Algorithms for the treatment of motor problems in Parkinson's disease.

Several different strategies are effective for medical treatment of motor problems in Parkinson's disease (PD). Many guidelines and evidence-based reviews are available, but there is no documentation or consensus in favor of just one treatment strategy. This review presents two algorithms that may be helpful when deciding how to treat a PD patient at various stages of the disease. The first algorithm suggests one way to treat PD from the first onset of motor symptoms. It is largely based on treatment recommendations from the Scandinavian countries and Germany. The other algorithm is meant as assistance for choosing among the different device-aided treatments for advanced PD. There is not sufficient comparative data to recommend one particular line of treatment, neither in early PD nor in advanced disease with motor complications. Individualized treatment is needed for each patient. The current algorithms only represent an alternative for aiding treatment decisions.

Major involvement of trunk muscles in myotonic dystrophy type 1.

OBJECTIVES: The motor impairments in Myotonic Dystrophy 1 (DM1) are assumed to progress from distal toward proximal parts of the extremities in the Juvenile and Adult forms of DM1. On occasion and late in progress spine deformity is observed. In this study we have examined whether and to what extent trunk muscles are impaired in DM1, and if this impairment is correlated with the duration of the disorder, walking capacity, mobility, balance, and CTG-repeats. MATERIALS & METHODS: Manual muscle testing (MMT) of skeletal muscle strength in trunk and extremities, reassessment of the mutation size, time since first symptom, the 6 min walk test (6MWT), Rivermead mobility index (RIM) and Timed up & go (TUG) were sampled in 38 adult DM1 outpatients. RESULTS: We found significant impairment in trunk muscles. Trunk muscle strength decreased significantly with increasing mutation size (r = -0.64, P < 0.001). Reduced walking capacity, mobility and balance were significantly related to decreased trunk muscle strength. CONCLUSION: DM1 affects trunk muscle groups. The trunk impairments seem to occur relatively early in disease progression. Awareness of trunk impairments may be of importance for everyday functioning and for understanding the risk of injuries due to falls reported among DM1 patients. It may also help in identification of DM1 patients and considered outcome measure in future clinical trials.

Longitudinal assessment of probable rapid eye movement sleep behaviour disorder in Parkinson's disease.

BACKGROUND AND PURPOSE: Rapid eye movement (REM) sleep behaviour disorder (RBD) is frequently present in patients with Parkinson's disease (PD) and may have prognostic implications. There are few longitudinal studies of RBD in patients with PD. Our aim was to investigate whether RBD was a persistent feature in a follow-up study of 107 patients with PD. METHODS: After a mean follow-up time of 3 years, 96 patients were available for reassessment. Probable RBD (pRBD) was diagnosed by the REM sleep behaviour disorder screening questionnaire. RESULTS: At follow-up, pRBD was found in 49% of the patients, versus 38% at baseline. The pRBD status remained unchanged in three-quarters of the patients, whilst 17% had new pRBD symptoms. Disease duration was longer in the pRBD group, 9.4 vs. 7.6 years (P = 0.02). CONCLUSIONS: Probable RBD is a persistent feature in PD and probably increases over time.

Progression and survival in Parkinson's disease with subthalamic nucleus stimulation.

BACKGROUND: Treatment for Parkinson's disease (PD) is symptomatic. Surgical treatment with continuous high-frequency stimulation of the subthalamic nucleus (STN-DBS) is established as a safe symptomatic treatment with long-term beneficial effects. It has been postulated that STN-DBS could halt the progression of PD through a disease modifying or neuroprotective effect. OBJECTIVE: To investigate the postulated disease modifying or neuroprotective effect of STN-DBS by comparing the rate of deterioration of parkinsonism and mortality over time in two selected and matched groups of patients with PD with and without surgery. METHODS: Group A was derived from all patients who received STN-DSB surgery at Oslo University Hospital, from January 2001 to December 2007. Group B was derived from a prevalence study of PD in the Stavanger area of Western Norway in 1993. The two groups were individually matched and the disease progression measured by Unified Parkinson's Disease Rating Scale-motor scores, and the mortality was compared. RESULTS: The mean annual change based on baseline and last observation scores in individually matched groups was 0.97 (SD = 3.57) for the surgery group and 1.04 (SD = 3.33) for the controls and thus not significantly different, F(1, 104) = .21, P = 0.89. The long-term mortality was also similar in the two groups during long-term follow-up, hazard ratio = 1.76, CL 0.91-3.40, P = 0.091. CONCLUSION: This study gives no support to a postulated disease modifying or neuroprotective effect of STN-DBS in patients with PD.

Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease.

OBJECTIVE: To summarize the 2010 EFNS/MDS-ES evidence-based treatment recommendations for the management of Parkinson's disease (PD). This summary includes the treatment recommendations for early and late PD. METHODS: For the 2010 publication, a literature search was undertaken for articles published up to September 2009. For this summary, an additional literature search was undertaken up to December 2010. Classification of scientific evidence and the rating of recommendations were made according to the EFNS guidance. In cases where there was insufficient scientific evidence, a consensus statement ('good practice point') is made. RESULTS AND CONCLUSIONS: For each clinical indication, a list of therapeutic interventions is provided, including classification of evidence.

Good long-term efficacy of pallidal stimulation in cervical dystonia: a prospective, observer-blinded study.

BACKGROUND AND PURPOSE: Deep brain stimulation of the internal globus pallidus (GPi-DBS) is established as an effective treatment of primary generalised dystonia in controlled studies. In cervical dystonia (CD), only one previous study has reported observer-blinded outcome assessment of long-term GPi-DBS, with 1-year follow-up. METHODS: In this prospective, single-centre study, eight patients with CD (7 women:1 man, 4 focal:4 segmental) treated with bilateral GPi-DBS for median (range) 30 (12-48) months, were evaluated by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS; Severity, Disability and Pain scores), the Short-Form Health Survey-36 (SF-36), and the Becks Depression Index in an open design. In addition, a blinded rater assessed the TWSTRS Severity score from videos obtained preoperatively and at the last follow-up. RESULTS: In the blinded evaluation, median (range) TWSTRS Severity score improved from 25 (19-30) to 8 (4-23) (P = 0.028), thus a 70% (23-82) score reduction. In the open evaluation, median Severity score improvement at the last follow-up was 73%, representing a significant further improvement from 50% at 6 months. The Disability and Pain scores improved by median 91% and 92%, respectively, and the SF-36 subdomain scores improved significantly. A reversible right hemiparesis and aphasia occured in one patient 4 days postoperatively, because of reversible oedema around the left electrode. No other serious adverse effects and no permanent morbidity were observed. CONCLUSIONS: This single-blinded study shows good long-term efficacy of GPi-DBS in CD patients and supports using this treatment in those who have insufficient response to medical treatment.

Altered brain myelin sheath morphology after rewarming in situ.

In this study cerebral ultrastructure was examined in an in vivo rat model, after rewarming from profound hypothermia (15-13 degrees C). Animals held at 37 degrees C served as controls. After rewarming, brains were examined by electron microscope. Micrographs were taken randomly, analyzed anonymously, and quantified by morphometry. Serum analysis of the stress marker S-100beta was carried out in identical groups. The most striking findings in rewarmed animals, when compared to controls, were alterations of myelin sheaths (p<.008) and elevated S-100beta (p<.0001). This indicates that cells in the central nervous system are susceptible to injury in an experimental model of accidental hypothermia and rewarming.

Cerebellar autonomic function: direct hypothalamocerebellar pathway.

A direct hypothalamocerebellar projection in the cat was revealed by means of retrograde transport of wheat germ agglutinin--horseradish peroxidase complex. This appears to be the first demonstration of a significant autonomic input to the cerebellum. The projection has a widespread origin and is bilateral with an ipsilateral preponderance.

Cerebrospinal fluid cytokine levels in migraine, tension-type headache and cervicogenic headache.

Cytokines have been measured in cerebrospinal fluid (CSF) from headache patients [infrequent episodic tension-type headache (TTH) and migraine with or without aura, all during attack, and cervicogenic headache] and compared with levels in pain-free individuals. Both proinflammatory [interleukin (IL)-1beta, tumour necrosis factor-alpha and monocyte chemoattractant protein-1 (MCP-1)] and anti-inflammatory cytokines [IL-1 receptor antagonist (IL-1ra), IL-4, IL-10 and transforming growth factor-beta1 (TGF-beta1)] were included. There were significant group differences in IL-1ra, TGF-beta1 and MCP-1 in episodic TTH and migraine compared with controls, and a significant difference in MCP-1 between cervicogenic headache and migraine with aura. Intrathecal MCP-1 correlated with IL-1ra, IL-10 and TGF-beta1 in episodic TTH, and MCP-1 with IL-10 in migraine with aura. Cytokine increases were modest compared with those often accompanying serious neurological conditions, and may represent a mild response to pain. We believe this to be the first comparative study of CSF cytokine levels in connection with headache.

Clinical manifestation of focal cerebellar disease as related to the organization of neural pathways.

Neural pathways connect different parts of the cerebellum to different parts of the central nervous system. The cerebellum may be divided anatomically and functionally into three major regions. The cerebellar hemispheres and a small part of the posterior lobe vermis form the pontocerebellum, which receives inputs from the cerebral cortex via the pontine nuclei. The anterior lobe and most of the posterior lobe vermis make up the spinocerebellum, which receives afferents from the spinal cord. The nodulus and flocculus are connected with the vestibular nuclei and constitute the vestibulocerebellum. Most cases of cerebellar disease affect more than one region and different pathways. Hence, they cause generalized cerebellar symptoms dominated by impaired motor control and balance. Focal syndromes after restricted cerebellar lesions are rare. Isolated spinocerebellar affection may give gait ataxia. Vestibulocerebellar disease causes equilibrium disturbances with truncal ataxia and nystagmus. Pontocerebellar lesions typically give ipsilateral limb ataxia, but also dysartria and oculomotor dysfunction if vermal parts are involved. The clinical picture is in most cases of cerebellar disease dominated by motor disturbances, but the cerebellum also participates in the modulation of autonomic and affective responses and in cognitive functions. The cerebrocerebellar and hypothalamocerebellar circuits may be important for these tasks.

Unmasking psychiatric symptoms after STN deep brain stimulation in Parkinson's disease.

BACKGROUND: Stereotactic implantation of electrodes for deep brain stimulation (DBS) in the subthalamic nucleus (STN) is a well-established treatment for Parkinson's disease. The treatment gives stable effect over years on the motor symptoms of Parkinson's disease. Psychiatric effects of STN-DBS have attracted increasing attention, with a growing number of reports on psychiatric side effects or exacerbations of known psychiatric disease. However, little is known about the possible unmasking of hidden psychiatric symptoms after surgery. AIMS: The aim of this clinical commentary is to illustrate unmasking of psychiatric disease by STN-DBS through the presentation of a case from our clinic. PATIENT: A patient with Parkinson's disease underwent implantation of STN stimulation electrodes with good results on his motor symptoms. He did not disclose his previous psychiatric history. Soon after the onset of stimulation he developed affective symptoms with manic, aggressive and depressive behaviour, and also an attempted suicide. The stimulation was reduced and his dopaminergic medication increased after the attempted suicide. His previous history of depression and anxiety was now revealed. He received psychiatric attention, and the affective symptoms resolved. The effect of the stimulation on motor symptoms remained stable. CONCLUSIONS: The unmasking of previous psychiatric problems after STN stimulation may be an underestimated problem. It is necessary to fully penetrate the psychiatric anamnesis, especially in patients with a strong wish to be operated and a consequent reluctance to reveal previous problems. Patients with a previous history of a psychiatric disorder are not the best candidates for implantation of STN electrodes.

Acute headache: a prospective diagnostic work-up of patients admitted to a general hospital.

BACKGROUND AND PURPOSE: To find a specified diagnosis for every patient investigated in the hospital emergency room for acute headache suspicious of subarachnoid haemorrhage (SAH), and to describe similarities and differences between the diagnostic groups. METHODS: We used a standardized set of questionnaires and supplementary tests, including cerebral computed tomography (CT) and if needed lumbar puncture, in the investigation of the patients. Two neurologists diagnosed the same cases independently. RESULTS: We found 30 different diagnoses as the cause of acute headache. Sixteen per cent had a SAH, and 57% had a primary headache. Patient characteristics, conditions at headache onset and accompanying symptoms were surprisingly similar in the diagnostic groups. For three SAH patients, it took 30 min to reach maximum pain intensity. In all diagnostic groups, a large proportion of the patients reached maximum pain within 60 s. CONCLUSIONS: To distinguish between benign and malignant causes of acute headache is difficult based on clinical features. The consistent use of CT and lumbar puncture is valuable when investigating sudden onset 'first or worst headache ever'. This can reduce the risk of missing a SAH diagnosis, and make it possible to give more exact diagnoses to patients suffering from both primary and secondary headaches.

Microvascular decompression for hemifacial spasm: postoperative neurologic follow-up and evaluation of life quality.

Microvascular decompression (MVD) is an effective and safe treatment in hemifacial spasm (HFS). Postoperative evaluations are usually made by neurosurgeons. Follow-up studies performed by neurologists and postoperative quality of life (QoL) investigations are lacking. All 25 HFS patients operated with MVD in our centre between 2000 and 2004 were evaluated with the recently validated HFS-7 scheme, extended with the item 'sleep disturbance due to HFS' (HFS-8). The patients underwent a careful neurological examination median 3 years after the operation. The evaluation focused on clinical aspects, changes in blood pressure and time until observable effect of MVD. The evaluation of HFS-7 questionnaire and the extended form (HFS-8) showed significant improvement in QoL after MVD. Neurological outcome was in almost all cases excellent or good. Eleven (44%) patients had no neurological deficits at all. Only one patient had serious complications with ipsilateral facial palsy, deafness, balance problems and vertigo. The other patients had minor neurological findings or symptoms. Eighteen (72%) patients experienced early effect within 3 months after MVD; seven (28%) patients had late effect between 6 and 14 months. Median age of the patients with late effect (62.6 years) was significantly higher than in those with early effect (52.7 years).

Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: Consensus from an international survey and discussion program.

Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as 'critically important;' these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome 'off' periods (>1-2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS.

An HRP study of hypothalamo-cerebellar and cerebello-hypothalamic connections in squirrel monkey (Saimiri sciureus).

This study describes the distribution of labeled hypothalamic neurons in squirrel monkey following pressure injections of horseradish peroxidase (HRP) into cerebellar cortex and the pattern of labeling in the cerebellar nuclei subsequent to iontophoretic injections localized in the hypothalamus. Two types of HRP (HRP and a wheat germ agglutinin conjugate, HRP-WGA) were used as tracers; tetramethylbenzidine was the chromogen. Retrogradely filled neurons were found in lateral (LHAr) and posterior (PHAr) hypothalamic areas, and in the lateral mammillary (LMNu) and supramammillary (SMNu) nuclei following injections into ansiform and paramedian lobules and into the paraflocculus. Labeled cells were occasionally seen in the medial mammillary nucleus (parafloccular cases) and among fascicles of the mammillothalamic tract (all posterior lobe cases) immediately above the medial nucleus. After injections into the anterior lobe, labelling was again found in the LHAr, PHAr, LMNu, and SMNu. In addition, retrogradely filled cells were present in ventromedial, dorsomedial, and dorsal hypothalamic nuclei and in the dorsal hypothalamic area. Labeled cells were occasionally found among fascicles of the fornix along its intrahypothalamic course. In general, labeling extends into slightly more rostral hypothalamic levels in anterior lobe cases when compared to posterior lobe experiments. We interpret these data as indicating that some hypothalamic neurons project directly to the cerebellar cortex (i.e., hypothalamo-cerebellar fibers); this projection is bilateral with an ipsilateral preponderance. In experiments with injections of HRP-WGA into the cerebellar nuclei, anterogradely filled axons were traced into the contralateral PHAr and LHAr; this was suggestive of a direct cerebello-hypothalamic projection. Following iontophoretic injections localized in the LHAr and the medial mammillary nucleus, labeling was seen in the medial (NM), posterior interposed (NIP), and lateral (NL) cerebellar nuclei; this is essentially a contralateral projection. Retrogradely labeled cells were found in the rostral and ventral NM, the ventral and dorsocaudal NL, and diffusely throughout the NIP. On the basis of the known distribution of cerebello-thalamic fibers and other criteria, these labeled cells are representative of a true cerebello-hypothalamic projection. It is suggested that the cerebellum, through these pathways, may have a relatively direct influence on visceral centers in the brainstem and spinal cord.

Neuronal connections between the cerebellar nuclei and hypothalamus in Macaca fascicularis: cerebello-visceral circuits.

The purpose of this study was to identify the basic pattern of interconnections between the cerebellar nuclei and hypothalamus in Macaca fascicularis. The distribution of retrogradely labeled cells and anterogradely filled cerebellofugal axons in the hypothalamus of M. fascicularis was investigated after pressure injections of a horseradish peroxidase mixture (HRP + WGA-HRP) in the cerebellar nuclei. Following injections in the lateral, anterior, and posterior interposed cerebellar nuclei retrogradely labeled cells were present in the following areas (greatest to least concentration): lateral and dorsal hypothalamic areas, dorsomedial nucleus, griseum periventriculare hypothalami, supramammillary and tuberomammillary nuclei, posterior hypothalamic area, ventromedial nucleus and periventricular hypothalamus, around the medial mammillary nucleus, lateral mammillary nucleus, and infundibular nucleus. Cell labeling was bilateral with an ipsilateral preponderance. In these same experiments anterogradely labeled cerebellar efferent fibers terminated in the contralateral posterior, dorsal and lateral hypothalamic areas, and the dorsomedial nucleus. In these regions retrogradely labeled hypothalamic cells were occasionally found in areas that also contained anterogradely filled cerebellar axons. This suggests a partial reciprocity in this system. In addition, sparse numbers of labeled cerebellar fibers recross in the hypothalamus to distribute to homologous areas ipsilateral to the injection site. Subsequent to an injection in the medial cerebellar nucleus (NM), cell labeling was present in more rostral hypothalamic levels including the lateral and dorsal hypothalamic areas, the dorsomedial nucleus, around or in fascicles of the column of the fornix, and in the periventricular hypothalamic area. Although no fastigiohypothalamic fibers were seen in this study, on the basis of information available from the literature it is likely that such a connection exists in primates. In summary, hypothalamic projections to NM originated mainly from rostral to midhypothalamic levels, whereas those projections to the lateral three cerebellar nuclei came from mid and more caudal levels. The existence of direct hypothalamic projections to cerebellar nuclei in M. fascicularis and of cerebellofugal projection to some hypothalamic centers indicates that circuitry is present through which the cerebellum may influence visceral functions. Furthermore, the fact that projections to NM versus the other cerebellar nuclei originate from somewhat different regions of the hypothalamus would suggest that the visceral functions modulated by each pathway is not the same.

The organization of hypothalamocerebellar cortical fibers in the squirrel monkey (Saimiri sciureus).

The organization and distribution of hypothalamocerebellar cortical fibers in squirrel monkey were investigated by using horseradish peroxidase (HRP, WGA-HRP) and 3H-leucine as anterograde tracers. Following hypothalamic injections, anterogradely labeled fibers coursed bilaterally through the periventricular gray (ipsilateral preponderance) and into the cerebellar white matter. Sparse numbers of labeled fibers appeared to descend into the reticular formation and enter the cerebellum via the brachium pontis. The pattern of cerebellar cortical labeling does not conform to that of mossy or climbing fibers. Labeled axons enter and branch within the granular layer, proceed around Purkinje cell somata, and enter the molecular layer. Within the latter some labeled fibers branch outwardly in a fanlike manner whereas others ascend before branching. Many fibers within the molecular layer ultimately assume an orientation that is similar to that of parallel fibers. The distribution patterns of hypothalamocerebellar cortical axons resemble those reported for monoaminergic fibers in the cerebellar cortex. Afferent fibers to the cerebellar cortex (including hypothalamocerebellar) that do not terminate as mossy or climbing fibers may collectively constitute a third general category of cerebellar afferent axons. On the basis of their distribution within all cortical layers these fibers are designated as multilayered fibers. The morphology of multilayered fibers stands in contrast to the presumptive mossy fiber labeling seen in lobules IX and X following large injections. Such labeling may represent a subpopulation of hypothalamocerebellar fibers or result from enzyme deposition in areas bordering the hypothalamus that project to cerebellar structures.

Ultrastructure of spinal efferents to the lateral reticular nucleus: an EM study using anterograde transport of WGA-HRP complex.

Anterograde transport of lectin-conjugated horseradish peroxidase and subsequent incubation with tetramethylbenzidine were employed to label the spinal terminals within the feline lateral reticular nucleus (NRL) for ultrastructural identification. Quantitative studies demonstrated that compared to the unlabelled terminals the spinal boutons were more than twice as large and contained fewer synaptic vesicles. Most of the synaptic contacts of the labelled terminals were located on dendritic shafts but contacts on dendritic spines as well as perikarya were also present. In four cases (all with cervical injections), the postsynaptic cells could be studied in the transversal sections of the medulla in the nuclear plane. The neurons were large and elongated with longest and shortest diameters of about 60 X 30 microns, belonging to the largest category of cells within the NRL. The observations were discussed and related to the findings made in other studies of the NRL.

Cerebellar cortical and nuclear afferents from the feline locus coeruleus complex.

The origin and distribution of cerebellar cortical and nuclear afferents from the locus coeruleus complex (the nucleus locus coeruleus, the nucleus subcoeruleus, the medial and lateral subdivisions of the parabrachial nucleus and the Kölliker-Fuse nucleus) have been studied by means of retrograde transport of the wheat germ agglutinin-horseradish peroxidase complex in the cat. Cerebellar cortical depositions of the tracer were made by pressure injections, while nuclear depositions were made by implanting the tracer in crystalline form. The projection is bilateral with an ipsilateral preponderance. It reaches all the cerebellar nuclei as well as vermal, intermediate and lateral parts of the cerebellar cortex. The highest cell counts were made after tracer depositions in vermal and intermediate parts of the cerebellum. The projection in the cat has a more widespread origin than previously reported. It originates mainly within the nucleus locus coeruleus and the parabrachial nucleus (especially in its lateral subdivision), but retrogradely labelled neurons were also found in nucleus subcoeruleus, the Kölliker-Fuse nucleus and the A4 cell group. The cells of origin were of different shapes, but usually had a maximum diameter of the cell body between 15 and 30 micron. Cerebellar efferent axons passing through the locus coeruleus complex were anterogradely labelled following implants in all the cerebellar nuclei, but definite terminal labelling was not observed within the nuclei of the locus coeruleus complex.

Hypothalamocerebellar and cerebellohypothalamic projections--circuits for regulating nonsomatic cerebellar activity?

Cerebellar involvement in visceral and affective responses is known from physiological and behavioral studies, but the pathways involved in these responses have remained enigmatic. Over the last ten years neuroanatomical studies have shown that the cerebellum and hypothalamus are interconnected by direct hypothalamocerebellar and cerebellohypothalamic projections and by a multitude of indirect pathways. The hypothalamocerebellar projection terminates in the cerebellar nuclei and in all layers of the cerebellar cortex as multilayered fibres. This projection is, at least in part, histaminergic. New immunocytochemical experiments indicate that small numbers of hypothalamocerebellar neurones may contain GABA- or glycine-like immunoreactivity. GABA may function as a transmitter in hypothalamocerebellar fibres, probably in conjunction with histamine, but it is not clear whether glycine may also function as a transmitter or only serve metabolic functions. The bidirectional pathways between the cerebellum and hypothalamus may be part of the circuits through which the cerebellum participates in the modulation of a variety of nonsomatic events. In addition, new observations on patients with well localized cerebellar lesions reveal simultaneous somatic and visceral dysfunction. Recent research on direct hypothalamocerebellar pathways and on other connections between hypothalamus and cerebellum is reviewed. It is hypothesized that the cerebellum may act as a general modulator and coordinator of a wide range of central nervous activities, somatic as well as nonsomatic.