N.B. Reese

The pedunculopontine nucleus—Auditory input, arousal and pathophysiology

This review describes the role of the pedunculopontine nucleus (PPN) in various functions, including sleep-wake mechanisms, arousal, locomotion and in several pathological conditions. Special emphasis is placed on the auditory input to the PPN and the possible role of this nucleus in the manifestation of the P1 middle latency auditory evoked response. The importance of these considerations is evident because the PPN is part of the cholinergic arm of the reticular activating system. As such, the auditory input to this region may modulate the level of arousal of the CNS and, consequently, abnormalities in the processing of this input can be expected to have serious consequences on the level of excitability of the CNS. The involvement of the PPN in such disorders as schizophrenia, anxiety disorder and narcolepsy is discussed.

Restoration of frequency-dependent depression of the H-reflex by passive exercise in spinal rats

Study design:Hyper-reflexia, measured as a decrease of low frequency-dependent depression of the H-reflex, is known to occur in both humans and animals after spinal cord injury (SCI). Previous studies have shown that passive exercise for 3 months could be used to restore low frequency-dependent depression of the H-reflex after SCI.Objective:To determine the effects of various periods of time on the ability of passive exercise to restore low frequency-dependent depression of the H-reflex.Setting:Spinal Cord Injury Mobilization Program of the Center for Translational Neuroscience, the research arm of the Jackson T Stephens Spine & Neuroscience Institute, Little Rock, AR, USA.Methods:Adult rats underwent complete spinal cord transection at the T10 level. The hindlimbs were passively exercised in different groups of rats for 1 h/day, 5 days/week for 15, 30, 45, 60, or 90 days, and low frequency-dependent depression of the H-reflex was tested.Results:Statistically significant low frequency-dependent depression of the H-reflex was evident by 30 days of exercise, although numerical reductions were seen even at 15 days. There was a linear decrease in low frequency-dependent depression of the H-reflex with duration of passive exercise.Conclusions:Passive exercise can restore frequency-dependent depression of spinal reflexes in a time-dependent manner if used following complete spinal transection.Sponsorship:Supported by USPHS award RR020146 and the Arkansas Biosciences Institute.

Auditory input to the pedunculopontine nucleus: II. Unit responses

The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control, arousal responses, and motor functions. The PPN also has been implicated in the generation of the P1 middle-latency auditory-evoked potential. The present study was undertaken to determine the nature of the responsiveness of single neurons in and around the PPN following auditory stimulation. Somatosensory responsiveness also was tested in some cells. These results demonstrate a) the presence of a significant proportion of PPN neurons that respond to auditory click stimuli; b) two populations of neurons showing either low threshold/short latency/low habituation or high threshold/longer latency/high habituation; c) the responses of longer latency neurons precede the onset and peak of depth- and vertex-recorded middle-latency auditory-evoked potentials; d) thresholds of longer latency neurons similar to the threshold for wave A in the intact cat, the P13 potential in the intact rat, or the startle reflex; and e) convergent somatosensory and auditory responses at a similar latency in a number of PPN neurons. These findings suggest that neurons in and around the PPN may participate in auditory and somatosensory information processing related to arousal, and may contribute to the manifestation of the P1 auditory middle-latency evoked potential.

A middle-latency auditory-evoked potential in the rat

Previous studies have established the presence of a middle-latency auditory-evoked potential that is characterized by a) sleep-state dependence, b) low following frequency (i.e., rapid habituation to repetitive stimulation), and c) blockade by the cholinergic antagonist, scopolamine. A vertex-recorded evoked potential having these characteristics was described in humans at a 50-80 ms latency (termed the P1 or.P50 potential) and in the cat at a 20-25 ms latency (termed wave A). These studies were undertaken to determine if a click stimulus-evoked potential having the same characteristics was present in the intact rat. Vertex and auditory cortex recordings in intact rats studied in a sound-attenuating chamber and exposed to free-field click stimuli showed a) the presence of a vertex recorded potential at a 11-15 ms latency, termed P13, and of an auditory cortex recorded potential at a 7-11 ms latency, termed Pa; b) the P13 was present during waking and paradoxical sleep but absent in slow-wave sleep, while Pa was present in all sleep-wake states; c) the P13 habituated markedly at stimulation rates above 1 Hz while Pa did not; and d) the P13 was blocked by low doses of scopolamine while Pa was not. These studies demonstrate the presence of a P1-like potential in the rat at a 13 +/- 2 ms latency.

