Locomotor Areas Research Articles

The effect of deep brain stimulation on cortico-subcortical networks in Parkinson's disease patients with freezing of gait: Exhaustive exploration of a basic model.

Current treatments of Parkinson's disease (PD) have limited efficacy in alleviating freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanisms underlying this approach are unknown. While the current rationale relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs, it is still unclear how simultaneous high-frequency DBS in two interconnected basal ganglia nuclei affects large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare effects of different stimulation modes of the network underlying FoG based on the mouse brain connectivity atlas. We develop a network-based computational framework to compare subcortical DBS targets through exhaustive analysis of the brain attractor dynamics in the healthy, PD, and DBS states. We show that combined STN+SNr DBS outperforms STN DBS in terms of the normalization of spike propagation flow in the FoG network. The framework aims to move toward a mechanistic understanding of the network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders.

Cervical neurons control locomotion

The locomotor neural network consisting of genetically defined interneuronal populations is primarily located in the ventromedial region of the lumbar enlargement. Long direct reticulospinal projections have shown to be critical for the activation of this lumbar locomotor network. While, much less is known about the functional connectivity of the cervical propriospinal input during overground locomotion. Here, we first prove that the cervical neurons constitute a major excitatory pathway to locomotor areas of the lumbar spinal cord. Further, we found that cervical spondylotic myelopathy (CSM), the most common form of spinal cord injury selectively disrupts the cervical propriospinal input, and not the reticulospinal, to the lumbar locomotor network. This finding was associated with specific loss of glutamatergic neurons in the rhythmogenic segments of lumbar cord and subsequent decrease in cadence, speed and mobility during overground locomotion. The gradual loss of speed and cadence over time with intact reticulospinal tracts and early disruption of the cervical excitatory monosynaptic input onto excitatory lumbar neurons early in CSM indicate an important role of specific cervico–lumbar pathway in locomotion. To further prove this, we initially ablated the lumbar projecting cervical neurons in naïve mice by employing a dual‐injection experiment. Gait analysis during overground locomotion demonstrated that ablation of these neurons resulted in progressively decreased speed and cadence compared to controls. These neurobehavioural results closely mirrored the locomotion deficits seen in severe human and mice CSM. In addition and similar to the neuroanatomical changes noticed in the severe CSM, stereological analysis demonstrated a decreased number of neurons in the lumbar enlargement of the AAV‐DTA treated animals compared to controls. To further confirm the role of lumbar projecting cervical neurons in initiating and maintaining locomotion, we next selectively silenced the lumbar‐projecting cervical neurons using TeLC. Overtime, TeLC treated animals demonstrated decreased locomotor speed, cadence and overall mobility compared to controls. This phenotype was characterized by a significant increase in the inactive time and decrease in the mobile time and mobile counts compared to control mice indicative of a perturbed ability to initiate and maintain mobility. TeLC‐mediated silencing closely reproduced the locomotor phenotype of CSM and DTA treated animals.

Descending Command Neurons in the Brainstem that Halt Locomotion

The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.

Are white matter abnormalities associated with “unexplained dizziness”?

IntroductionAlthough cerebral small vessel disease is a significant contributor to the development of imbalance and falls in the elderly, whether it causes dizziness is not known. MethodsA retrospective case analysis was conducted for 122 dizzy patients referred to two neuro-otology tertiary centres in London and Pisa. Patients were divided into ‘explained’ causes of dizziness (e.g. benign positional vertigo, vestibular neuritis, orthostatic hypotension, cerebellar ataxias) and ‘unexplained’ dizziness. White matter hyperintensities (WMH) in MRI (T2 weighted and FLAIR sequences) were blindly rated according to the Fazekas scale. Results122 patients; 58 (mean age=72, SD=7.95years) in the ‘unexplained’ group and 64 (mean age=72.01, SD=8.28years) in the ‘explained’ group were recruited. The overall frequency of lesions (Fazekas 1–3) significantly differed between groups (p=0.011). The frequency of severe lesions (Fazekas 3) was significantly higher in the ‘unexplained’ group (22%) than in the ‘explained’ group (5%; p=0.003). ConclusionIncreased severity of WMH in cases of unexplained dizziness suggests that such abnormalities are likely contributory to the development of dizziness. WM lesions may induce dizziness either because patients perceive a degree of objective unsteadiness or by a disconnection syndrome involving vestibular or locomotor areas of the brain.

