Jens Schouenborg

Topography and nociceptive receptive fields of climbing fibres projecting to the cerebellar anterior lobe in the cat.

1. The cutaneous receptive fields of 225 climbing fibres projecting to the forelimb area of the C3 zone in the cerebellar anterior lobe were mapped in the pentobarbitone‐anaesthetized cat. Responses in climbing fibres were recorded as complex spikes in Purkinje cells. 2. A detailed topographical organization of the nociceptive climbing fibre input to the C3 zone was found. In the medial C3 zone climbing fibres with receptive fields covering proximal and/or lateral parts of the forelimb projected most medially. Climbing fibres with receptive fields located more medially on the forelimb projected successively more laterally. The sequence of receptive fields found in the lateral C3 zone was roughly the reverse of that in the medial C3 zone. Climbing fibres with receptive fields restricted to the digits projected preferentially to the caudal part of the forelimb area, whereas those with receptive fields covering both proximal and ventral areas of the forearm projected to more rostral parts. 3. The representation of the forelimb was uneven. Receptive fields with a focus on the digits or along the lateral side of the forearm dominated. 4. The proximal borders of the receptive fields were located close to joints. The area from which maximal responses were evoked was usually located eccentrically within the receptive field. Based on spatial characteristics the receptive fields could be divided into eight classes, which in turn were tentatively divided into subclasses. Similar subclasses of receptive fields were found in different cats. This classification was further supported by the results of a quantitative analysis of eighty‐nine climbing fibres. The receptive fields of these climbing fibres were mapped with standardized noxious stimulation. 5. Climbing fibres terminating within sagittal strips (width, 100‐300 microns; length, greater than 1 mm) had receptive fields which belonged to the same subclass. There were commonly abrupt changes in receptive fields between such microzones. Most classes of receptive fields were found in both the medial and the lateral parts of the C3 zone. However, receptive fields with a focus on the ventral side of either the metacarpals, the wrist or the forearm were found only in the medial part of the C3 zone. Furthermore, the class of receptive fields restricted to the lateral side of the upper arm and shoulder was only found in the lateral part of the C3 zone. 6. In the discussion, it is proposed that climbing fibres projecting to each microzone carry information from spinal multireceptive reflex arcs acting on a single muscle or a group of synergistic muscles.(ABSTRACT TRUNCATED AT 400 WORDS)

Spontaneous muscle twitches during sleep guide spinal self-organization.

During development, information about the three-dimensional shape and mechanical properties of the body is laid down in the synaptic connectivity of sensorimotor systems through unknown adaptive mechanisms. In spinal reflex systems, this enables the fast transformation of complex sensory information into adequate correction of movements. Here we use a computer simulation to show that an unsupervised correlation-based learning mechanism, using spontaneous muscle twitches, can account for the functional adaptation of the withdrawal reflex system. We also show that tactile feedback resulting from spontaneous muscle twitches during sleep does indeed modify sensorimotor transformation in young rats in a predictable manner. The results indicate that these twitches, corresponding to human fetal movements, are important in spinal self-organization.

Functional organization of the nociceptive withdrawal reflexes

Summary1. The organization of the nociceptive hind-limb withdrawal reflexes was investigated in 93 halothane/nitrous oxide anesthetized rats. Electromyographical techniques were used to record reflex activity in single motor units. 2. Most of the hindlimb muscles were activated by noxious mechanical stimulation of the skin of the ipsilateral hindlimb. These were the plantar flexors of the digits, the pronators of the paw, the dorsiflexors and the plantar flexors of the ankle, the flexors of the knee, the flexors of the hip and the adductors. By grading the stimulus intensity it was shown that all these muscles received input from cutaneous nociceptors. 3. Noxious stimulation of the skin failed to activate the obturator, knee extensors and m. tibialis posterior and, in most rats tested, m. semimembranosus and m. adductor magnus. The plantar flexors of the ankle, while exhibiting a clear nocireceptive field in all rats tested, had a high threshold and responded much more weakly than the dorsiflexors of the ankle. Thus, responses in muscles which oppose gravity in the standing position were either very weak or absent. 4. The present study shows that each of the activated hindlimb muscles has a highly organized noci-receptive field on the skin, which is related to the withdrawal movement caused by the muscle itself. Each of the muscles normally causes the withdrawal of its receptive field when the foot is on the ground. The skin area most effectively withdrawn, in this situation, corresponds to the most sensitive area of the nocireceptive field. However, with the exception of the plantar flexors of the digits and/or the ankle, each of the hindlimb muscles also withdraws the major parts of their receptive fields when the foot is off the ground. The locations of the noci-receptive fields were independent of the position of the hindlimb. These characteristics of the nociceptive withdrawal reflexes are the basis for their “local sign” (Sherrington 1906). 5. The threshold and the time course of reflex activation were different in different muscles. However, muscles with a similar action; the plantar flexors of the digits, the pronators of the paw, the dorsiflexors of the digits, the flexors of the knee and the adductors, respectively, had similar thresholds and time courses. Furthermore, the threshold and latency of activation of each muscle increased towards the border of its nocireceptive field, reflecting a decreasing sensitivity. These findings explain the progressive recruitment of muscles during increasing strength of noxious stimulation, termed “irradiation” (Sherrington 1906). 6. It is suggested that the nociceptive withdrawal reflexes are organized as separate reflex paths to individual muscles, each of which has a well organized cutaneous nocireceptive field.

The effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n = 34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160-200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115-160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the A beta evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160-200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.

A survey of spinal dorsal horn neurones encoding the spatial organization of withdrawal reflexes in the rat

The withdrawal reflex pathways to hindlimb muscles have an elaborate spatial organization in the rat. In short, the distribution of sensitivity within the cutaneous receptive field of a single muscle has a spatial pattern that is a mirror image of the spatial pattern of the withdrawal of the skin surface ensuing on contraction in the respective muscle. In the present study, a search for neurones encoding the specific spatial input-output relationship of withdrawal reflexes to single muscles was made in the lumbosacral spinal cord in halothane/nitrous oxide-anaesthetized rats. The cutaneous receptive fields of 147 dorsal horn neurones in the L4-5 segments receiving a nociceptive input and a convergent input from A and C fibres from the hindpaw were studied. The spatial pattern of the response amplitude within the receptive fields of 118 neurones was quantitatively compared with those of withdrawal reflexes to single muscles. Response patterns exhibiting a high similarity to those of withdrawal reflexes to single muscles were found in 27 neurones located in the deep dorsal horn. Twenty-six of these belonged to class 2 (responding to tactile and nociceptive input) and one belonged to class 3 (responding only to nociceptive input). None of the neurones tested (n=20) with reflex-like response patterns could be antidromically driven from the upper cervical cord, suggesting that they were spinal interneurones. With some overlap, putative interneurones of the withdrawal reflexes to the plantar flexors of the digits, the plantar flexors of the ankle, the pronators, the dorsiflexors of the ankle, and a flexor of the knee, were found in succession in a mediolateral direction. It is concluded that neurones that are able to encode the specific spatial input-output organization of the withdrawal reflexes to single muscles do exist in the deep dorsal horn. Such reflex encoders appear to have a “musculotopic” organization. A hypothesis of the organization of the withdrawal reflex system is presented.

Cutaneous field stimulation (CFS): a new powerful method to combat itch

Abstract Scratching the skin, while instantly relieving itch, often aggravates itch over time due to skin injury. To relieve itch, without damaging the skin, a new technique termed cutaneous field stimulation (CFS) was developed and tested on 21 subjects. CFS uses a flexible plate with needle‐like electrodes (n=16) to electrically stimulate nerve fibres in the superficial skin. The electrodes were stimulated consecutively (4 Hz per electrode, pulse duration 1 ms, intensity 0.4–0.8 mA, 25 min). CFS resulted in a pricking and burning sensation that usually faded rather quickly. The burning sensation was still present during a selective block of impulse conduction in myelinated fibres indicating that nociceptive C‐fibres are activated by CFS. Furthermore, a flare reaction developed around the CFS electrodes indicating activation of axon reflexes in nociceptive C‐fibres. Itch, elicited by transdermal iontophoresis of histamine, was abolished within the skin area pre‐treated with CFS, and was reduced to 14% of control 10 cm distally. Contralateral effects were small or non‐existent. After 4 h, itch was reduced ipsilaterally to 32% of control. In comparison, 2 h after transcutaneous electrical nerve stimulation (TENS; 10–20 mA, 100 Hz, 25 min) ipsilateral itch was reduced to 56% of control. In conclusion, CFS offers a powerful new method for combating itch. It is suggested that CFS acts through endogenous central inhibitory mechanisms that are normally activated by scratching the skin.

