Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Components of heart rate variability have attracted considerable attention in psychology and medicine and have become important dependent measures in psychophysiology and behavioral medicine. Quantification and interpretation of heart rate variability, however, remain complex issues and are fraught with pitfalls. The present report (a) examines the physiological origins and mechanisms of heart rate variability, (b) considers quantitative approaches to measurement, and (c) highlights important caveats in the interpretation of heart rate variability. Summary guidelines for research in this area are outlined, and suggestions and prospects for future developments are considered.

https://www.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1469-8986.1997.tb02140.x

Heart rate variability: Origins, methods, and interpretive caveats

Muscle fatigue is an exercise-induced reduction in maximal voluntary muscle force. It may arise not only because of peripheral changes at the level of the muscle, but also because the central nervous system fails to drive the motoneurons adequately. Evidence for “central” fatigue and the neural mechanisms underlying it are reviewed, together with its terminology and the methods used to reveal it. Much data suggest that voluntary activation of human motoneurons and muscle fibers is suboptimal and thus maximal voluntary force is commonly less than true maximal force. Hence, maximal voluntary strength can often be below true maximal muscle force. The technique of twitch interpolation has helped to reveal the changes in drive to motoneurons during fatigue. Voluntary activation usually diminishes during maximal voluntary isometric tasks, that is central fatigue develops, and motor unit firing rates decline. Transcranial magnetic stimulation over the motor cortex during fatiguing exercise has revealed focal cha...

Spinal and Supraspinal Factors in Human Muscle Fatigue

1. In ten normal volunteers, a transcranial magnetic or electric stimulus that was subthreshold for evoking an EMG response in relaxed muscles was used to condition responses evoked by a later, suprathreshold magnetic or electric test shock. In most experiments the test stimulus was given to the lateral part of the motor strip in order to evoke EMG responses in the first dorsal interosseous muscle (FDI). 2. A magnetic conditioning stimulus over the hand area of cortex could suppress responses produced in the relaxed FDI by a suprathreshold magnetic test stimulus at interstimulus intervals of 1-6 ms. At interstimulus intervals of 10 and 15 ms, the test response was facilitated. 3. Using a focal magnetic stimulus we explored the effects of moving the conditioning stimulus to different scalp locations while maintaining the magnetic test coil at one site. If the conditioning coil was moved anterior or posterior to the motor strip there was less suppression of test responses in the FDI. In contrast, stimulation at the vertex could suppress FDI responses by an amount comparable to that seen with stimulation over the hand area. With the positions of the two coils reversed, conditioning stimuli over the hand area suppressed responses evoked in leg muscles by vertex test shocks. 4. The intensity of both conditioning and test shocks influenced the amount of suppression. Small test responses were more readily suppressed than large responses. The best suppression was seen with small conditioning stimuli (0.7-0.9 times motor threshold in relaxed muscle); increasing the intensity to motor threshold or above resulted in less suppression or even facilitation. 5. Two experiments suggested that the suppression was produced by an action on cortical, rather than spinal excitability. First, a magnetic conditioning stimulus over the hand area failed to produce any suppression of responses evoked in active hand muscles by a small (approximately 200 V, 50 microsecond time constant) anodal electric test shock. Second, a vertex conditioning shock had no effect on forearm flexor H reflexes even though responses in the same muscles produced by magnetic cortical test shocks were readily suppressed at appropriate interstimulus intervals. 6. Small anodal electric conditioning stimuli were much less effective in suppressing magnetic test responses than either magnetic or cathodal electric conditioning shocks.(ABSTRACT TRUNCATED AT 400 WORDS)

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1993.sp019912

Corticocortical inhibition in human motor cortex.

Microneurography was originally developed by Vallbo and Hagbarth in the 1960s to bridge the gap between human psychophysical studies and neurophysiological investigations in animal preparations. Soon after the first recordings of single nerve fibre potentials were made in large-diameter myelinated cutaneous and muscle afferents, microneurography was used to examine human C-fibres (e.g. Torebjork, 1974). Despite its technical difficulties and limited yield, microneurography enables an extraordinarily detailed examination of the properties of single fibres in human peripheral nerves in vivo. This intact, physiological protocol can also be used to explore subjective sensations arising from intraneural stimulation of individual nerve fibres, an application ideally suited to the study of pain. These and like studies have helped cement the view that many features of a percept are directly related to the afferent species and its discharge, as much as, if not more than, central mechanisms.

The resurgent field of pain research has been constrained by the difficulty of defining the neural origins of pain to quantify what is ultimately a subjective experience. Functional imaging techniques have provided an objective means to quantify some pain responses and newer techniques have discriminated patterns of responses in the brain arising from selective activation of cutaneous Aδ and C-fibres (Weiss et al. 2008). There are limitations to such techniques: they cannot determine which class or subclass of C-fibre mediates specific pain sensations, such as those evoked by nociceptive thermal stimuli. Most of our present physiological concepts about sensory transduction have been derived from studies in rats, cats and monkeys. However we know there are fundamental differences between animal and human skin. These include the presence of Ruffini endings or slowly adapting type II afferents (SA II) in human glabrous skin, found in neither cat nor monkey; the termination of Aδ fibres in unmyelinated C-fibre type endings; and the strong synaptic coupling between cutaneous afferents, particularly SA IIs, and the motoneurone pool (McNulty & Macefield, 2001).