Auditory input to the pedunculopontine nucleus. I: Evoked potentials

The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control, arousal responses, and motor functions. The PPN also has been implicated in the generation of the P1 middle-latency auditory-evoked potential. The present study was undertaken to determine the topographical distribution, threshold, and response properties of depth-recorded potentials following auditory click stimulation. Experiments were conducted in both decerebrate cat and rat, with a view towards determining the presence of P1-like middle-latency auditory-evoked potentials in the midbrain of both species. These results demonstrate a) the presence in and around the PPN of a P1-like potential in the decerebrate rat similar to that described in the accompanying article as the P13 in the intact rat; b) the presence in and around the PPN of a P1-like potential in the decerebrate cat similar to that previously described by others as wave A in the intact cat; c) although thresholds for these potentials were similar to those of intact preparations, following frequencies were higher in the decerebrate preparations, i.e., responsiveness to repetitive stimulation was higher; and d) depth-recorded somatosensory-evoked potentials also were studied in the cat and found to show an evoked potential at a similar latency as middle-latency auditory depth-recorded potentials. These findings suggest that click stimulus-evoked, depth-recorded potentials are present in and around the PPN in the decerebrate rat and cat, i.e., in the absence of cortex, at a similar latency as in intact preparations.

Use of a motorized bicycle exercise trainer to normalize frequency-dependent habituation of the H-reflex in spinal cord injury.

Abstract Background/Objectives: Spasticity in patients with spinal cord injury (SCI) is difficult to manage. Exercise and stretching is advocated as a management tool, butthese activities are difficult to perform for mostpatients as a result of multiple barriers. This report shows the effect of passive range-of-motion exercise ina walking-like pattern on frequency-dependent habituation of the H-reflex in the lower extremities of anindividual with spastic tetraplegia due to SCI. Methods: The participant, a man with a chronic ASIA B C7 SCI due to a gunshot wound, used a motorized bicycle exercise trainer (MBET) developed at the Jackson T. Stephens Spine & Neurosciences Institute at theUniversity of Arkansas for Medical Sciencesthat could be operated from the individuals wheelchair. He usedthe MBET for 1 hour, 5 days a week, for 13 weeks. H-reflexhabituation was tested at the beginningof thestudy and then periodically over the course of 1 7 weeks,including 4 weeks after exercise had ceased. Results: Significant habituation of the H-reflex was evident beginning atthe 1Oth week of training. The habituation in the H-reflex reached a normal level at 5- and 10-Hz frequencies at 12 weeks. Subjective assessment of spasticity indicated that it was significantly reduced. The H-reflex amplitude was maintained at normal levels during the remaining week of the course of exercise and for 2 additional weeks after exerciseceased.The H-reflex habituation, however, returned to near baseline when reassessed at week 17,4 weeks after the exercise program had concluded. Subjective assessment indicated thatspasticity also had returned to pretraining levels. Conclusions: Habituation of the H-reflex, and perhaps spasticity, can be managed by aroutine passive range-of-motion exercise program using a MBET, but the exercise program may need to be continuous. The benefit of reduced medication for spasticity and possibly improved quality of lifecould be a motivating factor for an individual with SCI and spasticity to continue the program. Because of thelow complexity ofthe program, ease of use, and small size, this system could be inexpensive and could be used by an individual in the home. Ongoing studies will determine the minimum amount of MBET training required formaintaining long-term H-reflex habituation.

Chapter 25 Arousal and locomotion: from schizophrenia to narcolepsy

Publisher Summary This chapter focuses on the brain stem control of locomotion and control the level of arousal of the nervous system. The level of arousal of the nervous system is essential to displaying a normal pattern of even simple movements. The locomotor step cycle of the manic individual is obviously hyperkinetic and that of the depressive abnormally sluggish. If the level of excitability is too high, “hyperactivity” results, if too low, bradykinesia or akinesia are evident. Such disorders can be differentiated not only by the locomotor pattern manifested but also by the unusual postures these patients exhibit. The dissociation between the “emotional” and the “motor” can only lead to an abnormal pattern of movements of varying degrees depending on the distance of the dissociation. These results suggest that there is a strong relationship between those brain stem systems modulating posture and locomotion and those modulating arousal. It is, therefore, not surprising that an integral part of movement and posture is its “emotional” context and that normal movement strategies hinge on the level of excitability or state of the system.

