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Edgar Garciarill - One of the best experts on this subject based on the ideXlab platform.
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bottom up gamma the Pedunculopontine Nucleus and reticular activating system
Translational Brain Rhythmicity, 2017Co-Authors: Edgar Garciarill, Stasia Donofrio, Susan MahaffeyAbstract:: Gamma rhythms have been proposed to promote the feed forward or "bottom-up" flow of information from lower to higher regions in the brain during perception. On the other hand, beta rhythms have been proposed to represent feed back or "top-down" influence from higher regions to lower. The Pedunculopontine Nucleus (PPN) has been implicated in sleep-wake control and arousal, and is part of the reticular activating system (RAS). This review describes the properties of the cells in this Nucleus. These properties are unique, and perhaps it is the particular characteristics of these cells that allow the PPN to be involved in a host of functions and disorders. The fact that all PPN neurons fire maximally at gamma band frequency regardless of electrophysiological or transmitter type, make this an unusual cell group. In other regions, for example in the cortex, cells with such a property represent only a sub-population. More importantly, the fact that this cell group's functions are related to the capacity to generate coherent activity at a preferred natural frequency, gamma band, speaks volumes about how the PPN functions. We propose that "bottom-up" gamma band influence arises in the RAS and contributes to the build-up of the background of activity necessary for preconscious awareness and gamma activity at cortical levels.
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Pedunculopontine Nucleus region deep brain stimulation in parkinson disease surgical anatomy and terminology
Stereotactic and Functional Neurosurgery, 2016Co-Authors: Clement Hamani, Edgar Garciarill, Tipu Z Aziz, Terry Coyne, Stephan Chabardes, Bastiaan R Bloem, Peter Brown, Kelly D Foote, Etienne C Hirsch, Andres M LozanoAbstract: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.
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Pedunculopontine Nucleus gamma band activity preconscious awareness waking and rem sleep
Frontiers in Neurology, 2014Co-Authors: Francisco J. Urbano, Paige Beck, Stasia Donofrio, James Hyde, Brennon Luster, Veronica Bisagno, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular Nucleus (Pf), and pontine subcoeruleus Nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS.
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mechanism behind gamma band activity in the Pedunculopontine Nucleus
European Journal of Neuroscience, 2011Co-Authors: Nebojsa Kezunovic, James Hyde, Francisco J. Urbano, Christen Simon, Kristen Smith, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN), part of the reticular activating system, modulates waking and paradoxical sleep. During waking and paradoxical sleep, EEG responses are characterized by low-amplitude, high-frequency oscillatory activity in the beta-gamma band range (~20-80 Hz). We have previously reported that gamma band activity may be intrinsically generated by the membrane electroresponsiveness of PPN neurons, and that the neuronal ensemble generates different patterns of gamma activity in response to specific transmitters. This study attempted to identify the voltage-gated calcium and potassium channels involved in the rising and falling phases of gamma oscillations in PPN neurons. We found that all rat (8-14 day) PPN cell types showed gamma oscillations in the presence of TTX and synaptic blockers when membrane potential was depolarized using current ramps. PPN neurons showed gamma oscillations when voltage-clamped at holding potentials above -30 mV, suggesting that their origin may be spatially located beyond voltage-clamp control. The average frequency for all PPN cell types was 23 ± 1 Hz and this increased under carbachol (47 ± 2 Hz; anova df = 64, t = 12.5, P < 0.001). The N-type calcium channel blocker ω-conotoxin-GVIA partially reduced gamma oscillations, while the P/Q-type blocker ω-agatoxin-IVA abolished them. Both ω-CgTX and ω-Aga blocked voltage-dependent calcium currents, by 56 and 52% respectively. The delayed rectifier-like potassium channel blocker α-dendrotoxin also abolished gamma oscillations. In carbachol-induced PPN population responses, ω-agatoxin-IVA reduced higher, and ω-CgTx mostly lower, frequencies. These results suggest that voltage-dependent P/Q- and, to a lesser extent, N-type calcium channels mediate gamma oscillations in PPN.