Activation of spinal locomotor circuits in the decerebrated cat by spinal epidural and/or intraspinal electrical stimulation

The present study was designed to further compare the stepping-like movements generated via epidural (ES) and/or intraspinal (IS) stimulation. We examined the ability to generate stepping-like movements in response to ES and/or IS of spinal lumbar segments L1–L7 in decerebrate cats. ES (5–10Hz) of the dorsal surface of the spinal cord at L3–L7 induced hindlimb stepping-like movements on a moving treadmill belt, but with no rhythmic activity in the forelimbs. IS (60Hz) of the dorsolateral funiculus at L1–L3 (depth of 0.5–1.0mm from the dorsal surface of the spinal cord) induced quadrupedal stepping-like movements. Forelimb movements appeared first, followed by stepping-like movements in the hindlimbs. ES and IS simultaneously enhanced the rhythmic performance of the hindlimbs more robustly than ES or IS alone. The differences in the stimulation parameters, site of stimulation, and motor outputs observed during ES vs. IS suggest that different neural mechanisms were activated to induce stepping-like movements. The effects of ES may be mediated more via dorsal structures in the lumbosacral region of the spinal cord, whereas the effects of IS may be mediated via more ventral propriospinal networks and/or brainstem locomotor areas. Furthermore, the more effective facilitation of the motor output during simultaneous ES and IS may reflect some convergence of pathways on the same interneuronal populations involved in the regulation of locomotion.

Brain activation pattern related to gait disturbances in Parkinson's disease

Gait disturbances represent a therapeutic challenge in Parkinson's disease (PD). To further investigate their underlying pathophysiological mechanisms, we compared brain activation related to mental imagery of gait between 15 PD patients and 15 age-matched controls using a block-design functional MRI experiment. On average, patients showed altered locomotion relatively to controls, as assessed with a standardized gait test that evaluated the severity of PD-related gait disturbances on a 25-m path. The experiment was conducted in the subjects as they rehearsed themselves walking on the same path with a gait pattern similar as that during locomotor evaluation. Imagined walking times were measured on a trial-by-trial basis as a control of behavioral performance. In both groups, mean imagined walking time was not significantly different from that measured during real gait on the path used for evaluation. The between-group comparison of the mental gait activation pattern with reference to mental imagery of standing showed hypoactivations within parieto-occipital regions, along with the left hippocampus, midline/lateral cerebellum, and presumed pedunculopontine nucleus/mesencephalic locomotor area, in patients. More specifically, the activation level of the right posterior parietal cortex located within the impaired gait-related cognitive network decreased proportionally with the severity of gait disturbances scored on the path used for gait evaluation and mental imagery. These novel findings suggest that the right posterior parietal cortex dysfunction is strongly related to the severity of gait disturbances in PD. This region may represent a target for the development of therapeutic interventions for PD-related gait disturbances.

Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate

The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro-cuneiform nucleus pathway could control axial posture whereas the pallido-pedunculopontine nucleus pathway could modulate locomotion.

Turning the PAGe on central control of the exercise pressor reflex in humans

experiments in biological science are often envisioned as ultimately providing rational approaches to problems confronting human health. Additionally, pragmatic solutions evoked by clinical problems often provoke new questions in basic science. Deep brain stimulation therapy in human patients with

Localization, pharmacology, and organization of brain locomotor areas in larval lamprey

In larval lamprey, spinal locomotor activity can be initiated by pharmacological microstimulation from the following higher order brain locomotor areas [Paggett et al. (2004) Neuroscience 125:25–33; Jackson et al. (2007) J Neurophysiol 97:3229–3241]: rostrolateral rhombencephalon (RLR); ventromedial diencephalon (VMD); or dorsolateral mesencephalon (DLM). In the present study, pharmacological microstimulation with excitatory amino acids (EAAs) or their agonists in the brains of in vitro brain/spinal cord preparations was used to determine the sizes, pharmacology, and organization of these locomotor areas. First, the RLR, DLM and VMD locomotor areas were confined to relatively small areas of the brain, and stimulation as little as 50 μm outside these areas was ineffective or elicited tonic or uncoordinated motor activity. Second, pharmacological stimulation with NMDA, kainate, or AMPA in the VMD or DLM reliably initiated well-coordinated spinal locomotor activity. In the RLR, stimulation with all three ionotropic EAA receptor agonists could initiate spinal locomotor activity, but NMDA or AMPA was more reliable than kainate. Third, with synaptic transmission blocked only in the brain, stimulation in the RLR, VMD, or DLM no longer initiated spinal locomotor activity, suggesting that these locomotor areas do not directly activate spinal locomotor networks. Fourth, following a complete transection at the mesencephalon-rhombencephalon border, stimulation in the RLR no longer initiated spinal motor activity. Thus, the RLR locomotor area does not appear able to initiate spinal locomotor activity by neural circuits confined entirely within the rhombencephalon but requires more rostral neural centers, such as those in the VMD and DLM, as previously proposed [Paggett et al. (2004) Neuroscience 125:25–33].

