and that somatosensation plays a significant role in modulation of acoustic processing, and indicate that crossmodal plasticity following deafness may unmask these existing non‐auditory functions.

Multisensory and unisensory neurons in ferret parietal cortex exhibit distinct functional properties

Despite the fact that unisensory and multisensory neurons are comingled in every neural structure in which they have been identified, no systematic comparison of their response features has been conducted. Towards that goal, the present study was designed to examine and compare measures of response magnitude, latency, duration and spontaneous activity in unisensory and bimodal neurons from the ferret parietal cortex. Using multichannel single‐unit recording, bimodal neurons were observed to demonstrate significantly higher response levels and spontaneous discharge rates than did their unisensory counterparts. These results suggest that, rather than merely reflect different connectional arrangements, unisensory and multisensory neurons are likely to differ at the cellular level. Thus, it can no longer be assumed that the different populations of bimodal and unisensory neurons within a neural region respond similarly to a given external stimulus.

Crossmodal plasticity in auditory, visual and multisensory cortical areas following noise-induced hearing loss in adulthood.

ABSTRACT Complete or partial hearing loss results in an increased responsiveness of neurons in the core auditory cortex of numerous species to visual and/or tactile stimuli (i.e., crossmodal plasticity). At present, however, it remains uncertain how adult‐onset partial hearing loss affects higher‐order cortical areas that normally integrate audiovisual information. To that end, extracellular electrophysiological recordings were performed under anesthesia in noise‐exposed rats two weeks post‐exposure (0.8–20 kHz at 120 dB SPL for 2 h) and age‐matched controls to characterize the nature and extent of crossmodal plasticity in the dorsal auditory cortex (AuD), an area outside of the auditory core, as well as in the neighboring lateral extrastriate visual cortex (V2L), an area known to contribute to audiovisual processing. Computer‐generated auditory (noise burst), visual (light flash) and combined audiovisual stimuli were delivered, and the associated spiking activity was used to determine the response profile of each neuron sampled (i.e., unisensory, subthreshold multisensory or bimodal). In both the AuD cortex and the multisensory zone of the V2L cortex, the maximum firing rates were unchanged following noise exposure, and there was a relative increase in the proportion of neurons responsive to visual stimuli, with a concomitant decrease in the number of neurons that were solely responsive to auditory stimuli despite adjusting the sound intensity to account for each rats hearing threshold. These neighboring cortical areas differed, however, in how noise‐induced hearing loss affected audiovisual processing; the total proportion of multisensory neurons significantly decreased in the V2L cortex (control 38.8 ± 3.3% vs. noise‐exposed 27.1 ± 3.4%), and dramatically increased in the AuD cortex (control 23.9 ± 3.3% vs. noise‐exposed 49.8 ± 6.1%). Thus, following noise exposure, the cortical area showing the greatest relative degree of multisensory convergence transitioned ventrally, away from the audiovisual area, V2L, toward the predominantly auditory area, AuD. Overall, the collective findings of the present study support the suggestion that crossmodal plasticity induced by adult‐onset hearing impairment manifests in higher‐order cortical areas as a transition in the functional border of the audiovisual cortex. HighlightsHigher‐order cortical areas show crossmodal plasticity following noise exposure.Noise exposure caused an increase in audiovisual processing in AuD, not V2L cortex.Extensive sensory reorganization, yet firing rates unchanged in AuD cortex.Noise‐induced hearing loss shifted the functional border of the audiovisual cortex.

Differential Effects of Pannexins on Noise-Induced Hearing Loss

Hearing loss, including noise-induced hearing loss, is highly prevalent and severely hinders an individuals quality of life, yet many of the mechanisms that cause hearing loss are unknown. The pannexin (Panx) channel proteins, Panx1 and Panx3, are regionally expressed in many cell types along the auditory pathway, and mice lacking Panx1 in specific cells of the inner ear exhibit hearing loss, suggesting a vital role for Panxs in hearing. We proposed that Panx1 and/or Panx3 null mice would exhibit severe hearing loss and increased susceptibility to noise-induced hearing loss. Using the auditory brainstem response, we surprisingly found that Panx1-/- and Panx3-/- mice did not harbor hearing or cochlear nerve deficits. Furthermore, while Panx1-/- mice displayed no protection against loud noise-induced hearing loss, Panx3-/- mice exhibited enhanced 16- and 24-kHz hearing recovery 7 days after a loud noise exposure (NE; 12 kHz tone, 115 dB sound pressure level, 1 h). Interestingly, Cx26, Cx30, Cx43, and Panx2 were up-regulated in Panx3-/- mice compared with wild-type and/or Panx1-/- mice, and assessment of the auditory tract revealed morphological changes in the middle ear bones of Panx3-/- mice. It is unclear if these changes alone are sufficient to provide protection against loud noise-induced hearing loss. Contrary to what we expected, these data suggest that Panx1 and Panx3 are not essential for baseline hearing in mice tested, but the therapeutic targeting of Panx3 may prove protective against mid-high-frequency hearing loss caused by loud NE.

