Non-motor connections of the pedunculopontine nucleus of the rat and human brain.

INTRODUCTION: The connections of the pedunculopontine nucleus (PPN) with motor areas of the central nervous system (CNS) are well described in the literature, in contrast relations with non-motor areas are lacking. Thus, the aim of the present study is to define the non-motor connections of the PPN in rats using the fluoro-gold (FG) tracer and compare the presence of these connections in healthy human adults using diffusion tensor tractography (DTI). MATERIALS AND METHODS: We injected FG into the PPN of 12 rats. The non-motor connections of the PPN with cortical, subcortical, and brainstem structures were documented. The non-motor connections of the rats were compared with the DTI obtained from 35 healthy adults. RESULTS: The results of the tract-tracing study in the rat showed that the PPN was connected to non-motor cortical (cingulate, somatosensory, visual, auditory, medial frontal cortices), subcortical (amygdala, hypothalamus, thalamus, habenular, and bed nucleus of stria terminalis), and brainstem (medullary reticular, trigeminal spinal, external cuneate, pontine reticular, vestibular, superior and inferior colliculus, locus ceruleus, periaqueductal gray, parabrachial, dorsal raphe, pretectal, lateral lemniscus nuclei, and the contralateral PPN) structures. The DTI obtained from healthy adults showed similar PPN non-motor connections as in rats. CONCLUSION: Understanding the connections of the PPN with non-motor cortical, subcortical, and brainstem areas of the CNS will enrich our knowledge of its contribution in various circuits and the areas that PPN activity can influence. Further, it will provide insight into the role of Parkinson's disease and related disorders and explain the non-motor complications which occur subsequent to deep brain stimulation (DBS) of the PPN.

Whole-brain mapping of monosynaptic inputs to midbrain cholinergic neurons.

The cholinergic midbrain is involved in a wide range of motor and cognitive processes. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental nucleus (LDT) send long-ranging axonal projections that target sensorimotor and limbic areas in the thalamus, the dopaminergic midbrain and the striatal complex following a topographical gradient, where they influence a range of functions including attention, reinforcement learning and action-selection. Nevertheless, a comprehensive examination of the afferents to PPN and LDT cholinergic neurons is still lacking, partly due to the neurochemical heterogeneity of this region. Here we characterize the whole-brain input connectome to cholinergic neurons across distinct functional domains (i.e. PPN vs LDT) using conditional transsynaptic retrograde labeling in ChAT::Cre male and female rats. We reveal that input neurons are widely distributed throughout the brain but segregated into specific functional domains. Motor related areas innervate preferentially the PPN, whereas limbic related areas preferentially innervate the LDT. The quantification of input neurons revealed that both PPN and LDT receive similar substantial inputs from the superior colliculus and the output of the basal ganglia (i.e. substantia nigra pars reticulata). Notably, we found that PPN cholinergic neurons receive preferential inputs from basal ganglia structures, whereas LDT cholinergic neurons receive preferential inputs from limbic cortical areas. Our results provide the first characterization of inputs to PPN and LDT cholinergic neurons and highlight critical differences in the connectome among brain cholinergic systems thus supporting their differential roles in behavior.

Identification of the pedunculopontine nucleus and surrounding white matter tracts on 7T diffusion tensor imaging, combined with histological validation.

BACKGROUND: The pedunculopontine nucleus (PPN) has been studied as a possible target for deep brain stimulation (DBS) for Parkinson's disease (PD). However, identifying the PPN can be challenging as the PPN is poorly visualized on conventional or even high-resolution MR scans. From histological studies it is known that the PPN is surrounded by major white matter tracts, which could function as possible anatomical landmarks. METHODS: This study aimed to localize the PPN using 7T magnetic resonance (MR) imaging and diffusion tensor imaging (DTI) of its white matter borders in one post-mortem brain. Histological validation of the same specimen was performed. The PPN was segmented in both spaces, after which the two masks were compared using the Dice Similarity Index (DSI). The DSI compared the similarity of two samples on an inter-individual level and validated the MR findings. The error in distance between the center of the two 3D segmentations was measured by use of the Euclidean distance. RESULTS: The PPN can be found in between the superior cerebellar peduncle and the medial lemniscus on both the FA-maps of the DTI images and the histological sections. The histological transverse sections showed to be superior to recognize the PPN (DSI: 1.0). The DTI images have a DSI of 0.82. The overlap-masks of both spaces showed a DSI of 0.32, whereas the concatenation-masks of both spaces showed a remarkable overlap, a DSI of 0.94. Euclidean distance of the overlap- and concatenation-mask in the two spaces showed to be 1.29 mm and 1.59 mm, respectively. CONCLUSION: This study supports previous findings that the PPN can be identified using FA-maps of DTI images. For possible clinical application in DBS localization, in vivo validation of the findings of our study is needed.

