The history of Danish neuroscience.

The history of Danish neuroscience starts with an account of impressive contributions made at the 17th century. Thomas Bartholin was the first Danish neuroscientist, and his disciple Nicolaus Steno became internationally one of the most prominent neuroscientists in this period. From the start, Danish neuroscience was linked to clinical disciplines. This continued in the 19th and first half of the 20th centuries with new initiatives linking basic neuroscience to clinical neurology and psychiatry in the same scientific environment. Subsequently, from the middle of the 20th century, basic neuroscience was developing rapidly within the preclinical university sector. Clinical neuroscience continued and was even reinforced during this period with important translational research and a close co-operation between basic and clinical neuroscience. To distinguish 'history' from 'present time' is not easy, as many historical events continue in present time. Therefore, we decided to consider 'History' as new major scientific developments in Denmark, which were launched before the end of the 20th century. With this aim, scientists mentioned will have been born, with a few exceptions, no later than the early 1960s. However, we often refer to more recent publications in documenting the developments of initiatives launched before the end of the last century. In addition, several scientists have moved to Denmark after the beginning of the present century, and they certainly are contributing to the present status of Danish neuroscience-but, again, this is not the History of Danish neuroscience.

Testing spasticity mechanisms in chronic stroke before and after intervention with contralesional motor cortex 1 Hz rTMS and physiotherapy.

BACKGROUND: Previous studies showed that repetitive transcranial magnetic stimulation (rTMS) reduces spasticity after stroke. However, clinical assessments like the modified Ashworth scale, cannot discriminate stretch reflex-mediated stiffness (spasticity) from passive stiffness components of resistance to muscle stretch. The mechanisms through which rTMS might influence spasticity are also not understood. METHODS: We measured the effects of contralesional motor cortex 1 Hz rTMS (1200 pulses + 50 min physiotherapy: 3×/week, for 4-6 weeks) on spasticity of the wrist flexor muscles in 54 chronic stroke patients using a hand-held dynamometer for objective quantification of the stretch reflex response. In addition, we measured the excitability of three spinal mechanisms thought to be related to post-stroke spasticity: post-activation depression, presynaptic inhibition and reciprocal inhibition before and after the intervention. Effects on motor impairment and function were also assessed using standardized stroke-specific clinical scales. RESULTS: The stretch reflex-mediated torque in the wrist flexors was significantly reduced after the intervention, while no change was detected in the passive stiffness. Additionally, there was a significant improvement in the clinical tests of motor impairment and function. There were no significant changes in the excitability of any of the measured spinal mechanisms. CONCLUSIONS: We demonstrated that contralesional motor cortex 1 Hz rTMS and physiotherapy can reduce the stretch reflex-mediated component of resistance to muscle stretch without affecting passive stiffness in chronic stroke. The specific physiological mechanisms driving this spasticity reduction remain unresolved, as no changes were observed in the excitability of the investigated spinal mechanisms.

Multistable properties of human subthalamic nucleus neurons in Parkinson's disease.

To understand the function and dysfunction of neural circuits, it is necessary to understand the properties of the neurons participating in the behavior, the connectivity between these neurons, and the neuromodulatory status of the circuits at the time they are producing the behavior. Such knowledge of human neural circuits is difficult, at best, to obtain. Here, we study firing properties of human subthalamic neurons, using microelectrode recordings and microstimulation during awake surgery for Parkinson's disease. We demonstrate that low-amplitude, brief trains of microstimulation can lead to persistent changes in neuronal firing behavior including switching between firing rates, entering silent periods, or firing several bursts then entering a silent period. We suggest that these multistable states reflect properties of finite state machines and could have implications for the function of circuits involving the subthalamic nucleus. Furthermore, understanding these states could lead to therapeutic strategies aimed at regulating the transitions between states.

Immobilization leads to reduced stretch reflexes but increased central reflex gain in the rat.

