Effects of intrathecal triamincinolone-acetonide treatment in MS patients with therapy-resistant spasticity.

OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease affecting young people and is a major cause of disability. In the course of time, disability progresses and symptoms like spasticity may occur. Spasticity is a major cost factor in MS patients. Various agents are approved for the treatment of spasticity, but each of those agents may have several side effects. Intrathecally administered steroids (triamcinolone-acetonide (TCA)) may be efficient in treating spasticity in patients with lesions in the spinal cord and no response to first-line therapeutics. The aim of this study is to show effects of TCA treatment on clinical parameters in patients with MS. METHODS: This multicentre open label study included 54 patients with MS. The clinical outcome parameters were spasticity, disability, maximum walking distance, bladder function and quality of life. All patients received physiotherapy in addition to TCA treatment to obtain optimal effects on clinical parameters. RESULTS: Spasticity, maximum walking distance as well as disability improved significantly (P ⩽ 0.001) during TCA applications. Bladder function improved in every seventh patient. CONCLUSION: We observed the effects of intrathecally administered TCA on different clinical parameters including bladder function. TCA administration is a safe method to treat different symptoms in MS patients. Longitudinal trials with repeated TCA cycles are needed to show long-term effects. Besides TCA treatment, physiotherapy contributes to the improvement of clinical parameters.

Supercontinuum generation with a chirped-pulse oscillator.

We demonstrate the generation of a high power ultrabroadband supercontinuum by coupling the uncompressed pulses from a Ti:Sapphire Chirped-pulse oscillator into a photonic crystal fibre that exhibits a highly anomalous dispersion at the centre wavelength of the laser. Our simulations show that the pulses first undergo quasi-linear compression before the actual supercontinuum is generated by soliton fission dynamics. This two-step process results in an optical spectrum that is remarkably independent on the input pulse energy. Moreover, the reduced peak intensity at the input facet of the fibre mitigates damage problems and allows the generation of high power white-light radiation.

Morphology, number, and distribution of putative GABA-ergic neurons in the basilar pontine gray of the monkey.

We used an antibody raised against the inhibitory transmitter gamma-aminobutyric acid (GABA) in the basilar pontine gray (bpg) of the monkey. Somata, dendrites, and a plexus of probably axonal fibers exhibited GABA-like immunoreactivity. Labeled neurons were small with oval, triangular, or circular soma shape. They gave rise to 2 to 4 dendrites with little branching. No axons were seen issuing from the soma. Occasionally, appendages consisting of spheroidal bodies positioned at the distal end of tenuous stalks and (in 1 cell) axonlike processes were observed to originate from dendrites. According to their morphology, we suggest that these putative GABA-ergic neurons may correspond to the type II neurons observed in Golgi material. The average number of putative GABA-ergic cells in 40-micron sections was about 30/mm2. When compared with Nissl-stained sections, these amounted to about 5% of all cells. There was no substantial variation in average density in different parts of the bpg. However, labeled cells tended to lie in clusters, perhaps related to the well-established input-output compartments of the bpg. The demonstration of a significant population of putative inhibitory neurons challenges the traditional view of the bpg, which suggests that this brainstem cell group functions as a simple relay exchanging signals between cortex and cerebellum.

Morphology and mosaics of VIP-like immunoreactive neurons in the retina of the rhesus monkey.

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has been demonstrated to reside in cells ( = VIP+ cells) of the retinae of various vertebrate species. In an attempt to study the morphology and distribution of VIP+ cells in the retina of the rhesus monkey in more detail, we subjected VIP+ cells observed in cryostat sections or wholemounts rhesus monkey retinae to a quantitative analysis. VIP+ cells were found to reside in the innermost row of the inner nuclear layer (INL) and in the ganglion cell layer (GCL) in similar numbers (estimate: 50 cells/mm2 at 6-10 mm eccentricity each) and only on rare occasions (12% of all VIP+ cells) in varying positions within the inner plexiform layer (IPL). Somata of VIP+ cells were circular and had a mean diameter of 9.1 microns. They gave rise to 1-3 main dendrites, which were usually oriented toward the IPL. Main dendrites ramified widely into thin fibers (dendritic field diameter less than = 1 mm), carrying varicose swellings. The fibers that contributed to one and the same plexus of VIP+ fibers preferred the middle third of the IPL, independent of the positions of the parent somata. A quantitative analysis of nearest-neighbour distances in the retinal wholemount preparation suggested that VIP+ cells in the GCL and in the INL might be distributed according to 2 independent mosaics. A comparison with Golgi-stained material leads to the tentative equation of VIP+ cells with the "spiny" A12 amacrine cell of Mariani ('90). Whereas the low density and large dendritic field size of VIP+ cells might suggest a more widespread function, the varicose dendritic morphology seems to be more compatible with functionally independent dendritic subunits mediating localized effects.