Rethinking the Pedunculopontine Nucleus: From Cellular Organization to Function.

The pedunculopontine nucleus (PPN) has long been considered an interface between the basal ganglia and motor systems, and its ability to regulate arousal states puts the PPN in a key position to modulate behavior. Despite the large amount of data obtained over recent decades, a unified theory of its function is still incomplete. By putting together classical concepts and new evidence that dissects the influence of its different neuronal subtypes on their various targets, we propose that the PPN and, in particular, cholinergic neurons have a central role in updating the behavioral state as a result of changes in environmental contingencies. Such a function is accomplished by a combined mechanism that simultaneously restrains ongoing obsolete actions while it facilitates new contextual associations.

Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology.

Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.

Mesencephalic representations of recent experience influence decision making.

Decisions are influenced by recent experience, but the neural basis for this phenomenon is not well understood. Here, we address this question in the context of action selection. We focused on activity in the pedunculopontine tegmental nucleus (PPTg), a mesencephalic region that provides input to several nuclei in the action selection network, in well-trained mice selecting actions based on sensory cues and recent trial history. We found that, at the time of action selection, the activity of many PPTg neurons reflected the action on the previous trial and its outcome, and the strength of this activity predicted the upcoming choice. Further, inactivating the PPTg predictably decreased the influence of recent experience on action selection. These findings suggest that PPTg input to downstream motor regions, where it can be integrated with other relevant information, provides a simple mechanism for incorporating recent experience into the computations underlying action selection.

The pedunculopontine tegmental nucleus-A functional hypothesis from the comparative literature.

We present data from animal studies showing that the pedunculopontine tegmental nucleus-conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs-has functions that involve formation and updates of action-outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first-pass analysis of incoming sensory data. Such a function-rapid decision making-has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society.

Pedunculopontine nucleus evoked potentials from subthalamic nucleus stimulation in Parkinson's disease.

The effects of subthalamic nucleus (STN) stimulation on the pedunculopontine nucleus area (PPNR) evoked activities were examined in two patients with Parkinson's disease. The patients had previously undergone bilateral STN deep brain stimulation (DBS) and subsequently received unilateral DBS electrodes in the PPNR. Evoked potentials were recorded from the local field potentials (LFP) from the PPNR with STN stimulation at different frequencies and bipolar contacts. Ipsilateral and contralateral short latency (<2ms) PPNR responses were evoked from left but not from right STN stimulation. In both patients, STN stimulation evoked contralateral PPNR responses at medium latencies between 41 and 45ms. Cortical evoked potentials to single pulse STN stimulation were observed at latencies between 18 and 27ms. These results demonstrate a functional connection between the STN and the PPNR. It likely involves direct projections between the STN and PPNR or polysynaptic pathways with thalamic or cortical relays.

Regional anatomy of the pedunculopontine nucleus: relevance for deep brain stimulation.

The pedunculopontine nucleus (PPN) is currently being investigated as a potential deep brain stimulation target to improve gait and posture in Parkinson's disease. This review examines the complex anatomy of the PPN region and suggests a functional mapping of the surrounding nuclei and fiber tracts that may serve as a guide to a more accurate placement of electrodes while avoiding potentially adverse effects. The relationships of the PPN were examined in different human brain atlases. Schematic representations of those structures in the vicinity of the PPN were generated and correlated with their potential stimulation effects. By providing a functional map and representative schematics of the PPN region, we hope to optimize the placement of deep brain stimulation electrodes, thereby maximizing safety and clinical efficacy.

Critical evaluation of the anatomical location of the Barrington nucleus: relevance for deep brain stimulation surgery of pedunculopontine tegmental nucleus.

Deep brain stimulation (DBS) has become the standard surgical procedure for advanced Parkinson's disease (PD). Recently, the pedunculopontine tegmental nucleus (PPN) has emerged as a potential target for DBS in patients whose quality of life is compromised by freezing of gait and falls. To date, only a few groups have published their long-term clinical experience with PPN stimulation. Bearing in mind that the Barrington (Bar) nucleus and some adjacent nuclei (also known as the micturition centre) are close to the PPN and may be affected by DBS, the aim of the present study was to review the anatomical location of this structure in human and other species. To this end, the Bar nucleus area was analysed in mouse, monkey and human tissues, paying particular attention to the anatomical position in humans, where it has been largely overlooked. Results confirm that anatomical location renders the Bar nucleus susceptible to influence by the PPN DBS lead or to diffusion of electrical current. This may have an undesirable impact on the quality of life of patients.

Pedunculopontine nucleus: functional organization and clinical implications.