Plastic adaptations are known to take place in muscles, tendons, joints, and the nervous system in response to changes in muscle activity. However, few studies have addressed how these plastic adaptations are related. Thus this study focuses on changes in the mechanical properties of the ankle plantarflexor muscle-tendon unit, stretch reflex activity, and spinal neuronal pathways in relation to cast immobilization. The left rat hindlimb from toes to hip was immobilized with a plaster cast for 1, 2, 4, or 8 wk followed by acute electrophysiological recordings to investigate muscle stiffness and stretch reflex torque. Moreover, additional acute experiments were performed after 4 wk of immobilization to investigate changes in the central gain of the stretch reflex. Monosynaptic reflexes (MSR) were recorded from the L4 and L5 ventral roots following stimulation of the corresponding dorsal roots. Rats developed reduced range of movement in the ankle joint 2 wk after immobilization. This was accompanied by significant increases in the stiffness of the muscle-tendon complex as well as an arthrosis at the ankle joint at 4 and 8 wk following immobilization. Stretch reflexes were significantly reduced at 4-8 wk following immobilization. This was associated with increased central gain of the stretch reflex. These data show that numerous interrelated plastic changes occur in muscles, connective tissue, and the central nervous system in response to changes in muscle use. The findings provide an understanding of coordinated adaptations in multiple tissues and have important implications for prevention and treatment of the negative consequences of immobilization following injuries of the nervous and musculoskeletal systems.NEW & NOTEWORTHY Immobilization leads to multiple simultaneous adaptive changes in muscle, connective tissue, and central nervous system.

The Subprimary Range of Firing Is Present in Both Cat and Mouse Spinal Motoneurons and Its Relationship to Force Development Is Similar for the Two Species.

In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (the I-f relation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated the I-f relation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of the I-f relation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37°C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.SIGNIFICANCE STATEMENT This work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematically addresses the proposed discrepancies between mice and larger species (cats) and demonstrates that mouse motoneurons, in fact, use rate modulation as a mechanism of force modulation in a similar manner to the classical descriptions in larger animals.

Muscle disuse caused by botulinum toxin injection leads to increased central gain of the stretch reflex in the rat.

Botulinum toxin (Btx) is used in children with cerebral palsy and in other neurological patients to diminish spasticity and reduce the risk of development of contractures. We investigated changes in the central gain of the stretch reflex circuitry in response to Btx injection in the triceps surae muscle in rats. Experiments were performed in 21 rats. Eight rats were a control group, and 13 rats were injected with 6 IU of Btx in the left triceps surae muscle. Two weeks after Btx injection, larger monosynaptic reflexes (MSR) were recorded from the left (injected) than the right (noninjected) L4 + L5 ventral roots following stimulation of the corresponding dorsal roots. A similar increase on the left side was observed in response to stimulation of descending motor tracts, suggesting that increased excitability of spinal motor neurons may at least partly explain the increased reflexes. However, significant changes were also observed in postactivation depression of the MSR, suggesting that plastic changes in transmission from Ia afferent to the motor neurons also may be involved. The data demonstrate that muscle paralysis induced by Btx injection is accompanied by plastic adaptations in the central stretch reflex circuitry, which counteract the antispastic effect of Btx.NEW & NOTEWORTHY Injection of botulinum toxin into ankle muscles causes increased gain of stretch reflex. This is caused by adaptive changes in regulation of transmitter release from Ia afferents and increased excitability of spinal motor neurons.

Spinal cord injury enables aromatic L-amino acid decarboxylase cells to synthesize monoamines.

Serotonin (5-HT), an important modulator of both sensory and motor functions in the mammalian spinal cord, originates mainly in the raphe nuclei of the brainstem. However, following complete transection of the spinal cord, small amounts of 5-HT remain detectable below the lesion. It has been suggested, but not proven, that this residual 5-HT is produced by intraspinal 5-HT neurons. Here, we show by immunohistochemical techniques that cells containing the enzyme aromatic l-amino acid decarboxylase (AADC) occur not only near the central canal, as reported by others, but also in the intermediate zone and dorsal horn of the spinal gray matter. We show that, following complete transection of the rat spinal cord at S2 level, AADC cells distal to the lesion acquire the ability to produce 5-HT from its immediate precursor, 5-hydroxytryptophan. Our results indicate that this phenotypic change in spinal AADC cells is initiated by the loss of descending 5-HT projections due to spinal cord injury (SCI). By in vivo and in vitro electrophysiology, we show that 5-HT produced by AADC cells increases the excitability of spinal motoneurons. The phenotypic change in AADC cells appears to result from a loss of inhibition by descending 5-HT neurons and to be mediated by 5-HT1B receptors expressed by AADC cells. These findings indicate that AADC cells are a potential source of 5-HT at spinal levels below an SCI. The production of 5-HT by AADC cells, together with an upregulation of 5-HT2 receptors, offers a partial explanation of hyperreflexia below a chronic SCI.

Information to cerebellum on spinal motor networks mediated by the dorsal spinocerebellar tract.