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gamma band unit activity and population responses in the Pedunculopontine Nucleus
Journal of Neurophysiology, 2010Co-Authors: Christen Simon, James Hyde, Nebojsa Kezunovic, Abdallah Hayar, David K Williams, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN) is involved in the activated states of waking and paradoxical sleep, forming part of the reticular activating system (RAS). The studies described tested the hypothesis that single unit and/or population responses of PPN neurons are capable of generating gamma band frequency activity. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. Regardless of cell type (I, II, or III) or type of response to the nonselective cholinergic receptor agonist carbachol (excitation, inhibition, biphasic), almost all PPN neurons fired at gamma band frequency, but no higher, when subjected to depolarizing steps (50 ± 2 Hz, mean ± SE). Nonaccommodating neurons fired at 18–100 Hz throughout depolarizing steps, while most accommodating neurons exhibited gamma band frequency of action potentials followed by gamma band membrane oscillations. These oscillations were blocked by the sodium channel blocker tetrodotoxin (TTX), suggesting that at least some are mediated by sodium currents. Population responses in the PPN showed that carbachol induced peaks of activation in the theta and gamma range, while glutamatergic receptor agonists induced overall increases in activity at theta and gamma frequencies, although in differing patterns. Gamma band activity appears to be a part of the intrinsic membrane properties of PPN neurons, and the population as a whole generates different patterns of gamma band activity under the influence of specific transmitters. Given sufficient excitation, the PPN may impart gamma band activation on its targets.
Tipu Z Aziz - One of the best experts on this subject based on the ideXlab platform.
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gait phase modulates alpha and beta oscillations in the Pedunculopontine Nucleus
The Journal of Neuroscience, 2021Co-Authors: Alceste Deli, Tipu Z Aziz, Alexander L Green, Peter Brown, Petra Fischer, Christoph Wiest, Yongzhi Huang, Sean Martin, Saed Khawaldeh, Huiling TanAbstract:The Pedunculopontine Nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson’s disease (PD) or multiple system atrophy (MSA) suffering gait-related atypical parkinsonian syndromes. In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated by gait cycles during locomotion. PPN local field potential (LFP) activities were recorded from PD or MSA patients suffering from gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the gait phase within gait cycles, with a higher modulation index when the stepping rhythm was more regular. Meanwhile, the PPN-cortical coherence was most prominent in the alpha band. Both gait-phase related modulation in the alpha/beta power and the PPN-cortical coherence in the alpha frequency band were spatially specific to the PPN and did not extend to surrounding regions. These results suggest that alternating PPN modulation may support gait control. Whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control remains to be tested. Significance The therapeutic efficacy of PPN DBS and the extent to which it can improve quality of life is still inconclusive. Understanding how PPN activity is modulated by stepping or walking may offer insight into how to improve the efficacy of PPN DBS in ameliorating gait difficulties. Our study shows that PPN alpha and beta activity was modulated by the gait phase, and this was most pronounced when the stepping rhythm was regular. It remains to be tested whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control.
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gait phase modulates alpha and beta oscillations in the Pedunculopontine Nucleus
The Journal of Neuroscience, 2021Co-Authors: Alceste Deli, Tipu Z Aziz, Alexander L Green, Peter Brown, Petra Fischer, Christoph Wiest, Yongzhi Huang, Sean Martin, Saed Khawaldeh, Huiling TanAbstract:The Pedunculopontine Nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson's disease (PD) or multiple system atrophy (MSA) who have gait-related atypical parkinsonian syndromes. In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated by gait cycles during locomotion. PPN local field potential (LFP) activities were recorded from PD or MSA patients with gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the gait phase within gait cycles, with a higher modulation index when the stepping rhythm was more regular. Meanwhile, the PPN-cortical coherence was most prominent in the alpha band. Both gait phase-related modulation in the alpha/beta power and the PPN-cortical coherence in the alpha frequency band were spatially specific to the PPN and did not extend to surrounding regions. These results suggest that alternating PPN modulation may support gait control. Whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control remains to be tested.SIGNIFICANCE STATEMENT The therapeutic efficacy of Pedunculopontine Nucleus (PPN) deep brain stimulation (DBS) and the extent to which it can improve quality of life are still inconclusive. Understanding how PPN activity is modulated by stepping or walking may offer insight into how to improve the efficacy of PPN DBS in ameliorating gait difficulties. Our study shows that PPN alpha and beta activity was modulated by the gait phase, and that this was most pronounced when the stepping rhythm was regular. It remains to be tested whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control.