Behavioural, histochemical and molecular studies in animal models provide a framework on which to explore the structural differences and paradoxical sensations of human skin. In this issue of The Journal of Physiology, Campero et al. (2009) explore one such paradox, that of an unpleasant burning sensation in response to innocuous cooling stimuli. Using microneurography they provide compelling evidence for a specific subclass of C-fibre afferent that responds to both warming and cooling, a class of afferents that they have termed type 2 afferent C fibres (‘C2’). Their intriguing hypothesis is that these fibres do not transduce thermal sensation per se but mediate an unconscious modulation of thermoregulation to preserve homeostatic stability. It implies a trade-off between the metabolic costs of sustaining this sensory channel and the greater efficiency of long-term maintenance within a physiologically safe thermal range. Their findings specifically differentiate between the noxious sensations mediated by type 1 C-fibres and the unpleasant sensations that can sometimes be evoked by apparently innocuous cooling.

The results from this study suggest a simple mechanism to test for interrupted biological functioning of Aδ fibres clinically. The presence of a paradoxical burning sensation in response to a cold stimulus, in the absence of ischaemia, implies the dysfunction of A-fibre signalling (Fruhstorfer, 1984). It is conceivable that thermal dysregulation may be associated with a specific C2 neuropathy. The potential for pharmacological targeting of C2 fibres is raised by the differences in membrane properties of these afferents in comparison to the two classes of type 1 C-fibres (Bostock et al. 2003). This differentiation can only be made using microneurography.

This paper is one of a remarkable series of experiments led by Ochoa and Bostock. The difficulty of recording from single nerve fibres in human peripheral nerves is compounded when specifically targeting type-identified C-fibres, and cannot be overstated. To distinguish the activity of single C-fibres is technically quite challenging using microneurography. The diameter of C-fibres is at least one order of magnitude smaller than Aα and Aβ fibres and their aggregation into Remak bundles further lessens the likelihood of selective recordings. In practice this reduces the ability to distinguish between individual fibres using spike morphology and amplitude, and Campero et al. (2009) have developed sophisticated procedures to assist in this. When this is combined with firing rates <5 Hz and sluggish response times to external thermal and mechanical stimulation, only limited identification is possible based on firing patterns, as is used in microneurographic studies of large-diameter myelinated afferents. Selective recordings of C-fibre potentials therefore rely on the cardinal identifiers of latency and the pattern of activity-dependent slowing in axonal conduction velocity. To distinguish sub-populations of C-fibres unambiguously, an extended sequence of electrical stimulation and baseline recordings is required before the receptive fields can be mapped in response to natural stimuli. Only then can experimental interventions be implemented. The work of Campero and colleagues is the latest in a series of papers that together elucidate the physiological properties of C-fibre afferents in detail similar to that well established for larger diameter afferents.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2009.183483

When cold becomes hot.

RECORDING TECHNIQUE MUSCLE AFFERENTS Clinically Relevant Insights Sensory Role of Muscle Spindles Fusimotor Function at Rest Fusimotor Function During Voluntary Contractions Fusimotor Function During Contractions of Remote Muscles, Motor Imagery, and Preparation for a Contraction Fusimotor Function in Motor Disorders CUTANEOUS AND JOINT AFFERENTS Large Myelinated Cutaneous Afferents Cutaneous Afferent C Fibers Joint Afferents Clinically Relevant Insights SYMPATHETIC EFFERENT ACTIVITY Clinically Relevant Insights CONDUCTION BLOCK AND ECTOPIC IMPULSE ACTIVITY Clinically Relevant Insights

