Identifying the role of the reticulospinal tract for strength and motor recovery: A scoping review of nonhuman and human studies.

In addition to the established postural control role of the reticulospinal tract (RST), there has been an increasing interest on its involvement in strength, motor recovery, and other gross motor functions. However, there are no reviews that have systematically assessed the overall motor function of the RST. Therefore, we aimed to determine the role of the RST underpinning motor function and recovery. We performed a literature search using Ovid Medline, Embase, CINAHL Plus, and Scopus to retrieve papers using key words for RST, strength, and motor recovery. Human and animal studies which assessed the role of RST were included. Studies were screened and 32 eligible studies were included for the final analysis. Of these, 21 of them were human studies while the remaining were on monkeys and rats. Seven experimental animal studies and four human studies provided evidence for the involvement of the RST in motor recovery, while two experimental animal studies and eight human studies provided evidence for strength gain. The RST influenced gross motor function in two experimental animal studies and five human studies. Overall, the RST has an important role for motor recovery, gross motor function and at least in part, underpins strength gain. The role of RST for strength gain in healthy people and its involvement in spasticity in a clinical population has been limitedly described. Further studies are required to ascertain the role of the RST's role in enhancing strength and its contribution to the development of spasticity.

Cortical, Corticospinal, and Reticulospinal Contributions to Strength Training.

Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in 2 female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor-evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST), and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6 kg, close to the animal's body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a 2 week washout period without weights. After a further 3 months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared with the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST.SIGNIFICANCE STATEMENT We provide the first report of a strength training intervention in nonhuman primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whereas corticospinal and motoneuronal adaptations are not dominant factors.

Properties of short-latency responses in the upper limbs evoked by axial impulses during leaning: evidence for reticulospinal projections.

We studied the short-latency (SL) effects of postural perturbations produced by impulses applied over the spine of the C7 vertebra or the sternum ("axial impulses") in 12 healthy subjects. EMG recordings were made bilaterally from the triceps brachii, biceps brachii, soleus, and tibialis anterior muscles, and unilaterally from the deltoid, forearm flexors, forearm extensors, and first dorsal interosseous (FDI) muscles. Sternal impulses evoked short-latency responses in the biceps when subjects leaned posteriorly to support approximately 12% of their body weight with the arms, but these responses were only modestly larger than for isometric contraction of the arms (26.3 vs. 14.7%). In contrast, clear excitatory responses could be evoked in the deltoid, triceps, forearm muscles, and FDI when leaning anteriorly to support similar amounts of body weight. These responses were significantly larger than during isometric contraction. The deltoid (42.5%) and triceps (44.7%) had the largest responses in supported anterior lean and onset latencies increased distally in this condition (mean 31.8 ms in deltoid to 53.7 ms in FDI). There was a disproportionate delay between the forearm muscles and FDI. For both directions of lean, postural reflex responses normally present in the legs were severely attenuated. SL upper limb excitatory responses were bigger in proximal muscles as well as larger and more widespread for anterior axial perturbations compared to posterior axial perturbations when using the arms to support body weight. Our findings also provide further evidence of a role for reticulospinal pathways in mediating these rapid postural responses to accelerations of the trunk.

Mapping the functional connectivity of the substantia nigra, red nucleus and dentate nucleus: A network analysis hypothesis associated with the extrapyramidal system.

This study aimed to examine the functional networks related to the extrapyramidal system using a temporal oscillation signal correlation analysis method based on critical nodes in the substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN). Nineteen healthy subjects underwent resting-state fMRI and susceptibility weighted imaging (SWI). For the brain network analysis, the SN, RN and DN were positioned on susceptibility weighted images and used as seeds for temporal correlations analyzed via BOLD data. T-tests were performed for the correlation coefficients of each seed. We demonstrated that the SN, RN and DN were functionally connected to each other, and, in general, their connectivity maps overlapped in a series of subcortical extrapyramidal structures and regions of cerebral cortices. A Granger causality analysis indicated that the effective connectivity graphs within extrapyramidal structures mainly exhibited a spacial up-down pattern for the positive and negative influences, respectively. Our findings suggest that extensive regions involved in the extrapyramidal system constituted a relatively exclusive network via spatial-temporal correlation signals that analogously corresponded to the anatomical structures. The investigation of extrapyramidal system networks may have potential clinical implications.

