No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Reese NB, Garcia-Rill E, Skinner RD. The pedunculopontine nucleus-auditory input, arousal and pathophysiology. Prog Neurobiol 47: 105-133
Abstract
This review describes the role of the pedunculopontine nucleus (PPN) in various functions, including sleep-wake mechanisms, arousal, locomotion and in several pathological conditions. Special emphasis is placed on the auditory input to the PPN and the possible role of this nucleus in the manifestation of the P1 middle latency auditory evoked response. The importance of these considerations is evident because the PPN is part of the cholinergic arm of the reticular activating system. As such, the auditory input to this region may modulate the level of arousal of the CNS and, consequently, abnormalities in the processing of this input can be expected to have serious consequences on the level of excitability of the CNS. The involvement of the PPN in such disorders as schizophrenia, anxiety disorder and narcolepsy is discussed.
... These findings led to the implementation years later of PPN DBS for the treatment of gait and postural disorders in PD. Of particular concern were regions immediately posterior to PPN close to pain and micturition pathways that could affect responses to stimulation Reese et al., 1995). Given our discovery that every PPN cell manifests intrinsic gamma oscillations (see above), it became clear why the optimal frequencies for inducing locomotion on a treadmill were 40-60 Hz, and why this is also the optimal frequency for some of the beneficial effects of PPN DBS (Garcia-Rill et al., 2014a. ...
... The PPN sends descending projections to the pons and medulla, but only minor efferents to the spinal cord (reviewed in Garcia-Rill, 1991;Reese et al., 1995). The PPN sends projections to a REM sleep-inducing region, the SubCoeruleus dorsalis (SubCD) nucleus, which is activated by cholinergic agonists to elicit paradoxical sleep with atonia (Baghdoyan et al., 1984). ...
... Descending projections from the PPN to the medioventral medulla instead produce increases in stepping. Medioventral medulla reticulospinal outputs in turn activate spinal pattern generators to induce locomotion (Garcia-Rill and Skinner, 1991Skinner, , 2004Reese et al., 1995). Thus, the pontomedullary region is heterogeneous, such that electrical or chemical (with cholinergic agonists) stimulation of the pontomedullary reticular formation can induce decreased muscle tone at some sites and stepping movements at other sites Reese et al., 1995). ...
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.
... For a detailed description of the morphology of these cells, see Reese et al. [12]. This review also lists most of the many projection sites of the PPN, which include thalamic nuclei, mainly in the intralaminar region, as well as substantia nigra, pallidum, lateral hypothalamus, striatum, basal forebrain, and cortex. ...
... In addition, the PPN sends descending projections to the pons, medulla, and cerebellum, with very few projections to the spinal cord. The inputs to the PPN originate in the spinal cord and sensory tracts, as well as all of the targets to which it projects [12]. Basically, when the PPN is activated, it will have extensive effects at rostral and caudal regions of the brain. ...
... What are the effects of generating such high frequency activity in the PPN on its descending targets? Application of electrical or chemical, in particular, cholinergic agonists, to the pontomedullary region will induce decreases in muscle tone at some sites but at other sites elicit locomotor movements [12,53]. Specifically, descending PPN projections to large reticulospinal neurons (presumably involved in the atonia of REM sleep) induce long duration hyperpolarization; however, PPN projections to medium size interneurons induce depolarization that drives spinal locomotor pattern generators [54,55]. ...
Our discovery of low-threshold stimulation-induced locomotion in the pedunculopontine nucleus (PPN) led to the clinical use of deep brain stimulation (DBS) for the treatment of disorders such as Parkinson’s disease (PD) that manifest gait and postural disorders. Three additional major discoveries on the properties of PPN neurons have opened new areas of research for the treatment of motor and arousal disorders. The description of (a) electrical coupling, (b) intrinsic gamma oscillations, and (c) gene regulation in the PPN has identified a number of novel therapeutic targets and methods for the treatment of a number of neurological and psychiatric disorders. We first delve into the circuit, cellular, intracellular, and molecular organization of the PPN, and then consider the clinical results to date on PPN DBS. This comprehensive review will provide valuable information to explain the network effects of PPN DBS, point to new directions for treatment, and highlight a number of issues related to PPN DBS.
... A C C E P T E D M A N U S C R I P T 11 frequency of this region would activate all of its efferent projections, including ascending ones projecting to the thalamus modulating arousal, and descending ones to reticulospinal systems modulating posture and gait (Garcia-Rill, 1991;Reese et al. 1995). It was not until years later that we discovered the reason for the need of using 40-60 Hz stimulation, the fact that all PPN cells, regardless of transmitter type, as described above, manifest intrinsic membrane oscillations in the beta/gamma range mediated by high threshold calcium channels (Simon et al. 2010;Kezunovic et al. 2011). ...
... However, stimulation of only lateral, but not medial cuneiform nucleus, was effective, suggesting that it is the posterior PPN (which is embedded in the lateral cuneiform) that is responsible for the induced stepping, and not the cuneiform nucleus as a whole (Garcia-Rill 1986, 1991Skinner, 1988, 1991;Garcia-Rill et al. 1996;Reese et al. 1995). ...
... Based on suggestions over the years that the PPN is involved in the locomotor deficits in Parkinson's disease (Garcia-Rill 1986, 1991Skinner, 1988, 1991;Garcia-Rill et al. 1983, 1996Reese et al. 1995 (2010,2012) showed that stimulation at 20-35 Hz improved reaction time and fall scores, and that gait freezing was significantly improved, particularly with bilateral stimulation. The latter study is one of the few that used double-blind analysis and established that bilateral stimulation was more effective than unilateral. ...
Maintained gamma band activity is a key element of higher brain function, participating in perception, executive function, and memory. The pedunculopontine nucleus (PPN), as part of the reticular activating system (RAS), is a major source of the "bottom-up" flow of gamma activity to higher regions. However, interruption of gamma band activity is associated with a number of neurological and psychiatric disorders. This review will focus on the role of the PPN in activating higher regions to induce arousal and descending pathways to modulate posture and locomotion. As such, PPN deep brain stimulation (DBS) can not only help regulate arousal and stepping, but continuous application may help maintain necessary levels of gamma band activity for a host of other brain processes. We will explore the potential future applications of PPN DBS for a number of disorders that are characterized by disturbances in gamma band maintenance.
... The pedunculopontine nucleus (PPN) is a cholinergic nucleus in the brainstem, having a significant role in modulation of sleep and wakefulness, as well as in regulation of movement (see e.g., Steriade et al., 1990;Garcia-Rill, 1991;Reese et al., 1995). It is composed of cholinergic and non-cholinergic (GABAergic, glutamatergic) neurons, which display different activity patterns correlated with cortical activity (Mena-Segovia et al., 2008;Ros et al., 2010;Petzold et al., 2015). ...
... The PPN is known as a regulator of sleep-wake cycles ( Steriade et al., 1990Steriade et al., , 1991Garcia-Rill, 1991;Reese et al., 1995). In order to participate in its regulation, PPN neurons display firing patterns correlated with global brain states (see Saper et al., 2005;Mena-Segovia et al., 2008;Ros et al., 2010;Lee and Dan, 2012). ...
Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep. Using slice electrophysiology, optogenetics and morphological reconstruction, we revealed that SICs are present in a population of PPN neurons. The frequency of SICs recorded on PPN neurons was higher when the soma of the given neuron was close to an astrocytic soma. SICs do not appear simultaneously on neighboring neurons, thus it is unlikely that they synchronize neuronal activity in this structure. Occurrence of SICs is regulated by cannabinoid, muscarinic and serotonergic neuromodulatory mechanisms. In most cases, SICs occurred independently from tonic neuronal currents. SICs were affected by different neuromodulatory agents in a rather uniform way: if control SIC activity was low, the applied drugs increased it, but if SIC activity was increased in control, the same drugs lowered it. SICs of PPN neurons possibly represent a mechanism which elicits network-independent spikes on certain PPN neurons; forming an alternative, astrocyte-dependent pathway of neuromodulatory mechanisms.
... It should be noted, however, that in animal studies of PPN stimulation-induced locomotion, the activation of the posterior pars compacta was efficacious while stimulation of the anterior PPN was not [19,20] . A recent study on an animal model of PD showed that stimulation of the anterior PPN induced freezing and worsened gait, but gait was improved by posterior PPN stimulation [21] . ...
... As part of the reticular activating system, the PPN may also respond directly to sensory inputs [20] . In humans, the midlatency auditory evoked P50 potential recorded at the vertex has been proposed to be generated by the PPN [49] , but such studies have not been carried out in PD patients [50] . ...
The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS.
... It should be noted, however, that in animal studies of PPN stimulation-induced locomotion, the activation of the posterior pars compacta was efficacious while stimulation of the anterior PPN was not [19,20] . A recent study on an animal model of PD showed that stimulation of the anterior PPN induced freezing and worsened gait, but gait was improved by posterior PPN stimulation [21] . ...
... As part of the reticular activating system, the PPN may also respond directly to sensory inputs [20] . In humans, the midlatency auditory evoked P50 potential recorded at the vertex has been proposed to be generated by the PPN [49] , but such studies have not been carried out in PD patients [50] . ...
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.
... In the latter, PPN neurons displaying saccade-and fixation-related firing patterns could be documented [26]. Moreover, the PPN is known to project to all thalamic nuclei including sensory relay nuclei [28]. Hence, there is a potential role for the PPN in modulating attention and perceptual processes more directly via cholinergic connectivity with relay nuclei of the thalamus as the lateral and medial geniculate nucleus (LGN, MGN) or the pulvinar [29]. ...
... Hence, there is a potential role for the PPN in modulating attention and perceptual processes more directly via cholinergic connectivity with relay nuclei of the thalamus as the lateral and medial geniculate nucleus (LGN, MGN) or the pulvinar [29]. The majority of cholinergic brain-stem projections to the LGN in fact come from the PPN [30] and it has been hypothesized that respective projections contribute to the modulation of thalamo-cortical transmission (thalamic gating) underlying selective attention [28]. One such gating pathway could rely on projections to the thalamic reticular nucleus (TRN). ...
