7. 0T ultrahigh-field MRI directly visualized the pedunculopontine nucleus in Parkinson's disease patients

OBJECTIVES: The pedunculopontine nucleus (PPN) is considered a promising new target for neurostimulation in Parkinson's disease (PD) patients with postural instability and gait disturbance that is refractory to other treatment modalities. However, the PPN is typically difficult to visualize with magnetic resonance imaging (MRI) at clinical field strengths, which greatly limits the PPN as a viable surgical target for deep brain stimulation (DBS). Thus, the aim of this study is to directly visualize the PPN based on 7.0T ultrahigh-field MRI. METHODS: Five PD patients were enrolled and scanned using the MP2RAGE sequence on a 7.0T ultrahigh-field MRI scanner. Then, the MP2RAGE sequences were imported into a commercially available navigation system. The coordinates of the directly localized PPN poles were recorded in the navigation system relative to the anterior commissure-posterior commissure plane. RESULTS: Our results indicated that the PPN presented intermediate signal intensity in the 7.0T ultrahigh-field MR images in comparison with the surrounding structure, such as the hypo-intensity of the periaqueductal gray and the hyperintensity of the neighboring white matter tracts, in PD patients. The mean coordinates for the rostral and caudal poles of PPN were 6.50 mm and 7.20 mm lateral, 1.58 mm and 2.21 mm posterior, and 8.89 mm and 13.83 mm relative to the posterior commissure. CONCLUSION: Our findings provide, for the first time, direct visualization of the PPN using the MP2RAGE sequence on a 7.0T ultrahigh-field MRI, which may improve the accuracy of stereotactic targeting of the PPN and improve the outcomes in patients undergoing DBS.

Utilidad de la estimulación continua del núcleo pedunculopontino para el tratamiento de la enfermedad de Parkinson / Utility Continuous Stimulation of Pedunculopontine Nucleus for treating Parkinson's Disease

El núcleo pedunculopontmo contiene gran cantidad de conexiones que modulan la actividad motora en los humanos; por este motivo, se ha planteado que su estimulación profunda tendría beneficios significativos en el tratamiento de la enfermedad de Parkinson. Con una carga orgánica y social significativa, la enfermedad de Parkinson reúne una serie de signos y síntomas, principalmente motores, que afectan significativamente la calidad de vida de los pacientes que la padecen. Actualmente, se encuentran dentro de un área de investigación con gran potencial para dar manejo a los síntomas de esta enfermedad, y se desconoce si su estimulación cerebral profunda podría orientar futuras intervenciones con resultados óptimos. Por esta razón, la revisión busca esclarecer la utilidad de este procedimiento; sin embargo, es bastante controvertido y su evidencia escasa, además de que es difícil centrarse únicamente en un núcleo para resolver los problemas relacionados con dicha enfermedad.

The pendunculopontine nucleus contains many connections responsible or modulate motor activity. It has been suggested that deep stimulation would have significant benefits in the treatment of Parldnson's disease, intervention that could improve the patient5s quality of life and generare a positive impact in public health due Parkmson's disease has important organic and social burden. There is a growmg area of research in this fíeld, however is still uncertain if deep brain stimulation could guide future interventíons with optimal results. For this reason, we pretend to darify the existing knowledge of this procedure, nevertheless, it is quite controversial, we consider that it is difficult to focusing on a unique nucleus to solve the problems associated with this disease.

Excessive daytime sleepiness and unintended sleep episodes associated with parkinson's disease

This article looks at the issues of excessive daytime sleepiness and unintended sleep episodes in patients with Parkinson's disease [PD] and explores the reasons why patients might suffer from these symptoms, and what steps could be taken to manage them. During the last decade, understanding of sleep/wake regulation has increased. Several brainstem nuclei and their communication pathways in the ascending arousing system through the hypothalamus and thalamus to the cortex play key roles in sleep disorders. Insomnia is the most common sleep disorder in PD patients, and excessive daytime sleepiness is also common. Excessive daytime sleepiness affects up to 50% of PD patients and a growing body of research has established this sleep disturbance as a marker of preclinical and premotor PD. It is a frequent and highly persistent feature in PD, with multifactorial underlying pathophysiology. Both age and disease-related disturbances of sleep-wake regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also contribute to excessive daytime sleepiness. Effective management of sleep disturbances and excessive daytime sleepiness can greatly improve the quality of life for patients with PD