Convergent synaptic inputs from the caudal fastigial nucleus and the superior colliculus onto pontine and pontomedullary reticulospinal neurons.

The caudal fastigial nucleus (FN) is known to be related to the control of eye movements and projects mainly to the contralateral reticular nuclei where excitatory and inhibitory burst neurons for saccades exist [the caudal portion of the nucleus reticularis pontis caudalis (NRPc), and the rostral portion of the nucleus reticularis gigantocellularis (NRG) respectively]. However, the exact reticular neurons targeted by caudal fastigioreticular cells remain unknown. We tried to determine the target reticular neurons of the caudal FN and superior colliculus (SC) by recording intracellular potentials from neurons in the NRPc and NRG of anesthetized cats. Neurons in the rostral NRG received bilateral, monosynaptic excitation from the caudal FNs, with contralateral predominance. They also received strong monosynaptic excitation from the rostral and caudal contralateral SC, and disynaptic excitation from the rostral ipsilateral SC. These reticular neurons with caudal fastigial monosynaptic excitation were not activated antidromically from the contralateral abducens nucleus, but most of them were reticulospinal neurons (RSNs) that were activated antidromically from the cervical cord. RSNs in the caudal NRPc received very weak monosynaptic excitation from only the contralateral caudal FN, and received either monosynaptic excitation only from the contralateral caudal SC, or monosynaptic and disynaptic excitation from the contralateral caudal and ipsilateral rostral SC, respectively. These results suggest that the caudal FN helps to control also head movements via RSNs targeted by the SC, and these RSNs with SC topographic input play different functional roles in head movements.

Evidence for reticulospinal contributions to coordinated finger movements in humans.

The reticulospinal tract was recently shown to have synaptic connections to the intrinsic muscles of the fingers in nonhuman primates, indicating it may contribute to hand function long thought to be controlled exclusively through corticospinal pathways. Our objective was to obtain evidence supporting the hypothesis that these same anatomical connections exist in humans. startReact, an involuntary release of a planned movement via the startle reflex, provides a noninvasive means to examine the reticulospinal tract in humans. We found that startReact was triggered during coordinated grasp but not individuated finger movements. This result suggests that the reticulospinal tract does have connections to the intrinsic muscles of the fingers in humans but its functional role is limited to coordinated movement of the whole hand. These results do not diminish the well-established role of corticospinal pathways in the control of hand movement. Indeed, they cement the significance of corticospinal pathways in individuated finger movement control. Still, these results point to an updated and expanded view of distal hand control where reticulospinal and corticospinal pathways work in parallel to generate a large repertoire of diverse, coordinated movement in the hand. Finally, the presence of reticulospinal pathways to the muscles of the hand makes this pathway an attractive therapeutic target for clinical populations where the corticospinal tract is absent or injured.

[Molecular, neurochemical and neurophysiological mechanisms of plasticity: realization of behavior, learning, consolidation, storage and retrieval of memory].

Described the real pyramidal and extrapyramidal neural networks of the mammalian brain, realizing asbehavior, motor control and involved in learning and memory. The algorithm of postsynaptic excitatory glutamatergic synapses plasticity analyzed, which leads to the modification and storage for a long time, the efficiency of synaptic transmission --ong-term potentiation, long-term depression. Analyzed the mechanisms of plasticity allosteric GABAA(-)redcptors. Described the molecular and cellular mechanisms of the trafficking of GABAA(-)receptors and its role in the dynamic modulation of neuronal inhibition. Analyzed molecular and cellular plasticity algorithm of allosteric GABAA(-)receptors. Discussed hypoth-sis update neural networks that is realized on a molecular level with the internalization and recycling mechanism specific GABAA(-)receptor cluster. It is assumed that the process of transfer from the memory stage storage to the stage of working memory. Deactualization of neural network, which is implemented at the molecular level by the mechanism of internalization specific cluster of GABAA(-)receptor, is a pro-ess of transferring from stage of working or random access memory in the storage stage.

The human extrapyramidal system.