The parapontine nucleus of the thalamus (PPN) is a neuromodulatory midbrain structure with widespread connectivity to cortical and subcortical motor structures, as well as the spinal cord. The PPN also projects to the thalamus, including visual relay nuclei like the LGN and the pulvinar. Moreover, there is intense connectivity with sensory structures of the tegmentum in particular with the superior colliculus (SC). Given the existence and abundance of projections to visual sensory structures, it is likely that activity in the PPN has some modulatory influence on visual sensory selection. Here we address this possibility by measuring the visual discrimination performance (luminance contrast thresholds) in a group of patients with Parkinson's Disease (PD) treated with deep-brain stimulation (DBS) of the PPN to control gait and postural motor deficits. In each patient we measured the luminance-contrast threshold of being able to discriminate an orientation-target (Gabor-grating) as a function of stimulation frequency (high 60Hz, low 8/10, no stimulation). Thresholds were determined using a standard staircase-protocol that is based on parameter estimation by sequential testing (PEST). We observed that under low frequency stimulation thresholds increased relative to no and high frequency stimulation in five out of six patients, suggesting that DBS of the PPN has a frequency-dependent impact on visual selection processes at a rather elementary perceptual level.
... Stimulation at high frequency (300 Hz) typically induced reduction in extensor muscle tone [40], while stimulation at 40-60 Hz induced locomotion [37][38][39]. We concluded that the optimal site of stimulation was in the lateral cuneiform nucleus, and that stimulation "recruited", rather than "induced" locomotion, since it required $1 s of stimulation to have the desired effect [37][38][39]41]. It was this line of research that led us to propose the use of PPN DBS for the treatment of PD. ...
... This suggests the presence of a heterogeneous, distributed system of reticulospinal motor control. The required parameters of stimulation for eliciting these differing effects are important such that instantaneous, high frequency (4100 Hz) trains (similar to high frequency bursting activity in the range of ponto-geniculo-occipital (PGO) burst neurons that may drive the atonia of REM sleep) trigger pathways which lead to decreased muscle tone, while lower frequency (40-60 Hz) tonic stimulation leads gradually to the "recruitment" of locomotor movements [38,41]. Therefore, given the extensive evidence, it is to be expected that the PPN, as part of the RAS, should modulate both posture and locomotion in addition to arousal. ...
This review describes the wake/sleep symptoms present in Parkinson׳s disease, and the role of the pedunculopontine nucleus in these symptoms. The physiology of PPN cells is important not only because it is a major element of the reticular activating system, but also because it is a novel target for deep brain stimulation in the treatment of gait and postural deficits in Parkinson׳s disease. A greater understanding of the physiology of the target nuclei within the brainstem and basal ganglia, amassed over the past decades, has enabled increasingly better patient outcomes from deep brain stimulation for movement disorders.
... The human P50 potential has three main characteristics: 1) it is sleep state-dependent, that is, it is present during waking and rapid eye movement (REM) sleep, but is absent during deep slow-wave sleep (SWS) [20,21] [19,[24][25][26]. The P50 potential has been localized to the frontal lobes in the region of the vertex, a source we confirmed using magnetoencephalography [27]. ...
... have been due to suddenly switching on the stimulus (see below). Stimulation of more medial regions such as the MCN, laterodorsal tegmental nucleus (LDT), the medial partner of the PPN, or anteroventrally in the region of the substantia nigra, did not induce locomotion[24,26,[40][41][42]. This explains why stimulation of only LCN, but not MCN, in which the PPN is embedded, produces reliable stepping on a treadmill. ...
This review highlights the most important discovery in the reticular activating system (RAS) in the last 10 years,
the manifestation of gamma (γ) band activity in cells of the RAS, especially in the pedunculopontine nucleus
(PPN), which is in charge of the high frequency states of waking and rapid eye movement sleep. This discovery
is critical to understanding the modulation of movement by the RAS and how it sets the background over which
we generate voluntary and triggered movements. The presence of γ band activity in the RAS is proposed to
participate in the process of preconscious awareness, and provide the essential stream of information for the
formulation of many of our actions. Early findings using stimulation of this region to induce arousal, and also
to elicit stepping, are placed in this context. This finding also helps explain the novel use of PPN deep brain
stimulation for the treatment of Parkinson’s disease, although considerable work remains to be done.
... Projections from the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nuclei (LDT), parts of the brainstem network collectively known as the ascending arousal system (AAS-but previously known as the reticular activating system), enter the intralaminar nuclei of the thalamus (IL) and thence on to the cortex through the thalamocortical matrix connections. The AAS is thought to modulate wake and sleep states as well as arousal and vigilance levels (Moruzzi and Magoun, 1949;Reese et al., 1995;Jones, 2003). The IL matrix connections project diffusely and somewhat non-specifically to large portions of the cortex, which in turn project back to the IL through the thalamic reticular nucleus (RN). ...
... The slow oscillations and global coupling seen at low AAS input levels in the CXC network are similar to the strong delta oscillations and very low dynamical complexity observed during deep (non-REM) sleep (Massimini et al., 2005;Murphy et al., 2009). In mammals, AAS input levels, particularly input from the pedunculopontine nucleus (PPN, or sometimes PPT or PPTg) are significantly reduced during periods of non-REM sleep (Moruzzi and Magoun, 1949;Reese et al., 1995;Jones, 2003), with slow delta oscillations at 0.5-4 Hz the predominant neural activity signature of this state. The transition between sleep and active cortical states is thought to be driven by cholinergic neuromodulation. ...
Cortical activity exhibits persistent metastable dynamics. Assemblies of neurons transiently couple (integrate) and decouple (segregate) at multiple spatiotemporal scales; both integration and segregation are required to support metastability. Integration of distant brain regions can be achieved through long range excitatory projections, but the mechanism supporting long range segregation is not clear. We argue that the thalamocortical matrix connections, which project diffusely from the thalamus to the cortex and have long been thought to support cortical gain control, play an equally-important role in cortical segregation. We present a computational model of the diffuse thalamocortical loop, called the competitive cross-coupling (CXC) spiking network. Simulations of the model show how different levels of tonic input from the brainstem to the thalamus could control dynamical complexity in the cortex, directing transitions between sleep, wakefulness and high attention or vigilance. The model also explains how mutually-exclusive activity could arise across large portions of the cortex, such as between the default-mode and task-positive networks. It is robust to noise but does not require noise to autonomously generate metastability. We conclude that the long range segregation observed in brain activity and required for global metastable dynamics could be provided by the thalamocortical matrix, and is strongly modulated by brainstem input to the thalamus.
... 62,100 Interestingly, these patients (in particular those with PSP, and likely PD-patients with postural instability) also have absent or reduced startle reflexes. 135,195,349,367 As the pedunculopontine nucleus (PPN) is the main structure governing the primary startle circuit 174,193,298 and its function is affected in PD and PSP, patients with implanted PPN stimulators provide a unique study population to investigate the presumed interaction between startle and motor circuits in the pmRF. Recently, Thevathasan and co-workers indeed demonstrated that for arm movements, the StartReact phenomenon was absent without, but present with PPN stimulation ON. 349 In line with the presently suggested involvement of startle pathways in postural responses, these patients also benefited from PPN stimulation with regard to their scores on the gait and falls questionnaire. ...
... The latter could be the result of enhanced inhibitory drive from other structures, likely involving the PPN, as it has strong inhibitory projections on the pmRF. 174,193,298 This notion is coherent with the reported effects of PPN-stimulation on StartReact effects. 349 ...
... sensory stimuli, imaginary gait, and passive lower limb movement, and PPN DBS can modulate the response of PPN activity to sensory stimuli (Grunwerg et al., 1992;Reese et al., 1995;Tattersall et al., 2014;Lau et al., 2015;Strumpf et al., 2016;Yousif et al., 2016). Thus, it is not clear from the current study whether the observed PPN LFP modulation represents the efferent motor command or is an outcome of sensory feedback during stepping or free walking. ...
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.
... Several brainstem nuclei also showed higher activity during subjective recognition. These nuclei, including the pedunculopontine nucleus 68 , locus coeruleus 69 , ventral tegmental area 70 , and dorsal raphe nucleus 71 , all modulate arousal. Arousal-related activity in the brainstem neuromodulatory system correlates with stimulus detection 26 and the precision of visual cortical representations 72 . ...
The neural mechanisms underlying conscious recognition remain unclear, particularly the roles played by the prefrontal cortex, deactivated brain areas and subcortical regions. We investigated neural activity during conscious object recognition using 7 Tesla fMRI while human participants viewed object images presented at liminal contrasts. Here, we show both recognized and unrecognized images recruit widely distributed cortical and subcortical regions; however, recognized images elicit enhanced activation of visual, frontoparietal, and subcortical networks and stronger deactivation of the default-mode network. For recognized images, object category information can be decoded from all of the involved cortical networks but not from subcortical regions. Phase-scrambled images trigger strong involvement of inferior frontal junction, anterior cingulate cortex and default-mode network, implicating these regions in inferential processing under increased uncertainty. Our results indicate that content-specific activity in both activated and deactivated cortical networks and non-content-specific subcortical activity support conscious recognition.
... In addition, sensory gating is related to the sleep cycle and excitability (25). According to the central inhibition theory, which is a variant of the neuronal theory of migraine pathogenesis, an uninhibited increase in firing rate of the serotonergic system in the raphe area is responsible for the pain. ...