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Tractography patterns of Pedunculopontine Nucleus deep brain stimulation
Journal of Neural Transmission, 2021Co-Authors: Ashley L. B. Raghu, Tipu Z Aziz, Tariq Parker, Amir P. Divanbeighi Zand, Stephen Payne, Jesper Andersson, John Stein, Alexander L GreenAbstract:Deep brain stimulation of the Pedunculopontine Nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson’s disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the Pedunculopontine Nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus ( r = 0.81, p = 0.01), Brodmann areas 1 ( r = 0.78, p = 0.02) and 2 ( r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle ( r = −0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.
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gait phase modulates alpha and beta oscillations in the Pedunculopontine Nucleus
bioRxiv, 2021Co-Authors: Alceste Deli, Tipu Z Aziz, Alexander L Green, Peter Brown, Petra Fischer, Christoph Wiest, Yongzhi Huang, Sean Martin, Saed Khawaldeh, Huiling TanAbstract:Abstract Backgroud The Pedunculopontine Nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson’s disease (PD) or multiple system atrophy (MSA) suffering gait-related atypical parkinsonian syndromes. Objective In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated during locomotion. Methods PPN local field potential (LFP) activities were recorded from PD or MSA patients suffering from gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Results Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the gait phase within gait cycles, with a higher modulation index when the stepping rhythm was more regular. Meanwhile, the PPN-cortical coherence was most prominent in the alpha band. Both gait-phase related modulation in the alpha/beta power and the PPN-cortical coherence in the alpha frequency band were spatially specific to the PPN and did not extend to surrounding regions. Conclusions These results raise the possibility that alternating PPN stimulation in tandem with the gait rhythm may be more beneficial for gait control than continuous stimulation, although this remains to be established in future studies.
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Pedunculopontine Nucleus deep brain stimulation in parkinson s disease a clinical review
Movement Disorders, 2018Co-Authors: Wesley Thevathasan, Bettina Debû, Tipu Z Aziz, Valérie Fraix, Thomas Foltynie, Bastiaan R Bloem, Christian Blahak, Christopher R Butson, Virginie Czernecki, David GrabliAbstract:Pedunculopontine Nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone Pedunculopontine Nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic Nucleus or internal pallidum. Both rostral and caudal Pedunculopontine Nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether Pedunculopontine Nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of Pedunculopontine Nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society.
Andres M Lozano - One of the best experts on this subject based on the ideXlab platform.
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focus on the Pedunculopontine Nucleus consensus review from the may 2018 brainstem society meeting in washington dc usa
Clinical Neurophysiology, 2019Co-Authors: Edga Garciarill, Andres M Lozano, Clifford Sape, David Rye, Markus Kofle, J Nonnekes, J Vallssole, Mark HalleAbstract:Abstract The Pedunculopontine Nucleus (PPN) is located in the mesopontine tegmentum and is best delimited by a group of large cholinergic neurons adjacent to the decussation of the superior cerebellar peduncle. This part of the brain, populated by many other neuronal groups, is a crossroads for many important functions. Good evidence relates the PPN to control of reflex reactions, sleep-wake cycles, posture and gait. However, the precise role of the PPN in all these functions has been controversial and there still are uncertainties in the functional anatomy and physiology of the Nucleus. It is difficult to grasp the extent of the influence of the PPN, not only because of its varied functions and projections, but also because of the controversies arising from them. One controversy is its relationship to the mesencephalic locomotor region (MLR). In this regard, the PPN has become a new target for deep brain stimulation (DBS) for the treatment of parkinsonian gait disorders, including freezing of gait. This review is intended to indicate what is currently known, shed some light on the controversies that have arisen, and to provide a framework for future research.
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Pedunculopontine Nucleus region deep brain stimulation in parkinson disease surgical anatomy and terminology
Stereotactic and Functional Neurosurgery, 2016Co-Authors: Clement Hamani, Edgar Garciarill, Tipu Z Aziz, Terry Coyne, Stephan Chabardes, Bastiaan R Bloem, Peter Brown, Kelly D Foote, Etienne C Hirsch, Andres M LozanoAbstract: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.