Evidence for a dopaminergic innervation of the pedunculopontine nucleus in monkeys, and its drastic reduction after MPTP intoxication

The involvement of the pedunculopontine nucleus (PPN) and the adjacent cuneiform nucleus (CuN), known as the mesencephalic locomotor area, in the pathophysiology of parkinsonian symptoms is receiving increasing attention. Taking into account the role of dopamine (DA) in motor control and its degeneration in Parkinson's disease, this neurotransmitter could induce dysfunction in the PPN and CuN through a direct dopaminergic innervation of these brainstem structures. This study provides the first demonstration that the PPN and CuN are innervated by dopamine transporter-bearing fibres in normal monkeys, which points to a novel dopaminergic system that targets the lower brainstem. Intoxication with MPTP induced a significant loss of dopamine transporter-positive fibres in the PPN and CuN of young (3-5 years old) acutely or chronically intoxicated monkeys compared with control animals. The more severe DA depletion found after chronic intoxication may explain, at least in part, deficits that appear late in the evolution of Parkinson's disease. A drastic loss of DA fibres was also observed in aged acutely intoxicated monkeys (about 30 years old) suggesting that age- and disease-related loss of dopaminergic fibres might be responsible for symptoms, such as gait disorders, that are more severe in elderly parkinsonian patients.

Exercise and cardiovascular risk reduction: time to update the rationale for exercise?

although it is generally accepted that the promotion of exercise accords with clinical best practice, the anecdotal experience of many primary care physicians, cardiologists, and exercise physiologists is that, even when exercise prescriptions are adhered to, risk factors often fail to demonstrate

Movements and Muscle Activity Initiated by Brain Locomotor Areas in Semi-Intact Preparations From Larval Lamprey

In in vitro brain/spinal cord preparations from larval lamprey, locomotor-like ventral root burst activity can be initiated by pharmacological (i.e., "chemical") microstimulation in several brain areas: rostrolateral rhombencephalon (RLR); dorsolateral mesencephalon (DLM); ventromedial diencephalon (VMD); and reticular nuclei. However, the quality and symmetry of rhythmic movements that would result from this in vitro burst activity have not been investigated in detail. In the present study, pharmacological microstimulation was applied to the above brain locomotor areas in semi-intact preparations from larval lamprey. First, bilateral pharmacological microstimulation in the VMD, DLM, or RLR initiated symmetrical swimming movements and coordinated muscle burst activity that were virtually identical to those during free swimming in whole animals. Unilateral microstimulation in these brain areas usually elicited asymmetrical undulatory movements. Second, with synaptic transmission blocked in the brain, bilateral pharmacological microstimulation in parts of the anterior (ARRN), middle (MRRN), or posterior (PRRN) rhombencephalic reticular nucleus also initiated symmetrical swimming movements and muscle burst activity. Stimulation in effective sites in the ARRN or PRRN initiated higher-frequency locomotor movements than stimulation in effective sites in the MRRN. Unilateral stimulation in reticular nuclei elicited asymmetrical rhythmic undulations or uncoordinated movements. The present study is the first to demonstrate in the lamprey that stimulation in higher-order locomotor areas (RLR, VMD, DLM) or reticular nuclei initiates and sustains symmetrical, well-coordinated locomotor movements and muscle activity. Finally, bilateral stimulation was a more physiologically realistic test of the function of these brain areas than unilateral stimulation.

