Cuneiform Nucleus Research Articles

The anterior and posterior pedunculopontine tegmental nucleus are involved in behavior and neuronal activity of the cuneiform and entopeduncular nuclei

Loss of cholinergic neurons in the mesencephalic locomotor region, comprising the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), is related to gait disturbances in late stage Parkinson’s disease (PD). We investigate the effect of anterior or posterior cholinergic lesions of the PPN on gait-related motor behavior, and on neuronal network activity of the PPN area and basal ganglia (BG) motor loop in rats.Anterior PPN lesions, posterior PPN lesions or sham lesions were induced by stereotaxic microinjection of the cholinergic toxin AF64-A or vehicle in male Sprague–Dawley rats. First, locomotor activity (open field), postural disturbances (Rotarod) and gait asymmetry (treadmill test) were assessed. Thereafter, single-unit and oscillatory activities were measured in the non-lesioned area of the PPN, the CnF and the entopeduncular nucleus (EPN), the BG output region, with microelectrodes under urethane anesthesia. Additionally, ECoG was recorded in the motor cortex.Injection of AF64-A into the anterior and posterior PPN decreased cholinergic cell counts as compared to naive controls (P<0.001) but also destroyed non-cholinergic cells. Only anterior PPN lesions decreased the front limb swing time of gait in the treadmill test, while not affecting other gait-related parameters tested. Main electrophysiological findings were that anterior PPN lesions increased the firing activity in the CnF (P<0.001). Further, lesions of either PPN region decreased the coherence of alpha (8–12Hz) band between CnF and motor cortex (MCx), and increased the beta (12–30Hz) oscillatory synchronization between EPN and the MCx.Lesions of the PPN in rats had complex effects on oscillatory neuronal activity of the CnF and the BG network, which may contribute to the understanding of the pathophysiology of gait disturbance in PD.

Functional magnetic resonance imaging of pain-related brainstem nuclei in single subjects at 7 Tesla

Background The function or dysfunction of pain-related nuclei in the brainstem has only been scarcely studied in humans due to the lack of non-invasive measurement methods. The performance of functional magnetic resonance imaging (fMRI), a standard non-invasive technique, is hampered by the close vicinity of the brainstem to large arteries and ventricles as well as its propensity to spatial distortions caused by the oral cavity. Furthermore, the small average size of brainstem nuclei necessitates higher spatial resolution and accuracy than in studies of the cortex. Here, we present a new approach based on ultra-high field fMRI acquisition at 7 Tesla and a brainstem-optimized analysis method (mICA), which we apply to study pain-related activity and connectivity of brainstem nuclei in single subjects. Methods Following a multi-modal imaging approach based entirely on echo-planar imaging, we acquired distortion matched functional, T1-weighted structural as well as diffusion-weighted images at a resolution of 1.2 mm isotropic. Five 6 min runs of resting-state fMRI were acquired, during two of which subjects received a continuous pressure pain stimulus applied to their lower leg by an inflatable cuff. Results Pain intensity was percept matched at 50/100 points on a visual analogue scale. Applying our recently developed mICA approach (masked independent component analysis), we were able to detect reproducible resting-state activity for specific brainstem nuclei, like the cuneiform nuclei, periaqueductal grey and as well as brainstem-cortex functional connectivity at the single-subject level. We identified a number of pain-related nuclei that showed distinctive activity changes during pain stimulation. Conclusions Identification of nuclei was greatly aided by fractional anisotropy (FA) maps created from the diffusion data. Finally, assessing activity and functional connectivity of brainstem nuclei on the single-subject level may soon give us a deeper understanding of disease subtypes, individual differences in pain processing, as well as other functions localized in the brainstem.

Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control

IntroductionChronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in patients with cough is...

