Kaoru Takakusaki

Basal Ganglia Efferents to the Brainstem Centers Controlling Postural Muscle Tone and Locomotion ; A New Concept for Understanding Motor Disorders in Basal Ganglia Dysfunction

The present study is designed to elucidate how basal ganglia afferents from the substantia nigra pars reticulata (SNr) to the mesopontine tegmental area of the brainstem contribute to gait control and muscle-tone regulation. We used unanesthetized and acutely decerebrated cats (n=27) in which the striatum, thalamus and cerebral cortex were removed but the SNr was preserved. Repetitive stimulation (50 Hz, 10-60 microA, for 5-20 s) applied to a mesencephalic locomotor region (MLR), which corresponded to the cuneiform nucleus, and adjacent areas, evoked locomotor movements. On the other hand, stimulation of a muscle-tone inhibitory region in the pedunculopontine tegmental nucleus (PPN) suppressed postural muscle tone. An injection of either glutamatergic agonists (N-methyl-D-aspartic acid and kainic acid) or GABA antagonists (bicuculline and picrotoxin) into the MLR and PPN also induced locomotion and muscle-tone suppression, respectively. Repetitive electrical stimuli (50-100 Hz, 20-60 microA for 5-20 s) delivered to the SNr alone did not alter muscular activity. However stimulating the lateral part of the SNr attenuated and blocked PPN-induced muscle-tone suppression. Moreover, weaker stimulation of the medial part of the SNr reduced the number of step cycles and disturbed the rhythmic alternation of limb movements of MLR-induced locomotion. The onset of locomotion was delayed as the stimulus intensity was increased. At a higher strength SNr stimulation abolished the locomotion. An injection of bicuculline into either the PPN or the MLR diminished the SNr effects noted above. These results suggest that locomotion and postural muscle tone are subject to modulation by GABAergic nigrotegmental projections which have a partial functional topography: a lateral and medial SNr, for regulation of postural muscle tone and locomotion, respectively. We conclude that disorders of the basal ganglia may include dysfunction of the nigrotegmental (basal ganglia-brainstem) systems, which consequently leads to the production of abnormal muscle tone and gait disturbance.

Neurophysiology of gait: From the spinal cord to the frontal lobe

Locomotion is a purposeful, goal‐directed behavior initiated by signals arising from either volitional processing in the cerebral cortex or emotional processing in the limbic system. Regardless of whether the locomotion initiation is volitional or emotional, locomotion is accompanied by automatic controlled movement processes, such as the adjustment of postural muscle tone and rhythmic limb movements. Sensori‐motor integration in the brainstem and the spinal cord plays crucial roles in this process. The basic locomotor motor pattern is generated by spinal interneuronal networks, termed central pattern generators (CPGs). Responding to signals in proprioceptive and skin afferents, the spinal interneuronal networks modify the locomotor pattern in cooperation with descending signals from the brainstem structures and the cerebral cortex. Information processing between the basal ganglia, the cerebellum, and the brainstem may enable automatic regulation of muscle tone and rhythmic limb movements in the absence of conscious awareness. However, when a locomoting subject encounters obstacles, the subject has to intentionally adjust bodily alignment to guide limb movements. Such an intentional gait modification requires motor programming in the premotor cortices. The motor programs utilize ones bodily information, such as the body schema, which is preserved and updated in the temporoparietal cortex. The motor programs are transmitted to the brainstem by the corticoreticulospinal system, so that ones posture is anticipatorily controlled. These processes enable the corticospinal system to generate limb trajectory and achieve accurate foot placement. Loops from the motor cortical areas to the basal ganglia and the cerebellum can serve this purpose.