Reversibility of Exercise-Induced Neuroplasticity in Brain Cardiorespiratory and Locomotor Areas following Exercise Detraining

Reversibility of Exercise-Induced Neuroplasticity in Brain Cardiorespiratory and Locomotor Areas following Exercise Detraining

Reversibility of exercise-induced dendritic attenuation in brain cardiorespiratory and locomotor areas following exercise detraining

It has been shown previously that dendritic branching in cardiorespiratory and locomotor brain areas can be attenuated with exercise training (ET). It was not known whether this process was reversible. Twenty-three (n = 23) male Sprague-Dawley rats were individually caged and divided into two groups: untrained (UN; n = 11) and detrained (DTR; n = 12). DTR were provided with a running wheel at 21 days of age and exercised spontaneously. After 120 days (70 days of ET followed by 50 days of detraining), ET indexes were obtained, including maximal oxygen uptake, percent body fat, resting heart rate, and heart weight-to-body weight ratios. The brain was processed according to a modified Golgi-Cox procedure. Impregnated neurons from the periaqueductal gray (PAG), posterior hypothalamic area (PH), nucleus of the tractus solitarius (NTS), and cuneiform nucleus (CfN) were examined in coronal sections. Neurons were traced using a camera lucida technique and analyzed using the Sholl concentric ring analysis of dendritic branching. t-Tests compared the mean number of intersections per neuron by grouping inner rings, outer rings, and total number of intersections per animal. There were no significant differences between UN and DTR in PH, PAG, CfN, and NTS in the inner rings, outer rings, and total number of intersections per animal. A separate group of animals was used to show that a training effect in the CfN and NTS was present at 56 days of ET. Our results show that dendritic attenuation resulting from 70 days of ET in PH, PAG, CfN, and NTS is completely reversed with 50 days of detraining.

Neuroplastic adaptations to exercise: neuronal remodeling in cardiorespiratory and locomotor areas

Neuronal activity has been shown to be attenuated in cardiorespiratory and locomotor centers of the brain in response to a single bout of exercise in trained (TR) vs. untrained (UN) animals, but the mechanisms remain obscure. Based on this finding, dendritic branching patterns of seven brain areas associated with cardiorespiratory and locomotor activity were examined in TR and UN animals. Twenty-eight male Sprague-Dawley rats were kept in individual cages and divided into TR and UN. TR were provided with a running wheel and exercised spontaneously. After 85 or 120 days, exercise training indexes were obtained, including maximal oxygen consumption, percent body fat, resting heart rate, and heart weight-to-body weight ratios. The brain was removed and processed according to a modified Golgi-Cox procedure. Impregnated neurons from seven brain areas were examined in coronal sections: the periaqueductal gray, posterior hypothalamic area, nucleus of the tractus solitarius, rostral ventrolateral medulla, cuneiform nucleus, nucleus cuneatus, and cerebral cortex. Neurons were traced using a camera lucida technique and analyzed using the Sholl analysis of dendritic branching. t-tests were conducted to compare the mean number of intersections per neuron by grouping inner rings and outer rings and also comparing the total number of intersections per animal. There were significant differences between groups in the posterior hypothalamic area, periaqueductal gray, cuneiform nucleus, and nucleus of the tractus solitarius in the inner rings, outer rings, and the total number of intersections per animal. Our results show that dendritic fields of neurons in important cardiorespiratory and locomotor centers of the brain are attenuated in TR animals.

Comparing Motor Development of Deaf Children of Deaf Parents and Deaf Children of Hearing Parents

Deaf children of Deaf parents perform better academically (Ritter-Brinton & Stewart, 1992), linguistically (Courtin, 2000; M. Harris, 2001; Vaccari & Marschark, 1997), and socially (Hadadian & Rose, 1991; M. Harris, 2001) than Deaf children of hearing parents. Twenty-nine Deaf children in residential schools were assessed to determine if a significant difference also exists in motor development between Deaf children with Deaf parents and Deaf children with hearing parents. In the locomotor area, 78.6% of Deaf children of Deaf parents and 73.3% of Deaf children of hearing parents reached or surpassed average performance levels. In regard to object control, 92.9% of Deaf children of Deaf parents and 93.3% of Deaf children of hearing parents reached or surpassed average performance levels. The study results show no significant difference between the motor development of Deaf children of Deaf parents and Deaf children of hearing parents.