Effects and mechanism of low frequency stimulation of pedunculopontine nucleus on spontaneous discharges of ventrolateral thalamic nucleus in rats / 生理学报

Parkinson's disease is a progressive neurodegenerative disorder characterized clinically by rigidity, akinesia, resting tremor and postural instability. It has recently been suggested that low frequency stimulation of the pedunculopontine nucleus (PPN) has a role in the therapy for Parkinsonism, particularly in gait disorder and postural instability. However, there is limited information about the mechanism of low frequency stimulation of the PPN on Parkinson's disease. The present study was to investigate the effect and mechanism of low frequency stimulation of the PPN on the firing rate of the ventrolateral thalamic nucleus (VL) in a rat model with unilateral 6-hydroxydopamine lesioning of the substantia nigra pars compacta. In vivo extracellular recording and microiontophoresis were adopted. The results showed that the firing rate of 60.71% VL neurons in normal rats and 59.57% VL neurons in 6-hydroxydopamine lesioned rats increased with low frequency stimulation of the PPN. Using microiontophoresis to VL neurons, we found the firing rate in VL neurons responded with either an increase or decrease in application of acetylcholine (ACh) in normal rats, whereas with a predominant decrease in M receptor antagonist atropine. Furthermore, the VL neurons were mainly inhibited by application of γ-aminobutyric acid (GABA) and excited by GABA(A) receptor antagonist bicuculline. Importantly, the VL neurons responding to ACh were also inhibited by application of GABA. We also found that the excitatory response of the VL neurons to the low frequency stimulation of the PPN was significantly reversed by microiontophoresis of atropine. These results demonstrate that cholinergic and GABAergic afferent nerve fibers may converge on the same VL neurons and they are involved in the effects of low frequency stimulation of the PPN, with ACh combining M(2) receptors on the presynaptic membrane of GABAergic afferents, which will inhibit the release of GABA in the VL and then improve the symptoms of Parkinson's disease.

Effects of unilateral lesion of the nigrostriatal pathway by 6-OHDA on the neuronal activities of the pedunculopontine nucleus and the ventrolateral thalamic nucleus / 中国应用生理学杂志

<p><b>AIM</b>To investigate the changes in neuronal activities of the pedunculopontine nucleus (PPN) and the ventrolateral thalamic nucleus (VL) after unilateral 6-hydroxydopamin (6-OHDA) lesioning of the striatum in rats.</p><p><b>METHODS</b>Extracellular single-unit recordings were perin normal rats and 6-OHDA lesioned rats to observe the firing rate and firing pattern occurring in PPN and VL neurons.</p><p><b>RESULTS</b>The firing rate of PPN neurones significantly increased from (8.31 +/- 0.62) Hz in normal rats to (10.70 +/- 0.85) Hz in 6-OHDA lesioned rats. The firing pattern changed towards more irregular and bursty when compared with the normal rats, with the firing rate increasing in regular pattern. The firing rate of VL neurones in normal rats and 6-OHDA lesioned rats were (6.25 +/- 0.54) Hz and (5.67 +/- 0.46)Hz respectively, whereas to normal animals. Surthere were no significant differences in these two groups. In addition, the firing pattern did not change in VL compared prisingly, the firing rate in burst pattern decreased significantly.</p><p><b>CONCLUSION</b>These findings demonstrate that PPN neurons are overactive in 6-OHDAlesioned rats, indicating the participation of this nucleus in the pathophysiology of parkinsonism and the activities of VL neurons might be regulated by projection from PPN to VL.</p>

Neural mechanism of rapid eye movement sleep generation with reference to REM-OFF neurons in locus coeruleus.