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does dominant Pedunculopontine Nucleus exist
Brain, 2015Co-Authors: Susy Lam, Andres M Lozano, Elena Moro, Yuyan Poon, Alfonso FasanoAbstract:Sir, We read with great interest the paper by Fling et al. (2013) recently published in Brain . In this imaging study, patients with Parkinson’s disease with freezing of gait (FOG), without FOG, and age-matched controls were studied with diffusion tensor imaging to identify group and inter-hemispheric differences of tract quality and quantity in the Pedunculopontine Nucleus (PPN) network. Interestingly, patients with Parkinson’s disease with FOG had significantly less right PPN tract volume in terms of absolute values and ratio with the left side (i.e. greater laterality index) compared to patients without FOG. Furthermore, solely in the Parkinson’s disease with FOG group, linear regression analysis significantly correlated greater lateralization of PPN tract volume with poorer performance in action inhibition tasks. The authors concluded that right hemispheric circuitry might be uniquely involved in the pathophysiology of FOG (Fling et al. , 2013). In keeping with these findings, clinical evidence from the DATATOP cohort supports the notion …
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Pedunculopontine Nucleus evoked potentials from subthalamic Nucleus stimulation in parkinson s disease
Experimental Neurology, 2013Co-Authors: Bogdan Neagu, Clement Hamani, Andres M Lozano, Elena Moro, Eric W Tsang, Filomena Mazzella, Mojgan Hodaie, Robert ChenAbstract: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.
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regional anatomy of the Pedunculopontine Nucleus relevance for deep brain stimulation
Movement Disorders, 2013Co-Authors: Mariepierre Fourniergosselin, Jean A Saintcyr, Clement Hamani, Nir Lipsman, Andres M LozanoAbstract: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. © 2013 International Parkinson and Movement Disorder Society
James Hyde - One of the best experts on this subject based on the ideXlab platform.
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Modulation of gamma oscillations in the Pedunculopontine Nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder
Journal of neurophysiology, 2014Co-Authors: Stasia D'onofrio, James Hyde, Francisco J. Urbano, Erick Messias, Nebojsa Kezunovic, Brennon Luster, Edgar Garcia-rillAbstract:Reduced levels of gamma-band activity are present in schizophrenia and bipolar disorder patients. In the same disorders, increased neuronal calcium sensor protein-1 (NCS-1) expression was reported in a series of postmortem studies. These disorders are also characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). The discovery of gamma-band activity in the Pedunculopontine Nucleus (PPN), the cholinergic arm of the RAS, revealed that such activity was mediated by high-threshold calcium channels that are regulated by NCS-1. We hypothesized that NCS-1 normally regulates gamma-band oscillations through these calcium channels and that excessive levels of NCS-1, such as would be expected with overexpression, decrease gamma-band activity. We found that PPN neurons in rat brain slices manifested gamma-band oscillations that were increased by low levels of NCS-1 but suppressed by high levels of NCS-1. Our results suggest that NCS-1 overexpression may be responsible for the decrease in gamma-band activity present in at least some schizophrenia and bipolar disorder patients.
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Pedunculopontine Nucleus gamma band activity preconscious awareness waking and rem sleep
Frontiers in Neurology, 2014Co-Authors: Francisco J. Urbano, Paige Beck, Stasia Donofrio, James Hyde, Brennon Luster, Veronica Bisagno, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular Nucleus (Pf), and pontine subcoeruleus Nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS.