The pedunculopontine tegmental nucleus (PPN) is a neurochemically and functionally heterogeneous structure that occupies a strategic position in the dorsal tegmentum of the midbrain and upper pons. The PPN contains cholinergic, γ-aminobutyric acid (GABA)ergic, and glutamatergic neurons; it receives direct input from the cerebral cortex, is reciprocally connected with the basal ganglia, and provides inputs to the thalamus and motor areas of the brainstem and spinal cord. Via these connections, the PPN is involved in mechanisms of cortical arousal and behavioral state control and participates in control of locomotion and muscle tone. The PPN is affected in Parkinson disease (PD) and atypical parkinsonian syndromes such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Involvement of the PPN may have an important role in gait impairment in these disorders. The development of PPN deep brain stimulation (DBS) for treatment of this disabling symptom has also provided some insight into the function of the PPN in humans. There have been several recent reviews on the PPN focused on its neurochemical organization and connectivity, physiology, involvement in parkinsonian syndromes, and as a target for DBS.(1-12.)

Functional parcellation of the lateral mesencephalus.

The mesencephalic locomotor region (MLR), which includes the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CN), has been recently identified as a key structure for locomotion and gait control in mammals. However, the function and the precise anatomy of the MLR remain unclear in humans. To study the lateral mesencephalus, we used fMRI in 15 right-handed healthy volunteers performing two tasks: imagine walking in a hallway and imagine an object moving along the same hallway. Both tasks were performed at two different speeds: normal and 30% faster. We identified two distinct networks of cortical activation: one involving motor/premotor cortices and the cerebellum for the walking task and the other involving posterior parietal and dorsolateral prefrontal cortices for the object moving task. In the lateral mesencephalus, we found that two different but anatomically connected parts of the MLR were activated during the fast condition of each task. The CN and the dorsal part of the PPN were activated during the fast imaginary walking task, whereas the ventral part of the PPN and the ventral part of the reticular formation were activated while subjects were imagining the object moving fast. Our data suggest that the lateral mesencephalus participates in different aspects of gait in humans, with the CN and dorsal PPN controlling motor aspects of locomotion and the ventral PPN being involved in integrating sensory information.

[Interconnections of the pallidum, pedunculopontine nucleus, zona incerta, and deep mesencephalic nucleus--the structures of the basal ganglia morpho-functional system].

Method of anterograde and retrograde axonal transport of horseradish peroxidase was used to study the organization of projections of different substructures of zona incerta (ZI), pedunculopontine nucleus (PPN), deep mesencephalic nucleus (DMN) complex, and functionally distinct structures of the pallidum of dog brain (n=20). It was found that pallidum and nucleus entope-duncularis are connected by reciprocal projections with dorsal, ventral and caudal sectors of ZI, as well as with DMN, lateral segment of the pars dissipata, and the pars compacta of PPN. The rostral sector of ZI, cuneiform and subcuneiform nuclei of DMN complex, the medial region of PPN pars dissipata are connected by ipsilateral projections with the same pallidal nuclei. Among all the structures studied, the presence of reciprocal connections with the ventral pallidum was found only in the lateral segment of the pars dissipata and pars compacta of PPN. The possible pathways of transfer of functionally different information and its integration in the investigated projection systems, are discussed.

Anatomical location of the pedunculopontine nucleus in the human brain: diffusion tensor imaging study.

We investigated the anatomical location of the pedunculopontine nucleus (PPN) in the human brain using diffusion tensor imaging. Forty normal healthy subjects were recruited. To confirm the boundary of the PPN, we analyzed the superior cerebellar peduncle and medial lemniscus using DTI-Studio software. We identified the PPN on red green blue (RGB) images, and defined four points of the PPN and four boundaries of the midbrain: point a - the most anterior point, point b - the most posterior point, point c - the most medial point, point d - the most lateral point; anterior boundary - the line of the most posterior point of the interpeduncular fossa, posterior boundary - the line of the upper part of the inferior colliculus, lateral boundary - the line of the most lateral point of the midbrain, medial boundary - the line of the midline of the midbrain. Points a and b were located at an average of 20.19 and 30.52% from the anterior boundary, respectively. By contrast, points c and d were located at an average of 22.50 and 41.65% from the medial boundary, respectively. We believe that the methodology and data of this study would be helpful in research and procedures on the PPN.

The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation.