Métabosensibilité musculaire et adaptations physiologiques au cours de l’exercice

The first role played by group III (thin myelinated) and group IV (unmyelinated) afferent fibres from skeletal muscle is to transmit nociceptive information from muscle to the central nervous system. The second role of these free endings located in the interstitium of the muscle is to induce cardiovascular and respiratory adjustments during muscular exercise. These respiratory and circulatory responses during muscular exercise may be reflexly induced via muscular afferents. Indeed, static contraction of hindlimb muscles in anaesthetised mammals has been shown to reflexly increase the ventilatory function, the myocardial contractility and heart rate. The mechanical muscle deformation and the accumulation of metabolites in its intersitium are the cause of raised activity in small nerve fibres which in turn induces the physiological responses. It is also admitted that the central locomotor areas on the medullary and spinal neuronal pools control ventilatory and cardiovascular function during exercise. This mechanism is called "central command". Furthermore, adjustments of the locomotor activity during exercise is mediated by the thinly myelinated and unmyelinated fibres with endings in the working muscle. These fibres, also called "metaboreceptor" may be responsible of the coupling between the ventilation and the locomotion. Thickly myelinated muscle afferents (i.e. group I and II) appear to play little role in causing the reflex autonomic responses to contraction.

Organization of higher-order brain areas that initiate locomotor activity in larval lamprey

In the lamprey, spinal locomotor activity can be initiated by pharmacological microstimulation in several brain areas: rostrolateral rhombencephalon (RLR); dorsolateral mesencephalon (DLM); ventromedial diencephalon (VMD); and reticular nuclei. During DLM- or VMD-initiated locomotor activity in in vitro brain/spinal cord preparations, application of a solution that focally depressed neuronal activity in reticular nuclei often attenuated or abolished the locomotor rhythm. Electrical microstimulation in the DLM or VMD elicited synaptic responses in reticulospinal (RS) neurons, and close temporal stimulation in both areas evoked responses that summated and could elicit action potentials when neither input alone was sufficient. During RLR-initiated locomotor activity, focal application of a solution that depressed neuronal activity in the DLM or VMD abolished or attenuated the rhythm. These new results suggest that neurons in the RLR project rostrally to locomotor areas in the DLM and VMD. These latter areas then appear to project caudally to RS neurons, which probably integrate the synaptic inputs from both areas and activate the spinal locomotor networks. These pathways are likely to be important components of the brain neural networks for the initiation of locomotion and have parallels to locomotor command systems in higher vertebrates.

The cellular and fiber organization of the locomotor areas of the brain stem of the cat.

The cellular and fiber organization of the locomotor areas of the brain stem of the cat.

The effect of selective brainstem or spinal cord lesions on treadmill locomotion evoked by stimulation of the mesencephalic or pontomedullary locomotor regions

The descending pathways from the brainstem locomotor areas were investigated by utilizing reversible cooling (to block synaptic or fiber transmission) and irreversible subtotal lesions of the brainstem or spinal cord (C2-C3 level). Experiments were conducted on decerebrate cats induced to walk on a treadmill by electrical stimulation of the brainstem. Locomotion produced by stimulation of the mesencephalic locomotor region (MLR) was not abolished by caudal brainstem lesions that isolated the lateral tegmentum or by extended rostral/caudal dorsal hemisections of the spinal cord. These results demonstrate that the MLR does not require a pathway projecting through the lateral tegmentum of the brainstem or the dorsal half of the spinal cord, as previously suggested (Mori et al., 1977, 1978b; Shik and Yagodnitsyn, 1978; Shik, 1983). Rather, the results indicate that the descending pathway originating from the MLR projects through the medial reticular formation (MedRF) and the ventral half of the spinal cord. Locomotion produced by stimulation of the pontomedullary locomotor region (PLR) was blocked by reversible cooling of either the MedRF or the ventrolateral funiculus of the spinal cord. In some cases, locomotion could be produced by stimulation of the PLR following extended dorsal hemisections of the spinal cord. These results demonstrate that the PLR can also produce locomotion by activation of cells in the MedRF that project caudally through the ventral half of the spinal cord. Stimulation of the PLR could also elicit locomotion following its surgical isolation from the MedRF of the brainstem. Furthermore, lesions of the dorsal spinal cord resulted in the loss of PLR-evoked locomotion in some, but not all, cases. Thus, an alternative projection of the PLR through the dorsal half of the spinal cord (Kazennikov et al., 1980, 1983a,b; Shik, 1983) cannot be ruled out. Overall, these results demonstrate that the PLR is not an essential component of the motor pathway originating from the MLR. The organizational scheme of "brainstem locomotor regions" is discussed in the context of recent information demonstrating a link between the sensory component of the trigeminal system and locomotor pathways (Noga et al., 1988).