The noradrenergic (NA-ergic) rapid eye movement (REM)-OFF neurons in locus coeruleus (LC) and cholinergic REM-ON neurons in laterodorsal/pedunculopontine tegmentum show a reciprocal firing pattern. The REM-ON neurons fire during REM sleep whereas REM-OFF neurons stop firing during REM sleep. The cessation of firing of REM-OFF neurons is a pre-requisite for the generation of REM sleep and non-cessation of those neurons result in REM sleep loss that is characterized by symptoms like loss of memory retention, irritation, hypersexuality, etc. There is an intricate interplay between the REM-OFF and REM-ON neurons for REM sleep regulation. Acetylcholine from REM-ON neurons excites the GABA-ergic interneurons in the LC that in turn inhibit the REM-OFF neurons. The cessation of firing of REM-OFF neurons withdraws the inhibition from the REM-ON neurons, and facilitates the excitation of these neurons resulting in the initiation of REM sleep. GABA modulates the generation of REM sleep in pedunculopontine tegmentum (PPT) by acting pre-synaptically on the NA-ergic terminals that synapse on the REM-ON neurons whereas in LC it modulates the maintenance of REM sleep by acting post-synaptically on REM-OFF neurons. The activity of REM sleep related neurons is modulated by wakefulness (midbrain reticular formation/ascending reticular activating system) and sleep inducing (caudal brainstem/medullary reticular formation) areas. Thus, during wakefulness the wake-active neurons keep on firing that excites the REM-OFF neurons, which in turn keeps the REMON neurons inhibited; therefore, during wakefulness REM sleep episodes are not expressed. Additionally, the wakefulness inducing area keeps the REM-ON neurons inhibited. In contrast, the sleep inducing area excites the REM-ON neurons. Thus, the wakefulness inducing area excites and inhibits the REM-OFF and REM-ON neurons, respectively, while the sleep inducing area excites the REM-ON neurons that facilitate the generation of REM sleep.

Neuroanatomy of Sleep-Wake Regulation and its Application to Pharmacotherapy / 대한정신약물학회지

A current hypothesis of sleep-wake regulation proposes that the sleep process starts with the activation of sleep-promoting neurons located in the preoptic area of the anterior hypothalamus. This activation leads to the inhibition of wake-promoting neurons located in the posterior hypothalamus, basal forebrain, and mesopontine tegmentum, which, in turn removes inhibition from the sleep-promoting structures(i.e., disinhibition) to initiate the sleep process. Mutual inhibition between these wake- and sleep-promoting neurons results in switching properties that define discrete wakeful and sleep states with sharp transitions between them. Wake-promoting nuclei include the orexinergic lateral hypothalamic/perifornical area, the histaminergic tuberomammillary nucleus, the cholinergic pedunculopontine tegmental nucleus, the noradrenergic locus coeruleus, the 5-hydroxytryptaminergic raphe nuclei, and possibly the dopaminergic ventral tegmental area. The major sleep-promoting nucleus is the GABAergic ventrolateral preoptic nucleus of the hypothalamus. The regulation of sleep is classically viewed as the dual interaction of circadian(SCN-based) and homeostatic processes, and the propensity to be asleep or awake at any given time is a consequence of a sleep debt and its interaction with signals from the SCN circadian clock. To better understand the mechanisms of sleep and wakefulness, the focus of pharmacotherapy is on targeting specific therapies to the particular defect in sleep-wake regulation.

Immunohistochemical Study on the Nitric Oxide Synthase Neurons in the Brain Stem of Rats / 대한해부학회지

Nitric oxide (NO), a free radical that has been postulated to act as a neurotransmitter, neuromodulator, or second messenger molecule in nervous system, is synthesized from L-arginine by nitric oxide synthase (NOS). The NADPH-diaphorase (NADPH-d) histochemical techenique provides a simple and robust method to stain the selected populations of NOS neurons in the brain. This study was aimed to clarify the distribution of NOS neurons in the brain stem of rats. To verify the distribution of NOS neurons in the brain stem, the neurons were stained by the NOS immunohis-tochemistry and NADPH-d histochemistry. Image analyzer-assisted densitometry and cell counting method have been used to quantitatively characterize groups of neuronal cells. Double labeling of NOS immunohistochemistry and NADPH-d histochemistry showed the coexistence of NOS and NADPH-d in same neurons. Neuronal cell bodies exhibiting NOS/NADPH-d staining were found in particular nuclei throughout the brain stem. The number of NOS/NADPH-d neurons were variable in brain stem nuclei. The NADPH-d neurons exhibited different intensities of reaction product. Some groups, including paradorsal raphe nucleus, laterodorsal tegmental nucleus and pedunculopontine tegmental nucleus were extremely heavily stained. Other neurons such as those in the interpeduncular nucleus, central gray, substantia nigra lateralis, nucleus solitarius and raphe obscurus nucleus were moderately stained, while other neurons such supragenual nucleus, lateral paragigantocellular nucleus and prepositus hypoglossal nucleus were weakly stained. The present study describes the many locations within the brain stem in which NADPH-d occurs. Since NADPH-d activity colocalizes with NOS, the results indicate the likely involvement of nitric oxide in the neuronal functions of many brain stem nuclei of rats.