... The F4 module includes pontine, midbrain, and thalamic nuclei implicated in arousal and vigilance, consistent with classical reports of fastigial contributions to the ascending reticular activating system (Moruzzi and Magoun, 1949) and to regulation of affect (Schmahmann and Sherman, 1998). Robust connections with cholinergic and noncholinergic neurons in the LDTg and PTg, which are associated with vigilance and arousal (Steriade et al., 1990;Reese et al., 1995;Lee and Dan, 2012), have not been previously reported, possibly reflecting restricted tracer uptake or selective cytotoxicity of small F4 neurons. Connections with the nucleus incertus, supramammillary region, and VM thalamic nuclei enable F4 neurons to coordinate activity of the hippocampus (Martínez-Bellver et al., 2017), basal forebrain (Brown and McKenna, 2015;Pedersen et al., 2017), and broad regions of the cerebral cortex (Steriade, 1995;Ma et al., 2017;Honjoh et al., 2018). ...
The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions could be mediated by modular synaptic connections of distinct fastigial cell types with posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.
... The F4 module includes pontine, midbrain, and thalamic nuclei implicated in arousal and vigilance, consistent with classical reports of fastigial contributions to the ascending reticular activating system (Moruzzi and Magoun, 1949) and to regulation of affect (Schmahmann and Sherman, 1998). Robust connections with cholinergic and noncholinergic neurons in the LDTg and PTg, which are associated with vigilance and arousal (Steriade et al., 1990;Reese et al., 1995;Lee and Dan, 2012), have not been previously reported, possibly reflecting restricted tracer uptake or selective cytotoxicity of small F4 neurons. Connections with the nucleus incertus, supramammillary region, and VM thalamic nuclei enable F4 neurons to coordinate activity of the hippocampus (Martínez-Bellver et al., 2017), basal forebrain (Brown and McKenna, 2015;Pedersen et al., 2017), and broad regions of the cerebral cortex (Steriade, 1995;Ma et al., 2017;Honjoh et al., 2018). ...
The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions could be mediated by modular synaptic connections of distinct fastigial cell types with posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.
... We found that chemical stimulation of the PPN could be used to induce locomotion [44], suggesting that the consequences of electrical stimulation were not due to activation of fibers of passage; and we also found that single cell activity was present in the PPN in relation to locomotion [45], suggesting that the PPN contains cells active in relation to the start, cessation, and period of stepping. Moreover, descending projections of the PPN modulated regions related to postural muscle tone as well as regions driving spinal pattern generators responsible for stepping [2,46,47]. Further details of the determination of the role of the PPN are discussed in a recent review [4]. ...
In this review, we discuss first an example of one of the symptoms of PD, freezing of gait (FOG), then we will turn to the use of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) to treat PD, and the original studies that led to identification of the PPN as one source of locomotor control and why stimulation frequency is critical, and then describe the intrinsic properties of PPN neurons that require beta/gamma stimulation in order to fully activate all types of PPN neurons. Finally, we will describe recent findings on the proteomic and molecular consequences of gamma band activity in PPN neurons, with emphasis on the potential neuroepigenetic sequelae. These considerations will provide essential information for the appropriate refining and testing of PPN DBS as a potential therapy for PD, as well as alternative options.
... Given that contact 0 was the intended to be placed in the SNr, then contact 01 was likely to be picking up activity from the SNr or associative areas of the STN. These findings are supported by previous reports that PPN has direct reciprocal connections to STN and SNr (Reese et al., 1995). At a systems level, it has been proposed that the "crosstalk" between motor, cognitive and limbic circuits may overload information processing capacity in the striatum in PD, and lead to synchronized activities in the output structures of the basal ganglia, including the GPi and SNr. ...
... The cholinergic PPNc induces locomotion (Garcia-Rill et al., 1987) together with other brainstem regions via prominent sensory nuclei stimulating locomotion through direct outputs to spinal cord regions of recognized locomotor generators (Pahapill and Lozano, 2000). PPN neuronal response to somatosensory excitation (Grunwerg et al., 1992;Reese et al., 1995) combined with cholinergic PPN neuronal thalamic projections and inputs from lamina 1 of the spinal cord, advocates that the PPN modulates sensory information to thalamic nuclei. Thus, the PPN plays a role as a dispatch amid the cerebral cortex and spinal cord, providing feedback information vital for posture and gait initiation modulation. ...
The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.
... The interest in the PPTg is a valuable example of translational research across a well-defined area of the brain that has disclosed new data for a better understanding of the physiology of the brainstem and basal ganglia and offered new perspectives in the development of treatments for motor and non-motor disorders. Undoubtedly, the PPTg is one of the most investigated brain structures in the last three decades, and several reviews devoted to the brainstem area in which the PPTg is located prove this increasing interest [2,18,24,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. ...
... The pedunculopontine tegmental (PPT) nucleus, a mesencephalic nucleus, participates in several functions including motor control, rapid eye movement sleep (REM), orientation, attention and autonomic regulation (1,2). The role of PPT in the regulation of cardiovascular events has also been shown in prev i ous studies (2,3). ...
Objectives:
Nitric oxide (NO) is an important neurotransmitter in central nervous system involved in central cardiovascular regulation. The presence of NO in the pedunculopontine tegmental (PPT) nucleus has been shown, but its cardiovascular effect has not been determined. In the present study, the cardiovascular effect of NO in the PPT nucleus was evaluated.
Materials and methods:
After induction of anesthesia, a polyethylene catheter (PE-50) filled with heparinized saline inserted into the femoral artery, and the blood pressure (BP) and heart rate (HR) were continuously recorded. Animals were then placed in a stereotaxic apparatus and maximum changes of mean arterial pressure (∆MAP) and heart rate (∆HR) after microinjection of two doses of N(G)-nitro-L-arginine methyl ester (L-NAME, 30 and 90 nmol), L-arginine (L-Arg 10 and 50 nmol) and sodium nitroprusside (SNP, 9 and 27 nmol) into the PPT were provided and compared with control group (One-way ANOVA).
Results:
Both doses of L-NAME significantly increased ∆MAP compared to control (P<0.05 and P<0.01, respectively). ∆HR only in higher dose (90 nmol) significantly increased compared to control (P<0.05). Two doses of L-Arg (10 and 50 nmol/150 nl) had no significant effect on ∆MAP or ∆HR. Higher dose of SNP (27 nmol) significantly decreased ∆MAP (P<0.05) and its both doses significantly decreased ∆HR compared to control (P<0.05 and P<0.001, respectively). Effect of higher dose on ∆HR was significantly higher than the lower dose (P<0.05).
Conclusion:
Our results show an inhibitory effect of the nitrergic system of the PPT on central cardiovascular system.
... Indeed, the use of chronic implant allowing MER in the MRF and polysomnic investigations over long period of waking/sleep cycle together with locomotion sessions or goal-directed movement will allow a better understanding of the discharge characteristic of MRF neurons during different brain states. In conclusion, the involvement of some MRF neurons during locomotion and TWS is in accordance with a ''unified mechanism'' (Reese et al. 1995) to provide modulation of the optimal level of attention for an efficient locomotion. ...
The mesencephalic reticular formation (MRF) mainly composed by the pedunculopontine and the cuneiform nuclei is involved in the control of several fundamental brain functions such as locomotion, rapid eye movement sleep and waking state. On the one hand, the role of MRF neurons in locomotion has been investigated for decades in different animal models, including in behaving nonhuman primate (NHP) using extracellular recordings. On the other hand, MRF neurons involved in the control of waking state have been consistently shown to constitute the cholinergic component of the reticular ascending system. However, a dual control of the locomotion and waking state by the same groups of neurons in NHP has never been demonstrated in NHP. Here, using microelectrode recordings in behaving NHP, we recorded 38 neurons in the MRF that were followed during transition between wakefulness (TWS) and sleep, i.e., until the emergence of sleep episodes characterized by typical cortical slow wave activity (SWA). We found that the MRF neurons, mainly located in the pedunculopontine nucleus region, modulated their activity during TWS with a decrease in firing rate during SWA. Of interest, we could follow some MRF neurons from locomotion to SWA and found that they also modulated their firing rate during locomotion and TWS. These new findings confirm the role of MRF neurons in both functions. They suggest that the MRF is an integration center that potentially allows to fine tune waking state and locomotor signals in order to establish an efficient locomotion.
... The pedunculopontine nucleus is known as one of the mesencephalic cholinergic nuclei, which provides cholinergic fibers for several subcortical locations (i.e., the thalamus, basal ganglia or pontine structures). Besides its contribution to motor regulation, it modulates transitions between sleep and wakefulness and between slow-wave and REM sleep (Garcia-Rill 1991;Garcia-Rill et al. 2011;Reese et al. 1995;Petzold et al. 2015). ...
The pedunculopontine nucleus (PPN), a cholinergic nucleus of the reticular activating system, is known to be involved in the regulation of sleep and wakefulness. Endogenous and exogenous cannabinoids, by systemic or local administration to the pedunculopontine nucleus, can both influence sleep. We previously demonstrated that activation of astrocytes by cannabinoid type 1 (CB1) receptor agonists was able to modulate the membrane potential of PPN neurons, even in the presence of blockers of fast synaptic neurotransmission. In the present work, we provide evidence that synaptic inputs of PPN neurons are also affected by activation of presynaptic and astrocytic CB1 receptors. Using slice electrophysiology combined with calcium imaging, optogenetics and immunohistochemistry, we revealed a direct presynaptic inhibitory action on inhibitory postsynaptic currents, along with a mild increase of excitatory postsynaptic currents during CB1 receptor stimulation. Besides inhibition of excitatory and inhibitory neurotransmission through stimulation of presynaptic CB1 receptors, astrocyte- and mGluR-dependent tonic inhibition and excitation also developed. The mild stimulatory action of CB1 receptor activation on excitatory neurotransmission is the combination of astrocyte-dependent tonic excitation on excitatory neurons and the canonical presynaptic CB1 receptor activation and consequential inhibition of excitatory synaptic neurotransmission, whereas the astrocyte-dependent stimulatory action was not observed in inhibitory neurotransmission within the PPN. Our findings demonstrate that endocannabinoids act in the PPN via a dual pathway, consisting of a direct presynaptic and an indirect, astrocyte-mediated component, regulating synaptic strength and neuronal activity via independent mechanisms.
