Descending Monosynaptic and Reflex Control of γ-Motoneurones

The supraspinal and reflex control of γ-motoneurones has been studied with intra- and extracellular recording from lumbosacral γ-motoneurones in the cat. Monosynaptic EPSPs were recorded in some γ-motoneurones on stimulation of the brain stem. These effects were evoked from the Deiters' nucleus and from fibres descending in the medial longitudinal fascicle probably originating in the pontine reticular formation. Previous investigations have revealed monosynaptic connections to α-motoneurones from these regions and our results suggest parallel effects to α- and part of the γ-motoneurone population supplying one muscle. Indirect evidence suggests that this monosynaptic effect is exerted only on static γ-motoneurones, thus implying a linkage between the descending monosynaptic control of α- and static γ-motoneurones via these pathways. The reflex effects to γ-motoneurones have been studied with graded electrical stimulation of ipsi- and contralateral hindlimb nerves. Five γ-motoneurones, presumably all belonging to extensor motor nuclei, were found to receive IPSPs from group I afferents and it is suggested that only static γ-motoneurones are influenced. It has not been possible to decide if these IPSPs are evoked from Ib or Ia afferents. The reflex effects from group II and III muscular afferents, joint and cutaneous afferents seem to conform to the effects evoked in α-motoneurones from these afferents.     

Facilitation from Contralateral Primary Afferents of Interneuronal Transmission in the la Inhibitory Pathway to Motoneurones

The action of volleys in contralateral primary afferents on transmission in the la inhibitory pathways to motoneurones was investigated with intracellular recording from motoneurones. Ia IPSPs in flexor as well as most extensor motoneurones were regularly facilitated by volleys in contralateral high threshold muscle, cutaneous and joint afferents in spinal cats under chloralose anaesthesia. In decerebrate cats with a low pontine lesion transmission in la inhibitory pathways was not facilitated but rather depressed by volleys in these afferents. The recurrent effects from motor axon collaterals were investigated on inhibitory transmission from different contralateral afferents to motoneurones. Previous investigations have shown that the interneurones mediating the reciprocal la inhibition receive recurrent inhibition via motor axon collaterals and Renshaw cells. Now a strong positive correlation was revealed between recurrent depression of IPSPs evoked from different contralateral afferents and facilitation of la IPSPs by the same afferent volleys. These results suggest that the recurrent depression of IPSPs from different contralateral primary afferents depends on their excitatory convergence onto the la inhibitory interneurones, which then partly mediate the IPSP evoked in the motoneurone from these afferents.     

Convergence on Interneurones Mediating the Reciprocal Ia Inhibition of Motoneurones

Interneurones identified as mediating the disynaptic reciprocal Ia inhibition of motoneurones (referred to as “Ia inhibitory interneurones”) were recorded in the lumbar spinal cord of the cat. Volleys in ipsilateral and contralateral high threshold muscle afferents, cutaneous afferents and high threshold joint afferents evoked a mixture of polysynaptic excitation and inhibition. These effects were ascribed to pathways activated by flexor reflex afferents (FRA) and in addition a specific ipsilateral low threshold cutaneous pathway. Ia inhibitory interneurones excited monosynaptically from flexor nerves received stronger net excitation by volleys in ipsilateral FRA than did extensor coupled interneurones, while the opposite pattern was seen from the contralateral FRA. These patterns are similar to those found in flexor and extensor motoneurones respectively. The FRA inhibition in Ia inhibitory interneurones was partly mediated by “opposite” Ia inhibitory interneurones, i.e. those which are mediating the Ia inhibition of la inhibitory interneurones. The extent to which the FRA inhibition is transmitted by Ia inhibitory interneurones was roughly estimated by its susceptibility to recurrent depression by antidromic ventral root stimulation. The main conclusion is that most segmental pathways seem to evoke their effects in parallel to motoneurones and Ia inhibitory interneurones which are monosynaptically linked to the same muscle. The functional importance of this conclusion is discussed in a following report.     

