Primary Afferent Depolarization and the Gate Control Theory of Pain: A Tutorial Simulation.

The gate control theory of pain postulates that the sensation of pain can be reduced or blocked by closing a "gate" at the earliest synaptic level in the spinal cord, where nociceptive (pain) afferents excite the ascending interneurons that transmit the signal to the brain. Furthermore, the gate can be induced to close by stimulating touch afferents with receptive fields in the same general area as the trauma that is generating the pain (the "rub it to make it better" effect). A considerable volume of research has substantiated the theory and shown that a key mechanism mediating the gate is pre-synaptic inhibition, and that this inhibition is generated by depolarizing IPSPs in the nociceptor central terminals (primary afferent depolarization; PAD). Both pre-synaptic inhibition and depolarizing IPSPs are topics that students often regard as matters of secondary importance (if they are aware of them at all), and yet they are crucial to a matter of primary importance to us all - pain control. This report describes some simple computer simulations that illustrate pre-synaptic inhibition and explore the importance of the depolarizing aspect of the IPSPs. These concepts are then built into a model of the gate control of pain itself. Finally, the simulations show how a small change in chloride homeostasis can generate the dorsal root reflex, in which nociceptor afferents generate antidromic spikes which may increase neurogenic inflammation and actually exacerbate pain. The hope is that the simulations will increase awareness and understanding of a topic that is important in both basic neuroscience and medical neurology.

Vibration training after chronic spinal cord injury: Evidence for persistent segmental plasticity.

H-reflex paired-pulse depression is gradually lost within the first year post-SCI, a process believed to reflect reorganization of segmental interneurons after the loss of normal descending (cortical) inhibition. This reorganization co-varies in time with the development of involuntary spasms and spasticity. The purpose of this study is to determine whether long-term vibration training may initiate the return of H-reflex paired-pulse depression in individuals with chronic, complete SCI. Five men with SCI received twice-weekly vibration training (30Hz, 0.6g) to one lower limb while seated in a wheelchair. The contra-lateral limb served as a within-subject control. Paired-pulse H-reflexes were obtained before, during, and after a session of vibration. Untrained limb H-reflex depression values were comparable to chronic SCI values from previous reports. In contrast, the trained limbs of all 5 participants showed depression values that were within the range of previously-reported Acute SCI and Non-SCI H-reflex depression. The average difference between limbs was 34.98% (p=0.016). This evidence for the return of H-reflex depression suggests that even for people with long-standing SCI, plasticity persists in segmental reflex pathways. The spinal networks involved with the clinical manifestation of spasticity may thus retain adaptive plasticity after long-term SCI. The results of this study indicate that vibration training may hold promise as an anti-spasticity rehabilitation intervention.

Pre-Synaptic Inhibition of Afferent Feedback in the Macaque Spinal Cord Does Not Modulate with Cycles of Peripheral Oscillations Around 10 Hz.

Spinal interneurons are partially phase-locked to physiological tremor around 10 Hz. The phase of spinal interneuron activity is approximately opposite to descending drive to motoneurons, leading to partial phase cancellation and tremor reduction. Pre-synaptic inhibition of afferent feedback modulates during voluntary movements, but it is not known whether it tracks more rapid fluctuations in motor output such as during tremor. In this study, dorsal root potentials (DRPs) were recorded from the C8 and T1 roots in two macaque monkeys following intra-spinal micro-stimulation (random inter-stimulus interval 1.5-2.5 s, 30-100 µA), whilst the animals performed an index finger flexion task which elicited peripheral oscillations around 10 Hz. Forty one responses were identified with latency < 5 ms; these were narrow (mean width 0.59 ms), and likely resulted from antidromic activation of afferents following stimulation near terminals. Significant modulation during task performance occurred in 16/41 responses, reflecting terminal excitability changes generated by pre-synaptic inhibition (Wall's excitability test). Stimuli falling during large-amplitude 8-12 Hz oscillations in finger acceleration were extracted, and sub-averages of DRPs constructed for stimuli delivered at different oscillation phases. Although some apparent phase-dependent modulation was seen, this was not above the level expected by chance. We conclude that, although terminal excitability reflecting pre-synaptic inhibition of afferents modulates over the timescale of a voluntary movement, it does not follow more rapid changes in motor output. This suggests that pre-synaptic inhibition is not part of the spinal systems for tremor reduction described previously, and that it plays a role in overall-but not moment-by-moment-regulation of feedback gain.

Age-related Differences in Pre- and Post-synaptic Motor Cortex Inhibition are Task Dependent.

BACKGROUND: Previous research has shown age-related differences in short- (SICI) and long-interval intracortical inhibition (LICI) in both resting and active hand muscles, suggesting that healthy ageing influences post-synaptic motor cortex inhibition. However, it is not known how the ageing process effects the pre-synaptic interaction of SICI by LICI, and how these pre- and post-synaptic intracortical inhibitory circuits are modulated by the performance of different motor tasks in older adults. OBJECTIVE: To examine age-related differences in pre- and post-synaptic motor cortex inhibition at rest, and during index finger abduction and precision grip. METHODS: In 13 young (22.3 ± 3.8 years) and 15 old (73.7 ± 4.0 years) adults, paired-pulse transcranial magnetic stimulation (TMS) was used to measure SICI (2 ms inter-stimulus interval; ISI) and LICI (100 and 150 ms ISI), whereas triple-pulse TMS was used to investigate SICI when primed by LICI. RESULTS: We found no age-related difference in SICI at rest or during index finger abduction, but significantly greater SICI in older subjects during precision grip. Older adults showed reduced LICI in resting muscle (at an ISI of 150 ms), with no age-related differences in LICI during either task. When SICI was primed by LICI, disinhibition of motor cortex was reduced in older adults at rest (100 ms ISI) and during index finger abduction (150 ms ISI), but not during precision grip. CONCLUSIONS: Our results support age-related differences in pre- and post-synaptic motor cortex inhibition, which may contribute to impaired hand function during task performance in older adults.

Criterion learning in rule-based categorization: simulation of neural mechanism and new data.

In perceptual categorization, rule selection consists of selecting one or several stimulus-dimensions to be used to categorize the stimuli (e.g., categorize lines according to their length). Once a rule has been selected, criterion learning consists of defining how stimuli will be grouped using the selected dimension(s) (e.g., if the selected rule is line length, define 'long' and 'short'). Very little is known about the neuroscience of criterion learning, and most existing computational models do not provide a biological mechanism for this process. In this article, we introduce a new model of rule learning called Heterosynaptic Inhibitory Criterion Learning (HICL). HICL includes a biologically-based explanation of criterion learning, and we use new category-learning data to test key aspects of the model. In HICL, rule selective cells in prefrontal cortex modulate stimulus-response associations using pre-synaptic inhibition. Criterion learning is implemented by a new type of heterosynaptic error-driven Hebbian learning at inhibitory synapses that uses feedback to drive cell activation above/below thresholds representing ionic gating mechanisms. The model is used to account for new human categorization data from two experiments showing that: (1) changing rule criterion on a given dimension is easier if irrelevant dimensions are also changing (Experiment 1), and (2) showing that changing the relevant rule dimension and learning a new criterion is more difficult, but also facilitated by a change in the irrelevant dimension (Experiment 2). We conclude with a discussion of some of HICL's implications for future research on rule learning.