... In addition, pontine structures, such as the reticular formation and pedunculopontine nucleus, receive auditory input 82 and modulate the cholinergic activities of basal ganglia, limbic, thalamic, and hypothalamic structures, 54,76,89 all of which are implicated in sleep regulation 12,43 . Cholinergic neurotransmissions in pontine structures and the basal forebrain thus might contribute to disturbing sleep after acute exposure to noise (Figure 1). ...
Noise has both auditory and extra-auditory effects. Some of the most deleterious extra-auditory effects of noise are those leading to sleep disturbances. These disturbances seem to be related to both endogenous (physical parameters) and exogenous (sex, age) factors of noise. Despite correlative relations between noise level and awakenings, the scientific community has not reached consensus regarding a specific action of these factors on the different sleep stages. In animal research, 2 complementary main fields of research exist. One is focused on the positive modulation of sleep by repeated tone stimulation. The other concerns noise-related sleep disturbances. The few studies that have investigated noise-related sleep disturbances suggest the following conclusions. First, sleep disturbances are greater upon exposure to environmental noise, whose frequency spectrum is characterized by high and ultrasonic sounds, than white noise. Second, unpredictability and pattern of noise events are responsible for extractions from both SWS and PS. Third, chronic exposure to noise permanently reduces and fragments sleep. Finally, in chronic noise exposure, an inter-individual variability in SWS deficits is observed and correlated to a psychobiological profile related to an incapability to face stressful situations. Based on results from other research, acute noise-related sleep perturbations could result from an imbalance in the sleep-wake cycle in favor of arousing ascending systems. Chronic noise-related sleep disturbances may arise due to imbalance of the sleep-wake cycle and malfunctioning of the hypothalamo-pituitary-adrenal axis which may both contribute to the development of pathology.
... Hence, a direct involvement of the cuneiform nucleus in the effects we observed following PPTg DBS may be excluded. In this regard, it should be noted that the former concept expressed by Takakusaki et al. (2003Takakusaki et al. ( , 2004, who ascribed to the cuneiform nucleus a major role in initiating gait and to the PPTg a major role in modulating skeletal muscle tone during locomotor movements in decerebrated cats, should not be interpreted as suggestive of two functionally separated structures since the axons of PPTg cholinergic axons give raise to widespread ascending projections in the upper brainstem (Dautan et al. 2014) and, in addition, these neurons may have 2-9 primary dendrites that extend for hundreds of microns (Reese et al. 1995c). Thus, further studies would be needed to elucidate if and how stimulation of the cuneiform nucleus may affect gait and posture in the absence of PPTg neurons and taking also into account the interspecies differences existing in the several pathways that may have a role in the effects of PPTg DBS (Alam et al. 2011). ...
The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region.
... Stimulation of locomotion-inducing sites in the midbrain have universally required several seconds of stimulation before the first step ensued (Shik et al. 1966;Garcia-Rill 1986, 1991Skinner and Garcia-Rill 1984;Takakusaki et al. 2004). This prompted us to propose that locomotion is not induced, but rather recruited over a period of time (Garcia-Rill 1991;Garcia-Rill and Skinner 1991;Reese et al. 1995). Therefore, the practice of applying continuous DBS throughout the day may not result in creating a continuous The pedunculopontine tegmental nucleus facilitation of locomotion. ...
This issue is dedicated to a potential new target for the treatment of movement disorders, the pedunculo-pontine tegmental nucleus (PPTg), or, more simply, the pedunculopontine nucleus, that some authors abbreviate as PPN. We provide an overview of the field as an introduction to the general reader, beginning with the clinical experience to date of Mazzone and co-workers in Rome, some basic questions that need to be addressed, and potential future directions required in order to ensure that the potential benefits of this work are realized.
... Nuclei abbreviations are shown in the ovals. (Modified from Mittleman et al. (2008) with permission from Wiley) (Garcia-Rill et al. 2001;Reese et al. 1995;Vertes et al. 1986). Excitatory cholinergic and glutamatergic neurons, including neurons co-containing glutamate and acetylcholine, within the rostral and caudal aspects of the PPT project to dopaminecontaining cells in the ventral tegmental area (VTA) and substantia nigra compacta (SNc) (Oakman et al. 1995(Oakman et al. , 1999Lavoie and Parent 1994). ...
In this chapter we present data from two mutant mouse strains (lurcher and Fmr1) that share in common with patients diagnosed with an autism spectrum disorder, the characteristic of developmental cerebellar neuropathology involving Purkinje cells. Evidence is presented indicating that Purkinje cell number has a profound influence on behaviors that are commonly disrupted in autism spectrum disorders including hyperactivity, increased repetitive behavior, and deficits in executive function. Additional experiments are presented which indicate that these behavioral deficits stem from developmental loss of cerebellar output that occurs as a function of Purkinje cell loss. Loss or dysregulation of Purkinje cell output to the deep cerebellar nuclei such as the cerebellar dentate nucleus in turn results in alterations in the functionality of cerebellar projections via the thalamus and ventral tegmental area to the medial prefrontal cortex (mPFC). This loss of functionality prominently includes reductions in cerebellar-mediated mPFC dopamine release. The reduction in mPFC dopamine release is likely caused by coincident reductions in glutamate available for release from cerebellar projections to the thalamus and ventral tegmental area (VTA). This loss of functionality also includes a shift in the balance of influence of the cerebellum on the mPFC, away from the cerebellar circuitry projecting to the ventral tegmental area, towards cerebellar projections to the thalamus. All of these changes consistently occurred in both lurcher and Fmr1 mutant mice. In addition to modulating mPFC dopamine, the possibility that the cerebellum may also influence dopamine dynamics in the caudate and nucleus accumbens is also considered.
... Olfactory input to the limbic system is provided by olfactory projections to the lateral hypothalamus, amygdala, and hippocampus [107], and influences feeding, mating, and other goal-oriented behaviors. Auditory inputs activate the limbic midbrain region [157], pedunculopontine nucleus [158], the amygdala and ventral striatum [159], hippocampus and cingulate [160], and, predominantly from secondary auditory association areas, the insular cortex [161]. Somatosensory input arising from the spinal cord and spinal trigeminal nucleus carry nociceptive input to the PAG and thermoreceptive and nociceptive inputs to the parabrachial complex; the latter subsequently projects to the hypothalamus and amygdala. ...
…from nothing else but the brain come joy, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations…By this we distinguish objects of relish and disrelish…And by the same organ we become mad and delirious, and fears and terrors assail us…All these things we endure from the brain…Hippocrates, On the Sacred Disease, 4th century BC (in [1], p. 159). Emotions and emotional feelings arise through the integrated processing of bodily sensations, environmental events, thoughts and recollections, and they shape new learning, facilitate decision-making, and guide behavior [2–6]. In most circumstances, emotions and emotional feelings promote learning, adaptation, and survival. The generation and expression of emotions are fundamental (i.e., evolutionarily preserved and relatively primitive) neurobehavioral functions that are expressed similarly between individuals, across cultures, and over the lifespan [7–10]. As noted by LeDoux (1991) [11] and Ekman (1999) [9], the generation of emotion is predicated on evolutionarily preserved neural circuits that respond rapidly to primitive sensory events. By contrast, nuanced emotional experience, its interpretation in oneself and others, and context-relevant emotional control are among the most complex and evolutionarily advanced neurobehavioral functions of humans [12, 13]. When disease or injury compromises normal emotional generation, expression, experience, or control, the effects on patients, families, and societies are adverse and substantial [14–19].
In vivo calcium imaging of neural activity is an indispensable approach for understanding the mechanisms and functions of neural system. Development of advanced imaging tools and various genetically encoded calcium indicators allows us to simultaneously record the activity of different neural populations. Here, we present a protocol for acquiring neural activity of two discrete neural populations in mice using dual-color fiber photometry. We describe steps for injecting viral constructs and implanting the fiber optic through stereotaxic surgery, calcium signal acquisition, and data analysis. We also describe the incorporation of electroencephalogram and electromyography recordings with dual-color fiber photometry analysis.
For complete details on the use and execution of this protocol, please refer to Shin et al.¹
The brainstem pedunculopontine (PPN) and laterodorsal tegmental (LDTg) nuclei are involved in multifarious activities, including motor control. Yet, their exact cytoarchitectural boundaries are still uncertain. We therefore initiated a comparative study of the topographical and neurochemical organization of the PPN and LDTg in cynomolgus monkeys ( Macaca fascicularis ) and humans. The distribution and morphological characteristics of neurons expressing choline acetyltransferase (ChAT) and/or nicotinamide adenine dinucleotide phosphate diaphorase (Nadph‐δ) were documented. The number and density of the labeled neurons were obtained by stringent stereological methods, whereas their topographical distribution was reported upon corresponding magnetic resonance imaging (MRI) planes. In both human and nonhuman primates, the PPN and LDTg are populated by three neurochemically distinct types of neurons (ChAT‐/Nadph‐δ+, ChAT+/Nadph‐δ‐, and ChAT+/Nadph‐δ+), which are distributed according to a complex spatial interplay. Three‐dimensional reconstructions reveal that ChAT+ neurons in the PPN and LDTg form a continuum with some overlaps with pigmented neurons of the locus coeruleus, dorsally, and of the substantia nigra (SN) complex, ventrally. The ChAT+ neurons in the PPN and LDTg are —two to three times more numerous in humans than in monkeys but their density is —three to five times higher in monkeys than in humans. Neurons expressing both ChAT and Nadph‐δ have a larger cell body and a longer primary dendritic arbor than singly labeled neurons. Stereological quantification reveals that 25.6% of ChAT+ neurons in the monkey PPN are devoid of Nadph‐δ staining, a finding that questions the reliability of Nadph‐δ as a marker for cholinergic neurons in primate brainstem.
