Restless legs syndrome (RLS) is a sensory-motor disorder in which cortical, subcortical, brainstem and spinal cord generators have been suggested to be neurophysiologically involved. Accordingly, most studies have shown changes of cortical-subcortical and spinal circuits functioning, usually resulting in an enhanced excitability and decreased inhibition [1]. In particular, it has been hypothesized that RLS symptoms may be due to a dysfunction of inhibitory dopaminergic projections from hypothalamic area A11 to dorsal horn cells. This may result in disinhibition of sensory inputs to the dorsal horn, thus leading to increased activity in the somatosensory tracts of the spinal cord and subliminal muscle preactivation. Based on electrophysiological and polysomnographic results, it was suggested that periodic leg movements (PLMs) in RLS also result from this spinal hyperexcitability [2]. Nevertheless, a diminished central inhibition may contribute to the excitation state of the segmental spinal pathways. Most of the studies using transcranial magnetic stimulation (TMS) highlight an involvement of supra-spinal motor inhibitory mechanisms in RLS, and, conversely, make a cortical origin of PLMs rather unlikely. Indeed, TMS measures that are thought to reflect mostly the excitability of inhibitory GABAergic intracortical circuits (i.e. the cortical silent period and the intracortical inhibition) were reported to be decreased in several studies on RLS, being reversed after dopaminergic treatment in many cases (for a comprehensive review, see [3]). This finding was attributed to an impairment of the subcortical dopaminergic system and was proposed to reflect a disruption of GABA-mediated intracortical pathways [3]. Impaired inhibition at the TMS level is in agreement with the observation of a hyperarousal state in RLS patients, who show increased EEG high frequencies during both the sleep onset period and the quiet wakefulness preceding sleep [4]. Although TMS does not provide hallmark of a disease, the set of abnormalities observed in RLS might be considered to be somewhat specific of this sleep disorder rather than being a general consequence of sleep architecture alteration. This hypothesis is supported by the distinct changes of responses at TMS recently found in RLS compared to patients with obstructive sleep apnea syndrome, probably related with the different neurophysiological substrates underlying these two disorders [5]. Other investigations have also pointed out a dysfunctional motor skill learning process after experimentally-induced sleep fragmentation in RLS, reversible with dopaminergic treatment, suggesting a dopamine-mediated alteration in sensory-motor cortical plasticity. In addition, TMS allowed also to study the circadian changes in cortical excitability in RLS, demonstrating the possible predominant loss of subcortical inhibition at night time [3]. Interestingly, it is noteworthy that abnormal peripheral nerve function can affect spinal activity and its supraspinal connections. In this context, data from the evaluation of H-reflex, blink reflex, cutaneous silent period or quantitative sensory testing in RLS might support the pathophysiological hypothesis of spinal cord hyperexcitability, although alone they are not sufficiently accurate for the evaluation of the single subject. It should also be noted that iron 2 deficiency anemia does not seem to cause changes in the peripheral nerves, spinal cord and brainstem electrophysiological activity. Finally, further insights come from recent investigations using non-invasive stimulation techniques. For instance, transcutaneous direct current stimulation has proved to be a painless way to reduce spinal cord excitability [6], whereas repetitive TMS of the motor cortical areas is able to induce the release of dopamine in the putamen [7], and, in turn, probably enhance the descending inhibitory pathway and prevent abnormal central somatosensory processing [8]. Although the preliminary value of the results, these non-pharmacological tools showed to be effective in modulating neural excitability in RLS patients, together with subjective clinical improvement [9,10], thus possibly expanding the therapeutic repertoire for RLS. Taken together, all the available findings “from muscle to cortex”, i.e., peripheral reflexes enhancement, altered spinal interneuronal activity, cortical-subcortical structures disinhibition, and the response to neuromodulatory techniques, conclude for the presence of a specific electrophysiological profile in RLS. Therefore, from a pure neurophysiological prospective, RLS arises at different levels of the nervous system networks encompassing somatosensory perception and motion [1], and result in a modified, possibly temporary and circadian, excitability of a complex cortical-spinal drive.