Amplitude reduction of motor unit twitches during repetitive activation is accompanied by relative increase of hyperpolarizing membrane potential trajectories in homonymous alpha-motoneurons.

In anaesthetized cats, medial gastrocnemius motor units (MUs) were electrically stimulated via their ventral-root axons with independent random patterns. Isometric muscle tension and homonymous alpha-motoneuron (MN) membrane-potential fluctuations in response to these stimuli were recorded simultaneously, usually for periods of about 2 min. The tension and membrane potential were averaged with respect to a stimulus train over two disjoint time intervals, one stretching 20-40 s at record beginning, and the other a similar duration at the end of recording. Whereas average MU twitch amplitudes usually decreased between these periods, average membrane potential trajectories did not do so, such that, when normalized to the change in twitch amplitude, the membrane potential trajectories usually increased in size. This suggests that the decline in the mechanical effect of MU activation was accompanied by an increase in the gain of the afferent pathway to homonymous MNs, which was confirmed by gain computations in the frequency domain. This compensation could be a mechanism to maintain the high quality of information about MU contractions transmitted to MNs in the course of MU fatigue.

Linear and non-linear summation of alpha-motoneuron potential changes elicited by contractions of homonymous motor units in cat medial gastrocnemius.

An analysis is made of linear and non-linear summation of the motor unit (MU) tension and motoneuron (MN) membrane potential (PSP) trajectories evoked by stimulation of MUs as previously reported. In most cases, summation of both averaged responses was linear. Seldom, PSPs summed non-linearly, then usually coinciding with non-linear summation of the responsible MU twitches. The results suggest that the afferent pathways mediating the mechanical events in muscle to MNs behave rather linearly, at least in the small-signal range of interest here.

Contractions of single motor units are reflected in membrane potential changes of homonymous alpha-motoneurons.

In anesthetized cats 3 medial gastrocnemius (MG) motor units (MUs) were electrically activated with independent pseudorandom patterns at physiological mean rates. Recordings of isometric MG tension (T) and membrane potential changes (PSPs) in MG alpha-motoneurons (MNs) were averaged with respect to each stimulus train. The resulting T and PSP trajectories displayed the responses of each MN to the 3 average MU twitches. These responses could vary from no response to a sequence of depolarizing and hyperpolarizing waves in a PSP trajectory. The results are consistent with the known behavior of muscle stretch receptors to muscle and MU twitches and the receptors' connections to homonymous MNs.

Stimulus-related correlations between medial gastrocnemius muscle tension and homonymous motoneuron membrane potential result from non-linearities.

In anesthetized cats, medial gastrocnemius motor units (MUs) were electrically stimulated via their ventral-root axons with independent random patterns. Muscle tension and homonymous alpha-motoneuron (alpha-MN) membrane potential fluctuations in response to these stimuli were recorded simultaneously. Cross-correlating these two signals in temporal relation to the stimuli showed the covariance of the two signals around their respective means. With moderate to strong MU-MN couplings indicated by clear and large average membrane potential changes (PSP trajectories), the correlation coefficients tended to be positive at times when the PSP hyperpolarized, and vice versa. These relations are probably caused by the non-linear behavior of MUs, muscle receptors and afferent pathways. Thus, the signal transfer from motor efferents back to homonymous alpha-MNs depended upon the level of background tension, upon which MU twitches were superimposed.

Diverging influences on Renshaw cell responses and monosynaptic reflexes from stimulation of capsula interna.