Motor behaviors are often planned long before execution but only released after specific sensory events. Planning and execution are each associated with distinct patterns of motor cortex activity. Key questions are how these dynamic activity patterns are generated and how they relate to behavior. Here, we investigate the multi-regional neural circuits that link an auditory “Go cue” and the transition from planning to execution of directional licking. Ascending glutamatergic neurons in the midbrain reticular and pedunculopontine nuclei show short latency and phasic changes in spike rate that are selective for the Go cue. This signal is transmitted via the thalamus to the motor cortex, where it triggers a rapid reorganization of motor cortex state from planning-related activity to a motor command, which in turn drives appropriate movement. Our studies show how midbrain can control cortical dynamics via the thalamus for rapid and precise motor behavior.
Mounting evidence suggests an association between aberrant sleep phenomena and dissociative experiences. However, no wake-sleep boundary theory provides a compelling explanation of dissociation or specifies its physiological substrates. We present a theoretical account of dissociation that integrates theories and empirical results from multiple lines of research concerning the domain of dissociation and the regulation of rapid eye movement (REM) sleep. This theory posits that individual differences in the circuitry governing the REM sleep promoting Pedunculopontine Nucleus and Laterodorsal Tegmental Nucleus determine the degree of similarity in the cortical connectivity profiles of wakefulness and REM sleep. We propose that a latent trait characterized by elevated dissociative experiences emerges from the decoupling of frontal executive regions due to a REM sleep-like aminergic/cholinergic balance. The Pedunculopontine-Induced Cortical Decoupling Account of Dissociation (PICDAD) suggests multiple fruitful lines of inquiry and provides novel insights. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
The medial nucleus of trapezoid body (MNTB) is a major source of inhibition in auditory brainstem circuitry. The MNTB projects well-timed inhibitory output to principal sound-localization nuclei in the superior olive (SOC) as well as other computationally important centers. Acoustic information is conveyed to MNTB neurons through a single calyx of Held excitatory synapse arising from the cochlear nucleus. The encoding efficacy of this large synapse depends on its activity rate, which is primarily determined by sound intensity and stimulus frequency. However, MNTB activity rate is additionally influenced by inhibition and possibly neuromodulatory inputs, albeit their functional role is unclear. Happe and Morley (2004) discovered prominent expression of α7-nicotinic acetylcholine receptors (nAChRs) in rat SOC, suggesting possible engagement of acetylcholine (ACh)-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation has never been physiologically demonstrated. We probed nicotinic cholinergic influences on acoustic responses of MNTB neurons from adult gerbils (Meriones unguiculatus) of either sex. We recorded tone evoked MNTB single neuron activity in vivo using extracellular single-unit recording. Piggyback multi-barrel electrodes enabled pharmacological manipulation of nAChRs by reversibly applying antagonists to two receptor types, α7 and α4β2. We observed that tone-evoked responses are dependent on ACh modulation by both nAChR subtypes. Spontaneous activity was not affected by antagonist application. Functionally, we demonstrate that ACh contributes to sustaining high discharge rates and enhances signal encoding efficacy. Additionally, we report anatomical evidence revealing novel cholinergic projections to MNTB arising from pontine and superior olivary nuclei.SIGNIFICANCE STATEMENTThis study is the first to physiologically probe how acetylcholine, a pervasive neuromodulator in the brain, influences the encoding of acoustic information by the MNTB, the most prominent source of inhibition in brainstem sound-localization circuitry. We demonstrate that this cholinergic input enhances neural discrimination of tones from noise stimuli, which may contribute to processing important acoustic signals such as speech. Additionally, we describe novel anatomical projections providing cholinergic input to the MNTB. Together, these findings shed new light on the contribution of neuromodulation to fundamental computational processes in auditory brainstem circuitry and to a more holistic understanding of modulatory influences in sensory processing.
The inferior colliculus processes nearly all ascending auditory information. Most collicular cells respond to sound, and for a majority of these cells, the responses can be modulated by acetylcholine (ACh). The cholinergic effects are varied and, for the most part, the underlying mechanisms are unknown. The major source of cholinergic input to the inferior colliculus is the pedunculopontine tegmental nucleus (PPT), part of the pontomesencephalic tegmentum known for projections to the thalamus and roles in arousal and the sleep-wake cycle. Characterization of PPT inputs to the inferior colliculus has been complicated by the mixed neurotransmitter population within the PPT. Using selective viral-tract tracing techniques in a ChAT-Cre Long Evans rat, the present study characterizes the distribution and targets of cholinergic projections from PPT to the inferior colliculus. Following the deposit of viral vector in one PPT, cholinergic axons studded with boutons were present bilaterally in the inferior colliculus, with the greater density of axons and boutons ipsilateral to the injection site. On both sides, cholinergic axons were present throughout the inferior colliculus, distributing boutons to the central nucleus, lateral cortex, and dorsal cortex. In each inferior colliculus (IC) subdivision, the cholinergic PPT axons appear to contact both GABAergic and glutamatergic neurons. These findings suggest cholinergic projections from the PPT have a widespread influence over the IC, likely affecting many aspects of midbrain auditory processing. Moreover, the effects are likely to be mediated by direct cholinergic actions on both excitatory and inhibitory circuits in the inferior colliculus.
The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions could be mediated by modular synaptic connections of distinct fastigial cell types with posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.
Stimulation of the pedunculopontine nucleus (PPN) is known to induce changes in arousal and postural/locomotor states. Previously, PPN stimulation was reported to induce prolonged responses (PRs) in extracellularly recorded PnC neurons in the decerebrate cat. The present study used intracellular recordings in semihorizontal slices from rat brain stem ( postnatal days 12–21) to determine responses in PnC neurons following PPN stimulation. Two-thirds (65%) of PnC neurons showed PRs after PPN stimulation. PnC neurons with PRs had higher amplitude afterhyperpolarizations (AHP) than non-PR (NPR) neurons. Both PR and NPR neurons were of mixed cell types characterized by “A” and/or “LTS,” or neither of these types of currents. PnC cells showed decreased AHP duration with age, due mostly to decreased AHP duration in NPR cells. The longest mean duration PRs were induced by stimulation at 60 and 90 Hz compared with 10 or 30 Hz. Maximal firing rates in PnC cells during PRs were induced by PPN stimulation at 60 Hz compared with 10, 30, or 90 Hz. BaCl 2 superfusion blocked PPN stimulation-induced PRs, suggesting that PRs may be mediated by blockade of potassium channels, in keeping with increased input resistance observed during PRs. Depolarizing pulses failed to elicit, and hyperpolarizing pulses failed to reset, PPN stimulation-induced PRs, suggesting that PRs may not be plateau potentials. Pharmacological testing revealed that nifedipine superfusion failed to block PPN stimulation-induced PRs; i.e., PRs may not be calcium channel-dependent. The muscarinic cholinergic agonist carbachol induced depolarization in most PR neurons tested, and the muscarinic cholinergic antagonist scopolamine reduced or blocked PPN stimulation-induced PRs in some PnC neurons, suggesting that some PRs may be due to muscarinic receptor activation. The nonspecific ionotropic glutamate receptor antagonist kynurenic acid failed to block PPN stimulation-induced PRs, as did the metabotropic glutamate receptor antagonist (R, S)-αmethyl-4-carboxyphenylglycine, suggesting that PRs may not be mediated by glutamate receptors. These findings suggest that PPN stimulation-induced PRs may be due to increased excitability following closing of muscarinic receptor-sensitive potassium channels, allowing PnC neurons to respond to a transient, frequency-dependent depolarization with long-lasting stable states. PPN stimulation appears to induce PRs using parameters known best to induce locomotion. This mechanism may be related to switching from one state to another (e.g., locomotion vs. standing or sitting, waking vs. non-REM sleep or REM sleep).
Dall’acquisizione della deambulazione nel corso dello sviluppo fino alla vecchiaia, i disturbi della marcia, come quelli dell’equilibrio e della postura, sono motivi di consultazione medica frequente e specialmente presso il neurologo, il reumatologo e il fisioterapista. L’approccio di questi disturbi si basa principalmente su un’analisi clinica sistematica associata a un esame neurologico completo. La classificazione proposta in questo articolo allo scopo molto pratico di fare diagnosi si basa sul deficit principale del disturbo, equilibrio, deficit motorio e disturbo iper- o ipocinetico, cosa che richiede la conoscenza dei principali fondamenti fisiopatologici della locomozione. Alcuni disturbi etichettati come complessi includono diverse disfunzioni tra cui una dimensione cognitiva. L’identificazione del disturbo specifico della marcia può, in certi casi, avvalersi di una condotta terapeutica adeguata: rieducazione funzionale e trattamento chimico (levodopa) o chirurgico (derivazione ventricoloperitoneale). Le innovazioni in questo settore sono numerose; occorre, in particolare, sottolineare il ruolo che occupa la stimolazione cerebrale profonda che dà, già nei bersagli classici, dei risultati in numerosi campi della patologia del movimento (globus pallidus interno e distonia, nucleo subtalamico e morbo di Parkinson), ma che conosce uno sviluppo diretto ai disturbi posturolocomotori con il bersaglio del nucleo peduncolopontino in relazione diretta con gli studi più recenti di neuroscienze nell’animale e nell’uomo sui centri locomotori.