http://www.doody.com/rev400images/pdf/2012/SampleChapter/9781455703081.pdf

Chapter 14 – Microneurography and its Potential Clinical Applications

Spinal cord reflexes can be depressed by inhibiting the motoneuron or by decreasing the excitation by afferent inputs. With ‘postsynaptic inhibition’ there is a change in membrane potential due to inhibitory postsynaptic potentials and associated conductance changes. This contrasts with mechanisms that reduce transmitter release at the Ia-motoneuron synapse and do not alter the postsynaptic membrane. Release of less transmitter can be achieved by ‘presynaptic inhibition’, thought to be due to a GABAergic (GABAA receptor) axo-axonic synapse producing primary afferent depolarisation of the afferent terminals, and by post-activation depression, in which activity of the afferent is believed to lead to exhaustion of transmitter in the presynaptic terminals. The former has effects that are widespread, while the latter affects only the active afferents. Another distinguishing feature is that classically ‘presynaptic inhibition’ lasts <300 ms while post-activation depression can last up to 10 s. There are paradoxes with the classical explanations for these phenomena. If transmitter depletion is responsible for the reflex attenuation produced by post-activation depression, why is the attenuation less in contracting muscles and less in spasticity (Pierrot-Deseilligny & Burke, 2012)? Less depression is the only spinal mechanism that correlates with the degree of spasticity. The inhibition of spinal reflexes by sustained vibration is now believed to be due to post-activation depression. It was once attributed to GABAA-ergic presynaptic inhibition, and its attenuation in patients with spasticity led to the misconception that loss of GABAA-ergic presynaptic inhibition led to spasticity. A paradox for classical presynaptic inhibition is that GABAA receptors are mainly located at internodes proximal to the terminals, not on axon terminals (Hari et al., 2022), such that their role in modulating afferent transmission cannot be presynaptic inhibition. Validated tests have been used to assess the level of ‘presynaptic inhibition’ in human subjects (Pierrot-Deseilligny & Burke, 2012). Using them, it has been shown that, when healthy subjects contract a muscle voluntarily, presynaptic inhibition of Ia afferents to the contracting muscle is suppressed, maximally so at the onset of the contraction. It is unchanged when remote muscles contract (as in reflex reinforcement), and is increased on Ia afferents projecting to inactive synergists and to antagonists. Decreased presynaptic inhibition occurs when standing freely and during the swing phase of locomotion. It is also decreased in patients with spasticity due to spinal cord lesions (Faist et al., 1994), and in some studies also in hemiplegia, though greater age of the patients could have contributed to this. Changes were bilateral in the hemiplegic patients and, in both cases, there was no correlation with the degree of spasticity. There is evidence for suppression of presynaptic inhibition in patients with amyotrophic lateral sclerosis, but with no significant correlation with the degree of spasticity (Howells et al., 2020). This extensive literature needs to be reassessed in the light of work published in this issue of The Journal of Physiology by Metz et al. (2023). Complex experiments were performed in healthy human volunteers, and the underlying mechanisms were then explored in careful studies on rats and genetically engineered mice. The authors provide cogent evidence that primary afferent depolarization (the putative mechanism of GABAergic presynaptic inhibition) can instead help secure conduction in Ia afferents at nodal branch points (where the security of conduction is reduced), and can generate ectopic activity in the afferents at these sites. They report that conditioning stimuli to tibialis anterior Ia afferents can produce a short-latency excitation of soleus motoneurons (presumably due to ectopic activity) and that only when this occurred was it followed by long-lasting depression of the H reflex. The reflex depression was accompanied by a decrease in motoneuron firing rate, interpreted as evidence of postsynaptic inhibition of the motoneuron. At the same time, the ectopic activity in the Ia afferents led to post-activation depression at the Ia-motoneuron synapse, thereby accentuating the H reflex suppression. In contrast to the classical literature, they find no role for GABAA-ergic presynaptic inhibition due to primary afferent depolarisation (PAD): ‘extensor H-reflex inhibition by brief flexor afferent conditioning is produced by both post-activation depression of extensor Ia-afferents and long-lasting inhibition of extensor motoneurons, rather than from PAD inhibiting Ia-afferent terminals.’ All human studies have limitations, but here these are not critical. The experimental conditions can never be identical in human and animal studies. With deep peroneal nerve stimulation, it is possible that, despite care, the stimulus was not confined to the innervation of tibialis anterior. There are potent monosynaptic excitatory Ia projections from peroneal muscles to soleus motoneurons (Pierrot-Deseilligny & Burke, 2012), though they cannot explain the long-lasting depression of motoneuron excitability. In intact humans, there is rarely just one active mechanism, in part, because controls cannot be as stringent as in animals. Comparable latencies and durations in human and animal experiments do not necessarily establish identical mechanisms, particularly when opposing mechanisms can interact. Single motor unit studies in humans require a weak voluntary contraction, and this means that only low-threshold motoneurons can be studied. Voluntary contraction biases spinal cord circuitry, and there is evidence that the contraction-associated changes are maximal when going from rest to weak contraction rather than weak to stronger contractions (Pierrot-Deseilligny & Burke, 2012). The strengths of the authors’ approach are (i) a comprehensive suite of studies, with parallel animal and human data, and (ii) that different experimental approaches yield data consistent with their hypotheses.

Has the importance of GABAA presynaptic inhibition been overestimated in human motor control?

Modelling and seizure prediction.

Objectives: The aim of this paper is to foster discussion about how best to design a new assessment system for the first three years of RANZCP Fellowship training, under the new regulations for training and assessment to be implemented in 2004. Conclusions: An integrated, flexible, reliable and valid system of formative and summative assessment is required. It should include a variety of assessment tools, measuring a range of domains on a number of occasions during basic training, and it should actively involve trainees, supervisors, patients and other consumers.

David Burke

Papers

When cold becomes hot.

Chapter 14 – Microneurography and its Potential Clinical Applications

Has the importance of GABAA presynaptic inhibition been overestimated in human motor control?

Modelling and seizure prediction.

Assessment in basic training: what is the matrix?