The main objective of this review is to re-examine the type of information transmitted by the dorsal and ventral spinocerebellar tracts (DSCT and VSCT respectively) during rhythmic motor actions such as locomotion. Based on experiments in the 1960s and 1970s, the DSCT was viewed as a relay of peripheral sensory input to the cerebellum in general, and during rhythmic movements such as locomotion and scratch. In contrast, the VSCT was seen as conveying a copy of the output of spinal neuronal circuitry, including those circuits generating rhythmic motor activity (the spinal central pattern generator, CPG). Emerging anatomical and electrophysiological information on the putative subpopulations of DSCT and VSCT neurons suggest differentiated functions for some of the subpopulations. Multiple lines of evidence support the notion that sensory input is not the only source driving DSCT neurons and, overall, there is a greater similarity between DSCT and VSCT activity than previously acknowledged. Indeed the majority of DSCT cells can be driven by spinal CPGs for locomotion and scratch without phasic sensory input. It thus seems natural to propose the possibility that CPG input to some of these neurons may contribute to distinguishing sensory inputs that are a consequence of the active locomotion from those resulting from perturbations in the external world.

Rhythmic activity of feline dorsal and ventral spinocerebellar tract neurons during fictive motor actions.

Neurons of the dorsal spinocerebellar tracts (DSCT) have been described to be rhythmically active during walking on a treadmill in decerebrate cats, but this activity ceased following deafferentation of the hindlimb. This observation supported the hypothesis that DSCT neurons primarily relay the activity of hindlimb afferents during locomotion, but lack input from the spinal central pattern generator. The ventral spinocerebellar tract (VSCT) neurons, on the other hand, were found to be active during actual locomotion (on a treadmill) even after deafferentation, as well as during fictive locomotion (without phasic afferent feedback). In this study, we compared the activity of DSCT and VSCT neurons during fictive rhythmic motor behaviors. We used decerebrate cat preparations in which fictive motor tasks can be evoked while the animal is paralyzed and there is no rhythmic sensory input from hindlimb nerves. Spinocerebellar tract cells with cell bodies located in the lumbar segments were identified by electrophysiological techniques and examined by extra- and intracellular microelectrode recordings. During fictive locomotion, 57/81 DSCT and 30/30 VSCT neurons showed phasic, cycle-related activity. During fictive scratch, 19/29 DSCT neurons showed activity related to the scratch cycle. We provide evidence for the first time that locomotor and scratch drive potentials are present not only in VSCT, but also in the majority of DSCT neurons. These results demonstrate that both spinocerebellar tracts receive input from the central pattern generator circuitry, often sufficient to elicit firing in the absence of sensory input.

Measuring resistance to externally induced movement of the wrist joint in chronic stroke patients using an objective hand-held dynamometer.

Objective: We evaluated the resistance to externally induced wrist extension in chronic stroke patients. We aimed to objectively measure and distinguish passive (muscle and soft tissue stiffness) and active (spasticity and spastic dystonia) components of the resistance. Methods: We used a hand-held dynamometer, which measures torque, joint movement and electromyography (EMG) simultaneously, to assess the resistance to externally induced wrist extension. Slow and fast stretches were applied to the affected and unaffected wrists in 57 chronic stroke patients (57 ±â€¯11 years). We extracted from the data parameters that represent passive and muscle activity components and assessed the validity, test-retest reliability and the clinical utility of the measurement. Results: The analysis showed (1) a significant difference in the passive and muscle activity components between the affected and unaffected sides; (2) a significant correlation between passive and muscle activity components and the modified Ashworth scale (MAS); (3) a significant difference between the subgroups of patients stratified by the MAS; (4) an excellent intra-rater reliability on each of the passive and muscle activity components with intra-class coefficients between 0.92 and 0.99; (5) and small measurement error. Conclusions: Using a hand-held dynamometer, we were able to objectively measure the resistance to muscle stretch in the wrist joint in chronic stroke patients and discriminate muscle overactivity components from muscle and soft tissue stiffness. We demonstrated validity, test-retest reliability and the clinical utility of the measurement. Significance: Quantification of the different components of resistance to externally induced movement enables the objective evaluation of neurorehabilitation effects in chronic stroke patients.

Reciprocal Ia inhibition contributes to motoneuronal hyperpolarisation during the inactive phase of locomotion and scratching in the cat.