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mechanism behind gamma band activity in the Pedunculopontine Nucleus
European Journal of Neuroscience, 2011Co-Authors: Nebojsa Kezunovic, James Hyde, Francisco J. Urbano, Christen Simon, Kristen Smith, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN), part of the reticular activating system, modulates waking and paradoxical sleep. During waking and paradoxical sleep, EEG responses are characterized by low-amplitude, high-frequency oscillatory activity in the beta-gamma band range (~20-80 Hz). We have previously reported that gamma band activity may be intrinsically generated by the membrane electroresponsiveness of PPN neurons, and that the neuronal ensemble generates different patterns of gamma activity in response to specific transmitters. This study attempted to identify the voltage-gated calcium and potassium channels involved in the rising and falling phases of gamma oscillations in PPN neurons. We found that all rat (8-14 day) PPN cell types showed gamma oscillations in the presence of TTX and synaptic blockers when membrane potential was depolarized using current ramps. PPN neurons showed gamma oscillations when voltage-clamped at holding potentials above -30 mV, suggesting that their origin may be spatially located beyond voltage-clamp control. The average frequency for all PPN cell types was 23 ± 1 Hz and this increased under carbachol (47 ± 2 Hz; anova df = 64, t = 12.5, P < 0.001). The N-type calcium channel blocker ω-conotoxin-GVIA partially reduced gamma oscillations, while the P/Q-type blocker ω-agatoxin-IVA abolished them. Both ω-CgTX and ω-Aga blocked voltage-dependent calcium currents, by 56 and 52% respectively. The delayed rectifier-like potassium channel blocker α-dendrotoxin also abolished gamma oscillations. In carbachol-induced PPN population responses, ω-agatoxin-IVA reduced higher, and ω-CgTx mostly lower, frequencies. These results suggest that voltage-dependent P/Q- and, to a lesser extent, N-type calcium channels mediate gamma oscillations in PPN.
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gamma band unit activity and population responses in the Pedunculopontine Nucleus
Journal of Neurophysiology, 2010Co-Authors: Christen Simon, James Hyde, Nebojsa Kezunovic, Abdallah Hayar, David K Williams, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN) is involved in the activated states of waking and paradoxical sleep, forming part of the reticular activating system (RAS). The studies described tested the hypothesis that single unit and/or population responses of PPN neurons are capable of generating gamma band frequency activity. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. Regardless of cell type (I, II, or III) or type of response to the nonselective cholinergic receptor agonist carbachol (excitation, inhibition, biphasic), almost all PPN neurons fired at gamma band frequency, but no higher, when subjected to depolarizing steps (50 ± 2 Hz, mean ± SE). Nonaccommodating neurons fired at 18–100 Hz throughout depolarizing steps, while most accommodating neurons exhibited gamma band frequency of action potentials followed by gamma band membrane oscillations. These oscillations were blocked by the sodium channel blocker tetrodotoxin (TTX), suggesting that at least some are mediated by sodium currents. Population responses in the PPN showed that carbachol induced peaks of activation in the theta and gamma range, while glutamatergic receptor agonists induced overall increases in activity at theta and gamma frequencies, although in differing patterns. Gamma band activity appears to be a part of the intrinsic membrane properties of PPN neurons, and the population as a whole generates different patterns of gamma band activity under the influence of specific transmitters. Given sufficient excitation, the PPN may impart gamma band activation on its targets.
Francisco J. Urbano - One of the best experts on this subject based on the ideXlab platform.
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Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the Pedunculopontine Nucleus
Nature Publishing Group, 2018Co-Authors: Francisco J. Urbano, Susan Mahaffey, Veronica Bisagno, Sang-hun Lee, Edgar Garcia-rillAbstract:Abstract Epigenetic mechanisms (i.e., histone post-translational modification and DNA methylation) play a role in regulation of gene expression. The Pedunculopontine Nucleus (PPN), part of the reticular activating system, manifests intrinsic gamma oscillations generated by voltage-dependent, high threshold N- and P/Q-type Ca2+ channels. We studied whether PPN intrinsic gamma oscillations are affected by inhibition of histone deacetylation. We showed that, a) acute in vitro exposure to the histone deacetylation Class I and II inhibitor trichostatin A (TSA, 1 μM) eliminated oscillations in the gamma range, but not lower frequencies, b) pre-incubation with TSA (1 μM, 90–120 min) also decreased gamma oscillations, c) Ca2+ currents (ICa) were reduced by TSA, especially on cells with P/Q-type channels, d) a HDAC Class I inhibitor MS275 (500 nM), and a Class IIb inhibitor Tubastatin A (150–500 nM), failed to affect gamma oscillations, e) MC1568, a HDAC Class IIa inhibitor (1 μM), blocked gamma oscillations, and f) the effects of both TSA and MC1568 were blunted by blockade of CaMKII with KN-93 (1 μM). These results suggest a cell type specific effect on gamma oscillations when histone deacetylation is blocked, suggesting that gamma oscillations through P/Q-type channels modulated by CaMKII may be linked to processes related to gene transcription
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Modulation of gamma oscillations in the Pedunculopontine Nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder
Journal of neurophysiology, 2014Co-Authors: Stasia D'onofrio, James Hyde, Francisco J. Urbano, Erick Messias, Nebojsa Kezunovic, Brennon Luster, Edgar Garcia-rillAbstract:Reduced levels of gamma-band activity are present in schizophrenia and bipolar disorder patients. In the same disorders, increased neuronal calcium sensor protein-1 (NCS-1) expression was reported in a series of postmortem studies. These disorders are also characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). The discovery of gamma-band activity in the Pedunculopontine Nucleus (PPN), the cholinergic arm of the RAS, revealed that such activity was mediated by high-threshold calcium channels that are regulated by NCS-1. We hypothesized that NCS-1 normally regulates gamma-band oscillations through these calcium channels and that excessive levels of NCS-1, such as would be expected with overexpression, decrease gamma-band activity. We found that PPN neurons in rat brain slices manifested gamma-band oscillations that were increased by low levels of NCS-1 but suppressed by high levels of NCS-1. Our results suggest that NCS-1 overexpression may be responsible for the decrease in gamma-band activity present in at least some schizophrenia and bipolar disorder patients.