Recently, the pedunculopontine nucleus has been highlighted as a target for deep brain stimulation for the treatment of freezing of postural instability and gait disorders in Parkinson's disease and progressive supranuclear palsy. There is great controversy, however, as to the exact location of the optimal site for stimulation. In this review, we give an overview of anatomy and connectivity of the pedunculopontine nucleus area in rats, cats, non-human primates and humans. Additionally, we report on the behavioural changes after chemical or electrical manipulation of the pedunculopontine nucleus. We discuss the relation to adjacent regions of the pedunculopontine nucleus, such as the cuneiform nucleus and the subcuneiform nucleus, which together with the pedunculopontine nucleus are the main areas of the mesencephalic locomotor region and play a major role in the initiation of gait. This information is discussed with respect to the experimental designs used for research purposes directed to a better understanding of the circuitry pathway of the pedunculopontine nucleus in association with basal ganglia pathology, and with respect to deep brain stimulation of the pedunculopontine nucleus area in humans.

Chronic pedunculopontine nucleus stimulation restores functional connectivity.

The mechanisms of deep brain stimulation (DBS) are poorly understood. Earlier, high-frequency DBS has been thought to represent a depolarization block of the target area and low-frequency stimulation has been thought to 'drive' neuronal activity. We investigated the long-term effect of low-frequency DBS in a longitudinal imaging study of a patient who received bilateral pedunculopontine nucleus stimulation. We used the diffusion tensor imaging techniques including probabilistic tractography and topographic mapping to analyze long-term changes in connectivity with low-frequency DBS. Post-DBS connectivity analysis suggested a normalization of pathological pedunculopontine nucleus connectivity with DBS therapy. These findings may help elucidate the mechanisms of DBS, suggesting neuroplasticity involving a reorganization of target connectivity long term. This is the first reported case showing neuroimaging evidence of neuroplasticity after low-frequency DBS.

A magnetic resonance imaging-directed method for transventricular targeting of midline structures for deep brain stimulation using implantable guide tubes.

OBJECTIVE: The periventricular gray/periaqueductal gray (PVG/PAG) is a target site for deep brain stimulation for chronic pain. The pedunculopontine nucleus (PPN) is a target for the treatment of axial disturbance in Parkinson's disease. Conventionally, a trajectory lateral to the ventricle is used in targeting deep subcortical structures; however, this limits the number of active contacts that can be placed in these midline targets. To maximize the number of contacts within these targets, a trajectory traversing the ventricles may be used; however, this is avoided because lead placement remains unpredictable with problems including ventricular lead migration and hemorrhage. We describe a novel method for accurate and safe transventricular targeting. METHODS: Magnetic resonance imaging is used for visualizing the target structure. A trajectory traversing the lateral ventricle is planned, avoiding blood vessels. The guide tube is inserted through the ventricle to a position short of the target site and its proximal end is fixed. A stylet is inserted in the guide tube with its distal end at the target site. After intraoperative radiological confirmation of placement, the indwelling stylet is removed and the guide tube acts as a port for delivering the stimulating electrode. RESULTS: The PVG/PAG matter and the PPN were targeted, taking a transventricular trajectory. We implanted unilateral PVG/PAG matter electrodes in 10 patients and bilateral PPN electrodes in 3 patients. All electrodes were implanted accurately within the desired target with no complications. CONCLUSION: The use of an implanted guide tube enables the safe and accurate transventricular targeting of the PVG/PAG matter and the PPN.

Imaging supraspinal locomotor control in balance disorders.

Patients with neurological gait disorders often present to their doctor with the key symptoms of dizziness and gait unsteadiness (e.g. cerebellar ataxia, progressive supranuclear palsy). In vestibular syndromes, on the other hand, the gait disturbance is a leading sign and many aspects of the syndrome can be recognized from the analysis of posture and gait (e.g. direction of falls). For therapy in particular it is important to better understand the physiological control of posture and gait to adapt rehabilitation programs. We recently succeeded in visualizing the hierarchic network for postural control in humans by means of functional imaging techniques. Growing evidence suggests that so-called "locomotor regions", groups of neurons able to initiate or modulate spinal stepping in the cat in response to electrical or chemical stimulation, also exist in humans. The most important locomotor regions are the mesencephalic, the subthalamic, and the cerebellar locomotor regions. Locomotor signals are transmitted from the midbrain to the spinal cord via the ponto-medullary reticular formation and integrate multisensory input at different levels. Functional imaging also demonstrated that the multisensory cortical areas are inhibited during locomotion, which is relevant for physical therapy of vestibular disorders which therefore should include exercises with different gait patterns and different speeds. The supraspinal network for locomotion is just beginning to be recognized as an important factor in the pathophysiology of common gait disorders. In Parkinson's disease, for example, low-frequency stimulation of the mesencephalic locomotor region (pedunculopontine nucleus) is already used to treat freezing and gait disturbance in selected patients. In this review we summarize different attempts to visualize human supraspinal locomotor control using functional neuroimaging techniques, both in healthy subjects and in patients suffering from balance disorders.