Recurrent Inhibition of Wrist Extensor Motoneurones: A Single Unit Study on a Deafferented Patient

In order to document the effects of recurrent inhibition on the firing times of human α-motoneurones during natural motor behaviour, a case study was performed on a deafferented patient. The fact that this subject had completely lost the large-diameter sensory afferents provided us with a unique opportunity of selectively stimulating the motor axons in the nerves. The tonic activity of single motor units (   n = 21  ) was recorded in the extensor carpi radialis muscles while applying randomly timed antidromic electrical stimuli to the radial nerve. The peristimulus time histogram analysis showed the presence of biphasic inhibitory effects, including an early, short-lasting component followed by a longer-lasting component occurring 20–40 ms later. The interspike interval (ISI) during which the stimulation occurred was generally lengthened as compared to the previous ISIs. The stimulation was most effective when delivered early (20–30 ms) after a spike. It was also effective, although less so, when delivered at the end of the ISI (70–100 ms after a spike). The lengthening effect sometimes extended over one or two of the subsequent ISIs. The lengthening effect of the motor axon stimulation was followed by an excitatory-like effect, which took the form of a shortening that affected up to five ISIs after the stimulation. The biphasic inhibitory effects and the subsequent facilitatory effects are discussed in terms of the dual nature of the synaptic processes involved in the recurrent inhibitory network, the postactivation facilitation/depression processes and the mutual inhibition occurring between Renshaw cells.     

Monosynaptic activation of a direct reticulo-spinal pathway by the dentate nucleus

Experiments were performed to test the hypothesis that the output of the dentate nucleus can affect the excitability of spinal neurons via the reticular formation. In the first group of studies, the response of neurons in the medial reticular formation to stimulation of the dentate nucleus was investigated. In the second set of experiments, stimuli were applied in the same region of the medial reticular formation in order to determine whether neurons in the dentate nucleus could be antidromically activated from this part of the brainstem. The results indicate that the output from the dentate nucleus monosynaptically activates medial reticular neurons which project to the spinal cord. This finding, together with the observation that stimulation of the medial reticular formation can antidromically activate neurons in the dentate nucleus, demonstrates that there is an anatomical substrate by which the dentate nucleus can affect the excitability of spinal neurons via a rapidly conducting reticulospinal pathway.     

Evidence for the Nitric Oxide Pathway as a Potential Mode of Action in Fenoldopam-induced Vascular Injury

Fenoldopam, a dopaminergic DA1 agonist, induces vasodilatation via nitric oxide (NO), and this may be associated with mesenteric arterial injury. NO is produced from the enzymatic action of nitric oxide synthase (NOS), which is regulated by the shear-stress mediating protein caveolin-1. Profound vasodilatation and accompanied decreased shear are early events that could initiate vascular injury. Therefore, it is of interest to determine the role of caveolin-1 and the NO pathway in fenoldopam-induced vascular injury. At sites of fenoldopam-induced mesenteric arterial injury, decreased caveolin-1 expression and apoptosis were prominent immunohistochemical findings. An additional finding at these sites of injury were loss and/or reduced expression of caveolin-1 regulated structural proteins, connexin-43, (gap junction) ZO-1, and claudin (tight junctions). Because functional loss of caveolin-1 is associated with increased NOS activity and vasodilatation via NO, studies were conducted to show a NO donor produced vascular lesions in the mesenteric arteries morphologically similar to those induced by fenoldopam. Moreover, the incidence and severity of fenoldopam-induced vascular injury were reduced when an NOS inhibitor or a scavenger of NO-generated free radicals were coadministered with fenoldopam. Collectively, these data suggest that caveolin-1 and its regulated NO pathway may play an important role in vasodilatory drug-induced vascular injury.     

The Muscular Branching Patterns of the Ulnar Nerve to the Flexor Carpi Ulnaris and Flexor Digitorum Profundus Muscles

The branching pattern of the ulnar nerve in the forearm is of great importance in anterior transposition of the ulnar nerve for decompression after neuropathy of cubital tunnel syndrom and malformations resulting from distal end fractures of the humerus. In this study, 37 formalin-fixed forearms were used to demonstrate the muscular branching patterns from the main ulnar nerve to the flexor carpi ulnaris muscle (FCU) and ulnar part of the flexor digitorum profundus muscle (FDP). Eight branching patterns were found and classified into four groups according to the number of the muscular branches leaving the main ulnar nerve. Two (Group I) and three (Group II) branches left the main ulnar nerve in 18 and 17 forearms respectively. The remaining two specimens had four (Group III) and five (Group IV) branches each. Usually one or two branches were associated with the innervation of the FCU. However, in 2 cases, three and in one, four branches to FCU were observed. The FDP received a single branch in all cases, except in four, all of which had two branches. In six forearms, a common trunk was observed arising from the ulnar nerve to supply the FCU and FDP. The distribution of the muscular branches to the revealed muscles was outlined in figures and the distance of the origin of these branches from the interepicondylar line was measured in millimeters. The first muscular branch leaving the main ulnar nerve was the FCU-branch in all specimens. The terminal muscular branch of the ulnar nerve to the forearm muscles arose at the proximal 1/3 of the forearm in all specimens. In 7 forearms, Martin-Gruber anastomosis in form of median to ulnar was observed.     