The effects of passive exercise therapy initiated prior to or after the development of hyperreflexia following spinal transection

Hyperreflexia develops after spinal cord injury (SCI) in the human and in the spinal cord transected animal, and can be measured by the loss of low frequency-dependent depression of the H-reflex. Previous studies demonstrated normalization of low frequency-dependent depression of the H-reflex using passive exercise when initiated prior to the development of hyperreflexia. We examined the effects of passive exercise prior to compared to after the development of hyperreflexia in the transected rat. Adult female rats underwent complete transection (Tx) at T10. Frequency-dependence of the H-reflex was tested following passive exercise for 30 days, initiated prior to hyperreflexia in one group compared to initiation after hyperreflexia became established, and compared to intact and untreated Tx groups. An additional Tx group completed 60 days of exercise initiated after hyperreflexia was established. Lumbar enlargement tissue was harvested for western blot to compare Connexin-36 protein levels in control vs Tx animals vs Tx animals that were passively exercised. No differences in whole tissue were evident, although regional differences may still be present in Connexin-36 levels. Statistically significant decreases in low frequency-dependent depression of the H-reflex were observed following 30 days of exercise initiated prior to the onset of hyperreflexia, and also after 60 days of exercise when initiated after hyperreflexia had been established, compared with Tx only animals. We concluded that modulation of spinal circuitry by passive exercise took place when initiated before and after the onset of hyperreflexia, but different durations of exercise were required.

Wind-up of stretch reflexes as a measure of spasticity in chronic spinalized rats: The effects of passive exercise and modafinil

Spasticity is a common disorder following spinal cord injury that can impair function and quality of life. While a number of mechanisms are thought to play a role in spasticity, the role of motoneuron persistent inward currents (PICs) is emerging as pivotal. The presence of PICs can be evidenced by temporal summation or wind-up of reflex responses to brief afferent inputs. In this study, a combined neurophysiological and novel biomechanical approach was used to assess the effects of passive exercise and modafinil administration on hyper-reflexia and spasticity following complete T-10 transection in the rat. Animals were divided into 3 groups (n=8) and provided daily passive cycling exercise, oral modafinil, or no intervention. After 6weeks, animals were tested for wind-up of the stretch reflex (SR) during repeated dorsiflexion stretches of the ankle. H-reflexes were tested in a subset of animals. Both torque and gastrocnemius electromyography showed evidence of SR wind-up in the transection only group that was significantly different from both treatment groups (p<0.05). H-reflex frequency dependent depression was also restored to normal levels in both treatment groups. The results provide support for the use of passive cycling exercise and modafinil in the treatment of spasticity and provide insight into the possible contribution of PICs.

Modafinil normalized hyperreflexia after spinal transection in adult rats

Study Design:Hyperreflexia occurs after spinal cord injury and can be assessed by measuring low frequency-dependent depression of the H-reflex in the anesthetized animal.Objective:To determine the effects of Modafinil (MOD), given orally, following a complete SCI compared with animals receiving MBET and transected untreated animals and examine if changes exist in Connexin 36 (Cx-36) protein levels in the lumbar enlargement of animals for the groups described.Setting:Center for Translational Neuroscience, Little Rock, AR, USA.Methods:Adult female rats underwent complete transection (Tx) at T10 level. H-reflex testing was performed 30 days following Tx in one group, and after initiation of treatment with MOD in another group, and after MBET training in the third group. The Lumbar enlargement tissue was harvested and western blots were performed after immunoprecipitation techniques to compare Cx-36 protein levels.Results:Statistically significant decreases in low frequency-dependent depression of the H-reflex were observed in animals that received MOD and those that were treated with MBET compared with the Tx, untreated group. Statistically significant changes in Cx-36 protein levels were not observed in animals treated with MOD compared with Tx, untreated animals.Conclusion:Normalization of the loss of low frequency -dependent depression of the H-reflex was demonstrated in the group receiving MOD and the group receiving MBET compared with the Tx, untreated group. Further work is needed to examine if Cx-36 protein changes occur in specific subregions of the spinal cord.Sponsors:NIH-NCRR Grant P20 RR020146 to the CTN and NINDS P30 NS047546