Overview of Research PolicyClinical ResearchReferences
Cholinergic modulation contributes to adaptive sensory processing by controlling spontaneous and stimulus-evoked neural activity and long term synaptic plasticity. In the dorsal cochlear nucleus, in vitro activation of muscarinic acetylcholine receptors (mAChRs) alters the spontaneous activity of DCN neurons and interacts with NMDA (N-methyl-D-aspartate) and endocannabinoid receptors to modulate the plasticity of parallel fiber synapses onto fusiform cells by converting Hebbian LTP to anti-Hebbian LTD. Because noise exposure and tinnitus are known to increase spontaneous activity in fusiform cells as well as alter stimulus-timing dependent plasticity (StTDP), it is important to understand the contribution of mAChRs to in vivo spontaneous activity and plasticity in fusiform cells. Here, we block mAChRs actions by infusing atropine, a mAChR antagonist, into the DCN fusiform cell layer in normal hearing guinea pigs. Atropine delivery leads to decreased spontaneous firing rates and increased synchronization of fusiform cell spiking activity. Consistent with StTDP alterations observed in tinnitus animals, atropine infusion induces a dominant pattern of inversion of StTDP mean population learning rule from a Hebbian to an anti-Hebbian profile. Units preserving their initial Hebbian learning rules shift towards more excitatory changes in StTDP while units with initial suppressive learning rules transition towards a Hebbian profile. Together, these results implicate muscarinic cholinergic modulation as a factor in controlling in vivo fusiform cell baseline activity and plasticity suggesting a central role in the maladaptive plasticity associated with tinnitus pathology.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder next to Alzheimer’s disease, affecting up to 1% of individuals aged 65–69 years and 3% of those over 80 years of age [1]. Among the cardinal features of parkinsonism (resting tremor, bradykinesia, rigidity, and postural instability), postural and gait disfunction leading to falls represents the largest single contributor to the number of emergency room visits and overall cost to the healthcare system relating to PD [2–4]. In addition, the fear of falling is associated with its recurrence, and frequently leads to a loss of independence and depression [5]. Postural and gait disfunction have proven particularly resistant to current dopamine and surgical therapies, which suggests a greater involvement of non-dopaminergic pathways and other brain loci distinct from the pallidal and subthalamic nuclei in their pathophysiology [6–14].
The electroencephalogram was invented by Hans Berger and was used in combination with brain stem transections to ascertain that the reticular activating system (RAS) was the main determinant of the fast activity seen during waking and rapid eye movement (REM) sleep. Lesions of the RAS or disconnection of the RAS from the forebrain generally led to low-frequency activity as seen during slow-wave sleep, but when the RAS was stimulated or remained connected to the forebrain, fast activity such as that observed during waking and REM sleep was manifested. The main nucleus within the RAS in charge of both waking and REM sleep, two states of low-amplitude, high-frequency activity, is the pedunculopontine nucleus.
The wiring diagram of the main nuclei of the reticular activating system (RAS) is well known, as are the intrinsic membrane properties of cells in these nuclei. The major transmitter inputs to these cells have also been described, as have the main cell types and their transmitter outputs. In addition, the presence of electrical coupling in some cells in these nuclei has been determined. These properties allow us to gain a measure of the types of firing patterns that these neurons are capable of maintaining. The firing patterns and transmitter inputs of these cells across the wake-sleep cycle have also been determined. Current research is directed at how the cell clusters within the RAS nuclei function to modulate thalamic and cortical EEG rhythms in the presence of sporadic and continuous sensory inputs. This information is critical for determining how the states of waking and REM sleep are modulated by the RAS.
In our industrialized world, we are surrounded by occupational, recreational, and environmental noise. Very loud noise damages the inner-ear receptors and results in hearing loss, subsequent problems with communication in the presence of background noise, and, potentially, social isolation. There is much less public knowledge about the noise exposure that produces only temporary hearing loss but that in the long term results in hearing problems due to the damage of high-threshold auditory nerve fibers. Early exposures of this kind, such as in neonatal intensive care units, manifest themselves at a later age, sometimes as hearing loss but more often as an auditory processing disorder. There is even less awareness about changes in the auditory brain caused by repetitive daily exposure to the same type of low-level occupational or musical sound. This low-level, but continuous, environmental noise exposure is well known to affect speech understanding, produce non-auditory problems ranging from annoyance and depression to hypertension, and to cause cognitive difficulties. Additionally, internal noise, such as tinnitus, has effects on the brain similar to low-level external noise. Noise and the Brain discusses and provides a synthesis of hte underlying brain mechanisms as well as potential ways to prvent or alleviate these aberrant brain changes caused by noise exposure.
The primary sensory pathways transmit information via rapidly conducting projections through the "specific" thalamic nuclei to the cortex, providing afferents in parallel to the RAS, which projects not only mainly through "nonspecific" thalamic nuclei but also to the cortex. Primary afferent projections through the "specific" thalamic nuclei are manifested in the primary cortical areas, such as the -primary auditory response on the superior temporal gyrus. However, RAS projections through the intralaminar thalamus are manifested at the vertex in the form of the midlatency auditory evoked P50 potential in the human and the rodent equivalent, the P13 potential. These are measures of RAS activity that is reflected at the level of the cortex. As such, they represent noninvasive assessment of RAS output and are extremely useful in determining the direction of RAS dysregulation neurological and psychiatric disorders.
The primary regions affected by descending projections of the pedunculopontine nucleus (PPN) are the subcoeruleus (SubC) nucleus, the pontine and medullary reticular formation, and, to a lesser extent, the spinal cord. The SubC modulates rapid eye movement (REM) sleep signs such as ponto-geniculo-occipital (PGO) waves, atonia, and outputs to the hippocampus. The pontine and medullary reticular formation controls reticulospinal pathways involved in locomotion and postural control. Descending projections to the spinal cord are sparse and their sites of termination have not been described. However, descending projections of the reticular activating system (RAS) are critical for the control of postural and locomotor events related to waking as well as to REM sleep.
This chapter describes the characteristics of mechanisms mediating sleep and arousal, their neurological substrates, and the cellular, neurochemical, and network properties of those substrates, with special emphasis on development from birth through puberty. Humans have three sleep and arousal states: waking, asleep (resting or slow-wave sleep), and asleep and dreaming (paradoxical, active, or rapid eye movement sleep). These states can be explained according to the firing properties of neurons based on their intrinsic membrane properties, their synaptic and neurochemical connectivity, and their responsiveness to sensory inputs.
The researchers studied whether 2 separate motivational systems in the brain underlie the rewarding effects of morphine. The brainstem tegmental pedunculopontine nucleus (TPP) is involved in mediating the motivational effects of opiates in nondeprived (drug-naive) rats, whereas dopamine transmission is necessary in mediating the motivational effects of opiates in deprived rats (opiate withdrawal). The results show that heroin's motivational properties obey the same boundary between a nondeprived and a deprived motivational state. Bilateral ibotenic acid lesions of the TPP blocked the acquisition of a place preference for an environment paired with 0.05 mg/kg heroin (a dose that induces no withdrawal aversion) but had no effect on place preference for an environment paired with 0.5 mg/kg heroin (a dose that does induce withdrawal aversion). Dopamine antagonist pretreatment produced the opposite pattern of results.
The only mesopontine neurons previously described as involved in the transfer of ponto-geniculo-occipital (PGO) waves from the brain stem to the thalamus were termed PGO-on bursting cells. We have studied, in chronically implanted cats, neuronal activities in brain-stem peribrachial (PB) and laterodorsal tegmental (LDT) cholinergic nuclei in relation to PGO waves recorded from the lateral geniculate (LG) thalamic nucleus during rapid-eye-movement (REM) sleep. We constructed peri-PGO histograms of PB/LDT cells' discharges and analyzed the interspike interval distribution during the period of increased neuronal activity related to PGO waves. Six categories of PGO-related PB/LDT neurons with identified thalamic projections were found: 4 classes of PGO-on cells: PGO-off but REM-on cells: and post-PGO cells. The physiological characteristics of a given cell class were stable even during prolonged recordings. One of these cell classes (1) represents the previously described PGO-on bursting neurons, while the other five (2–6) are newly discovered neuronal types. (1) Some neurons (16% of PGO-related cells) discharged stereotyped low-frequency (120– 180 Hz) spike bursts preceding the negative peak of the LG-PGO waves by 20–40 msec. These neurons had low firing rates (0.5–3.5 Hz) during all states. (2) A distinct cell class (22% of PGO-related neurons) fired high-frequency spike bursts (greater than 500 Hz) about 20–40 msec prior to the thalamic PGO wave. These bursts were preceded by a period (150–200 msec) of discharge acceleration on a background of tonically increased activity during REM sleep. (3) PGO-on tonic neurons (20% of PGO-related neurons) discharged trains of repetitive single spikes preceding the thalamic PGO waves by 100–150 msec, but never fired high- frequency spike bursts. (4) Other PGO-on neurons (10% of PGO-related neurons) discharged single spikes preceding thalamic PGO waves by 15–30 msec. On the basis of parallel intracellular recordings in acutely prepared, reserpine-treated animals, we concluded that the PGO-on single spikes arise from conventional excitatory postsynaptic potentials and do not reflect tiny postinhibitory rebounds. (5) A peculiar cellular class, termed PGO-off elements (8% of PGO-related neurons), consisted of neurons with tonic, high discharge rates (greater than 30 Hz) during REM sleep. These neurons stopped firing 100– 200 msec before and during the thalamic PGO waves. (6) Finally, other neurons discharged spike bursts or tonic spike trains 100–300 msec after the initially negative peak of the thalamic PGO field potential (post-PGO elements, 23% of PGO-related neurons).(ABSTRACT TRUNCATED AT 400 WORDS)
The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid- age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.