Implant Size and Fixation Mode Strongly Influence Tissue Reactions in the CNS

The function of chronic brain machine interfaces depends on stable electrical contact between neurons and electrodes. A key step in the development of interfaces is therefore to identify implant configurations that minimize adverse long-term tissue reactions. To this end, we here characterized the separate and combined effects of implant size and fixation mode at 6 and 12 weeks post implantation in rat (n = 24) cerebral cortex. Neurons and activated microglia and astrocytes were visualized using NeuN, ED1 and GFAP immunofluorescence microscopy, respectively. The contributions of individual experimental variables to the tissue response were quantified. Implants tethered to the skull caused larger tissue reactions than un-tethered implants. Small diameter (50 µm) implants elicited smaller tissue reactions and resulted in the survival of larger numbers of neurons than did large diameter (200 µm) implants. In addition, tethering resulted in an oval-shaped cavity, with a cross-section area larger than that of the implant itself, and in marked changes in morphology and organization of neurons in the region closest to the tissue interface. Most importantly, for implants that were both large diameter and tethered, glia activation was still ongoing 12 weeks after implantation, as indicated by an increase in GFAP staining between week 6 and 12, while this pattern was not observed for un-tethered, small diameter implants. Our findings therefore clearly indicate that the combined small diameter, un-tethered implants cause the smallest tissue reactions.

Authenticity, depression, and deep brain stimulation

In 2005 the journal Neuron published Mayberg et al.’s (2005) pioneering study on deep brain stimulation (DBS) targeting treatment-refractory major depressive disorder (MDD). Since then a handful of studies, in total encompassing little over 50 patients, have been published (Aouizerate et al., 2005; Jimenez et al., 2005; Mayberg et al., 2005; Kuhn et al., 2007; Lozano et al., 2008; Neimat et al., 2008; Schlaepfer et al., 2008; Malone et al., 2009; Bewernick et al., 2010; Sartorius et al., 2010) and larger trials are underway (Bell et al., 2009). A common ethical concern voiced when DBS is used for a psychiatric disorder such as MDD is that the stimulation specifically targets cognition, mood, and behavior; elements which are closely linked to the patients personality. Obviously, this holds true also for other antidepressants such as psychotherapy and medication. Apart from that these standard therapies have been of no avail for the patients considered for MDD DBS, one could still ask whether their potential to alter cognition, mood, and behavior, differ - with regard to ethical concerns - from that of DBS. Further, the relevant ethical concern is arguably not what functions the stimulation are intended to alter, as in psychiatric indications, but rather what functions that could be altered by DBS. Unintended alterations of cognition, mood and behaviour could occur as a consequence of both psychiatric and motoric DBS. Thus, potential alterations of personality seem, apart from the historical stigma connected with the former, to be relevant for most DBS indications. A lot of work remains to be done before a comprehensive analysis of these concerns could be presented. Our contribution is to introduce one question relevant to the intersection of DBS, MDD, and the notion(s) of authenticity.

Sensorimotor transformation in a spinal motor system

To use sensory information from the skin to guide motor behaviour the central nervous system must transform sensory coordinates into movement coordinates. As yet, the basic principles of this crucial neural computation are unclear. One motor system suitable as a model for the study of such transformations is the spinal withdrawal reflex system. The spatial organization of the cutaneous input to these reflexes has been characterized, and we now introduce a novel method of motion analysis permitting a quantitative analysis of the spatial input-output relationship in this motor system. For each muscle studied, a “mirror-image” relationship was found between the spatial distribution of reflex gain for cutaneous input and the pattern of cutaneous unloading ensuing on contraction. Thus, there is an “imprint” of the movement pattern on this motor system permitting effective sensorimotor transformation. This imprint may indicate the presence of a learning process which utilizes the sensory feedback ensuing on muscle contraction.

Modular organisation and spinal somatosensory imprinting

The withdrawal reflex system has been extensively used as a model system for studies of pain related mechanisms, sensorimotor integration, learning and memory. For a long time, this system was assumed to be organised as a flexion reflex system. However, recent studies indicate that this system has a modular organisation, each module performing a detailed and functionally adapted sensorimotor transformation related to the withdrawal efficacy of its output muscle(s). Each module appears to be a self-organising circuitry that uses sensory feedback on single muscle contractions to adjust its synaptic organisation during development. These findings and their implications for the understanding of higher motor functions as well as clinical aspects will be discussed.