Quadriceps fatigue caused by catchlike-inducing trains is not altered in old age

The relative loss of peak force from electrical stimulation protocols has provided inconsistent results when used to compare muscle fatigability between young and old adults. In addition to the effect of task on these comparisons, age‐related alterations in the development and relaxation of force are possible factors that have not been considered. The purposes of this study were to compare the fatigability of the quadriceps of young (26.7 ± 1.0 years) and old men (78.3 ± 1.3 years), as assessed by changes in peak force, force time integral (FTI), and half‐relaxation time (HRT), during intermittent electrical stimulation protocols, and to determine whether manipulation of the activation frequency affected the comparisons. Fatigue was caused by constant‐frequency (CF), and catchlike‐inducing (CI) train protocols, both of which consisted of intermittent trains (6 pulses on: 650 ms off) of stimulation. After each protocol, the force‐generating capacity of the fatigued muscle was assessed with three trains of stimuli: a CF train, a CI train and a 1‐s 50‐HZ train. There was no effect of age on the loss of peak force or the development of low‐frequency fatigue induced by either protocol. Conversely, irrespective of the protocol, the FTI was better maintained by ∼9% in the old than young men. Because peak force did not differ between groups during fatigue, it is likely that the FTI was preserved by the exacerbated slowing of HRT in the quadriceps of the old men. The results confirm an apparent paradox between muscle fatigue and stimulation with CI trains: a single CI train produces greater force than a CF train in a fatigued muscle, but there is greater fatigue induced by repetitive CI than CF train stimulation. Old age did not affect this fatigue paradox. Muscle Nerve, 2004

Anatomy of the nerves and ganglia of the aortic plexus in males

It is well accepted that the aortic plexus is a network of pre‐ and post‐ganglionic nerves overlying the abdominal aorta, which is primarily involved with the sympathetic innervation to the mesenteric, pelvic and urogenital organs. Because a comprehensive anatomical description of the aortic plexus and its connections with adjacent plexuses are lacking, these delicate structures are prone to unintended damage during abdominal surgeries. Through dissection of fresh, frozen human cadavers (n = 7), the present study aimed to provide the first complete mapping of the nerves and ganglia of the aortic plexus in males. Using standard histochemical procedures, ganglia of the aortic plexus were verified through microscopic analysis using haematoxylin & eosin (H&E) and anti‐tyrosine hydroxylase stains. All specimens exhibited four distinct sympathetic ganglia within the aortic plexus: the right and left spermatic ganglia, the inferior mesenteric ganglion and one previously unidentified ganglion, which has been named the prehypogastric ganglion by the authors. The spermatic ganglia were consistently supplied by the L1 lumbar splanchnic nerves and the inferior mesenteric ganglion and the newly characterized prehypogastric ganglion were supplied by the left and right L2 lumbar splanchnic nerves, respectively. Additionally, our examination revealed the aortic plexus does have potential for variation, primarily in the possibility of exhibiting accessory splanchnic nerves. Clinically, our results could have significant implications for preserving fertility in men as well as sympathetic function to the hindgut and pelvis during retroperitoneal surgeries.

Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function

HIGHLIGHTSNMDA and D1 receptor blockade act synergistically to cause behavioral inflexibility and perseveration.Subtle abnormalities of glutamatergic and dopaminergic systems are sufficient to cause executive functional deficits.Executive function is more sensitive to combined NMDA and D1 receptor dysfunction than learning or memory retrieval. ABSTRACT Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N‐methyl d‐aspartate (NMDA) or dopamine D1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of “behaviorally sub‐effective” doses of NMDA and dopamine D1 receptor antagonists on executive function. An operant conditioning‐based set‐shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK‐801, and the dopamine D1 receptor antagonist, SCH 23390, at low doses did not impair set‐shifting; however, the combined administration of these same behaviorally sub‐effective doses of the antagonists significantly impaired the performance during set‐shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function.

Histological verification of the prehypogastric and ovarian ganglia confirms a bilaterally symmetrical organization of the ganglia comprising the aortic plexus in female human cadavers.

The aortic plexus is a network of sympathetic nerves positioned along the infrarenal abdominal aorta. Recently, we characterized the aortic plexus and its ganglia (inferior mesenteric, left/right spermatic, and prehypogastric ganglion) in males; however, the literature minimally describes its anatomy in females. In the present study, we conducted the first histological examination of the left and right ovarian ganglia, while also investigating whether females, like males, exhibit a prehypogastric ganglion. The ganglia were dissected from embalmed (n = 32) and fresh (n = 1) human cadavers, and H&E staining was used to confirm the presence of a left ovarian ganglion in 31/31 specimens, a right ovarian ganglion in 29/29 specimens and a prehypogastric ganglion in 25/28 specimens. Comparable to the topographic arrangement in males, there is a bilateral organization of the ganglia comprising the aortic plexus in females. More specifically, the left and right ovarian ganglia were positioned in close relation to their respective ovarian artery, whereas the prehypogastric ganglion was positioned within the right cord of the aortic plexus, contralateral to the inferior mesenteric ganglion. Using immunohistochemistry, it was shown that all ganglia from the fresh cadaver stained positive for tyrosine hydroxylase, thereby confirming their sympathetic nature. Having provided the first topographical and histological characterization of the ovarian and prehypogastric ganglia in females, future studies should seek to determine their specific function.