Site-specific postural and locomotor changes evoked in awake, freely moving intact cats by stimulating the brainstem

Locomotor behaviors evoked by stimulating the hypothalamus and the brainstem were studied in freely moving, awake cats. To do this, stimulating microelectrodes were chronically implanted into the subthalamic locomotor region (SLR) in the lateral hypothalamic area (LHA), the mesencephalic locomotor region (MLR) corresponding to the nucleus cuneiformis, the dorsal tegmental field (DTF) and the ventral tegmental field (VTF) of caudal pons along its midline. After recovery from surgery (2-3 days), open field tests were performed to study stimulus effects upon posture and locomotor movements. The stimuli consisted of pulses of 0.2 ms duration of less than 80 microA delivered at 50 pulses/s for 5-20 s. DTF stimulation resulted in suppression of postural support by the hindlimbs. When the cat was in a standing posture, DTF stimulation simply resulted in a sequential alteration of posture to a squatting and then to a final lying posture. In contrast, VTF stimulation evoked an almost opposite series of postural changes to those induced by DTF stimulation. With VTF stimulation, the cat changed from a lying or a squatting position, and then started to walk during continuation of the stimulation. With MLR stimulation, the cat invariably exhibited fast walking and then running movements. It ran straight forward, avoiding collision with walls or other obstacles, and even tried to jump over a fence placed in front of it. With LHA stimulation, the cat started to walk slowly extending its head forward and looking around repeatedly. It tended to walk with a stoop and stealthy steps along the corners of the room. Induced postural and locomotor changes were always accompanied by behavioral arousal reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Substrates for normal gait and pathophysiology of gait disturbances with respect to the basal ganglia dysfunction

In this review, we have tried to elucidate substrates for the execution of normal gait and to understand pathophysiological mechanisms of gait failure in basal ganglia dysfunctions. In Parkinson’s disease, volitional and emotional expressions of movement processes are seriously affected in addition to the disturbance of automatic movement processes, such as adjustment of postural muscle tone before gait initiation and rhythmic limb movements during walking. These patients also suffer from muscle tone rigidity and postural instability, which may also cause reduced walking capabilities in adapting to various environments. Neurophysiological and clinical studies have suggested the importance of basal ganglia connections with the cerebral cortex and limbic system in the expression of volitional and emotional behaviors. Here we hypothesize a crucial role played by the basal ganglia-brainstem system in the integrative control of muscle tone and locomotion. The hypothetical model may provide a rational explanation for the role of the basal ganglia in the control of volitional and automatic aspects of movements. Moreover, it might also be beneficial for understanding pathophysiological mechanisms of basal ganglia movement disorders. A part of this hypothesis has been supported by studies utilizing a constructive simulation engineering technique that clearly shows that an appropriate level of postural muscle tone and proper acquisition and utilization of sensory information are essential to maintain adaptable bodily functions for the full execution of bipedal gait.In conclusion, we suggest that the major substrates for supporting bipedal posture and executing bipedal gait are 1) fine neural networks such as the cortico-basal ganglia loop and basal ganglia-brainstem system, 2) fine musculoskeletal structures with adequately developed (postural) muscle tone, and 3) proper sensory processing. It follows that any dysfunction of the above sensorimotor integration processes would result in gait disturbance.

Orexinergic projections to the cat midbrain mediate alternation of emotional behavioural states from locomotion to cataplexy.

Orexinergic neurones in the perifornical lateral hypothalamus project to structures of the midbrain, including the substantia nigra and the mesopontine tegmentum. These areas contain the mesencephalic locomotor region (MLR), and the pedunculopontine and laterodorsal tegmental nuclei (PPN/LDT), which regulate atonia during rapid eye movement (REM) sleep. Deficiencies of the orexinergic system result in narcolepsy, suggesting that these projections are concerned with switching between locomotor movements and muscular atonia. The present study characterizes the role of these orexinergic projections to the midbrain. In decerebrate cats, injecting orexin‐A (60 μm to 1.0 mm, 0.20–0.25 μl) into the MLR reduced the intensity of the electrical stimulation required to induce locomotion on a treadmill (4 cats) or even elicit locomotor movements without electrical stimulation (2 cats). On the other hand, when orexin was injected into either the PPN (8 cats) or the substantia nigra pars reticulata (SNr, 4 cats), an increased stimulus intensity at the PPN was required to induce muscle atonia. The effects of orexin on the PPN and the SNr were reversed by subsequently injecting bicuculline (5 mm, 0.20–0.25 μl), a GABAA receptor antagonist, into the PPN. These findings indicate that excitatory orexinergic drive could maintain a higher level of locomotor activity by increasing the excitability of neurones in the MLR, while enhancing GABAergic effects on presumably cholinergic PPN neurones, to suppress muscle atonia. We conclude that orexinergic projections from the hypothalamus to the midbrain play an important role in regulating motor behaviour and controlling postural muscle tone and locomotor movements when awake and during sleep. Furthermore, as the excitability is attenuated in the absence of orexin, signals to the midbrain may induce locomotor behaviour when the orexinergic system functions normally but elicit atonia or narcolepsy when the orexinergic function is disturbed.