Brainstem processing of peripheral punctate stimuli in patients with and without chemotherapy-induced peripheral neuropathy: a prospective cohort functional MRI study

BackgroundChemotherapy-induced peripheral neuropathy affects 30% of cancer survivors. Findings from animal studies suggest that brainstem descending inhibitory pathways are important in chronic neuropathic pain. An aberrant descending pain modulation system has been implicated in human neuropathic pain. Whether aberrant descending pain modulation before chemotherapy is associated with development of chemotherapy-induced peripheral neuropathy is unclear. We aimed to assess descending pain modulation systems using functional MRI (fMRI) in chemotherapy-naive patients with cancer to determine whether differences are associated with subsequent development of the neuropathy. MethodsIn this multicentre prospective cohort study, adult patients with cancer and no chronic pain, neuropathy, or risk factors for neuropathy were recruited from the oncology clinic before onset of chemotherapy. After patients had given written informed consent, descending inhibitory pathways were challenged (jittered punctate stimuli 256 mN Somedic von Frey filament) during a 3T fMRI scan, and images analysed with FSL software. Sample size was based on published fMRI estimates. Chemotherapy-induced peripheral neuropathy was diagnosed with the CIPN20 questionnaire. Findings30 patients were recruited (mean age 60·4 years [SD 7·9]). We report a preliminary analysis of the first 12 patients (60·6 [8·3], six women); six had colorectal cancer, four gynaecological cancer, and two lung cancer. Seven patients (three men, four women) developed chemotherapy-induced peripheral neuropathy. After data brain extraction, registration, B0 unwarping, and motion correction, FEAT was used for first and second level analysis. Mean group level comparisons between patients with and without the neuropathy were conducted with mixed-effects analysis (z threshold 2·3, regions considered significant at p<0·05, cluster uncorrected for preliminary analysis) and adjusted for sex, age, and cancer type. Patients with chemotherapy-induced peripheral neuropathy had increased activation in the nucleus cuneiformis and primary somatosensory cortex compared with patients who did not develop the disorder. InterpretationThese preliminary results suggest that baseline differences exist, before peripheral nerve injury, in the descending pain modulation system of patients who go on to develop chemotherapy-induced peripheral neuropathy. These differences might aid development of biomarkers to guide chemotherapy choices. Limitations of the study include the small sample size for the present analysis, the observational nature of the study, and the possibility of unknown confounders. Strengths include the prospective design in a unique patient cohort and the high sensitivity of fMRI. FundingWellcome Trust via Scottish Translational Medicine and Therapeutics Initiative (STMTI).

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

This study examined whether peripheral inflammatory injury increases the levels or changes the disposition of substance P (SubP) in the rostral ventromedial medulla (RVM), which serves as a central relay in bulbospinal pathways of pain modulation. Enzyme immunoassay and reverse transcriptase quantitative polymerase chain reaction were used to measure SubP protein and transcript, respectively, in tissue homogenates prepared from the RVM and the periaqueductal gray (PAG) and cuneiform nuclei of rats that had received an intraplantar injection of saline or complete Freund’s adjuvant (CFA). Matrix-Assisted Laser Desorption/Ionization Time of Flight analysis confirmed that the RVM does not contain hemokinin-1 (HK-1), which can confound measurements of SubP because it is recognized equally well by commercial antibodies for SubP. Levels of SubP protein in the RVM were unchanged four hours, four days and two weeks after injection of CFA. Tac1 transcripts were similarly unchanged in the RVM four days or two weeks after CFA. In contrast, the density of SubP immunoreactive processes in the RVM increased 2-fold within four hours and 2.7-fold four days after CFA injection; it was unchanged at two weeks. SubP-immunoreactive processes in the RVM include axon terminals of neurons located in the PAG and cuneiform nucleus. SubP content in homogenates of the PAG and cuneiform nucleus was significantly increased four days after CFA, but not at four hours or two weeks. Tac1 transcripts in homogenates of these nuclei were unchanged four days and two weeks after CFA. These findings suggest that there is an increased mobilization of SubP within processes in the RVM shortly after injury accompanied by an increased synthesis of SubP in neurons that project to the RVM. These findings are consonant with the hypothesis that an increase in SubP release in the RVM contributes to the hyperalgesia that develops after peripheral inflammatory injury.

Brainstem control of locomotion and muscle tone with special reference to the role of the mesopontine tegmentum and medullary reticulospinal systems.