The latency of the acoustic startle reflex in the rat is 8 msec, measured from tone onset to the beginning of the electromyographic response in the hindleg. This extremely short latency indicates that only a few synapses could be involved in some primary acoustic startle circuit. Acoustic startle is being used as a model system for studying habituation, sensitization, prepulse inhibition, classical conditioning, fear or anxiety, and drug effects on behavior. The present study attempted to delineate a short latency acoustic startle circuit, since this would provide critical information for further study in all of these areas. Bilateral lesions of the ventral cochlear nucleus, which receives the primary auditory input, abolish acoustic startle. Electrical, single pulse stimulation of the ventral cochlear nucleus elicits startle-like responses with a latency of about 7 msec. Bilateral lesions of the dorsal and ventral nuclei of the lateral lemniscus, which receive direct input from the ventral cochlear nuclei, abolish acoustic startle. Electrical stimulation of these nuclei elicits startle-like responses with a latency of about 6 msec. Bilateral lesions of ventral regions of the nucleus reticularis pontis caudalis, which contain cell bodies that give rise to the reticulospinal tract, abolish acoustic startle. Electrical stimulation of these points elicits startle-like responses with a latency of about 5 msec. Reaction product from horseradish peroxidase iontophoresed into this area is found in the nuclei of the lateral lemniscus. In contrast, lesions of the dorsal cochlear nuclei, vestibular nuclei, nucleus reticularis pontis oralis, nucleus reticularis gigantocellularis, and dorsal regions of the nucleus reticularis pontis caudalis fail to abolish acoustic startle. Also, "startle" cannot be elicited electrically from these areas. The data suggest that a primary acoustic startle circuit in the rat consists of auditory nerve, ventral cochlear nucleus, nuclei of the lateral lemniscus, nucleus reticularis pontis caudalis, spinal interneuron, lower motor neuron, and muscles. Hence, five synapses, plus the neuromuscular junction, are probably involved.
Neuroendocrine studies examining the hypothalamic-pituitar3'-adrenal (HPA) axis under baseline conditions and in response to neuroendocrine challenges have supported the hypothesis of altered HPA functioning in posttraumatic stress disorder (PTSD). However, to date, there is much debate concerning the nature of HPA changes in PTSD. Furthermore , in studies showing parallel findings in PTSD and major depressive disorder there is controversy regarding whether the HPA alterations suggest a specific pathophysiolog'y of PTSD, or, rather, reflect comorbid major depressive disorder. This review summarizes findings of HPA axis dysfunction in both PTSD and major depressive disorder, and shows distinct patterns of HPA changes, which are probably due to db~'erent mechanisms of action for cortisol and its regulatory factors.
Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations
One of the ultimate goals of neuroscience is to determine how the brain directs and changes behavior in man. Given the enormous complexity of this endeavor, an increasing number of neuroscientists have focused on invertebrates and lower vertebrates in an effort to simplify the problem. Eventually, however, it will be necessary to analyze the cellular basis of behavior in a complex mammalian brain. To approach the problem at this level, it would be useful to study a relatively simple behavior that can be elicited in mammals and that is sensitive to a variety of experimental treatments.
• In the context of a Finnish birth cohort, we tested the hypothesis that viral infection during the latter two thirds of fetal development would increase the risk of adult schizophrenic outcome. Psychiatric hospital diagnoses were recorded for all individuals in greater Helsinki who were fetuses during the 1957 type A2 influenza epidemic. Those exposed to the viral epidemic during their second trimester of fetal development were at elevated risk of being admitted to a psychiatric hospital with a diagnosis of schizophrenia. This was true for both males and females and independently in several psychiatric hospitals. The second-trimester effect was seen in the elevated proportion of schizophrenics among those admitted to a psychiatric hospital and also in higher rates of schizophrenia per 1000 live births in the city of Helsinki. The study has several limitations: (1) We have no direct evidence that the subjects actually suffered a viral Infection. (2) The psychiatric data were obtained only for subjects up to the age of 26 years, 56 days. (3) The findings are based on hospital diagnoses. (4) The determination of stage of gestation at time of exposure to the epidemic is based on date of birth. The viral Infection might have occurred outside the official epidemic window; the infant may have had a preterm or postterm delivery. These sources of error, however, should not serve to enhance the findings. The observed viral effect is interpreted as being one of many potential perturbations of gestation. We suggest that It is less the type than the timing of the disturbance during fetal neural development that is critical in determining risk for schizophrenia.
• Clonidine hydrochloride, an α2-adrenergic receptor agonist that decreases noradrenergic function, was administered to 21 healthy subjects and 26 drug-free patients with agoraphobia and panic attacks. Clonidine produced significantly greater decreases in plasma MHPG levels and sitting and standing diastolic blood pressure and significantly smaller increases in growth hormone levels and self-rated drowsiness in the patients. These findings indicate that the regulation of noradrenergic activity is aberrant in some patients with panic disorder, since a previous study demonstrated that patients with panic disorder exhibit increased plasma MHPG levels, blood pressure, and behavioral responses to the α2-adrenergic receptor antagonist yohimbine. The increased dynamic range of noradrenergic activity observed as an increased sensitivity to both clonidine and yohimbine may reflect abnormalities in the regulatory inputs to noradrenergic neurons, or dysfunction in the α2-adrenergic receptor effector coupling mechanism or the intracellular effector system.
The development of most regions of the vertebrate nervous system includes a distinct phase of neuronal degeneration during which a substantial proportion of the neurons initially generated die. This degeneration primarily adjusts the magnitude of each neuronal population to the size or functional needs of its projection field, but in the process it seems also to eliminate many neurons whose axons have grown to either the wrong target or an inappropriate region within the target area. In addition, many connections that are initially formed are later eliminated without the death of the parent cell. In most cases such process elimination results in the removal of terminal axonal branches and hence serves as a mechanism to "fine-tune" neuronal wiring. However, there are now also several examples of the large-scale elimination of early-formed pathways as a result of the selective degeneration of long axon collaterals. Thus, far from being relatively minor aspects of neural development, these regressive phenomena are now recognized as playing a major role in determining the form of the mature nervous system.
In this chapter, narcolepsy is discussed from the clinical point of view. Several areas of recent concern in research are described based on my personal experiences with Japanese narcoleptic patients. There is a large Japanese literature on narcolepsy which has not been known to the researchers of other countries because of the language barrier. Some of these studies are cited and explained briefly. First, the symptomatology associated with narcolepsy is discussed. This leads to the definition of the term “narcolepsy” and issues in the diagnostic criteria for narcolepsy and in differential diagnosis. Next, the pathophysiology of narcolepsy, neuroendocrine, neuropharmacological, and epidemiological findings are described, followed by recommendations of practical treatment plans and an introduction of the activities of the Japan Narcolepsy Association.
Parkinsonian tremor can be abolished by chronic high frequency thalamic stimulation of the ventral intermediate nucleus. We have studied six patients with unilateral Parkinson's disease. The patients had an electrode chronically implanted in the ventral intermediate nucleus of the thalamus. We measured changes in cerebral activity by positron emission tomography using an index of regional cerebral blood flow (rCBF). Each patient was scanned in three states: (i) tremor without stimulation (condition A); (ii) tremor with ineffective stimulation (condition B); (iii) tremor abolished by effective stimulation (condition C). The suppression of tremor (C compared with B) was specifically associated with a decrease of rCBF in the cerebellum, whereas the ineffective stimulation (B compared with A) induced a decrease of rCBF in homolateral cerebral cortex. The results give evidence for different contributions from cortex and cerebellum to the generation of parkinsonian tremor and suggest that tremor suppression is mainly associated with a decrease of synaptic activity in the cerebellum.
• The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics. DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.
• Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate—diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate—diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.
• We reviewed the literature to determine the characteristics of corticosteroid-induced mental disturbances. We conclude that (1) while dosage may be correlated to the risk of developing mental disturbances, neither dosage nor duration of treatment seems to affect the time of onset, duration, severity, or type of mental disturbances; (2) euphoria, depression, and psychotic reactions are the common manifestations of corticosteroidinduced mental disturbances; (3) females seem to be more prone to these disturbances than males; (4) patients with past mental illness are not necessarily predisposed to such disturbances; and (5) corticosteroid-induced mental disturbances are usually reversible on dose reduction or discontinuation of the drug. At present there are no simple models to explain the psychotic reactions, anxiety, or agitation seen in corticosteroidinduced mental disturbances.
In an effort to account for a large number of reported functions mediated by a small portion of the midbrain, a hypothesis is advanced as a basis for discussion and not as established fact and is guided by reports from a large number of laboratories working on the same region but using widely disparate preparations. Overall, the hypothesized model suggests an underlying mechanism of action for what is essentially the ascending reticular activating system. The model proposed will hopefully be tested stringently in order to arrive at a better understanding of brain stem mechanisms modulating a host of rhythmic functions.
THE stage 4 EEG (employing the Dement and Kleitman1 nomenclature) of sleep, as measured in our laboratory, consists of high-voltage (over 50V) slow (under 4 cycles per second) activity occurring with a stipulated density (over 16 waves per 20second epoch, or over 50% of the epoch occupied by such slow waves). Stage 3 EEG represents a lesser density (10 to 16 waves per 20-second epoch) of this slow-wave activity. Stage 3 and 4 EEG constitute, along with spindles and K-complexes, the distinguishing features of nonrapid eye-movement (NREM) or slow-wave sleep. Both stage 3 and 4 EEG are maximal during the first few hours of sleep1 and their distributions across the night may usefully be described as a function of the successive sleep cycles.2
Stage 4 EEG reaches its highest level in early childhood3 and then shows a hyper
DURING a recent polygraphic study of sleep patterns in patients receiving electric convulsive therapy (ECT),1 we found a statistically significant reduction in both total amount and percent of rapid eye movement (REM) sleep on nights recorded immediately after the final ECT in the series. On the other hand, nights recorded early in the treatment series showed either no change or minor elevations in the REM fraction. These findings were more or less uniform among all members of the group with the exception of a dramatically aberrant response in one patient, the consideration of which led to the formulation of the present study.
The exceptional patient was a paranoid schizophrenic whose sleep patterns were polygraphically monitored over four consecutive baseline nights and showed a total sleep time averaging seven hours, 11 minutes, of which 17.9%, or 77 minutes, were spent in the REM phase. After the eighth ECT in her
• Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron-emission tomography in eight patients with schizophrenia who were not receiving medication and in six age-matched normal volunteers. Subjects sat in an acoustically treated, darkened room with eyes closed after injection of 3 to 5 mCi of deoxyglucose 18F. After uptake, seven to eight horizontal brain scans parallel to the canthomeatal line were done. Scans were treated digitally, with a 2.3-cm strip peeled off each slice and ratios to whole-slice activity computed. Patients with schizophrenia showed lower ratios in the frontal cortex, indicating relatively lower glucose use than normal control subjects; this was consistent with previously reported studies of regional cerebral blood flow. Patients also showed diminished ratios for a 2.3-cm square that was positioned over central gray-matter areas on the left but not on the right side. These findings are preliminary; issues of control of mental activity, brain structure identification, and biologic and anatomic heterogeneity of schizophrenia remain to be explored.
Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness, cataplexy, and premature onset of rapid eye movement sleep. It can be differentiated from other disorders causing daytime drowsiness by its clinical symptoms and by sleep laboratory studies. The disorder usually begins in adolescence and remains present throughout life. Genetic susceptibility to narcolepsy is closely associated with specific HLAs that indicate the existence of a gene in the region of the major histocompatibility complex on chromosome 6 that increases susceptibility to narcolepsy. Neurochemical studies of human and canine narcolepsy have demonstrated disturbed monoaminergic and cholinergic function that may account for impaired regulation of rapid eye movement sleep, but the link between these abnormalities and the genetic factors is still unknown. Treatment of sleepiness with stimulants and cataplexy with tricyclic antidepressants leads to substantial improvement but does not fully resolve symptoms in most patients.
Bizarreness is a cognitive feature common to REM sleep dreams, which can be easily measured. Because bizarreness is highly specific to dreaming, we propose that it is most likely brought about by changes in neuronal activity that are specific to REM sleep. At the level of the dream plot, bizarreness can be defined as either discontinuity or incongruity. In addition, the dreamer's thoughts about the plot may be logically deficient.
We propose that dream bizarreness is the cognitive concomitant of two kinds of changes in neuronal dynamics during REM sleep. One is the disinhibition of forebrain networks caused by the withdrawal of the modulatory influences of norepinephrine (NE) and serotonin (5HT) in REM sleep, secondary to cessation of firing of locus coeruleus and dorsal raphe neurons. This aminergic demodulation can be mathematically modeled as a shift toward increased error at the outputs from neural networks, and these errors might be represented cognitively as incongruities and/or discontinuities.
We also consider the possibility that discontinuities are the cognitive concomitant of sudden bifurcations or “jumps” in the responses of forebrain neuronal networks. These bifurcations are caused by phasic discharge of pontogeniculooccipital (PGO) neurons during REM sleep, providing a source of cholinergic modulation to the forebrain which could evoke unpredictable network responses. When phasic PGO activity stops, the resultant activity in the brain may be wholly unrelated to patterns of activity dominant before such phasic stimulation began. Mathematically such sudden shifts from one pattern of activity to a second, unrelated one is called a bifurcation. We propose that the neuronal bifurcations brought about by PGO activity might be represented cognitively as bizarre discontinuities of dream plot.
We regard these proposals as preliminary attempts to model the relationship between dream cognition and REM sleep neurophysiology. This neurophysiological model of dream bizarreness may also prove useful in understanding the contributions of REM sleep to the developmental and experiential plasticity of the cerebral cortex.
When the neural systems which are responsible for postural atonia during paradoxical sleep are destroyed, sleeping cats periodically display stereotyped motor activity, revealing a rich repertoire of non-goal-directed 'oneiric behaviour'.
Cell-mediated immunity (CMI) is concerned with the elimination of cells that are modified by, for instance, infection with viruses1. The specific operators of CMI are the thymus-derived lymphocytes (T cells), which recognize viral (or other non-self) components presented in the context of self major histocompatibility complex (MHC) glycoproteins. Cells that do not express MHC antigen are not recognized by T lymphocytes2–4, even though they may be producing infectious virus. Many CNS cells present little, if any, MHC glycoprotein5,6. A new and important finding6 is that the level of MHC expression in cultured brain cells can be greatly enhanced by exposure to γ-interferon (IFN-γ), which is secreted by at least some clones of effector T cells7–9.
Compared digital computer sleep prints of schizophrenic patients with those of nonpsychotic Ss. Prints of the former showed significantly fewer deep sleep stages, more light sleep stages and awakening periods, a later onset of spindle sleep, and a marked variability in sleep profile, both within single nights and from night to night. No significant differences between the 2 groups were observed in length of REM sleep, amount of single REM and burst REM activity, and nature of REM cycles. Schizophrenics' EEG records have fewer slow delta waves, less frequency deviation, lower amplitude variability and average absolute amplitude, and more superimposed fast activity than nonpsychotic Ss. Nonpsychotics had fewer 5-8 cps and 12-16 cps waves. The comparison of the all-night sleep patterns of hallucinating and nonhallucinating schizophrenics did not reveal any significant differences in length of sleep stages, length of REM periods, length of REM burst activity, or in computer-analyzed EEG variables. (30 ref.) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
CNS inhibitory neuronal mechanisms were assessed in 15 18–54 yr old male medicated schizophrenics, 14 acutely psychotic unmedicated patients, and 17 normal male controls by measuring auditory evoked response in a conditioning-testing paradigm. At a .5-sec interstimulus interval, normal controls had a mean response decrement of 80%, whereas both schizophrenic groups showed a decrement of less than 10%. Data indicate that dysfunctional inhibitory mechanisms in unmedicated schizophrenics are not improved by neuroleptic treatment, although other aspects of sensory neural function may be altered. (41 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
As neurophysiological investigations of sleep cycle control have provided an increasingly detailed picture of events at the cellular level, the concept that the sleep cycle is generated by the interaction of multiple, anatomically distributed sets of neurons has gradually replaced the hypothesis that sleep is generated by a single, highly localized neuronal oscillator.
Cell groups that discharge during rapid-eye-movement (REM) sleep (REM-on) and neurons that slow or cease firing during REM sleep (REM-off) have long been thought to comprise at least two neurochemically distinct populations. The fact that putatively cholinoceptive and/or cholinergic (REM-on) and putatively aminergic (REM-off) cell populations discharge reciprocally over the sleep cycle suggests a causal interdependence.
In some brain stem areas these cell groups are not anatomically segregated and may instead be neurochemically mixed (interpenetrated). This finding raises important theoretical and practical issues not anticipated in the original reciprocal-interaction model. The electrophysiological evidence concerning the REM-on and REM-off cell groups suggests a gradient of sleep-dependent membrane excitability changes that may be a function of the connectivity strength within an anatomically distributed neuronal network. The connectivity strength may be influenced by the degree of neurochemical interpenetration between the REM-on and REM-offcells. Recognition of these complexities forces us to revise the reciprocal-interaction model and to seek new methods to test its tenets.
Cholinergic microinjection experiments indicate that some populations of REM-on cells can execute specific portions of the REM sleep syndrome or block the generation of REM sleep. This observation suggests that the order of activation within the anatomically distributed generator populations may be critical in determining behavioral outcome. Support for the cholinergic tenets of the reciprocal-interaction model has been reinforced by observations from sleep-disorders medicine.
Specific predictions of the reciprocal-interaction model and suggestions for testing these predictions are enumerated for future experimental programs that aim to understand the cellular and molecular basis of the mammalian sleep cycle.
The origins of the cholinergic and other afferents of several thalamic nuclei were investigated in the rat by using the retrograde transport of wheat germ agglutinin conjugated‐horseradish peroxidase in combination with the immunohistochemical localization of choline acetyltransferase immunoreactivity. Small injections placed into the reticular, ventral, laterodorsal, lateroposterior, posterior, mediodorsal, geniculate, and intralaminar nuclei resulted in several distinct patterns of retrograde labelling. As expected, the appropriate specific sensory and motor‐related subcortical structures were retrogradely labelled after injections into the principal thalamic nuclei. In addition, other basal forebrain and brainstem structures were also labelled, with their distribution dependent on the site of injection. A large percentage of these latter projections was cholinergic.
In the brainstem, the cholinergic pedunculopontine tegmental nucleus was retrogradely labelled after all thalamic injections, suggesting that it provides a widespread innervation to the thalamus. Neurons of the cholinergic laterodorsal tegmental nucleus were retrogradely labelled after injections into the anterior, laterodorsal, central medial, and mediodorsal nuclei, suggesting that it provides a projection to limbic components of the thalamus. Significant basal forebrain labelling occurred only with injections into the reticular and mediodorsal nuclei. Only injections into the reticular nucleus resulted in retrograde labelling of the cholinergic neurons in the nucleus basalis of Meynert.
The results provide evidence for an organized system of thalamic afferents arising from cholinergic and noncholinergic structures in the brainstem and basal forebrain. The brainstem structures, especially the cholinergic pedunculopontine tegmental nucleus, appear to project directly to principal thalamic nuclei, thereby providing a possible anatomical substrate for mediating the well‐known facilitory effects of brainstem stimulation upon thalamocortical transmission.
Graham (1975) demonstrated that a weak prestimulus could effectively inhibit or facilitate the eyeblink component of the startle reflex in humans, depending on the temporal duration of the prestimulus. This study had three goals: 1) to replicate the findings of Graham, 2) to establish the reliability of this phenomenon by a test-retest comparison, and 3) to compare the eyeblink reflex response of normal subjects with schizophrenic subjects. Seven prestimulus durations of continuous tone (from 0 to 2000 msec) were presented to 20 normal subjects and the results confirmed that maximal inhibition of eyeblink amplitude occurred in the 120 msec prestimulus condition. Increased amplitude occurred nonsignificantly when the prestimulus lasted for 2000 msec. On retest, 14 normal subjects showed a significant degree of reliability. When 20 normal subjects were compared to 12 schizophrenic subjects, significant differences in eyeblink response were found for blink amplitude and latency in the 60 msec prestimulus condition. This change is consistent with information processing “overload” theories of sensory overstimulation in schizophrenia. The blink reflex is a rather stable phenomenon and is probably altered in schizophrenia and/or by antipsychotic medication.