Despite decades of research, the classical idea that 'reciprocal inhibition' is involved in the hyperpolarisation of motoneurones in their inactive phase during rhythmic activity is still under debate. Here, we investigated the contribution of reciprocal Ia inhibition to the hyperpolarisation of motoneurones during fictive locomotion (evoked either by electrical stimulation of the brainstem or by l-DOPA administration following a spinal transection at the cervical level) and fictive scratching (evoked by stimulation of the pinna) in decerebrate cats. Simultaneous extracellular recordings of Ia inhibitory interneurones and intracellular recordings of lumbar motoneurones revealed the interneurones to be most active when their target motoneurones were hyperpolarised (i.e. in the inactive phase of the target motoneurones). To date, these results are the most direct evidence that Ia inhibitory interneurones contribute to the hyperpolarisation of motoneurones during rhythmic behaviours. We also estimated the amount of Ia inhibition as the amplitude of Ia IPSC in voltage-clamp mode. In both flexor and extensor motoneurones, Ia IPSCs were always larger in the inactive phase than in the active phase during locomotion (n = 14) and during scratch (n = 11). Results obtained from spinalised animals demonstrate that the spinal rhythm-generating network simultaneously drives the motoneurones of one muscle group and the Ia interneurones projecting to motoneurones of the antagonist muscles in parallel. Our results thus support the classical view of reciprocal inhibition as a basis for relaxation of antagonist muscles during flexion-extension movements.

Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury.

BACKGROUND: Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence of modulatory inputs from the brain correlates with the development of spasticity. RESULTS: Here we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time expression profiles. Analysis of these gene clusters identifies early immunological/inflammatory and late developmental responses as well as a regulation of genes relating to neuron excitability that support the development of motor neuron hyper-excitability and the reappearance of plateau potentials in the late phase of the injury response. Transcription factor motif analysis identifies differentially expressed transcription factors involved in the regulation of each gene cluster, shaping the expression of the identified biological processes and their associated genes underlying the changes in motor neuron excitability. CONCLUSIONS: This analysis provides important clues to the underlying mechanisms of transcriptional regulation responsible for the increased excitability observed in motor neurons in the late chronic phase of spinal cord injury suggesting alternative targets for treatment of spinal cord injury. Several transcription factors were identified as potential regulators of gene clusters containing elements related to motor neuron hyper-excitability, the manipulation of which potentially could be used to alter the transcriptional response to prevent the motor neurons from entering a state of hyper-excitability.

Thomas Graham Brown (1882--1965), Anders Lundberg (1920-), and the neural control of stepping.

Thomas Graham Brown (1882--1965) undertook experiments on the neural control of stepping in the University of Liverpool laboratory of Charles Sherrington (1857--1952) in 1910--13 and his own laboratory in 1913--15 at the University of Manchester. His results revealed the intrinsic capability of the spinal cord in the guinea pig and cat to generate a stepping output pattern whose timing did not depend upon descending or sensory inputs. This idea was then revolutionary because the prevailing viewpoint was that the stepping rhythm was generated by spinal reflexes. Sadly, Graham Brown's GBR peers gave little credence to this seminal accomplishment, except perhaps Sherrington, who waxed but largely waned on the potential significance of the work. It remained for the Swedish neuroscientist, Anders Lundberg (1920-), to rescue Graham Brown's concepts from obscurity: in seminars presented in several countries between 1957 and 1980, and in widely read articles and reviews (1965--1981). Graham Brown had proposed mutually inhibitory connections between a pair of intrinsically active flexor and extensor "half-centers" on each side of the spinal cord, with the rhythmic output modulated by sensory proprioceptive input. Lundberg, Elzbieta Jankowska (1930-), and their colleagues provided seminal, compelling evidence for spinal half-center interneuronal circuitry implicated in the control of stepping and Lundberg and Ingemar Engberg (1935--2005) made behavioral EMG observations on unrestrained cats that supported a central generation of the rhythm. Subsequently, models of the spinal pattern generators for mammalian locomotion have become progressively more complex but they mostly still include a half-center component.

Spinal reflexes, mechanisms and concepts: from Eccles to Lundberg and beyond.