In anaesthetized cats responses of lumbar Renshaw cells to anti- and orthodromic spinal root and muscle nerve shocks were recorded with and without conditioning stimulation of the contralateral capsula interna. Responses to antidromic test stimuli were decreased by supraspinal conditioning in 48 of 65 cases over their whole course and over a range up to 60 ms after the conditioning stimulation. The corresponding monosynaptic reflexes, however, were facilitated up to 250% under these conditions. Reduction of orthodromic responses was apparent in 12 of 44 cases, but might have been masked in others due to concomitant motoneurone facilitation. These results indicate divergent descending influences on motoneurones and related Renshaw cells, mediated via the capsula interna.

Effects of repeated intrathecal triamcinolone-acetonide application on cerebrospinal fluid biomarkers of axonal damage and glial activity in multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS). GCS may have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration. METHODS: In order to assess neurotoxic effects of TCA, neurofilament heavy-chain (NfH)(SMI35), tau protein, and S-100B protein levels were determined before and during treatment with TCA in 54 patients with primary progressive MS, as well as relapsing MS (relapsing-remitting and secondary progressive MS). RESULTS: NfH(SMI35) levels in the CSF of patients treated with TCA intrathecally did not increase significantly during the treatment cycle (p = 0.068). After application of TCA, tau protein levels were increased significantly at day 4 (p = 0.03) and at day 8 (p ≤ 0.001). S-100B protein levels decreased significantly (p ≤ 0.05) during treatment with TCA. CONCLUSION: NfH(SMI35) levels did not change significantly; however, tau protein levels did increase significantly within the reference range. Taking these findings together, the long-term effects of TCA on NfH(SMI35) and tau protein levels need to be investigated further to understand whether levels of both biomarkers will change over repeated TCA applications. Interestingly, S-100B protein levels decreased significantly during the first applications, which may have represented reduced astrocytic activity during TCA treatment.

Multi-loop representation of the segmental muscle stretch reflex. Its risk of instability.

The multi-channel system of the segmental muscle stretch reflex arc is modelled as an arrangement of two or three parallel "component" loops coupled to each other at spinal and at muscle level. Such a model is thought to be more realistic than the usually adopted representation of the stretch reflex as a single negative feedback loop. Anatomical and physiological data were taken from the literature for an extensive simulation of the compound system with special reference to the problem of its stability. Particular emphasis was put on the question of which kind of central (spinal) connectivity is appropriate to best reduce the risk for instability which arises easily in certain system configurations. This paper describes the system and presents simple introductory computations apt to demonstrate the problems the physiological system has to cope with.

Implications of the baby bust generation upon the health care market.

Implications of the Baby Boomers upon the American society are well known. However, the effects of its successor generation, the Baby Busters, have not been as well documented nor reviewed. The next twenty years (1990-2010) will see the fabric of American society unfolded and rewoven as this phenomenon undergoes its place in history. It is not too early to examine the implications of the Baby Bust phenomenon. This study examines the implications and consequences of the Baby Bust for Health Care Marketers.

Analysis of bimodal interspike interval histograms of primary muscle spindle endings in active triceps surae muscles of cats.

A feature frequently observed in interspike interval histograms (IH) derived from stationary Ia fibre discharge patterns was a bimodality suggesting a mixed population composed of two sub-populations of possibly different origins. To verify this hypothesis a separation of these subpopulations was attempted by assuming a Gaussian distribution for the longer intervals. The success of such a separation depended on the distinctness of the histogram peaks and the relative sizes of each mode. Both factors in turn depended on the overall muscle length and, hence, on the mean spindle discharge rate. The smaller intervals were then isolated from the spike trains and submitted to further statistical analysis. By averaging overall muscle tension with respect to the smaller intervals, the latter could often be linked to tension trajectories which were of higher amplitude and faster time course than the trajectories obtained by averaging with respect to the rest of the spikes. In some cases, auto-correlation histograms of isolated small intervals as well as serial correlograms computed for all intervals indicated that some muscle spindle afferents responded sensitively to activity of single motor units. This would confirm recent results of Cameron et al. (1980).

Frequency response characteristics of a multi-loop representation of the segmental muscle stretch reflex.