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Pedunculopontine Nucleus gamma band activity preconscious awareness waking and rem sleep
Frontiers in Neurology, 2014Co-Authors: Francisco J. Urbano, Paige Beck, Stasia Donofrio, James Hyde, Brennon Luster, Veronica Bisagno, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular Nucleus (Pf), and pontine subcoeruleus Nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS.
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Pedunculopontine Nucleus Gamma Band Activity-Preconscious Awareness, Waking, and REM Sleep
Frontiers Media S.A., 2014Co-Authors: Francisco J. Urbano, Stasia M D'onofrio, Brennon R Luster, Paige B Beck, James Robert Hyde, Veronica Ebisagno, Edgar Egarcia-rillAbstract:The Pedunculopontine Nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine Pedunculopontine Nucleus (PPN), intralaminar parafascicular Nucleus (Pf), and pontine Subcoeruleus Nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that, 1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, 2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, 3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and 4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high frequency activity related to waking and REM sleep by elements of the RAS
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mechanism behind gamma band activity in the Pedunculopontine Nucleus
European Journal of Neuroscience, 2011Co-Authors: Nebojsa Kezunovic, James Hyde, Francisco J. Urbano, Christen Simon, Kristen Smith, Edgar GarciarillAbstract:The Pedunculopontine Nucleus (PPN), part of the reticular activating system, modulates waking and paradoxical sleep. During waking and paradoxical sleep, EEG responses are characterized by low-amplitude, high-frequency oscillatory activity in the beta-gamma band range (~20-80 Hz). We have previously reported that gamma band activity may be intrinsically generated by the membrane electroresponsiveness of PPN neurons, and that the neuronal ensemble generates different patterns of gamma activity in response to specific transmitters. This study attempted to identify the voltage-gated calcium and potassium channels involved in the rising and falling phases of gamma oscillations in PPN neurons. We found that all rat (8-14 day) PPN cell types showed gamma oscillations in the presence of TTX and synaptic blockers when membrane potential was depolarized using current ramps. PPN neurons showed gamma oscillations when voltage-clamped at holding potentials above -30 mV, suggesting that their origin may be spatially located beyond voltage-clamp control. The average frequency for all PPN cell types was 23 ± 1 Hz and this increased under carbachol (47 ± 2 Hz; anova df = 64, t = 12.5, P < 0.001). The N-type calcium channel blocker ω-conotoxin-GVIA partially reduced gamma oscillations, while the P/Q-type blocker ω-agatoxin-IVA abolished them. Both ω-CgTX and ω-Aga blocked voltage-dependent calcium currents, by 56 and 52% respectively. The delayed rectifier-like potassium channel blocker α-dendrotoxin also abolished gamma oscillations. In carbachol-induced PPN population responses, ω-agatoxin-IVA reduced higher, and ω-CgTx mostly lower, frequencies. These results suggest that voltage-dependent P/Q- and, to a lesser extent, N-type calcium channels mediate gamma oscillations in PPN.