This review focuses on investigations by Sir John Eccles and co-workers in Canberra, AUS in the 1950s, in which they used intracellular recordings to unravel the organization of neuronal networks in the cat spinal cord. Five classical spinal reflexes are emphasized: recurrent inhibition of motoneurons via motor axon collaterals and Renshaw cells, pathways from muscle spindles and Golgi tendon organs, presynaptic inhibition, and the flexor reflex. To set the scene for these major achievements I first provide a brief account of the understanding of the spinal cord in "reflex" and "voluntary" motor activities from the beginning of the 20th century. Next, subsequent work is reviewed on the convergence on spinal interneurons from segmental sensory afferents and descending motor pathways, much of which was performed and inspired by Anders Lundberg's group in Gothenburg, SWE. This work was the keystone for new hypotheses on the role of spinal circuits in normal motor control. Such hypotheses were later tested under more natural conditions; either by recording directly from interneurons in reduced animal preparations or by use of indirect non-invasive techniques in humans performing normal movements. Some of this latter work is also reviewed. These developments would not have been possible without the preceding work on spinal reflexes by Eccles and Lundberg. Finally, there is discussion of how Eccles' work on spinal reflexes remains central (1) as new techniques are introduced on direct recording from interneurons in behaving animals; (2) in experiments on plastic neuronal changes in relation to motor learning and neurorehabilitation; (3) in experiments on transgenic animals uncovering aspects of human pathophysiology; and (4) in evaluating the function of genetically identified classes of neurons in studies on the development of the spinal cord.

Heterogenic Distribution of Aromatic L-Amino Acid Decarboxylase Neurons in the Rat Spinal Cord.

Aromatic L-amino acid decarboxylase (AADC) is an essential enzyme in the synthesis of serotonin, dopamine, and certain trace amines and is present in a variety of organs including the brain and spinal cord. It is previously reported that in mammalian spinal cord AADC cells (called D-cells) were largely confined to a region around the central canal and that they do not produce monoamines. To date, there has not been a detailed description of their distribution and morphology in mammals. In the present study this issue is systematically investigated using immunohistochemistry. We have found that AADC cells in the rat spinal cord are both more numerous and more widely distributed than previously reported. In the gray matter, AADC neurons immunolabeled for NeuN were not only found in the region around the central canal but also in the dorsal horn, intermediate zone, and ventral horn. In the white matter a large number of glial cells were AADC-immunopositive in different spinal segments and the vast majority of these cells expressed oligodendrocyte and radial glial phenotypes. Additionally, a small number of AADC neurons labeled for NeuN were found in the white matter along the ventral median fissure. The shapes and sizes of AADC neurons varied according to their location. For example, throughout cervical and lumbar segments AADC neurons in the intermediate zone and ventral horn tended to be rather large and weakly immunolabeled, whereas those in comparable regions of sacrocaudal segments were smaller and more densely immunolabeled. The diverse morphological characteristics of the AADC cells suggests that they could be further divided into several subtypes. These results indicate that AADC cells are heterogeneously distributed in the rat spinal cord and they may exert different functions in different physiological and pathological situations.

Localization of L-type calcium channel Ca(V)1.3 in cat lumbar spinal cord--with emphasis on motoneurons.

Voltage-dependent persistent inward currents (PICs) which underlie the plateau potentials are an important intrinsic property of spinal motoneurons. Electrophysiological experiments have indicated that a subtype of the low threshold L-type calcium channel, Ca(V)1.3, mediates this current. In mouse and turtle lumbar spinal cord it has been shown that these channel proteins are mainly found on motoneuron dendrites. In the present study we have used immunohistochemistry to locate these channels in lumbar spinal neurons, especially motoneurons, of the cat. The results indicate that Ca(V)1.3 immunoreactivity was unevenly distributed among the laminae of the spinal grey matter. The small neurons in superficial dorsal horn (laminae I-III) were sparsely and weakly labelled, while large neurons in ventral horn were frequently and densely labelled. Groups of motoneurons in lamina IX that were immunoreactive to choline acetyltransferase also co-expressed Ca(V)1.3. The immunoreactivity was mainly associated with neuronal somata and proximal dendrites. Double staining with antibodies against Ca(V)1.3 and MAP2 (a dendritic marker) showed that some fine fibres, which may include distal dendrites, were also labelled. These results in the cat spinal cord show some differences from studies in mouse and turtle motoneurons where the immunoreactivity against this channel was mainly localized to the dendrites.

Production of Dopamine by Aromatic l-Amino Acid Decarboxylase Cells after Spinal Cord Injury.