The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made.

Melanocortin-4 receptor expression in the cuneiform nucleus is involved in modulation of opioidergic signaling.

Substantial evidence has suggested that deep brain stimulation of the cuneiform nucleus has become a remarkable treatment option for intractable pain, but the possible mechanism is poorly understood. Using a melanocortin-4 receptor (MC4R)-green fluorescent protein (GFP) reporter knockin mouse, we showed that a large number of MC4R-GFP-positive neurons were expressed in the cuneiform nucleus. Immunofluorescence revealed that approximately 40%-50% of MC4R-GFP-positive neurons expressed mu opioid receptors, indicating that they were opioidergic signaling. Our findings support the hypothesis that MC4R expression in the cuneiform nucleus is involved in the modulation of opioidergic signaling.

Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons.

Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal-promoting effects of NPS make the NPS–NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 ± 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kölliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.

Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T

The brainstem is a major site of processing and modulation of nociceptive input and plays a key role in the pathophysiology of various headache disorders. However, human imaging studies on brainstem function following trigeminal nociceptive stimulation are scarce as brainstem specific imaging approaches have to address multiple challenges such as magnetic field inhomogeneities and an enhanced level of physiological noise. In this study we used a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation to achieve detailed insight into physiological brainstem mechanisms of trigeminal nociception. We conducted a study of 21 healthy participants using a nociceptive ammonia stimulation of the left nasal mucosa with an optimized MR acquisition protocol for high resolution brainstem echoplanar imaging in combination with two different noise correction techniques. Significant BOLD responses to noxious ammonia stimulation were observed in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, secondary somatosensory cortex, insular cortex and cerebellum as well as in a pain modulating network including the periaqueductal gray area, hypothalamus (HT), locus coeruleus and cuneiform nucleus (CNF). Activations of the left CNF were positively correlated with pain intensity ratings. Employing psychophysiological interaction (PPI) analysis we found enhanced functional connectivity of the sTN with the contralateral sTN and HT following trigeminal nociception. We also observed enhanced functional connectivity of the CNF with the RVM during painful stimulation thus implying an important role of these two brainstem regions in central pain processing. The chosen approach to study trigeminal nociception with high-resolution fMRI offers new insight into human pain processing and might thus lead to a better understanding of headache pathophysiology.

Pedunculopontine tegmental nucleus neurons provide reward, sensorimotor, and alerting signals to midbrain dopamine neurons

Dopamine (DA) neurons in the midbrain are crucial for motivational control of behavior. However, recent studies suggest that signals transmitted by DA neurons are heterogeneous. This may reflect a wide range of inputs to DA neurons, but which signals are provided by which brain areas is still unclear. Here we focused on the pedunculopontine tegmental nucleus (PPTg) in macaque monkeys and characterized its inputs to DA neurons. Since the PPTg projects to many brain areas, it is crucial to identify PPTg neurons that project to DA neuron areas. For this purpose we used antidromic activation technique by electrically stimulating three locations (medial, central, lateral) in the substantia nigra pars compacta (SNc). We found SNc-projecting neurons mainly in the PPTg, and some in the cuneiform nucleus. Electrical stimulation in the SNc-projecting PPTg regions induced a burst of spikes in presumed DA neurons, suggesting that the PPTg–DA (SNc) connection is excitatory. Behavioral tasks and clinical tests showed that the SNc-projecting PPTg neurons encoded reward, sensorimotor and arousal/alerting signals. Importantly, reward-related PPTg neurons tended to project to the medial and central SNc, whereas sensorimotor/arousal/alerting-related PPTg neurons tended to project to the lateral SNc. Most reward-related signals were positively biased: excitation and inhibition when a better and worse reward was expected, respectively. These PPTg neurons tended to retain the reward value signal until after a reward outcome, representing ‘value state’; this was different from DA neurons which show phasic signals representing ‘value change’. Our data, together with previous studies, suggest that PPTg neurons send positive reward-related signals mainly to the medial–central SNc where DA neurons encode motivational values, and sensorimotor/arousal signals to the lateral SNc where DA neurons encode motivational salience.

