TABLE 2.

Recommended animal model translations of restless legs syndrome (RLS) essential criteria and related clinical features

	Clinical features	Recommended animal model methods	Recommended animal model outcome measures (expected endpoints)
1	An urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensations in the legs	Activity monitoring for assessing urge to movea	• Increase in total activity (movements/distance traveled) in the home cage • Increase in EMG activation events/h in a restrainer • Increase in number of tibialis anterior EMG bursts/h during wakefulness in home cage • Decrease in total duration of periods of very low or no activity in the home cage
		Video recordings	• Increase in number of events of limb activity resembling leg rubbing, kicking, flexing, stretching, or fidgeting
2	The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting	Video recordings	• Increase in general activity in the home cage (including locomotion, rearing, grooming, limb stretching)
		Activity monitoring3	• Decrease in time spent at rest in the home cage • Increase in EMG activation events/h in a restrainer
2a	The urge to move the legs and any accompanying unpleasant sensations during rest occur or are worse in the transition from wake to the main sleep period, and potentially extend to wakefulness bouts throughout the main sleep period	Activity monitoring8	• Increase in total activity (movements/distance traveled) in the home cage occurs or is maximal in last part of the active period and during activity bouts in the rest period
		Video-PSG	• Increase in EMG activation events in the home cage occurs or is maximal during wakefulness in the last part of the active period and in the rest period
3	The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues	Activity monitoringa	• Decrease in the median duration of rest episodes when in home cage
3a	Behavior manifestations of lower extremity discomfort	Video recordings	• Increase in the ratio of time with hindlimbs vs. forelimbs at rest
		Activity monitoringa	• Increase in hindlimb vs. forelimb EMG activity
3b	The distal predominance of sensory symptoms: symptoms are worse in the legs (ie, from knee to ankle) compared to the rest of the body	Video recordings	• Increase in frequency of episodes of touching/rubbing/licking hindlimbs vs. forelimbs • Increase in frequency of episodes of hindlimb licking at the level of femur vs. at the level of tibia and foot
4	The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day	Activity monitoringa	• General activity in the home cage (increase vs. controls greater at the end of the dark period and during the light period than at the beginning of the active period)
		Video-PSG	• Number of tibialis anterior EMG bursts/h during wakefulness in the home cage (increase vs. controls greater at the end of the dark period and during the light period than at the beginning of active period)
4a	Circadian pattern	Activity monitoringa with measurement of a circadian marker (eg, core body temperature) in LD conditions, then switch to DD	• Phase-shift between the rhythm of incidence of tibialis anterior EMG bursts (classified as a function of their intermovement interval) and rhythms of the circadian marker during LD and DD (RLS-like phase shift in LD, preserved in DD)
		Video-PSG with measurement of a circadian marker (eg, core body temperature) in LD conditions, then switch to DD	• Phase-shift between rhythm of incidence of TA EMG bursts (classified as a function of their intermovement interval) and rhythms of the circadian marker during LD and DD (RLS-like phase shift in LD, preserved in DD)
5	The occurrence of the above features is not solely accounted for as symptoms primary to another medical or a behavioral condition (eg, myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping)	Exclude myopathy, neuropathy, severe arthritis with pathological assessment. Demonstrate at least partial phenotype rescue with pharmacological treatment (cf. Table 4)

EMG, electromyography; LD, light-dark cycle; DD, constant darkness conditions; PSG, polysomnography; RLS, restless legs syndrome; TA, tibialis anterior.

^aActivity monitoring methods include, but are not limited to, video tracking, piezoelectric floor sensor, infrared or laser beam grids, implanted accelerometers or activity telemeters or voluntary running wheel, and neck or limb EMG recordings (not suited for the evaluation of distance traveled, but the only method suited for assessment of periodic leg movements, for application in a restrainer, and for hindlimbs vs. forelimb activity).