Electrical and chemical stimulations of the pontine micturition center

In an acute decerebrate cat, electrical stimulation of the pontine micturition center (PMC) resulted in micturition. Carbachol injection into the PMC also resulted in micturition. The pattern of changes in bladder pressure and the sphincter activity observed during carbachol-induced micturition was almost identical to that observed during reflex micturition. The injection site corresponded to the nucleus locus coeruleus alpha (LC alpha). These results suggest that activation of cholinoceptive neurons in the LC alpha presumably becomes a trigger to recruit any one of a number of neuronal circuits involved in micturition.

Role of basal ganglia-brainstem systems in the control of postural muscle tone and locomotion.

This chapter argues that a basal ganglia-brainstem system throughout the mesopontine tegmentum contributes to an automatic control of movement that operates in conjunction with voluntary control processes. Activity of a muscle tone inhibitory system and the locomotion executing system can be steadily balanced by a net excitatory cortical input and a net inhibitory basal ganglia input to these systems. We further propose that dysfunction of the basal ganglia-brainstem system, together with that of the cortico-basal ganglia loop, underlies the pathogenesis of motor disturbances expressed in basal ganglia diseases.

Single medullary reticulospinal neurons exert postsynaptic inhibitory effects via inhibitory interneurons upon alpha-motoneurons innervating cat hindlimb muscles

SummaryThis study was aimed at elucidating the brainstem-spinal mechanisms of postural suppression evoked by stimulating the dorsal portion of the caudal tegmental field (DTP) in the pons. For this purpose, we first sampled a group of reticulospinal neurons located in the medial part of medullary reticular formation, which were activated ortho-dromically and antidromically by stimulating the DTF area and the first lumbar spinal segment, respectively (DTF-RS neurons; N = 26). These DTF-RS neurons were located within the nucleus reticularis gigantocellularis (NRGc) and projected their descending axons to the lumbar spinal cord through the ventrolateral funiculus. The postsynaptic inhibitory effects of single DTF-RS neurons upon hindlimb alpha-MNs intracellularly recorded (N = 78) were then studied with spike-triggered averaging. Twelve DTF-RS neurons evoked IPSPs in 21 hindlimb alpha-MNs. Five DTF-RS neurons exerted postsynaptic inhibitory effects upon more than one alpha-MNs. These alpha-MNs were located from L5 to S1 segments of the spinal cord. A mean latency of IPSPs which was measured from the onset of the trigger spike was 5.1 ms with time to peak of 1.8 ms, and the mean segmental delay of the IPSPs was 1.5 ms, which was measured from the onset of the descending axonal volley recorded extracellularly adjacent to alpha-MNs. Amplitudes of the IPSPs were augmented with an increase in the firing frequencies of the DTF-RS neurons, the increase being produced by iontophoretic application of glutamate. These characteristics of the IPSPs suggest that reticular effects are mediated at least by a single spinal inhibitory interneuron. These results suggest that the DTF-NRGc system participates in generalized motor inhibition.

Medullary reticulospinal tract mediating the generalized motor inhibition in cats: Parallel inhibitory mechanisms acting on motoneurons and on interneuronal transmission in reflex pathways