Spinal and supraspinal processing of thermal stimuli: an fMRI study.

To assess and characterize responses to innocuous/noxious thermal stimuli and heat allodynia using functional spinal magnetic resonance imaging (spinal fMRI). Spinal/supraspinal activation patterns of 16 healthy subjects were investigated by applying painful and nonpainful heat stimuli to dermatome C6 baseline and after sensitization with the heat/capsaicin model using fMRI (3T, single-shot TSE, TR 9000 msec, TE 38 msec, FOV 288 × 144 × 20 mm, matrix 192 × 96, voxel size 1 × 1 × 2 mm). Increased activity was observed in ipsi- and contralateral ventral and dorsal spinal horn during noxious heat and heat allodynia. During noxious heat, but not during heat allodynia, activations were visible in the periaqueductal gray, ipsilateral cuneiform nucleus, and ipsilateral dorsolateral pontine tegmentum (DLPT). However, during heat allodynia activations were observed in bilateral ruber nuclei, contralateral DLPT, and rostral ventromedial medulla oblongata (RVM). Activations in contralateral subnucleus reticularis dorsalis (SRD) were visible during both noxious heat and heat allodynia (T >2.5, P < 0.01 for all of the above). After sensitization, activations in RVM and SRD correlated with activations in the ipsilateral dorsal horn of the spinal cord (R = 0.52-0.98, P < 0.05). Spinal fMRI successfully demonstrates increased spinal activity and secondary changes in activation of supraspinal centers involved in pain modulation caused by peripheral nociceptor sensitization. J. Magn. Reson. Imaging 2015;41:1046-1055. © 2014 Wiley Periodicals, Inc.

Allodynia and Descending Pain Modulation in Migraine: A Resting State Functional Connectivity Analysis

Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions. Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls. Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls. Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.

Pedunculopontine Nucleus Area Oscillations during Stance, Stepping and Freezing in Parkinson’s Disease

The pedunculopontine area (PPNa) including the pedunculopontine and cuneiform nuclei, belongs to the mesencephalic locomotor region. Little is known about the oscillatory mechanisms underlying the function of this region in postural and gait control. We examined the modulations of the oscillatory activity of the PPNa and cortex during stepping, a surrogate of gait, and stance in seven Parkinson’s disease patients who received bilateral PPNa implantation for disabling freezing of gait (FOG). In the days following the surgery, we recorded behavioural data together with the local field potentials of the PPNa during sitting, standing and stepping-in-place, under two dopaminergic medication conditions (OFF and ON levodopa). Our results showed that OFF levodopa, all subjects had FOG during step-in-place trials, while ON levodopa, stepping was effective (mean duration of FOG decreasing from 61.7±36.1% to 7.3±10.1% of trial duration). ON levodopa, there was an increase in PPNa alpha (5–12 Hz) oscillatory activity and a decrease in beta (13–35 Hz) and gamma (65–90 Hz) bands activity. PPNa activity was not modulated during quiet standing and sitting. Our results confirm the role of the PPNa in the regulation of gait and suggest that, in Parkinson disease, gait difficulties could be related to an imbalance between low and higher frequencies.

Projections from the central amygdaloid nucleus to the precuneiform nucleus in the mouse

The mouse precuneiform nucleus has been proposed as the midbrain locomotion center, a function ascribed to its caudal neighbor, cuneiform nucleus, in the rat, cat and other species. The present study investigated the projections from the central amygdaloid nucleus to the precuneiform nucleus in the mouse using retrograde tracer injections (fluoro-gold) into the precuneiform nucleus and anterograde tracer injections (biotinylated dextran amine) into the central amygdaloid nucleus. The entire central amygdaloid nucleus except the rostral pole had retrogradely labeled neurons, especially in the middle portion where labeled neurons were densely packed. Anterogradely labeled amygdaloid fibers approached the precuneiform nucleus from the area ventrolateral to it and terminated in the entire precuneiform nucleus. Labeled fibers were also found in laminae 5 and 6 in the upper cervical cord on the ipsilateral side. The present study is the first demonstration of projections from the central amygdaloid nucleus to the precuneiform nucleus. This projection may underpin the role of the precuneiform nucleus in the modulation of the cardiovascular activity.