This paper continues the investigation of a three-loop representation of the segmental muscle stretch reflex system introduced in a preceding communication. Frequency response characteristics were computed for open-loop conditions, control and disturbance signal inputs under a variety of conditions: (i) "in parallel" and "in series" peripheral arrangements of muscle compartments, (ii) various patterns of central connectivity, (iii) various recruitment levels of motor units, (iv) various overall reflex gains, (v) absence or presence of muscle spindle acceleration sensitivity. These computations disclose a number of mechanisms by which the nervous system might improve system stability and behaviour. These mechanisms are discussed with regard to physiological data.

Responses of the spinal alpha-motoneurone-Renshaw cell system to various differentially distributed segmental afferent and descending inputs.

A previously presented multi-loop model of the mammalian spinal alpha-motoneurone-Renshaw cell system was extended to incorporate different physiological input patterns: Ia fibres from primary muscle spindle endings, spinal input systems descending in the ventral quadrant and from the nucleus ruber. The main goal of the computer simulation calculations was to present a number of dynamic input-output relations between these inputs which are distributed inhomogeneously to different types of alpha-MNs (that is, S-, FR-, and FF-type MNs) and the outputs of pools of the latter, for the purpose of experimental testing. The main outcome was that the phase relations of the outputs of the different types of MNs depend very much on the overall strength of recurrent inhibition, such that small changes of this strength, which appears to be small anyway, can significantly alter these phase relations. Since this strength is alterable through descending and segmental afferent inputs, this provides a physiological means of phase-decorrelation although it is unlikely to put the discharges of different MN types totally out of phase (by about 180 degrees). Also, the inhomogeneity of recurrent inhibition would help to prevent a strong phase separation of this kind. Yet a decorrelation at the microscopic level could help suppress physiological tremor.

Visual and vestibular signals in the lateral mesencephalic tegmental region of the cat.

Single unit recordings from two alert cats were used in an attempt to further elucidate the function of the lateral mesencephalic tegmental region (LTR), a part of the mesencephalon forming a link between the superior colliculus and the lower brain stem. A total of 155 units recorded from the LTR were tested with visual, vestibular and acoustic stimuli. Of these, 54 cells (36%) were characterized as either visually (n = 33) or vestibularly (n = 21) responsive and an additional 13 cells were driven by complex acoustic stimuli. Visually responsive cells typically were directionally selective with large, mainly contralateral receptive fields. Vestibularly responsive cells were modulated by stimulation of either the horizontal canals (yaw stimulation; n = 16) or of both pairs of vertical canals (pitch stimulation; n = 5). About half of the cells with activity modulated by rotation about the yaw axis increased discharge during ipsiversive (Type I), the other half during contraversive rotation (Type II). Of the 5 cells with activity modulated by pitch stimulation, 4 preferred the nose-down and only 1 the nose-up direction. Although the discharge of units responsive to yaw stimulation was roughly in phase with head velocity (mean phase lag with respect to head velocity: 10.6 deg), none of the vestibular cells had activity correlated with eye position, eye velocity or movement of visual stimuli. Our observations suggest that the LTR might introduce visual and vestibular signals into the tecto- facial pathway which may be used to adjust the size of pinna movements with respect to the size of ongoing head- or body movements.

Event-related cross-correlations between spike trains illustrated on interactions between motor units and muscle spindle afferents.

A method is presented for computing correlation coefficients of two (or more) output spike trains in temporal relation to one (or more) input even trains. These event-related correlation functions are computed by convolving the output spike trains, represented as point processes, with rectangular pulses of selectable width, and by then calculating linear correlation coefficients for the pairs of amplitude values obtained from the two convolved processes in temporal relation to the input events. The merits of this technique are illustrated on stimulus trains delivered to motor units (MUs) and output spike trains recorded from muscle spindle afferents of the same cat hindlimb muscle. The correlation functions obtained show the temporal course of the correlated firings of the two afferents (mostly Ia afferents from primary muscle spindle endings) as a function of time from MU activation; they are compared with the conventional cross-correlation histograms (CCHs) between afferents and with peri-stimulus time histograms (PSTHs) between stimulus and afferent firing patterns. Stimulus-related cross-correlation functions as displayed here can be calculated for any three spike trains. Possible extensions of the method to larger numbers of input and output channels are also discussed.