The term "extrapyramidal" originally described a collection of tegmentospinal pathways that conveyed the propagation of cortically-induced seizures to the spinal cord of dogs with bilateral transection of the pyramidal tracts. The extrapyramidal concept developed into unwarranted avenues to include forebrain structures involved in motor control, such as the basal ganglia, or as a broad synonym of clinical syndromes characterized by nonparalytic abnormal involuntary movements and postures. Clinicians and pathologists assumed that, similarly to mammals in general, the human extrapyramidal system was also organized in parallel with the pyramidal tracts. Several inconsistencies of this model, as applied to humans, were overlooked despite compelling clinicoanatomic evidence showing that (i) bilateral damage to the pyramidal tracts at any level from the pontomedullary transition to the motor cortex produces the locked-in syndrome and (ii) the extrapyramidal tracts are sparse in man. In the present essay I advance the hypothesis that the human extrapyramidal system is fundamentally different from its mammalian counterparts both anatomically and functionally. To test this hypothesis, a systematic analysis of the residual motor patterns observed on a natural model of a bilateral section of the human pyramidal tracts, the locked-in syndrome, is provided. This analysis reveals that the human extrapyramidal system underpins the organization of the following categories of motor synergies: (i) oculofacial and oculocephalic, (ii) faciorespiratory, (iii) axial-appendicular, and (iv) plurisegmental. Anatomically, these functional repertoires of motor integration are mediated by six collections of axons defined by their brainstem nuclei of origin and spinal cord destinations: reticulospinal (medial and lateral), vestibulospinal (medial and lateral), rubrospinal (lateral only), and tectospinal (medial only) fiber systems. I conclude that the extrapyramidal concept can reliably be extended to humans, albeit its physiological and anatomical scope is considerably narrower than traditionally assumed.

The location of the major ascending and descending spinal cord tracts in all spinal cord segments in the mouse: actual and extrapolated.

Information on the location of the major spinal cord tracts in the mouse is sparse. We have collected published data on the position of these tracts in the mouse and have used data from other mammals to identify the most likely position of tracts for which there is no mouse data. We have plotted the position of six descending tracts (corticospinal, rubrospinal, medial and lateral vestibulospinal, rostral and caudal reticulospinal) and eight ascending tracts (gracile; cuneate; postsynaptic dorsal columns; dorsolateral, lateral, and anterior spinothalamic; dorsal and ventral spinocerebellar) on diagrams of transverse sections of all mouse spinal cord segments from the first cervical to the third coccygeal segment.

The unbearable lightness of the extrapyramidal system.

The concept of the extrapyramidal system comprises an amalgam of disparate and often conflicting ideas with a tortuous history. To the theoretical neuroscientist or practicing clinician, it promptly evokes semantic associations that are hardly reminiscent of its original meaning. The purpose of this article is to revisit the sources of the extrapyramidal concept and to examine the transformations that it went through from its inception, in the late 1890s, up to the neuroimaging revolution of the 1980s. Our review shows that the use of "extrapyramidal" as a surrogate for the basal ganglia, disorders of movement, or certain manifestations of spastic hemiplegia does not apply to humans; rather, it represents the historical product of the unwarranted translation of results of animal experimentation into the interpretation of clinical findings on human patients, misguided clinico-anatomic deductions, and fanciful phylogenetic notions. We conclude that the extrapyramidal concept is a valid and robust anatomic concept as long as it strictly refers to the collection of descending fibers originating in a few discrete brainstem tegmental motor nuclei that project to the spinal cord.

[Clinical neurological examination of the geriatric patient]. / Klinisk nevrologisk undersøkelse av den geriatriske pasient.

BACKGROUND: Numerous physiological changes occur in the nervous system with increasing age. On clinical neurological examination, such changes may be misinterpreted as pathology in the nervous system. The objective of this article is to provide a review of the clinical neurological findings that may be caused by normal ageing. MATERIAL AND METHODS: The present manuscript is based on a non-systematic search in PubMed as well as on the clinical experience of the authors. RESULTS: Cognitive functions are usually fairly well preserved in old age, apart from executive functioning, psychomotor speed and episodic memory, which are reduced with increasing age. Physiological changes related to increasing age include, in particular, vertical eye movements (upwards), vibration sense, Achilles reflexes, primitive reflexes and motor speed. Muscle power is reduced by 20-40% in healthy individuals aged over 70 years. INTERPRETATION: A correct diagnosis based on findings in the neurological examination cannot be made without knowledge of how ageing affects the physiology of the nervous system. However, the evidence regarding physiological changes in the nervous system is limited, and more research is needed in this field.