Immediate-early gene expression in structures outside the basal ganglia is associated to l-DOPA-induced dyskinesia

Long-term l-3,4-dihydroxyphenylalanine (l-DOPA) treatment in Parkinson's disease (PD) leads to l-DOPA-induced dyskinesia (LID), a condition thought to primarily involve the dopamine D1 receptor-expressing striatal medium spiny neurons. Activation of the D1 receptor results in increased expression of several molecular markers, in particular the members of the immediate-early gene (IEG) family, a class of genes rapidly transcribed in response to an external stimulus. However, several dopaminoceptive structures in the brain that are likely to be affected by the exogenously produced DA have received little attention although they might play a key role in mediating those l-DOPA-induced abnormal behaviours. ΔFosB, ARC, FRA2 and Zif268 IEGs expression patterns were thus characterised, using unbiased stereological methods, in the whole brain of dyskinetic and non-dyskinetic rats to identify brain nuclei displaying a transcriptional response specifically related to LID. Within the basal ganglia, the striatum and the substantia nigra pars reticulata showed an increased expression of all four IEGs in dyskinetic compared to non-dyskinetic rats. Outside the basal ganglia, there was a striking increased expression of the four IEGs in the motor cortex, the bed nucleus of the stria terminalis, the dorsal hippocampus, the pontine nuclei, the cuneiform nucleus and the pedunculopontine nuclei. Moreover, the zona incerta and the lateral habenula displayed an overexpression of ΔFosB, ARC and Zif268. Among these structures, the IEG expression in the striatum, the bed nucleus of the stria terminalis, the lateral habenula, the pontine nuclei and the cuneiform nucleus correlate with LID severity. These results illustrate a global transcriptional response to a dyskinetic state in the whole brain suggesting the possible involvement of these structures in LID.

Decrease of Gray Matter Volume in the Midbrain is Associated with Treatment Response in Medication-Overuse Headache: Possible Influence of Orbitofrontal Cortex

Patients with chronic daily headache and overuse of analgesics, triptans, or other acute headache compounds, are considered to suffer from medication-overuse headache (MOH). This implies that medication overuse is the cause of headache chronification. It remains a key question why only two-thirds of patients with chronic migraine-like headache and overuse of pain medication improve after detoxification, whereas the remainder continue to have chronic headache. In the present longitudinal MRI study, we used voxel-based morphometry to investigate gray matter changes related to medication withdrawal in a group of humans with MOH. As a main result, we found that only patients with significant clinical improvement showed a significant decrease of previously increased gray matter in the midbrain including periaqueductal gray matter and nucleus cuneiformis, whereas patients without improvement did not. Patients without treatment response had less gray matter in the orbitofrontal cortex. Another striking result is the correlation of treatment response with the amount of orbitofrontal gray matter. Thus, we demonstrate adaptive gray matter changes within the pain modulatory system in patients with MOH who responded to detoxification, probably reflecting neuronal plasticity. Decreased gray matter in the orbitofrontal cortex at baseline may be predictive of poor response to treatment.

Pharmacological study of cholinergic system on cardiovascular regulation in the cuneiform nucleus of rat

In the present study the effect of cholinergic system of Cuneiform nucleus (CnF) on central regulation of cardiovascular system was investigated. Two doses of acetylcholine (Ach; 90 and 150nmol), atropine (3 and 9nmol) and hexamethonium (Hexa; 100 and 300nmol) were microinjected into the CnF. The maximum changes of MAP and HR were compared with control group (independent t-test). Both doses of Ach significantly decreased MAP but had no significant effect on HR. Administration of atropine and Hexa by themselves did not alter the MAP or HR. However, both doses of atropine and higher dose of Hexa significantly attenuated the hypotensive effect of Ach with no significant effect on HR. Our results suggest the involvement of CnF cholinergic system only on central blood pressure regulation that strongly mediated by muscarinic receptors.