The present study was designed to elucidate the spinal interneuronal mechanisms of motor inhibition evoked by stimulating the medullary reticular formation. Two questions were addressed. First, whether there is a parallel motor inhibition to motoneurons and to interneurons in reflex pathways. Second, whether the inhibition is mediated by interneurons interposed in known reflex pathways. We recorded the intracellular activity of hindlimb motoneurons in decerebrate cats and examined the effects of medullary stimulation on these neurons and on interneuronal transmission in reflex pathways to them. Stimuli (three pulses at 10-60microA and 1-10ms intervals) delivered to the nucleus reticularis gigantocellularis evoked inhibitory postsynaptic potentials in alpha-motoneurons (n=147) and gamma-motoneurons (n=5) with both early and late latencies. The early inhibitory postsynaptic potentials were observed in 66.4% of the motoneurons and had a latency of 4.0-5.5ms with a segmental delay of more than 1.4ms. The late inhibitory postsynaptic potentials were observed in 98.0% of the motoneurons and had a latency of 30-35ms, with a peak latency of 50-60ms. Both types of inhibitory postsynaptic potentials were evoked through fibers descending in the ventrolateral quadrant. The inhibitory postsynaptic potentials were not influenced by recurrent inhibitory pathways, but both types were greatly attenuated by volleys in flexor reflex afferents. Conditioning medullary stimulation, which was subthreshold to evoke inhibitory postsynaptic potentials in the motoneurons, neither evoked primary afferent depolarization of dorsal roots nor reduced the input resistance of the motoneurons. However, the conditioning stimulation often facilitated non-reciprocal group I inhibitory pathways (Ib inhibitory pathways) to the motoneurons in early (<20ms) and late (30-80ms) periods. In contrast, it attenuated test postsynaptic potentials evoked through reciprocal Ia inhibitory pathways, and excitatory and inhibitory pathways from flexor reflex afferent and recurrent inhibitory pathways. The inhibitory effects were observed in both early and late periods. The present results provide new information about a parallel inhibitory process from the medullary reticular formation that produces a generalized motor inhibition by acting on alpha- and gamma-motoneurons, and on interneurons in reflex pathways. Interneurons receiving inhibition from flexor reflex afferents and a group of Ib interneurons may mediate the inhibitory effects upon motoneurons.

Discharge properties of medullary reticulospinal neurons during postural changes induced by intrapontine injections of carbachol, atropine and serotonin, and their functional linkages to hindlimb motoneurons in cats

The present study was aimed at elucidating the pontomedullary and spinal cord mechanisms of postural atonia induced by microinjection of carbachol and restored by microinjections of serotonin or atropine sulfate into the nucleus reticularis pontis oralis (NRPo). Medullary reticulospinal neurons (n=132) antidromically activated by stimulating the L1 spinal cord segment were recorded extracellularly. Seventy-eight of them were orthodromically activated with mono- or disynaptic latencies by stimulating the NRPo area at the site where carbachol injections effectively induced postural atonia. Most of these reticulospinal neurons (71 of 78) were located in the nucleus reticularis gigantocellularis (NRGc). Following carbachol injection into the NRPo, discharge rates of the NRGc reticulospinal neurons (29 of 34) increased, while the activity of soleus muscles decreased bilaterally. Serotonin or atropine injections into the same NRPo area resulted in a decrease in the discharge rates of the reticulospinal neurons with a concomitant increase in the levels of hindlimb muscle tone. Membrane potentials of hindlimb extensor and flexor alpha motoneurons (MNs) were hyperpolarized and depolarized by carbachol and serotonin or atropine injections, respectively. In all pairs of reticulospinal neurons and MNs (n=11), there was a high correlation between the increase in the discharge rates and the degree of membrane hyperpolarization of the MNs. Spike-triggered averaging during carbachol-induced atonia revealed that inhibitory postsynaptic potentials (IPSPs) were evoked in 15 MNs by the discharges of nine reticulospinal neurons. Four of them evoked IPSPs in more than one MN. The mean segmental delay and the mean time to the peak of IPSPs were 1.6 ms and 2.0 ms, respectively. Axonal trajectories of reticulospinal neurons (n=6), which evoked IPSPs in MNs, were investigated in the lumbosacral segments (L1-S1) by antidromic threshold mapping. The stem axons descended through the ventral (n=2) and ventrolateral (n=4) funiculi in the lumbar segments. All axons projected their collaterals to the intermediate region (laminae V, VI) and ventromedial part (laminae VII, VIII) of the gray matter. All these results suggest that the reticulospinal pathway originating from the NRGc is involved in postural atonia induced by pontine microinjection of carbachol, and that the pathway is inactivated during the postural restoration induced by subsequent injections of serotonin or atropine. It is further suggested that the pontine inhibitory effect is mediated via segmental inhibitory interneurons projecting to MNs.