Aromatic l-amino acid decarboxylase (AADC) cells are widely distributed in the spinal cord, and their functions are largely unknown. We have previously found that AADC cells in the spinal cord could increase their ability to produce serotonin (5-hydroxytryptamine) from 5-hydroxytryptophan after spinal cord injury (SCI). Because AADC is a common enzyme catalyzing 5-hydroxytryptophan to serotonin and l-3,4-dihydroxyphenylalanine (l-dopa) to dopamine (DA), it seems likely that the ability of AADC cells using l-dopa to synthesize DA is also increased. To prove whether or not this is the case, a similar rat sacral SCI model and a similar experimental paradigm were adopted as that which we had used previously. In the chronic SCI rats (> 45 days), no AADC cells expressed DA if there was no exogenous l-dopa application. However, following administration of a peripheral AADC inhibitor (carbidopa) with or without a monoamine oxidase inhibitor (pargyline) co-application, systemic administration of l-dopa resulted in ∼94% of AADC cells becoming DA-immunopositive in the spinal cord below the lesion, whereas in normal or sham-operated rats none or very few of AADC cells became DA-immunopositive with the same treatment. Using tail electromyography, spontaneous tail muscle activity was increased nearly fivefold over the baseline level. When pretreated with a central AADC inhibitor (NSD-1015), further application of l-dopa failed to increase the motoneuron activity although the expression of DA in the AADC cells was not completely inhibited. These findings demonstrate that AADC cells in the spinal cord below the lesion gain the ability to produce DA from its precursor in response to SCI. This ability also enables the AADC cells to produce 5-HT and trace amines, and likely contributes to the development of hyperexcitability. These results might also be implicated for revealing the pathological mechanisms underlying l-dopa-induced dyskinesia in Parkinson's disease.

Modulation of spontaneous locomotor and respiratory drives to hindlimb motoneurons temporally related to sympathetic drives as revealed by Mayer waves.

In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in relation to periodic variations in blood pressure (Mayer waves). Seven decerebrate cats, under neuromuscular blockade, were used to study central respiratory drive potentials (CRDPs, usually enhanced by added CO2) and spontaneously occurring locomotor drive potentials (LDPs) in hindlimb motoneurons, together with hindlimb and phrenic nerve discharges. In four of the cats both drives and their voltage-dependent amplification were absent or modest, but in the other three, one or other of these drives was common and the voltage-dependent amplification was frequently strong. Moreover, in these three cats the blood pressure showed marked periodic variation (Mayer waves), with a slow rate (periods 9-104 s, mean 39 ± 17 SD). Profound modulation, synchronized with the Mayer waves was seen in the occurrence and/or in the amplification of the CRDPs or LDPs. In one animal, where CRDPs were present in most cells and the amplification was strong, the CRDP consistently triggered sustained plateaux at one phase of the Mayer wave cycle. In the other two animals, LDPs were common, and the occurrence of the locomotor drive was gated by the Mayer wave cycle, sometimes in alternation with the respiratory drive. Other interactions between the two drives involved respiration providing leading events, including co-activation of flexors and extensors during post-inspiration or a locomotor drive gated or sometimes entrained by respiration. We conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated.

Key mechanisms for setting the input-output gain across the motoneuron pool.

This chapter summarizes a number of factors that control the "input-output" function across the motoneurons (MNs) comprising a single spinal motor nucleus. The main focus is on intrinsic properties of individual MNs that can be controlled by neuromodulators. These include: (1) amplification of the synaptic input at the cell's dendritic level by voltage-gated, persistent inward currents (plateau potentials); and (2) transduction of the net synaptic excitation into a frequency code (the MN's stimulus current-spike frequency relation) at the cell's soma/initial segment. Two other aspects of the synaptic control of MNs, which may affect their input-output gain, are also discussed. They include the hypotheses that: (1) a non-uniform distribution of synaptic effects to low- and high-threshold motor units causes a change in recruitment gain; and (2) recurrent inhibition, via motor axon collaterals and Renshaw cells, functions as a variable gain regulator of MN discharge.

Changes in neuronal properties and spinal reflexes during development of spasticity following spinal cord lesions and stroke: studies in animal models and patients.

It is a well-known fact that spinal reflexes may gradually change and often become enhanced following spinal cord lesions. Although these phenomena are known, the underlying mechanisms are still unknown and under investigation, mainly in animal models. Over the last twenty years, new methods have been developed that can reliably estimate the activity of specific spinal pathways in humans at rest and during voluntary movement. These methods now make it possible to describe components of the spinal pathophysiology in spasticity in humans following spinal lesions or stroke. We now know that spinal networks are capable of generating the basic pattern of locomotion in a large number of vertebrates, including the monkey--and in all likelihood, humans. Although spinal networks are capable of generating locomotor-like activity in the absence of afferent signals, functional gait is not possible without sensory feedback. The results of animal studies on the sensory control of and the transmitter systems involved in the spinal locomotor centers are now being used to improve rehabilitation of walking in persons with spinal cord injury and hemiplegia.