Spinal and cortical excitability in RLS

Lanza G
2015

Abstract

Restless legs syndrome (RLS) is a sensory-motor disorder in which cortical, subcortical, brainstem and spinal cord generators have been suggested to be neurophysiologically involved. Accordingly, most studies have shown changes of cortical-subcortical and spinal circuits functioning, usually resulting in an enhanced excitability and decreased inhibition [1]. In particular, it has been hypothesized that RLS symptoms may be due to a dysfunction of inhibitory dopaminergic projections from hypothalamic area A11 to dorsal horn cells. This may result in disinhibition of sensory inputs to the dorsal horn, thus leading to increased activity in the somatosensory tracts of the spinal cord and subliminal muscle preactivation. Based on electrophysiological and polysomnographic results, it was suggested that periodic leg movements (PLMs) in RLS also result from this spinal hyperexcitability [2]. Nevertheless, a diminished central inhibition may contribute to the excitation state of the segmental spinal pathways. Most of the studies using transcranial magnetic stimulation (TMS) highlight an involvement of supra-spinal motor inhibitory mechanisms in RLS, and, conversely, make a cortical origin of PLMs rather unlikely. Indeed, TMS measures that are thought to reflect mostly the excitability of inhibitory GABAergic intracortical circuits (i.e. the cortical silent period and the intracortical inhibition) were reported to be decreased in several studies on RLS, being reversed after dopaminergic treatment in many cases (for a comprehensive review, see [3]). This finding was attributed to an impairment of the subcortical dopaminergic system and was proposed to reflect a disruption of GABA-mediated intracortical pathways [3]. Impaired inhibition at the TMS level is in agreement with the observation of a hyperarousal state in RLS patients, who show increased EEG high frequencies during both the sleep onset period and the quiet wakefulness preceding sleep [4]. Although TMS does not provide hallmark of a disease, the set of abnormalities observed in RLS might be considered to be somewhat specific of this sleep disorder rather than being a general consequence of sleep architecture alteration. This hypothesis is supported by the distinct changes of responses at TMS recently found in RLS compared to patients with obstructive sleep apnea syndrome, probably related with the different neurophysiological substrates underlying these two disorders [5]. Other investigations have also pointed out a dysfunctional motor skill learning process after experimentally-induced sleep fragmentation in RLS, reversible with dopaminergic treatment, suggesting a dopamine-mediated alteration in sensory-motor cortical plasticity. In addition, TMS allowed also to study the circadian changes in cortical excitability in RLS, demonstrating the possible predominant loss of subcortical inhibition at night time [3]. Interestingly, it is noteworthy that abnormal peripheral nerve function can affect spinal activity and its supraspinal connections. In this context, data from the evaluation of H-reflex, blink reflex, cutaneous silent period or quantitative sensory testing in RLS might support the pathophysiological hypothesis of spinal cord hyperexcitability, although alone they are not sufficiently accurate for the evaluation of the single subject. It should also be noted that iron 2 deficiency anemia does not seem to cause changes in the peripheral nerves, spinal cord and brainstem electrophysiological activity. Finally, further insights come from recent investigations using non-invasive stimulation techniques. For instance, transcutaneous direct current stimulation has proved to be a painless way to reduce spinal cord excitability [6], whereas repetitive TMS of the motor cortical areas is able to induce the release of dopamine in the putamen [7], and, in turn, probably enhance the descending inhibitory pathway and prevent abnormal central somatosensory processing [8]. Although the preliminary value of the results, these non-pharmacological tools showed to be effective in modulating neural excitability in RLS patients, together with subjective clinical improvement [9,10], thus possibly expanding the therapeutic repertoire for RLS. Taken together, all the available findings “from muscle to cortex”, i.e., peripheral reflexes enhancement, altered spinal interneuronal activity, cortical-subcortical structures disinhibition, and the response to neuromodulatory techniques, conclude for the presence of a specific electrophysiological profile in RLS. Therefore, from a pure neurophysiological prospective, RLS arises at different levels of the nervous system networks encompassing somatosensory perception and motion [1], and result in a modified, possibly temporary and circadian, excitability of a complex cortical-spinal drive.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/372436
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact