Degeneration Of Nuclei Research Articles

Spinocerebellar Ataxia Type 2 (SCA2): Identification of Early Brain Degeneration in One Monozygous Twin in the Initial Disease Stage

Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2.

CSF Levels of the Histamine Metabolite tele-Methylhistamine are only Slightly Decreased in Alzheimer's Disease

Neuropathological studies have reported a strong neurofibrillary degeneration of the tuberomamillary nucleus, the region of origin of histamine neurons, in Alzheimer's disease (AD). Histaminergic neurons enhance cognition and memory, suggesting that their degeneration may contribute to the cognitive decline of AD. Besides neurons, the brain histaminergic system comprises mast cells and microglia that can also produce histamine. The level of activity of this histaminergic system in AD remained unknown. In the present study, we have measured the levels of the main histamine metabolite in brain, tele-methylhistamine (t-MeHA), an index of histaminergic system activity, in the cerebrospinal fluid (CSF) of 97 non-AD (controls) and 91 AD patients, males or females. t-MeHA levels in CSF of controls tended to be higher, although non-significantly, in females than in males. t-MeHA levels of controls and AD significantly increased with age (1.66 ± 0.13, 2.04 ± 0.12, and 2.76 ± 0.12 pmol/ml at 40, 60 and 80 years, respectively). In spite of the strong degeneration of histamine neurons in the disease, t-MeHA levels in CSF were only slightly decreased in AD compared to controls (2.14 ± 0.10 vs 2.76 ± 0.13 pmol/ml, -22%, p < 0.01). This decrease was similar whatever the age, and was slightly higher in females than in males. The increase observed with age, and the limited magnitude of the decrease in AD even at late stages may result from the compensatory activation of spared neurons, as well as the neuroinflammation-induced activation of microglia occurring in senescence and AD.

827 Slc25A19 Mutation is a Novel Cause of Neuropathy and Bilateral Striatal Necrosis

Acute basal ganglia necrosis in the pediatric age group is a neurological disorder characterized by symmetrical degeneration of the caudate nucleus, putamen, and occasionally the globus pallidus. The outcome is less favorable for the familial cases where the course is relentlessly progressive or punctuated by recurrent episodes with involvement of additional brain regions and significant residual neurological damage. The differential diagnosis of the latter group includes mitochondrial respiratory chain defects organic acid disorders, Wilson disease, juvenile Huntington's chorea, pantothenate kinaseassociated neurodegeneration, biotin responsive basal ganglia disease, and the striatal necrosis associated with NUP62 mutation.In this study we report on four siblings from a consanguineous Arab Muslim family who suffered from recurrent episodes of flaccid paralysis and encephalopathy and chronic progressive polyneuropathy associated with bilateral striatal necrosis. Using homozygosity mapping the pathogenic homozygous missense mutation c.373G>A was identified. This mutation alters a highly conserved glycine residue at position 125 to serine in the SLC25A19 gene which encodes the mitochondrial thiamine pyrophosphate transporter. SLC25A19 mutation was previously reported only in the Amish congenital lethal microcephaly but our patients' phenotype is markedly different with normal head circumference, early childhood development, and age-appropriate cognitive skills. Based on the role of SLC25A19 in mitochondrial thiamine transport, supplementation with high dose thiamine was initiated in all patients. Preliminary results suggest a favorable effect.Our report suggests an allelic phenotype in SLC25A19 gene defects. Determination of the SLC25A19 sequence may be warranted in patients with bilateral striatal necrosis or progressive polyneuropathy.

Silicon amelioration of aluminium toxicity and cell death in suspension cultures of Norway spruce ( Picea abies (L.) Karst.)

A role for silicon (Si) in the amelioration of aluminium (Al) toxicity in gymnosperms is suggested by their codeposition in planta, including within needles. This study was designed to investigate Al/Si interactions at the cellular level using suspension cultures of Norway spruce. Toxic effects of Al were dependent on duration of Al exposure, concentration of Al, and pH. Toxicity was reduced when Si was present, and the effect was enhanced at pH 5.0 compared to pH 4.2. Study of the ultrastructure of Al-treated cells indicated that changes in cell wall thickening, degree of vacuolation, and the degeneration of mitochondria, Golgi bodies, ER and nucleus preceded cell death, and significant amelioration was noted when Si was also present. When the fluorescent dye Morin was employed to localise free Al, cells treated with Al and Si in combination showed less fluorescence than the cells treated with Al alone. Intensity of fluorescence depended on the concentration of Al, duration of treatment and pH. Notably, presence of Si reduced the concentration of free Al in the cell wall in parallel with amelioration of Al toxicity. We therefore propose that formation of aluminosilicate complexes in the wall and apoplasm provide a significant barrier to Al penetration and cell damage in Norway spruce.

Cerebellar dysfunction in progressive supranuclear palsy: A transcranial magnetic stimulation study

Progressive supranuclear palsy (PSP) rarely shows cerebellar signs and symptoms even though the cerebellar dentate nuclei are involved pathologically. This study evaluates cerebellar function using transcranial magnetic stimulation (TMS) to determine whether subclinical cerebellar involvement is present in PSP patients. We studied 11 patients with PSP, 11 patients with Parkinson's disease (PD), and 10 age-matched controls. Patients were examined with their usual medications and in their relative on state. Motor evoked potentials (MEPs) were recorded from the hand muscle. Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEPs elicited by TMS over the contralateral motor cortex, which we call cerebellar inhibition (CBI). Interstimulus intervals (ISIs) of 4 to 8 ms were used, and the time course of CBI was analyzed. The CBI was reduced in PSP patients. By contrast, the CBI was normal in PD patients in their on state. Although the CBI in their off state should be examined in future studies, the results described herein suggest that Purkinje cells or the dentato-thalamo-cortical pathway assessed by CBI is involved in PSP. Our results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients.

Neuropathology of variants of progressive supranuclear palsy

Neurodegenerative tauopathies, of which progressive supranuclear palsy (PSP) is one of the most common, are clinically heterogeneous, reflecting differences in distribution and biochemical composition of tau pathology. This review highlights the range of clinical and pathologic presentations of PSP and its variants. Progressive supranuclear palsy is a 4R tauopathy with neuronal and glial tau-immunoreactive lesions in neuroanatomically specific nuclei in the basal ganglia, diencephalon, brainstem and cerebellum, with restricted involvement of the neocortex. Hierarchical cluster analyses of clinical and pathologic features of PSP indicate that there are distinct clinicopathologic variants of PSP. In variants of PSP presenting with focal cortical syndromes, such as frontotemporal dementia, corticobasal syndrome and apraxia of speech, there is greater cortical pathology than in typical PSP. In variants of PSP presenting with levodopa-responsive Parkinsonism, as well as pure akinesia and gait failure, there is less cortical pathology and more severe degeneration in the cardinal nuclei - globus pallidus, subthalamic nucleus and substantia nigra - than in typical PSP. Clinical variants in PSP reflect varying anatomical distribution of tau pathology, but they share histopathologic, biochemical and genetic features with typical PSP. The basis for anatomical selective vulnerability in PSP and its variants remains to be determined.

Neuroinflammatory processes in Alzheimer’s disease

Generation of neurotoxic amyloid beta peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer's disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or gamma-secretase inhibition and activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.

Mating system, auxosporulation, species taxonomy and evidence for homoploid evolution in Amphora (Bacillariophyta)

Mann D.G. and Poulíčková A. 2010. Mating system, auxosporulation, species taxonomy and evidence for homoploid evolution in Amphora (Bacillariophyta). Phycologia 49: 183–201. DOI: 10.2216/09-08.1Cytological characteristics of the mitotic cycle, sexual reproduction and auxospore formation are described for three members of the type group of Amphora: A. ovalis, A. copulata and A. minutissima. All have a single lobed ventral chloroplast, nuclei with granular heterochromatin and a single nucleolus (unusually large in A. ovalis). Amphora copulata is heterothallic, with two mating types that do not differ in gamete behaviour. All three species reproduce allogamously via fusion of two rearranged gametes per gametangium to produce elongate zygotes enclosed within the volume delimited by the gametangial thecae. Pairing is strictly via the ventral sides of the cells, with tight apposition of the cells, and expansion of the auxospores is strictly perpendicular to the gametangium long axes. Comparisons are made with other Amphora species, particularly A. proteus (also belonging to the subgenus Amphora) and A. arcus. Meiosis is described in detail in A. copulata, revealing no movement of the nucleus away from the dorsal position it occupies during the mitotic cycle, a synizetic knot in early prophase, no cytokinesis accompanying meiosis II, and rapid degeneration of the supernumerary nuclei in the gametic cells; the usual two acytokinetic mitoses accompany formation of the initial epivalve (which lacks a functional raphe) and hypovalve. The potential for formation of autopolyploids is demonstrated in A. copulata. Nevertheless, chromosome counts of 2n = 34 in A. copulata, 2n = 28 or 30 in A. ovalis and an undetermined but not significantly lower number in A. minutissima, suggest that homoploid evolution is more likely than polyploid. In mixed sexualized populations of the species, no interbreeding occurs, supporting separation of minutissima from copulata. Measurements of initial cell sizes, coupled with slight differences in valve width and pattern, suggest that A. copulata may be a species complex.

Monocytes deliver bioactive nerve growth factor through a brain capillary endothelial cell-monolayer in vitro and counteract degeneration of cholinergic neurons

Alzheimer's disease is an age-dependent brain disorder, characterized by progressive memory deficits and cognitive decline and loss of cholinergic neurons. Nerve growth factor (NGF) is the most potent protein to protect cholinergic neurons against degeneration. However, problems of delivery to the brain limit the therapeutical use of NGF. The aim of the present study was to test, if primary rat monocytes can be loaded with recombinant NGF and pass an in vitro monolayer of brain capillary endothelial cells (BCEC), release NGF, and support the cholinergic neurons in an organotypic brain slice model. Monocytes were isolated from rat blood by negative magnetic selection, loaded with recombinant NGF using Bioporter™. The monocytes adhered and migrated through an in vitro rat BCEC-monolayer. NGF released at the basolateral side counteracted degeneration of cholinergic basal nucleus of Meynert neurons. In conclusion, our present study shows a proof-of-principle, that primary monocytes secreting NGF might be useful tools to deliver NGF into the brain, however, further in vivo studies are necessary.

Thalamic changes in Parkinson's disease

One of the most marked differences to be identified in Parkinson's disease is the change in activity of thalamic neurons in the motor circuits. Because dopamine replacement therapies largely alleviate these motor circuit abnormalities, it has been assumed that pathology in the basal ganglia is entirely responsible for the aberrant thalamic activity which then permeates the motor circuits. However, there is considerable evidence that pathology in the thalamus itself contributes to the abnormal neural activity characteristic of Parkinson's disease. In a series of studies examining the degree of degeneration in the thalamus, we have observed selective degeneration in the intralaminar thalamic nuclei in patients with levodopa-responsive Parkinson's disease. The nuclei involved are the caudal intralaminar nuclei (the centre-median/parafascicular complex), the parataenial, cucullar and central lateral nuclei. The centre-median/parafascicular complex provides important glutaminergic feedback from the thalamus to the putamen and is a pathway that is greatly enlarged in primates. There is 30-40% loss in this region of the thalamus in idiopathic Parkinson's disease, with non-parvalbumin-containing neurons degenerating the most (70% average loss). Our recent work suggests that the preservation of this pathway may contribute to dystonia in Parkinson's disease. The central lateral and cucullar thalamic nuclei degenerate 30-50%, while the parataenial nucleus sustains a 55% loss of neurons in association with significant alpha-synuclein deposition which correlates with disease duration. Damage to these regions appears to impact on cognition, awareness and perception. These studies suggest that direct thalamic pathology contributes to the symptoms of Parkinson's disease.

Frequency and Correlates of Involuntary Emotional Expression Disorder in Parkinson's Disease

Frequency and Correlates of Involuntary Emotional Expression Disorder in Parkinson's Disease

A systematic study of brainstem motor nuclei in a mouse model of ALS, the effects of lithium

Transgenic mice expressing the human superoxide dismutase 1 (SOD-1) mutant at position 93 (G93A) develop a phenotype resembling amyotrophic lateral sclerosis (ALS). In fact, G93A mice develop progressive motor deficits which finally lead to motor palsy and death. This is due to the progressive degeneration of motor neurons in the ventral horn of the spinal cord. Although a similar loss is reported for specific cranial motor nuclei, only a few studies so far investigated degeneration in a few brainstem nuclei. We recently reported that chronic lithium administration delays onset and duration of the disease, while reducing degeneration of spinal motor neuron. In the present study, we extended this investigation to all somatic motor nuclei of the brain stem in the G93A mice and we evaluated whether analogous protective effects induced by lithium in the spinal cord were present at the brain stem level. We found that all motor but the oculomotor nuclei were markedly degenerated in G93A mice, and chronic treatment with lithium significantly attenuated neurodegeneration in the trigeminal, facial, ambiguus, and hypoglossal nuclei. Moreover, in the hypoglossal nucleus, we found that recurrent collaterals were markedly lost in G93A mice while they were rescued by chronic lithium administration.

Imaging-Pathologic Correlation in Corticobasal Degeneration

The clinical diagnosis of corticobasal degeneration (CBD) is often difficult due to varied clinical manifestations. In 4 patients with neuropathologically confirmed CBD, characteristic imaging findings and correlations with neuropathologic features were evaluated. Furthermore, imaging findings in CBD were compared with neuropathologically confirmed progressive supranuclear palsy (PSP) for a differential diagnosis. Four patients with neuropathologically confirmed CBD were studied. We evaluated the area of the tegmentum in the midsagittal plane, subcortical white matter (SCWM) abnormality, asymmetric cerebral atrophy, and signal-intensity abnormality in the subthalamic nuclei on MR imaging and compared them with histopathologic findings. Then, MR imaging findings in CBD were compared with those in 13 patients with PSP. On MR imaging, 3 patients had asymmetric cerebral atrophy extending to the central sulcus. On midsagittal sections, the mean midbrain tegmentum area was 66 mm(2), being markedly smaller than normal, but there was no significant difference between PSP and CBD. All patients had signal-intensity abnormalities of the SCWM, constituting primary degeneration neuropathologically; however, no diffuse signal-intensity abnormality in the SCWM existed in the 13 patients with PSP. In 3 patients, T1-weighted images showed symmetric high signal intensity in the subthalamic nuclei. Neuropathologically, these areas showed characteristic CBD. MR imaging signal-intensity changes also existed in 4 patients with PSP; however, subthalamic nucleus degeneration was more severe in PSP than in CBD. In cases with midbrain tegmentum atrophy and signal-intensity changes in the subthalamic nuclei, the differential diagnosis distinguishing CBD from PSP based on MR imaging alone was difficult. White matter lesions and asymmetric atrophy can be useful for a differential diagnosis.

Spinocerebellar ataxia type 6 (SCA6): neurodegeneration goes beyond the known brain predilection sites

Spinocerebellar ataxia type 6 (SCA6) is a late onset autosomal dominantly inherited ataxic disorder, which belongs to the group of CAG repeat, or polyglutamine, diseases. Although, it has long been regarded as a 'pure' cerebellar disease, recent clinical studies have demonstrated disease signs challenging the view that neurodegeneration in SCA6 is confined to the well-known lesions in the cerebellum and inferior olive. We performed a systematic pathoanatomical study throughout the brains of three clinically diagnosed and genetically confirmed SCA6 patients. This study confirmed that brain damage in SCA6 goes beyond the known brain predilection sites. In all of the SCA6 patients studied loss of cerebellar Purkinje cells and absence of morphologically intact layer V giant Betz pyramidal cells in the primary motor cortex, as well as widespread degeneration of brainstem nuclei was present. Additional damage to the deep cerebellar nuclei was observed in two of three SCA6 patients. In view of the known functional role of affected central nervous grey components it is likely that their degeneration at least in part is responsible for the occurrence of a variety of SCA6 disease symptoms.

Selective impairment of prediction error signaling in human dorsolateral but not ventral striatum in Parkinson's disease patients: evidence from a model-based fMRI study

Animal studies have found that the phasic activity of dopamine neurons during reward-related learning resembles a “prediction error” (PE) signal derived from a class of computational models called reinforcement learning (RL). An apparently similar signal can be measured using fMRI in the human striatum, a primary dopaminergic target. However, the fMRI signal does not measure dopamine per se, and therefore further evidence is needed to determine if these signals are related to each other. Parkinson's disease (PD) involves the neurodegeneration of the dopamine system and is accompanied by deficits in reward-related decision-making tasks. In the current study we used a computational RL model to assess striatal error signals in PD patients performing an RL task during fMRI scanning. Results show that error signals were preserved in ventral striatum of PD patients, but impaired in dorsolateral striatum, relative to healthy controls, a pattern reflecting the known selective anatomical degeneration of dopamine nuclei in PD. These findings support the notion that PE signals measured in the human striatum by the BOLD signal may reflect phasic DA activity. These results also provide evidence for a deficiency in PE signaling in the dorsolateral striatum of PD patients that may offer an explanation for their deficits observed in other reward learning tasks.

Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver, by S. A. Kinnier Wilson, (From the National Hospital, and the Laboratory of the National Hospital, Queen Square, London) Brain 1912: 34; 295-509.

‘Progressive lenticular degeneration may be defined as a disease which occurs in young people, which is often familial but not congenital or hereditary; it is essentially and chiefly a disease of the extrapyramidal motor system, and is characterised by involuntary movements, usually of the nature of tremor, dysarthria, dysphagia, muscular weakness, spasticity, and contractures with progressive emaciation; with these may be associated emotionalism and certain symptoms of a mental nature. It is progressive, and, after a longer or shorter period, fatal. Pathologically it is characterised predominantly by bilateral degeneration of the lenticular nucleus, and in addition cirrhosis of the liver is constantly found, the latter morbid condition rarely, if ever, giving rise to symptoms during the life of the patient.’ This proposed definition appears midway through Samuel Alexander Kinnier Wilson's original and magisterial account of progressive lenticular degeneration. In publishing part of his thesis, submitted for the degree of MD at the University of Edinburgh in July 1911 for which a gold medal was awarded, Dr Kinnier Wilson has written, at 214 printed pages, the longest paper ever published in Brain . His aim is to describe, for the first time so far as he can ascertain, a disorder that is often familial, affects young people, and is invariably fatal. Dr Kinnier Wilson has encountered four cases (two of whom were siblings), making the diagnosis during life in three; but he acknowledges that the literature may contain six previous reports and he has located the case notes of two other affected individuals, previously not described, from these same families. The clinical symptoms can be considered a pure syndrome of the corpus striatum; manifesting as generalized tremor increasing with voluntary movement, spasticity especially of the face, bulbar involvement culminating in anarthria, and increased emotionalism. Balance is lost, despite a lack of …

Hypertrophic Olivary Degeneration Following Pontine Cavernoma Hemorrhage

Introduction The triangular neuronal circuit between the red nucleus, the ipsilateral inferior olivary nucleus and the contralateral dentate nucleus as part of the extrapyramidal motor system was first described by Guillain & Mollaret in 1931 [1]. It consists of fibers running in the central tegmental tract from the red nucleus to the ipsilateral inferior olivary nucleus, from here to the contralateral dentate nucleus through the inferior cerebellar peduncle and from there via the dentatorubral tract running in the superior cerebellar peduncle back to the ipsilateral red nucleus (Figure 1). This neuronal circuit acts as an inhibitory system on cortical generated impulses by comparing them with their performance in the peripheral motor effector organs. Lesions including parts of the Guillain-Mollaret triangle may result in a rare, but characteristic hypertrophic degeneration of the inferior olivary nucleus [2].

Cortical Lesion-Induced Visual Hemineglect Is Prevented by NMDA Antagonist Pretreatment

Large unilateral visual cortex lesions produce enduring contralesional visual orientation deficits. To examine whether glutamate excitotoxicity is involved in establishing these deficits, cats were pretreated with the NMDA receptor antagonist dizocilpine (MK-801) 30 min before unilateral visual cortex ablation. Pretreated MK-801 animals were trained first in an orientation task in which they were required to fixate directly ahead and then orient to stimuli introduced at various eccentricities throughout the visual field. They did not display the characteristic ipsilesional head and neck asymmetries and/or spontaneous ipsiversive rotational behaviors or show the profound contralesional visual neglect seen postoperatively in nonpretreated control animals. Rather, pretreated animals were able to orient to visual stimuli in the contralesional hemifield immediately following surgical recovery. Postmortem histology revealed severe retrograde degeneration of the ipsilesional lateral geniculate nucleus in both experimental groups, suggesting that postlesion visuomotor behavioral competencies in pretreated animals are attributable to preserved function in nongeniculocortical visual pathways. These observations are consistent with the hypothesis that visual cortex lesions normally induce secondary alterations via NMDA-mediated excitotoxicity in these other pathways that prevents them from supporting visuomotor behaviors. The similar behavioral competencies of MK-801-pretreated animals and those whose lesion-induced deficits are ameliorated by removing basal ganglia afferents to the ipsilesional superior colliculus are consistent with this hypothesis and highlight the normal functional capabilities of this circuit. It is likely that MK-801 pretreatment acts, at least in part, by preserving the normal interhemispheric control dynamics with which the basal ganglia influence superior colliculus-mediated orientation behaviors.

Degeneration of Nuclei and Mitochondria in Human Hairs

It is generally accepted that nuclei degrade in developing hair shafts but the point at which such occurs has not been investigated. The fate of mitochondria in the keratinizing hair shaft has been less clear. This study uses transmission electron microscopy to investigate when nuclei and mitochondria are no longer visible in the developing hair shaft. Serial sections were obtained from anagen head hairs absent follicles in order to determine the sequence of degradation of nuclei and mitochondria in the hair shaft by starting at the root bulb and proceeding toward the hair tip. It was demonstrated that nuclei and mitochondria become invisible in the keratinizing hair shaft at about the same time. This was found to occur fairly early in the process at the level of the hair shaft where the hair cuticle becomes permanent.

Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus

AbstractThe pedunculopontine nucleus is composed of cholinergic and non‐cholinergic neurones and is located in the caudal pontomesencephalic tegmentum. Evidence suggests that the nucleus plays a role in the production and control of movement. The nucleus has dense interconnections with the basal ganglia, as well as with other areas of the brain associated with motor control. Electrical stimulation of the pedunculopontine nucleus in the decerebrate cat or rat produces organized locomotor movements. Physiological studies show that the pedunculopontine nucleus modulates its activity in response to locomotion, as well as voluntary arm and eye movements. Degeneration of the pedunculopontine nucleus is seen in post‐mortem brains in humans with Parkinson's disease and Parkinsonian syndromes. In animal models of Parkinson's disease, metabolic changes are seen in the pedunculopontine nucleus, and chemical inhibition or mechanical disruption of the nucleus can produce an akinetic state in animals and man. In this paper we review the literature in support of the suggestion that some of the symptoms of Parkinson's disease are caused by dysfunction of the pedunculopontine nucleus. In accordance with this view, direct stimulation of the nucleus can ameliorate some symptoms of the disease, as demonstrated in both experimental animals and man. © 2008 Movement Disorder Society