Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry

Abstract

Mechanisms of motor deficits (e.g. hemiparesis and hemiplegia) secondary to stroke and traumatic brain injury remain poorly understood. In early animal studies, a unilateral lesion to the cerebellum produced postural asymmetry with ipsilateral hindlimb flexion that was retained after complete spinal cord transection. Here we demonstrate that hindlimb postural asymmetry in rats is induced by a unilateral injury of the hindlimb sensorimotor cortex, and characterize this phenomenon as a model of spinal neuroplasticity underlying asymmetric motor deficits. After cortical lesion, the asymmetry was developed due to the contralesional hindlimb flexion and persisted after decerebration and complete spinal cord transection. The asymmetry induced by the left-side brain injury was eliminated by bilateral lumbar dorsal rhizotomy, but surprisingly, the asymmetry after the right-side brain lesion was resistant to deafferentation. Pancuronium, a curare-mimetic muscle relaxant, abolished the asymmetry after the right-side lesion suggesting its dependence on the efferent drive. The contra- and ipsilesional hindlimbs displayed different musculo-articular resistance to stretch after the left but not right-side injury. The nociceptive withdrawal reflexes evoked by electrical stimulation and recorded with EMG technique were different between the left and right hindlimbs in the spinalized decerebrate rats. On this asymmetric background, a brain injury resulted in greater reflex activation on the contra- versus ipsilesional side; the difference between the limbs was higher after the right-side brain lesion. The unilateral brain injury modified expression of neuroplasticity genes analysed as readout of plastic changes, as well as robustly impaired coordination of their expression within and between the ipsi- and contralesional halves of lumbar spinal cord; the effects were more pronounced after the left side compared to the right-side injury. Our data suggest that changes in the hindlimb posture, resistance to stretch and nociceptive withdrawal reflexes are encoded by neuroplastic processes in lumbar spinal circuits induced by a unilateral brain injury. Two mechanisms, one dependent on and one independent of afferent input may mediate asymmetric hindlimb motor responses. The latter, deafferentation resistant mechanism may be based on sustained muscle contractions which often occur in patients with central lesions and which are not evoked by afferent stimulation. The unusual feature of these mechanisms is their lateralization in the spinal cord.

Ipsilesionalversuscontralesional postural deficits induced by unilateral brain trauma: a side reversal by opioid mechanism

“…The HL-PA is a proxy for the analysis of postural impairments and represents a translational model of ‘hemiplegic posture’ ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ). The HL-PA induced by a unilateral brain injury was evident in un-anesthetized decerebrate animals and in animals under anaesthesia that were used to measure the asymmetry size ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ).…”

“…The HL-PA is a proxy for the analysis of postural impairments and represents a translational model of ‘hemiplegic posture’ ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ). The HL-PA induced by a unilateral brain injury was evident in un-anesthetized decerebrate animals and in animals under anaesthesia that were used to measure the asymmetry size ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Lukoyanov et al , 2020 ; Zhang et al , 2020 ). As previously established, the stretch and postural limb reflexes were substantially decreased under anaesthesia ( Zhou et al , 1998 ; Fuchigami et al , 2011 ) and abolished immediately and for days after spinal cord transection ( Miller et al , 1996 ; Musienko et al , 2010 ; Frigon et al , 2011 ).…”

“…Stroke and TBI result in robust pathological changes in contralateral polysynaptic withdrawal reflexes that also control posture and locomotion in human patients ( Dewald et al , 1999 ; Schouenborg, 2002 ; Sandrini et al , 2005 ; Serrao et al , 2012 ; Spaich et al , 2014 ). Consistently, in animals with a unilateral cortical lesion the hindlimb nociceptive withdrawal reflexes evoked by electrical stimulation and recorded with EMG technique were activated on the contra- versus ipsilesional side ( Zhang et al , 2020 ). Changes in posture and reflexes persisted after complete spinal cord transection, suggesting that aberrant effects are encoded in spinal neurocircuits ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Hultborn and Malmsten, 1983a , b ; Malmsten, 1983 ; Frigon et al , 2009 ; Rossignol and Frigon, 2011 ; Tan et al , 2012 ; Wolpaw, 2012 ; Grau, 2014 ; Sist et al , 2014 ).…”

“…Similarly, a spinal cord hemisection produced ipsilateral changes in spinal reflexes that were paralleled by asymmetry in locomotion ( Hultborn and Malmsten, 1983a , b ; Malmsten, 1983 ; Frigon et al , 2009 ; Rossignol and Frigon, 2011 ). Hindlimb postural asymmetry (HL-PA) manifested as differences in the position of the ipsi- and contralesional hindlimbs was also induced by localized lesion to the hindlimb area of the sensorimotor cortex ( Zhang et al , 2020 ) as well as by a large hemispheric injury ( Varlinskaia et al , 1984 ). In contrast to cerebellar or spinal cord injuries, the contralesional hindlimb was flexed after injury to the sensorimotor cortex.…”

“…Changes in posture and reflexes persisted after complete spinal cord transection, suggesting that aberrant effects are encoded in spinal neurocircuits ( DiGiorgio, 1929 ; Chamberlain et al , 1963 ; Hultborn and Malmsten, 1983a , b ; Malmsten, 1983 ; Frigon et al , 2009 ; Rossignol and Frigon, 2011 ; Tan et al , 2012 ; Wolpaw, 2012 ; Grau, 2014 ; Sist et al , 2014 ). The brain injury also modified the expression of neuroplasticity genes and robustly impaired coordination of their expression between the ipsi- and the contralesional sides in the lumbar spinal cord ( Sist et al , 2014 ; Zhang et al , 2020 ). In summary, the hindlimb asymmetry phenomenon in rats recapitulates several pathophysiological features of the human upper motor neuron syndrome including the ‘hemiplegic posture’ and exaggerated asymmetric withdrawal reflexes.…”