Convergence in the Reciprocal la Inhibitory Pathway of Excitation from Descending Pathways and Inhibition from Motor Axon Collaterals

With intracellular recording from motoneurones and utilizing the technique of spatial facilitation it has been investigated if those la inhibitory interneurones which receive excitation from supraspinal centres also can be inhibited from recurrent motor axon collaterals. For each motoneurone the stimulation strengths were chosen so that separate stimulation of either the supraspinal system or la afferents did not evoke any 1PSP while a combined stimulation at suitable intervals gave a large IPSP. When preceded by stimulation of ventral roots this test IPSP was abolished or decreased. This was found in about 100 motoneurones belonging to different hindlimb muscles in which an IPSP appeared after facilitation from vestibulo-, rubro-or cortico-spinal tracts. It is thus concluded that a convergence of supraspinal excitation and recurrent inhibition occurs on the same la inhibitory interneurones.     

Descending projections of hypothalamic neurons with sympathetic nerve-related activity

1. Spike-triggered averaging was used to identify 104 hypothalamic (HYP) neurons whose spontaneous or L-glutamate-induced action potentials were synchronized to inferior cardiac postganglionic-sympathetic nerve discharge (SND) in 39 pentobarbital sodium-anesthetized cats. Neurons were located primarily in the lateral hypothalamus but also in the posterior, dorsal, ventromedial, and anterior hypothalamus, as well as in the paraventricular region. Most neurons tested (41/60) were classified as sympathoexcitatory (SE) because their firing rate decreased during baroreceptor reflex activation. Because the firing rate of 15 neurons increased during the pressor response produced by aortic obstruction, they were classified as sympathoinhibitory (SI). The firing rate of the other four neurons tested was unaffected by baroreceptor reflex activation. 2. Microstimulation of the medullary lateral tegmental field (LTF; stereotaxic plane P10.5-P12, 2.3-3 mm lateral to the midline) antidromically activated 11 of 58 HYP neurons with sympathetic nerve-related activity, including seven SE neurons and one SI neuron. Antidromic mapping was used to trace the axonal trajectories of HYP neurons that were activated by LTF microstimulation. The results of these experiments suggested that the axons of eight of these neurons branched or terminated in the LTF. The data obtained from another series of experiments were consistent with the view that these HYP neurons excited LTF-SE neurons. LTF-SE neurons were synaptically activated by electrical stimulation of the posterior or lateral hypothalamus. This stimulus also increased SND. The modal onset latency (36 +/- 7.2 ms, mean +/- SE) of synaptic activation of LTF-SE neurons was similar to the onset latency (38 +/- 6.8 ms) of antidromic activation of HYP neurons by LTF microstimulation. These data support the view that LTF-SE neurons are involved in mediating HYP influences on SND. 3. Rostral ventrolateral medullary (RVLM)-SE neurons, including those whose axons projected to the thoracic intermediolateral nucleus (IML), also appear to be involved in mediating HYP-stimulus-induced increases in SND. HYP stimulation synaptically activated these neurons with a modal onset latency of 36 +/- 9.6 ms. Microstimulation of the region containing RVLM-SE neurons antidromically activated 16 of 60 HYP neurons with sympathetic nerve-related activity. The nine neurons tested were classified as SE. antidromic mapping revealed that RVLM microstimulation activated the main axon rather than an axonal branch or terminal of 9 of 12 of these HYP neurons. 4. Microstimulation of the mesencephalic periaqueductal gray (PAG) at stereotaxic planes A2-A3.5 antidromically activated 30 of 61 HYP neurons with sympathetic nerve-related activity, including 13 SE neurons and three SI neurons.(ABSTRACT TRUNCATED AT 400 WORDS)     

Convergence on Interneurones Mediating the Reciprocal Ia Inhibition of Motoneurones III. Effects from supraspinal pathways

Supraspinal effects were investigated in interneurones identified as mediating the disynaptic reciprocal Ia inhibition of motoneurones (referred to as “Ia inhibitory interneurones”). It was revealed that volleys in the vestibulospinal tract may evoke mono- and disynaptic EPSPs in interneurones monosynaptically excited from extensor muscles, i.e. extensor coupled Ia inhibitory interneurones. Flexor coupled interneurones instead received disynaptic inhibition. Volleys in the rubrospinal tract evoked a dominating polysynaptic excitation, usually mixed with inhibition, in flexor as well as extensor coupled interneurones. Disynaptic rubrospinal EPSPs and IPSPs were also revealed. The pyramidal tract also gives rise to a dominating polysynaptic excitation, usually mixed with inhibition, in flexor as well as extensor coupled Ia inhibitory interneurones. Rubrospinal and pyramidal volleys were shown to facilitate transmission in various segmental reflex pathways to the Ia inhibitory interneurones. A detailed comparison reveals a striking parallelism of segmental and supraspinal effects on α-motoneurones and Ia inhibitory interneurones connected to the same muscles. This considerably strengthens the hypothesis of an “α–γ-linkage in the reciprocal inhibition”.     

The Cellular Biology of Flexor Tendon Adhesion Formation : An Old Problem in a New Paradigm

Intrasynovial flexor tendon injuries of the hand can frequently be complicated by tendon adhesions to the surrounding sheath, limiting finger function. We have developed a new tendon injury model in the mouse to investigate the three-dimensional cellular biology of intrasynovial flexor tendon healing and adhesion formation. We investigated the cell biology using markers for inflammation, proliferation, collagen synthesis, apoptosis, and vascularization/myofibroblasts. Quantitative immunohistochemical image analysis and three-dimensional reconstruction with cell mapping was performed on labeled serial sections. Flexor tendon adhesions were also assessed 21 days after wounding using transmission electron microscopy to examine the cell phenotypes in the wound. When the tendon has been immobilized, the mouse can form tendon adhesions in the flexor tendon sheath. The cell biology of tendon healing follows the classic wound healing response of inflammation, proliferation, synthesis, and apoptosis, but the greater activity occurs in the surrounding tissue. Cells that have multiple “fibripositors” and cells with cytoplasmic protrusions that contain multiple large and small diameter fibrils can be found in the wound during collagen synthesis. In conclusion, adhesion formation occurs due to scarring between two damaged surfaces. The mouse model for flexor tendon injury represents a new platform to study adhesion formation that is genetically tractable.The clinical problem of flexor tendon injuries can be complicated when healing results in adhesions forming between the tendon and the surrounding synovial sheath. Although difficult to predict following surgical repair, adhesions have long been accepted as a cause of restricted tendon movement. Recent clinical studies on 315 primary flexor tendon repairs reported that approximately 28% of flexor tendon repairs had a fair to poor functional recovery, likely to be attributable to adhesion formation.¹ The area where this is most problematic is known as “no man’s land,”² or zone II,³ where two tendons glide within a flexor tendon sheath in the fingers. The formation of adhesions leads to impairment of digit flexion through inhibiting normal tendon gliding. In an attempt to understand the pathophysiology of flexor tendon adhesions, a number of tendon healing concepts have been derived.The concepts surrounding our current understanding of flexor tendon healing have remained unchallenged for several decades. In 1963, Potenza had hypothesized that adhesion formation was a requirement for blood vessel in-growth into the tendon.⁴ This hypothesis supported the concept of extrinsic healing of tendon from the surrounding tissue. Matthews and Richards⁵ showed that flexor tendon healing could occur in the absence of adhesions and attributed this to certain cell populations within tendon. This concept of healing, later termed intrinsic healing, was attributed to the activity of cells within the tendon. These observations were supported by a series of histological, in vitro, and ultrastructural studies. Injured intrasynovial tendon was shown to heal independently of adhesions in a synovial environment,⁶ when explanted to culture⁷ and when transplanted to different body sites in diffusion chambers.⁸ It has been the concepts of intrinsic and extrinsic healing that have guided strategies to improve flexor tendon repair outcomes over the years. In the context of modern understanding of wound healing, these concepts of tendon healing are outdated and require revisiting. Many in vivo studies use mice as a reference model for studying mammalian systemic responses such as wound healing.⁹ The benefits of such a system include low maintenance, rapid and easy breeding programs, and genetic versatility.¹⁰ We have previously described the mouse hind paw anatomy and identified numerous similarities it has to the human hand.¹¹ Furthermore, we have shown that the mouse digit can be used as a model for studying tendon injury through using a single grasping suture technique.¹² Adhesion formation has been demonstrated in allograft and autograft studies in a murine flexor tendon model.¹³ The demonstration of intrasynovial flexor tendon adhesion formation in the clinically important “no man’s land” of the digit has yet to be shown in a mouse model.The development of an adhesion model would enable the quantification of adhesion formation and would also benefit the analysis of the cellular processes involved. The model may be used in developing strategies aimed at preventing adhesion formation.Many studies have investigated independently the processes involved in flexor tendon healing, including inflammation,¹⁴ proliferation,¹⁵ collagen synthesis,¹⁶ vascularization,¹⁷ and apoptosis.¹⁸ We have attempted to observe all these aspects of the tendon healing response to give a detailed overview of the healing process.This study aimed to give a broad understanding of the process of adhesion formation, using three-dimensional (3D) cellular mapping to investigate the interplay of cellular repair.     