The cuneiform nucleus may be involved in the regulation of skeletal muscle tone by motor pathway: a virally mediated trans-synaptic tracing study in surgically sympathectomized mice

ARTICLE Sir, The review article entitled ‘The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation’ by Alam et al. (2011), addressed that the cuneiform nucleus, an adjacent region of the pedunculopontine nucleus, was the important area of the mesencephalic locomotor region and played a major role in the initiation of gait. It has been suggested by many studies that neurons in the cuneiform nucleus are involved in the generation of locomotion, and signals from the cuneiform nucleus activate central pattern generators in the spinal cord, mainly through the medullary reticulospinal tract (Takakusaki et al. , 2003). The understanding of neuroanatomical motor circuitry and neuronal connections from cuneiform nucleus to skeletal muscle is important for studying the possible mechanism of cuneiform nucleus involved in the regulation of skeletal muscle tone by motor pathway. We would like to further complete the discussion of Alam et al. (2011) by introducing a virally-mediated trans-synaptic tracing study. Deep brain stimulation has become a remarkable treatment option for several different movement disorders, such as neuropsychiatric disorders, intractable pain, epilepsy, restless legs syndrome, Parkinson’s disease, and Alzheimer’s disease (Wichmann and Delong, 2006; Halpern et al. , 2007; Lyons, 2011; Thevathasan et al. , 2011). The mesencephalic pedunculopontine tegmental nucleus has been suggested as a target for deep brain stimulation, but the exact mechanism of deep brain stimulation in the pedunculopontine tegmental nucleus area is not fully understood. Because clinical data have demonstrated that the outcome of deep brain stimulation in the pedunculopontine nucleus area can be quite variable, there is great controversy about the …

Reply: The cuneiform nucleus may be involved in the regulation of skeletal muscle tone by motor pathway: a virally mediated trans-synaptic tracing study in surgically sympathectomized mice

Sir, We appreciate the opportunity to respond to the comment by Xiang et al. (2013) on our review on interspecies differences in the pedunculopontine nucleus area. As exemplified by the data of Xiang et al. (2013) it is evident that the mesencephalic locomotor region compromises several distinct structures that are involved in initiation and inhibition of gait, and certainly the implications of both the cuneiform nucleus and the subcuneiform nucleus need to be studied in more detail. Also, as mentioned in our review, there is a paucity of data on the downstream mechanisms mediating neuronal activity in the mesencephalic locomotor region. The role of the pedunculopontine nucleus area as a target site for deep brain stimulation for treatment of medically refractory gait and postural abnormalities in late stage Parkinson’s disease and progressive supranuclear palsy still needs further clarification. Because post-mortem studies in Parkinson’s disease and progressive supranuclear palsy show ∼60% loss of cholinergic neurons in the pedunculopontine nucleus (Jellinger, 1988) it should also …

The Multifunctional Mesencephalic Locomotor Region

In 1966, Shik, Severin and Orlovskii discovered that electrical stimulation of a region at the junction between the midbrain and hindbrain elicited controlled walking and running in the cat. The region was named Mesencephalic Locomotor Region (MLR). Since then, this locomotor center was shown to control locomotion in various vertebrate species, including the lamprey, salamander, stingray, rat, guinea-pig, rabbit or monkey. In human subjects asked to imagine they are walking, there is an increased activity in brainstem nuclei corresponding to the MLR (i.e. pedunculopontine, cuneiform and subcuneiform nuclei). Clinicians are now stimulating (deep brain stimulation) structures considered to be part of the MLR to alleviate locomotor symptoms of patients with Parkinson's disease. However, the anatomical constituents of the MLR still remain a matter of debate, especially relative to the pedunculopontine, cuneiform and subcuneiform nuclei. Furthermore, recent studies in lampreys have revealed that the MLR is more complex than a simple relay in a serial descending pathway activating the spinal locomotor circuits. It has multiple functions. Our goal is to review the current knowledge relative to the anatomical constituents of the MLR, and its physiological role, from lamprey to man. We will discuss these results in the context of the recent clinical studies involving stimulation of the MLR in patients with Parkinson's disease.