Impaired arpeggio movement in skilled reaching by rubrospinal tract lesions in the rat: a behavioral/anatomical fractionation.

Spinal cord injury damaging the rubrospinal tract (RST) interferes with skilled forelimb movement, but identification of the precise role of the RST in this behavior is impeded by the difficulty of surgically isolating the RST from other pathways running within the lateral funiculus (LF). The present study used a skilled reaching task and a behavioral/anatomical dissection method to identify the contribution of the RST to skilled forelimb movement. Rats were trained on the skilled reaching task and subjected to lesions of the LF. Based on histological evaluation, the animals were assigned to large, medium, or small LF lesion size groups. End point and arm/hand/digit movements were subsequently identified for each group. Success was impaired in all groups, but the impairment was not related to lesion size. Frame-by-frame qualitative analysis of the video recordings revealed that large LF lesions abolished the elements of digits close, digits open, arpeggio, grasp, supination 2, and release. Medium LF lesions interfered with a subset of the movement elements that were shown to be affected by the large LF lesions, namely arpeggio and grasp. Only the arpeggio movement was compromised after small LF lesions. The results show that not only does the LF contribute to skilled reaching, but because the RST was likely to have been damaged in all lesion groups, the RST is more involved in hand rotation than in digit use. The results are discussed in relation to the fiber tracts that are likely to be damaged in the different LF lesion groups.

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats.

The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.

[Features and mechanisms of realization the respiratory influences of the extrapyramydal system structures]. / Osobennosti i mechanizmy realizatsii respiratornykh vliianii struktur ékstrapiramidnoi sistemy.

In the publication the modern condition of the problem of suprabulbar regulation of breathing is analysed. The review on structure, neurochemistry and anatomic connections of the red nucleus and substantia nigra with the medullary respiratory center is submitted. The data on the respiratory effects of GABA and apomorphine microinjected into the red nucleus and substantia nigra as well as effects of their electrostimulation after the blockade of GABA and dopamine receptors in the respiratory center are discussed. The conceptual scheme of the mechanisms of realization the respiratory influences of the extrapyramydal system is offered.

Transient spinal inhibition induced by electrical stimulation of the rat brain.

Intracortical electrical stimulation of the rat brain using single pulse induced motor evoked potentials (MEPs) with shorter onset latencies in the bilateral extremity muscles. The MEPs appeared in the stimulation of cortical areas outside the motor cortex (MI) and subcortical areas. Train-pulse stimulation of the MI at a stimulus intensity just above the threshold induced MEPs with longer onset latency in muscles corresponding to the somatotopy of the MI stimulated. This implies that the potential characterizing shorter onset latency is equal to responses induced via the extrapyramidal tract, and responses with longer onset latency originate in the pyramidal tract. Corresponding to MEPs, we recorded two types of spinal potentials (SPs) via extrapyramidal and pyramidal tracts. In paired-pulse stimulation of the extrapyramidal tract, second MEPs showed a long-lasting inhibition up to 3 s after the first MEPs, while the changes in second SPs were not remarkable. Extrapyramidal tract stimulation inhibited H-reflex in the same manner as MEPs. These results suggest that the electrical stimulation of rat brain has a long-lasting effect in inhibiting lower motoneuron excitabilities. Our method may be a useful experimental model to induce the transient inhibition of spinal motoneuron excitabilities caused by supraspinal structures.

Organization of nonprimary motor cortical inputs on pyramidal and nonpyramidal tract neurons of primary motor cortex: An electrophysiological study in the macaque monkey.

To elucidate the functions of nonprimary motor cortical (nPMC) areas whose afferents synapse onto output neurons of the primary motor cortex (PMC), we examined the responses of pyramidal tract neurons (PTNs) and non-PTNs (nPTNs) to electrical stimulation in the three nPMCs, the supplementary motor area (SMA) and the dorsal and ventral divisions of the premotor cortex (PMd and PMv), with extracellular unit recording in alert monkeys. Typical responses of PTNs to nPMC stimulation were early orthodromic excitatory responses followed by inhibitory responses. Among 27 PTNs tested by constructing peri-stimulus time histograms, 19 (70.4%) showed inhibitory responses to stimulation in all of the nPMC areas. In contrast, 5/33 PTNs (15.2%) and 10/72 nPTNs (13.9%) showed excitatory responses to stimulation in all of the nPMCs. The inhibitory responses of PTNs were mediated by inhibitory interneurons, some of which may correspond to nPTNs in the superficial layers of the PMC. These interneurons probably possess widely extended axons and nonspecifically inhibit multiple PTNs in layer V. The excitatory and inhibitory influences, and the patterns of convergence of inputs from the nPMCs onto the PTNs, are important to understand motor control by the nPMC-PMC-spinal cord pathway.

Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRgamma1 isoform.

BACKGROUND: Retinoid X receptors RXRalpha, beta and gamma exert multiple functions in the genetic regulation of mammalian signalling systems by forming heterodimeric complexes with several nuclear ligand receptors. In contrast to the widespread expression of RXRalpha and RXRbeta, the expression of RXRgamma is restricted to particular tissues in which RXRgamma1 is the major isoform expressed in the mouse corpus striatum. RESULTS: To investigate the function of this particular isoform RXRgamma1, we generated RXRgamma1 gene-knockout mice by homologous recombination in ES cells. Both heterozygous and homozygous mice showed severe runting after birth, which often resulted in the early death of mice of the 129/C57BL-6 genetic background. Independent of genetic background, however, the expression of choline acetyltransferase (ChAT) in the cholinergic interneurones in the striatum (caudal putamen) was markedly reduced in the RXRgamma1 gene-null mice. Furthermore, the mutant exhibited an altered response to the administration of dopamine receptor antagonists, haloperidol and chlorpromazine, which normally induce catalepsy in mice. CONCLUSIONS: These results strongly suggest that RXRgamma1 plays an important role in either the development or activation of cholinergic neurones in nigrostriatal extrapyramidal pathways.

Dopamine D-1 regulation of caudate neurotensin mRNA in the presence or absence of the nigrostriatal dopamine pathway.

Changes in extrapyramidal dopamine (DA) function significantly alter the activity of striatal neurotensin (NT) systems. Specifically, stimulation of DA D-1 or D-2 receptors increases or decreases striatal NT tissue levels, respectively. In contrast, removal of D-2 receptor basal activity with either an antagonist or lesion of the nigrostriatal DA projection increases striatal NT content. To understand better the significance of these changes in the levels of NT peptide, we determined the effects of treatment with the selective D-1 agonist, SKF 82958, alone or in combination with a lesion of the nigrostriatal DA pathway, on the levels of NT mRNA in various regions of the caudate nucleus. Removal of at least 90% of this DA pathway significantly increased NT mRNA in most, but not all, regions throughout the caudate nucleus. In contrast, four, but not one, administrations of SKF 82958 (2 mg kg-1 dose-1) increased NT mRNA levels in principally middle, but not rostral, caudate regions. Lesioning the nigrostriatal DA pathway enhanced the effects of SKF 82958 so that a lower, single dose (1 mg/kg) of this D-1 agonist also increased NT mRNA levels predominantly in the middle caudate sections. These findings demonstrate that DA D-1 receptors profoundly regulate the striatal expression of NT mRNA in a regionally selective fashion, which appears to be unique from that principally influenced by DA D-2 regulation.

The involvement of the mediodorsal nucleus of the thalamus and the midbrain extrapyramidal area in locomotion elicited from the ventral pallidum.

Motor activity is regulated by projections from the nucleus accumbens to the ventral pallidum, but it is unclear which efferents regulate behavioral output from the ventral pallidum. Motor activity was elicited pharmacologically by microinjecting either the mu opioid receptor agonist, Tyr-D-Ala-Gly-NmePhe-Gly-OH (DAMGO) or the glutamate receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) into the ventral pallidum. The involvement of efferent projections was determined by microinjecting the local anesthetic procaine into the mediodorsal nucleus of the thalamus (MD) or the midbrain extrapyramidal area (MEA) prior to administering DAMGO or AMPA into the ventral pallidum. The motor activity induced by DAMGO was blocked by procaine microinjected into either the MD or the MEA. In contrast, procaine microinjected into the MD did not block motor activity elicited by AMPA while procaine into the MEA abolished the behavioral activation. These data indicate that the involvement of efferent projections from the ventral pallidum to either the MD or MEA in motor activation depends upon the type of receptor stimulated in the ventral pallidum.