Fluid Dynamic Analysis in a Human Left Anterior Descending Coronary Artery with Arterial Motion

A computational fluid dynamic (CFD) analysis is presented to describe local flow dynamics in both 3-D spatial and 4-D spatial and temporal domains from reconstructions of intravascular ultrasound (IVUS) and bi-plane angiographic fusion images. A left anterior descending (LAD) coronary artery segment geometry was accurately reconstructed and subsequently its motion was incorporated into the CFD model. The results indicate that the incorporation of motion had appreciable effects on blood flow patterns. The velocity profiles in the region of a stenosis and the circumferential distribution of the axial wall shear stress (WSS) patterns in the vessel are altered with the wall motion introduced in the simulation. The time-averaged axial WSS between simulations of steady flow and unsteady flow without arterial motion were comparable (–0.3 to 13.7 Pa in unsteady flow versus –0.2 to 10.1 Pa in steady flow) while the magnitudes decreased when motion was introduced (0.3–4.5 Pa). The arterial wall motion affects the time-mean WSS and the oscillatory shear index in the coronary vessel fluid dynamics and may provide more realistic predictions on the progression of atherosclerotic disease.     

Descending rhythmic pneumocompression as a medical treatment of atherosclerosis obliterans

About 2 percent of the population of the world suffers from atherosclerotic lesion of the lower extremity arteries. However, the treatment of this pathology is an unsolved problem so far. The authors used a method of rhythmic pneumocompression for medical treatment of patients with chronic arterial insufficiency due to lower extremity vascular atherosclerosis obliterans. A total of 56 patients with stages II-III atherosclerotic lesion were examined. The findings indicated that the method noticeably reduced the intensity of the pain syndrome and tissue ischemia. The procedure exerted a reflex action on the cardiovascular system: the patients had slower heart rate and lowered blood pressure.     

Monosynaptic connexions of low threshold muscle afferents with hindlimb motoneurones in the turtle spinal cord

Summary Excitatory postsynaptic potentials (EPSPs) were recorded intracellularly from hindlimb motoneurones of the anaesthetized fresh water turtle. The EPSPs were evoked from low threshold muscle afferents and the amplitudes saturated for stimuli less than two times the nerve threshold. The segmental latencies of these EPSPs, measured from the initial positive peak of the triphasic cord dorsum potential to the onset of the EPSP, ranged from 1.5 to 3.1 ms. The intraspinal conduction time of afferents was estimated by recording afferent volleys in the grey matter along the vertical course of intraspinal afferent fibres. The synaptic delay was estimated by subtracting the latency of the afferent volley at the deepest region of the dorsal horn from the segmental latency of the EPSP (in the range from 1.6 to 2.1 ms) recorded in the same microelectrode track. The average value was 0.99 ms (range: 0.9–1.1 ms), which was close to the known synaptic delay of cold-blooded animals. Therefore, the EPSPs in this range of segmental latencies were regarded as monosynaptic. Taking account of the intraspinal afferent conduction time (0.8 ms on average) and another synaptic delay, the latency for disynaptic transmission would be 2.8 ms or more. Thus, EPSPs having segmental latencies of 1.5–3.1 ms were suggested to be almost all monosynaptic in nature, at least under the present conditions of deep anaesthesia. On the basis of the above criteria for the monosynaptic nature of EPSPs, the pattern of convergence of monosynaptic excitatory inputs from various muscle afferents was investigated. Monosynaptic EPSPs were induced from the homonymous muscle nerve and the nerve innervating the synergist at the same joint. The heteronymous EPSPs were also found between muscles within each group of the anterodorsal musculature and the posteroventral musculature. No monosynaptic connexions were found between anterodorsal and posteroventral muscles except between the muscles innervated by the peroneal and the tibial nerve.